Barely three months into the new year and we are happy to announce a monumental milestone reached - 150 million downloads.
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This achievement solidifies IntechOpen’s place as a pioneer in Open Access publishing and the home to some of the most relevant scientific research available through Open Access.
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We are so proud to have worked with so many bright minds throughout the years who have helped us spread knowledge through the power of Open Access and we look forward to continuing to support some of the greatest thinkers of our day.
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Thank you for making IntechOpen your place of learning, sharing, and discovery, and here’s to 150 million more!
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They are crucial drugs in clinical control in a plethora of patients, despite recent advances resulting from the availability of new molecules with great selectivity for different receptors, cells, or biological mediators. This book includes high-quality scientific reviews of corticosteroids and their numerous uses.",isbn:"978-1-83969-482-0",printIsbn:"978-1-83969-481-3",pdfIsbn:"978-1-83969-483-7",doi:"10.5772/intechopen.94686",price:119,priceEur:129,priceUsd:155,slug:"corticosteroids-a-paradigmatic-drug-class",numberOfPages:128,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"d600ff66a3b0544bcbb713ea46287590",bookSignature:"Celso Pereira",publishedDate:"November 24th 2021",coverURL:"https://cdn.intechopen.com/books/images_new/10716.jpg",numberOfDownloads:910,numberOfWosCitations:0,numberOfCrossrefCitations:0,numberOfCrossrefCitationsByBook:0,numberOfDimensionsCitations:0,numberOfDimensionsCitationsByBook:0,hasAltmetrics:1,numberOfTotalCitations:0,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"February 10th 2021",dateEndSecondStepPublish:"April 13th 2021",dateEndThirdStepPublish:"June 12th 2021",dateEndFourthStepPublish:"August 31st 2021",dateEndFifthStepPublish:"October 30th 2021",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"66336",title:"Prof.",name:"Celso",middleName:null,surname:"Pereira",slug:"celso-pereira",fullName:"Celso Pereira",profilePictureURL:"https://mts.intechopen.com/storage/users/66336/images/system/66336.png",biography:"Prof. Celso Pereira, MD, Ph.D., is head-chief of the Clinical Immunology Unit and Clinical Herbal Medicine in Clinical Practice, Medicine Faculty, Coimbra University, Portugal. He is also a graduated specialist in immuno-allergy and has developed clinical activity at Coimbra Surgical Center. His main activities include clinical practice, education (pre and postgraduate), and clinical and laboratory research. He was president of the Immuno-Allergy Board of the Portuguese Medical Association. He is the coordinator of some Portuguese clinical guidelines and a member of the national committee for the diagnostic procedures for allergy and clinical immunology and the national committee for COVID vaccination. His scientific interests include research in the mechanisms of respiratory allergy, specific immunotherapy, and medicinal plant applications.",institutionString:"Faculty of Medicine University of Coimbra",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"4",totalChapterViews:"0",totalEditedBooks:"6",institution:{name:"University of Coimbra",institutionURL:null,country:{name:"Portugal"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"1197",title:"Pharmaceutical Drug",slug:"pharmaceutical-drug"}],chapters:[{id:"77382",title:"The Interaction between Maternal and Fetal Hypothalamic – Pituitary – Adrenal Axes",doi:"10.5772/intechopen.98722",slug:"the-interaction-between-maternal-and-fetal-hypothalamic-pituitary-adrenal-axes",totalDownloads:223,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:1,abstract:"The Hypothalamic – Pituitary – Adrenal (HPA) Axis is a unique system that mediates an immediate reactivity to a wide range of stimuli. It has a crucial role in synchronizing the behavioral and hormonal responses to internal and external threats, therefore, increases the chance of survival. It also enables the body systems to adapt to challenges put up by the pregnancy. Since the early stages of pregnancy and throughout delivery, HPA axis of the mother continuously navigates that of the fetus, and both have a specific cross talk even beyond the point of delivery and during postnatal period. Any disturbance in the interaction between the maternal and fetal HPA axes can adversely affect both. The HPA axis is argued to be the mechanism through which maternal stress and other suboptimal conditions during prenatal period can program the fetus for chronic disease in later life. In this chapter, the physiological and non-physiological communications between maternal and fetal HPA axes will be addressed while highlighting specific and unique aspects of this pathway.",signatures:"Aml M. Erhuma",downloadPdfUrl:"/chapter/pdf-download/77382",previewPdfUrl:"/chapter/pdf-preview/77382",authors:[{id:"149225",title:"Dr.",name:"Aml M.",surname:"Erhuma",slug:"aml-m.-erhuma",fullName:"Aml M. Erhuma"}],corrections:null},{id:"77335",title:"Applications of Corticosteroid Therapy in Inflammatory Rheumatic Diseases",doi:"10.5772/intechopen.98720",slug:"applications-of-corticosteroid-therapy-in-inflammatory-rheumatic-diseases",totalDownloads:141,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Corticosteroids still remain the anchor drugs in therapy strategies for patients with inflammatory rheumatic diseases even though new drugs such as biologic or targeted synthetic molecules have emerged in the past years, being the most commonly prescribed medicines in the world due to their powerful immune-modulating properties. In this chapter, we aim to discuss the main characteristics of the glucocorticoids, their mechanism of action and effects on the immune system given the fact that they reduce the activation, proliferation, differentiation and survival of inflammatory cells such as macrophages and lymphocytes. Nevertheless, of great importance are the indications and tapering regimens, but also the adverse effects and various methods of monitoring the corticosteroid therapy.",signatures:"Anca Emanuela Mușetescu, Cristina Criveanu, Anca Bobircă, Alesandra Florescu, Ana-Maria Bumbea and Florin Bobircă",downloadPdfUrl:"/chapter/pdf-download/77335",previewPdfUrl:"/chapter/pdf-preview/77335",authors:[{id:"350800",title:"Dr.",name:"Alesandra",surname:"Florescu",slug:"alesandra-florescu",fullName:"Alesandra Florescu"},{id:"420816",title:"Dr.",name:"Anca Emanuela",surname:"Mușetescu",slug:"anca-emanuela-musetescu",fullName:"Anca Emanuela Mușetescu"},{id:"420819",title:"Dr.",name:"Cristina",surname:"Criveanu",slug:"cristina-criveanu",fullName:"Cristina Criveanu"},{id:"420820",title:"Dr.",name:"Anca",surname:"Bobîrcă",slug:"anca-bobirca",fullName:"Anca Bobîrcă"},{id:"420821",title:"Dr.",name:"Ana Maria",surname:"Bumbea",slug:"ana-maria-bumbea",fullName:"Ana Maria Bumbea"},{id:"420822",title:"Dr.",name:"Florin",surname:"Bobircă",slug:"florin-bobirca",fullName:"Florin Bobircă"}],corrections:null},{id:"77381",title:"Corticosteroids in Otorhinolaryngology",doi:"10.5772/intechopen.98636",slug:"corticosteroids-in-otorhinolaryngology",totalDownloads:131,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"This paper aims to present the role of the therapy of corticosteroids in otorhinolaryngological diseases such as Meniere’s disease, partial deafness, sudden sensorineural hearing loss, and tinnitus. The effectiveness of treatment depends on many factors, for instance, the duration of the therapy, occurrence or not of adverse reactions, especially in those patients with additional risk factors as comorbidities. Additionally, the optimal way of administration has been widely discussed.",signatures:"Magdalena B. Skarzynska and Piotr H. Skarzynski",downloadPdfUrl:"/chapter/pdf-download/77381",previewPdfUrl:"/chapter/pdf-preview/77381",authors:[{id:"267071",title:"Prof.",name:"Piotr H.",surname:"Skarzynski",slug:"piotr-h.-skarzynski",fullName:"Piotr H. Skarzynski"},{id:"349501",title:"Ph.D.",name:"Magdalena B.",surname:"Skarżyńska",slug:"magdalena-b.-skarzynska",fullName:"Magdalena B. Skarżyńska"}],corrections:null},{id:"77497",title:"Pharmacogenomics and Pharmacotranscriptomics of Glucocorticoids in Pediatric Acute Lymphoblastic Leukemia",doi:"10.5772/intechopen.98887",slug:"pharmacogenomics-and-pharmacotranscriptomics-of-glucocorticoids-in-pediatric-acute-lymphoblastic-leu",totalDownloads:126,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Pharmacogenomics and pharmacotranscriptomics contribute to more efficient and safer treatment of many diseases, especially malignancies. Acute lymphoblastic leukemia (ALL) is the most common hematological malignancy during childhood. Glucocorticoids, prednisone and dexamethasone, represent the basis of chemotherapy in pediatric ALL. Therapy causes side effects in 75% of patients and 1–3% of pediatric ALL patients die because of therapy side effects rather than the disease itself. Due to this fact, pharmacogenomics and pharmacotranscriptomics have gained key positions in this field. There is a growing knowledge of pharmacogenomics and pharmacotranscriptomics markers relevant for the success of the glucocorticoid treatment of children with ALL. New technologies, such as next-generation sequencing (NGS) have created a possibility for designing panels of pharmacogenomics and pharmacotranscriptomics markers related to the response to glucocorticoid drugs. Optimization of these panels through population pharmacogenomic studies leads to new knowledge that could open the doors widely to pre-emptive pharmacogenomic testing.",signatures:"Vladimir Gasic, Djordje Pavlovic, Biljana Stankovic, Nikola Kotur, Branka Zukic and Sonja Pavlovic",downloadPdfUrl:"/chapter/pdf-download/77497",previewPdfUrl:"/chapter/pdf-preview/77497",authors:[{id:"73795",title:"Dr.",name:"Branka",surname:"Zukic",slug:"branka-zukic",fullName:"Branka Zukic"},{id:"352765",title:"Prof.",name:"Sonja",surname:"Pavlovic",slug:"sonja-pavlovic",fullName:"Sonja Pavlovic"},{id:"352768",title:"Dr.",name:"Vladimir",surname:"Gasic",slug:"vladimir-gasic",fullName:"Vladimir Gasic"},{id:"352770",title:"Dr.",name:"Biljana",surname:"Stankovic",slug:"biljana-stankovic",fullName:"Biljana Stankovic"},{id:"352772",title:"Dr.",name:"Nikola",surname:"Kotur",slug:"nikola-kotur",fullName:"Nikola Kotur"},{id:"352773",title:"MSc.",name:"Djordje",surname:"Pavlovic",slug:"djordje-pavlovic",fullName:"Djordje Pavlovic"}],corrections:null},{id:"78962",title:"Corticosteroids in Neuro-Oncology: Management of Intracranial Tumors and Peritumoral Edema",doi:"10.5772/intechopen.100624",slug:"corticosteroids-in-neuro-oncology-management-of-intracranial-tumors-and-peritumoral-edema",totalDownloads:144,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Corticosteroids have been in use for decades and are one of the most prescribed drugs in all specialties of medicine. Jerome Posner, in his classic textbook “Neurological Complications of Cancer,” refers to corticosteroids as widely used drugs in neuro-oncology leading to a remarkable decline in perioperative mortality and morbidity rates. Being the most powerful class of tumor-induced-edema reducing agents, they are adjuvant to chemotherapy and are also known to reduce the risk of encephalopathy and other associated neurological deficits in patients undergoing radiation therapy. They have been widely used in higher-than-normal doses in the management of pathologic, immunological, and inflammatory conditions and various other diseases. Novel insights into the mechanisms of action of corticosteroids and their effects on cancer patients are extensively being studied. While substantial clinical improvements can be seen in cancer patients, corticosteroids are also associated with adverse and well-characterized side effects leading to immediate as well as long-term complications in patients. This chapter reviews the clinical aspects of corticosteroid therapy used in neuro-oncological conditions and its effects on peritumoral edema. Although there is currently insufficient information on appropriate use, in most cases, corticosteroids are used in a supraphysiological and pharmacological manner to minimize the symptoms of cerebral edema. Due to limited clinical studies and evident side effects presenting synonymously with corticosteroid therapy, the emerging role of steroid-sparing drugs such as corticotrophin-releasing factors, tyrosine kinase inhibitors, and VEGF inhibitors will also be discussed.",signatures:"Sunbul S. Ahmed",downloadPdfUrl:"/chapter/pdf-download/78962",previewPdfUrl:"/chapter/pdf-preview/78962",authors:[{id:"418173",title:"Ms.",name:"Sunbul",surname:"S. Ahmed",slug:"sunbul-s.-ahmed",fullName:"Sunbul S. Ahmed"}],corrections:null},{id:"77380",title:"Corticosteroid Replacement Therapy",doi:"10.5772/intechopen.98803",slug:"corticosteroid-replacement-therapy",totalDownloads:145,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"The advent of synthetic corticosteroids in the 20th century provided a vital breakthrough in the management of adrenal insufficiency. In this chapter we review the main indications and guidance for appropriate hormone replacement and also look into the management of therapy during special circumstances. For decades hydrocortisone has remained the cornerstone for glucocorticoid replacement but we explore the alternatives including recently introduced modified-release drug preparations and the future treatment considerations currently undergoing research and pre-clinical trials.",signatures:"Michael C. Onyema",downloadPdfUrl:"/chapter/pdf-download/77380",previewPdfUrl:"/chapter/pdf-preview/77380",authors:[{id:"349089",title:"Dr.",name:"Michael",surname:"Onyema",slug:"michael-onyema",fullName:"Michael Onyema"}],corrections:null}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},subseries:null,tags:null},relatedBooks:[{type:"book",id:"934",title:"Allergic Diseases",subtitle:"Highlights in the Clinic, Mechanisms and Treatment",isOpenForSubmission:!1,hash:"0d8961a0f59ba85124b525aee52a4d8c",slug:"allergic-diseases-highlights-in-the-clinic-mechanisms-and-treatment",bookSignature:"Celso Pereira",coverURL:"https://cdn.intechopen.com/books/images_new/934.jpg",editedByType:"Edited by",editors:[{id:"66336",title:"Prof.",name:"Celso",surname:"Pereira",slug:"celso-pereira",fullName:"Celso Pereira"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited 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1. Introduction
Chagas disease is a parasitic disease caused by the Trypanosoma cruzi that affects over 12 million people in Central and South America, causing more deaths than any other disease of its kind. Large migrations of infected people from the endemic areas are usually observed mainly in the United States of America and Europe. The most frequent cardiac complications of chronic Chagas disease are left ventricular dilation and dysfunction, aneurysm, congestive heart failure, thromboembolism, ventricular arrhythmias, and sudden cardiac death. Chagas disease diagnosis is based on serology, namely immunopositivity for immunoglobulin G antibodies to T. cruzi.
Inflammatory dilated cardiomyopathy is, by far, the most important clinical consequence of T. cruzi infection. The chronic chagasic cardiomyopathy (CCC) is roughly progressive, and its treatment does not differ from that of any other non-chagasic cardiomyopathy in the absence of strong evidence. Clinical symptoms usually include dyspnea, palpitations, precordial pain, syncope and eventually, sudden death.
Epidemiological data show high mortality and morbidity resulting from the cardiovascular disease in chagasic patients. However, there are no hints to suspect cardiovascular risk in the silent period of the disease (asymptomatic form). Noticeably, inflammatory factors are upraised during the silent period of the Chagas disease. Like atherogenesis, immune-inflammatory-mediated effector mechanisms commanded by Th1/Th17 cells are involved in the pathophysiology of Chagas disease, having a similar histological hallmark which includes Th1/Th17 cells, macrophages, and a characteristic cytokine profile.
Host control of the T. cruzi appears to depend on both humoral and cell-mediated adaptive responses, and on the innate immune system as well [1]. The cytokines strongly activate multiple functions relevant to cardiovascular homeostasis. According to the literature on the subject, there is robust evidence of a systemic upraised level of inflammatory mediators in patients with Chagas disease suggesting that the interplay between the parasite aggressiveness and the host immune response might have a key role in the perpetuation of myocardial inflammation.
The role of the parasitemia is more controversial associated with immunosuppression, disease reactivation, and disease severity. Due to the arousal of a strong and specific immune response against the parasite, nearly two-thirds infected people become protected and may stay in an indeterminate stage of the infection characterized by low parasitemia level for 10 or even up to 40 years after the prime infection. The other one-third infected people, however, develop symptoms, entering the symptomatic chronic stage of infection typically characterized by cardiomyopathy.
The antigenic stimulation though persists all over the chronic stage. Then, the clinical outcome depends on multiple factors like parasite persistence, the particular T. cruzi strain, the infective load and virulence factors, the route of infection and sidestepping the host immune response by the parasite, the strength of the immune response at any time, and of course, genetic predisposition [2]. In fact, the sustained parasite-host immunity interactions induce systemic inflammatory mediators’ upregulation and fibrosis, both crucially involved in myocardial tissue damage and the resulting disturbances in the cardiac conduction system, mainly affecting the autonomic ganglia, nerves, and the microvasculature.
Unlike the study of the classical risk factors, research studies on how inflammatory status affects the development and determines the progression of cardiomyopathy have not yet identified or clinically validated relevant biomarkers [3]. Interestingly, secluded evidence suggests that the inflammatory status might be associated with increased morbidity and mortality. Deepening our understanding of the pathophysiology of Chagas disease, it will make way to identifying new molecular targets for the design of CCC prophylactic vaccines and therapeutic drugs.
2. Cardiomyopathy genes
Dilated cardiomyopathies (DCM) are characteristically defined by the presence of left ventricular dilatation, and contractile dysfunction [4]. Genetic mutations that involve genes encoding the cytoskeleton sarcomere, nuclear envelope proteins and others account for up to 35% of the total cases. Hypertrophic cardiomyopathies (HCM) and dilated (DCM) cardiomyopathies are heart muscle diseases related to genes variants encoding sarcomere proteins [5]. Among these proteins, the most common are the β-myosin heavy chain (MYH7) [6], the cardiac myosin-binding protein C (MYPBC3) while the myosin light chain (MYL3) and the regulatory myosin light chain (MYL2) are rare [7]. Certain variants in sarcomere genes also cause DCM, albeit less frequently. Of note, variant location does not absolutely predict whether it will trigger HCM or DCM.
Heart failure associated with cardiomyopathies is often caused by mutations in sarcomeric genes, resulting in contractile dysfunction and cellular damage. This may stimulate the production of a robust proinflammatory response. Intriguingly, flow cytometry analysis revealed a significant increase in total macrophages and classically activated proinflammatory (M1) macrophages in DCM hearts as compared with normal hearts. Serum cytokine analysis in dilated cardiomyopathy hearts showed a striking increase in interleukin IL-6 in rodents. Furthermore, RNA-seq analysis revealed the upregulation of inflammatory pathways in DCM hearts. Altogether, these data indicate a robust proinflammatory response in DCM hearts, likely in response to cellular damage triggered by an MYBPC3 mutation and the resultant contractile dysfunction [8]. In addition, other genes have been implicated in DCM, particularly the monocyte chemoattractant protein-1 gene polymorphism [9].
The epigenetic factors that contribute to myocarditis include consumption of alcohol or drugs, exposure to toxins, and metabolic and endocrine disturbances. The typically presenting symptoms are related to congestive heart failure, and can also include circulatory collapse, arrhythmias, and thromboembolic events [10].
3. Anatomopathological findings of Chagas cardiomyopathy
Chagas disease is typified in the WHO classification within the group of specific diseases of the myocardium. Alternatively, the denomination of cardioneuropathy has been proposed to express the frequent and severe importance of the autonomic affectation and the consequent dysautonomia associated with the functional and clinical alterations. The observed macroscopic alterations are: (a) cardiomegaly (more than 500 g weight) and (b) characteristic apical lesion associated with localized parietal thinning, rarely presenting as posterior basal or parietal, or an apex aneurysm. Some authors propose two characteristic morphological types of chronic chagasic cardiopathy: “type I” or concentric, is characterized by a predominance of left ventricular hypertrophy with little dilatation or none, and circumscribed closed apical lesion and “type II” or eccentric, characterized by a wide dilatation and opening of the apical zone and frequently associated with thrombosis. Pathological evolution can progress from the concentric to eccentric type (Figure 1).
Figure 1.
Anatomopathological findings. Figure courtesy of Dr. José Milei. Panel 1, left. High-grade heart dilatation. Thining of the apical wall of the left ventricle (white arrow) and cavitary thrombus (yellow arrow). Panel 1, right. Schematic representation. Panel 2, left. Characteristic apical aneurysm. Panel 2, right. Schematic representation. Panels 3–5. Histological features. Panels 3A and 3B. Microscopically, myocardial lesions consisted of a chronic inflammatory process with fibrotic scars and extensive mononuclear infiltrates. Panel 4. Immunostaining for T lymphocyte. Positive cells express CD45R0 antigen (brown); specialized myocardial cells have almost disappeared. Extensive mononuclear infiltrate, the majority of them being T lymphocytes. X20. Panel 5. Double immunostaining for the simultaneous demonstration of T lymphocytes (CD45RO) and macrophages (CD68). T lymphocytes (brown) in close contact with a macrophage (pinky cytoplasm). X1000.
4. Clinical expression of the acute phase of Chagas disease
The Chagas disease presents two phases [10]. The initial acute phase, lasting for about 2 months after the infection and characterized by high parasitemia and parasite invasion to the tissues, is asymptomatic or shows mild unspecific symptoms. In this phase, symptomatic patients usually develop characteristic skin lesions or unilateral purplish swelling of the lids, usually known as the Romana’s sign, and can present fever, headache, difficulty in breathing, lymphadenitis, vague myalgia, and abdominal or chest pain. In this phase too, immunosuppression, and the decreased inflammatory response result in increased parasite load in locally infected tissues upon generalized tissue invasion [11].
5. Clinical expression of the chronic phase of Chagas disease
To date, regardless the chronic phase be asymptomatic or symptomatic with cardiological alterations, the prognosis on the eventual development of heart disease in a given patient is not feasible.
5.1. Clinical asymptomatic expression of the chronic phase
The reason most patients with Chagas do not develop heart disease is uncertain. The first studies suggested that asymptomatic patients without clinical and cardiological alterations and the general population had a similar cardiovascular risk, but over time, epidemiological data suggest a higher risk than presumed.
Collectively, the studies highlight the importance of studying the early inflammatory parameters indicative of early cardiovascular damage, evaluating potential implication on morbidity and mortality, and prognostic and therapeutic relevance.
5.2. Clinical symptomatic expression of the chronic phase
The clinical expression of the chronic phase usually manifests as alterations in the cardiac conduction system, mainly arrhythmogenesis and dysrhythmias derived from the fibrotic and atrophic lesions compromising the AV nodule, and the His bundle and branches, and autonomic dysfunction as well. Dysautonomia may affect blood pressure and cardiac frequency, eventually leading to orthostatic hypotension, syncope, and heart failure. Myocardial alterations are associated with chronic inflammation, fibrous hypertrophy, fibrosis, myocytolysis, tissue depletion of neurons, and vascular damage contributing to sudden death or heart failure. Some clinical features may result from upstream molecular mimicry and cardioactive autoantibodies production. Patients with chagasic cardiomyopathy produce anti-ß1 and -ß2 adrenergic, and anti-M2 cholinergic autoantibodies in the heart. These autoantibodies, originally directed against the parasite, would indistinctly recognize similar antigenic determinants in the host, a phenomena known as mimicry.
6. Factors that define blood inflammatory outcome in Chagas disease
The sustained systemic inflammatory burden may result from many host-parasite interactions, whereby the interplay of the natural and adaptive immune host response with the parasite will result in a varying degree of tissue damage, host aggression, and clinical outcome. Then, the perpetuation of the Chagas disease inflammatory phenotype [10] is critical in understanding the complexity of the clinical outcome given that immunological homeostasis in chronically infected hosts could be spoiled by both parasite and host immune molecules and cells [10].
6.1. Factors that promote parasite evasion and persistence
The presence of the parasite [11] or its products like DNA, and other constitutive molecules in blood, myocardium, and the autonomic tissues lead to sustained immunological stimulation and T. cruzi evasive strategies. Today, the DNA amplification by polymerase chain reaction and other sensitive assays allow detecting parasites or their components in chronic symptomatic patients.
6.1.1. Parasitemia and sustained antigen stimulation
There is scarce evidence linking Chagas seropositivity with cardiovascular events in asymptomatic patients [9]. The perpetuation of T. cruzi antigens in cardiac tissue and the immune-mediated dysautonomia might be implicated in the cardiovascular pathogenesis [12] being responsible for the asymptomatic-to-the cardiac phenotype transition in Chagas disease. Different studies have shown the relevance of effector or memory CD4/CD8 lymphocytes and their effector cytokines not only in controlling parasite multiplication over the course of acute and chronic infection, but also participating in the pathogenesis of chronic Chagas disease [12]. The Th1 lymphocytes are critical in the control of Chagas disease during the acute stage unlike the chronic phase when they could be harmful. The adoptive transfer of T. cruzi-specific CD8+ T cells confers mice partial protection from T. cruzi inoculation [13], while cardiac damage may still develop. Conversely, the human being develops myocarditis in the presence of CD4+ and CD8+ T cells, and parasite components as well [14].
6.1.2. Cruzi virulence and immunomodulatory factors
Cruzi parasites cause pathology depending on factors like the parasite species and strains, the route of infection [15], and the host genetic background. Different parasite strains coexist in infected patients, and in natural reservoirs in domestic and peridomestic areas. The strain-dependent immunomodulatory effects of the parasite might influence parasite-host interactions [14]. Mucin-like sialic acid-acceptor glycoproteins and other parasite cell membrane products determine Cruzi virulence [15]. One of the hallmark parasite-derived molecules are the glycol-inositol-phospholipids (GIPLs) covering the parasite cell surface that alter the B cell compartment, work as TLR4 agonists, and mediate proinflammatory effects [16, 17]. In sum, T. cruzi virulence factors actively subvert the host immune system leading to chronic infection [18, 19, 20, 21].
6.1.3. White adipose tissue is an immune active endocrine organ
Another survival strategy of Cruzi parasites is targeting the adipose tissue (AT) [22], both brown (BAT) and white (WAT), the largest endocrine organ in the body shaped by adipocytes, fibroblasts, macrophages, and endothelial cells. The adipose tissue is involved in many physiologic functions including energy homeostasis and immunity [23], and might warrant long-term parasite persistence by providing a safe reservoir to avoid the host-defense mechanisms. Then, immune system suppression would result in parasite recrudescence and multiple tissue invasion [24]. Besides, the AT might be the major site for parasite reactivation as indicated by the finding of parasite-derived DNA in AT [25] in patients with CCC [25]. Likely, the AT serves as a parasite reservoir favoring opportunistic reinfection upon immunosuppression, as observed in chagasic transplanted or HIV patients, or those under immunosuppressive therapies [26]. As infection increases the level of TLR4 and TLR9, and of the mRNA of cytokines, chemokines, and of their receptors, the adipose tissue appears to be both a target and a sensor of parasitic infection even in the early, latent stage of T. cruzi infection. Recently, the T. cruzi was detected in the adipose tissue of chronically infected individuals [25].
6.2. Host-protective and pathogenic anti-T. cruzi immune-mediated-response
6.2.1. The innate immune system
Innate, nonspecific, immunity involves any pathogen-eliminating mechanism triggered promptly without memory requirement. The acute nonspecific inflammatory molecules serve not only as ‘gateway’ signals, generating conditions unfavorable for the invading agent, but they are also implicated in chronic inflammatory diseases. Chronic sustained inflammation actually contributes to cardiac hypertrophy.
6.2.1.1. Toll-like receptors agonists expressed by T. cruzi activate inflammatory pathways
Nonspecific immune system cells modify their functional repertoire (phagocytic activity, activation, antigenic presentation, migration, and adhesion) through pathogen-associated molecular pattern recognition receptors (PAMPs) like the toll-like receptors (TLRs), many of which can recognize several types of structurally unrelated PAMPs. These receptors trigger proinflammatory pathways’ activation interacting with their pathogen-derived ligands, and even with endogenous molecules, and releasing effector molecules like cytokines. This signal cascade triggers the expression of cytokine genes, where the type of TLRs bound determines the type of response.
Different T. cruzi-derived molecules belong to the PAMPs family and act as TLR agonists inducing the secretion of inflammatory cytokines, chemokines, and the production of nitric oxide (NO) by cells of the monocytic lineage. In this regard, the first evidence was the identification of the trypomastigotes-derived glycosylphosphatidylinositol (tGPI) that anchors mucin-like glycoproteins (tGPI-mucins), as a potent agonist of the human TLR2 [27] inducing proinflammatory responses on cells which express normal levels of TLR2 and TLR4 (Figure 2).
Figure 2.
T. cruzi molecules PAMPs members are TLR agonists. The variable lipid moiety composition of different GPI determines whether their recognition is mediated by TLR2 (alkylacylglycerol) or TLR4 (dihydroceramide). TLR4 agonist triggers powerful proinflammatory molecules release. FL: Phagolysosome; GPI: Glycosylphosphatidylinositol; tGPI: Trypomastigotes-derived glycosylphosphatidylinositol; eGPI epimastigote-derived glycosylphosphatidylinositol, HSP: Heat shock protein.
Another epimastigote-derived GPI family member, the glycoinositolphospholipid characterized by a lipid moiety, induced TLR4-mediated NF-κB activation. Many GIPLs freely anchor at the surface membrane of all the parasite life-cycle stage forms, whether infective metacyclic trypomastigotes or epimastigotes forms and have pleiotropic properties [28]. The variable lipid moiety composition of different GPI anchors determines the TLR type specificity for TLR2 (alkylacylglycerol) or TLR4 (dihydroceramide).
6.2.1.2. Toll-like receptors and resistance to infection
Direct testing of the hypothesis that TLR triggering by PAMPs is crucial for host resistance to infection but is currently not possible due to unavailability of T. cruzi strains lacking the expression of any TLR agonist. Nevertheless, studying the course of infection in TLR-encoding genes-deficient mice, evaluating mortality, parasitemia, and several parameters of the innate and acquired immune responses have brought an additional understanding of the impact of impairing TLR-mediated recognition of T. cruzi in developing host susceptibility to the infection. In this regard, MyD88-deficient mice lacking the transducer of multiple TLR-signaling pathways first evidenced the crucial involvement of TLRs in host resistance to T. cruzi [29, 30].
6.2.1.3. Cardiac toll-like receptors increase in ischemia/reperfusion-induced cardiac hypertrophy
The development of cardiac hypertrophy involves TLR signaling so that MyD88 blockage attenuates cardiac hypertrophy and extracellular heat shock protein 70 (HSP70) induces cardiomyocyte inflammation [31, 32].
6.2.2. The adaptive immune system
The immune-mediated-pathology (IMP) links to parasite persistence inducing protective effector and autoimmune response and has been a subject of debate in CCC for years. Immune effector cells along with autoantibodies participate in both protective and pathogenic adaptive responses in CCC. Typically, histopathological examination in chronic myocarditis reveals inflammatory polymorphism with macrophages, eosinophils, mast cells, B and T lymphocytes, and granuloma cells, and a predominance of B cells and plasma cells in the epicardium and T cells in the myocardium, which progresses towards fibrosis. The mononuclear infiltrate and its mediators would be, at least partly, primarily responsible for myocardial damage [33].
6.2.2.1. Autoimmunity
At first post-infectious autoimmune myocarditis was proposed to reasonably explain the mismatch between myocardial areas showing parasite invasion and those with myocardial damage revealed by pathology examination that hampered reliably establishing Chagas disease pathogenesis.
Cardiac epitopes share amino acid sequences with T. cruzi epitopes.
The transfer of lymphocytes to syngeneic recipients produces inflammatory lesions in cardiac and nervous tissue.
Chronic chagasic patients have autoantibodies in the bloodstream.
Plasma cells obtained from murine myocardial lesions release anti-cardiac antibodies.
T-lymphocytes obtained from human biopsies show cardiac muscle reactivity.
6.2.2.1.1. Evidence derived from the autoreactive immune response
While activation of autoreactive clones (possibly by polyclonal activation) occurs during the acute primary infection phase, autoantibodies appear to be generated during both the acute and chronic phases of the disease, likely perpetuated due to myocardial reactivity regardless of the etiologic agent. Both humoral and cellular cardiac autoimmunity might develop upon acute T. cruzi infection in the genetically susceptible host [34]. Another hypothesis sustained that autoimmunity develops only after sustained low-level stimulation of self-reactive cells over the chronic phase. Altogether, self-reactivity was initially proposed as a mechanism of tissue damage.
Many publications have mentioned the presence of cardiac tissue-parasite cross-reactivity. T. cruzi may induce antibodies and T cells also reactive to host antigens causing autoimmune reactions.
Certain antigens might induce nonspecific polyclonal activation, expanding clones that were in the anergic state as the polyclonal B cell activation associated with hypergammaglobulinemia and delayed specific humoral immunity reported in T. cruzi experimental infection in mice [35].
All in all, self-reactivity is accepted in Chagas disease though only subsidiarily contributing to myocardial tissue damage and deterioration as argued for the presence of autoantibodies and lymphocytes at the site of the lesion. Actually, immunosuppression not only does not cause improvement but rather aggravation of the course of the disease. Indeed, was self-reactivity relevant to injury, immunosuppression should be beneficial. Immunosuppression during acute infection reduces tissue inflammation while the parasite load increases in the infected tissues in mice. However, immunosuppression results in a generalized tissue invasion aggravating the disease. In chronically infected individuals, parasitemia is undetectable but any induced or acquired immunosuppression condition including pharmacological treatments, AIDS, a transplant, an autoimmune disease, leukemia or pregnancy, may trigger reactivation. When immunosuppression occurs during the chronic stage, skeletal and cardiac muscle inflammation increases, allegedly explaining why a subset of patients presenting an insufficient or suboptimal immune response develop heart disease [36].
6.2.2.1.2. Evidence derived from molecular mimicry and the formation of cardioactive autoantibodies
Cardioactive substances from sera from chagasic patients. Subsequently they were characterized as antibodies with specificity towards the cardiac β-adrenergic receptors that acting as partial agonists increased mechanical tension and sinus beating frecuency in chagasic patients. The Cardiology Service of the Ramos Mejía Hospital contributed to the characterization of the anti-cardiac receptor reactions, and the results indicated that self-reactivity of this kind was caused by parasite epitopes with low affinity for cardiac receptors, later proved by the identification of anti-T. cruzi P ribosomal proteins in chagasic individuals. In in vitro or ex vivo experiments, IgG-enriched serum fractions obtained from chagasic patients modify baseline heart beating frequency in cultured cardiomyocytes, increase cardiac inotropism, and trigger atrioventricular blockage in isolated hearts. Rabbits immunized with the major immunogenic region of β-adrenergic receptors develop cardiomyopathies and malignant arrhythmias, and cardioactive antibodies have also been observed in other pathologies. Patients with ethiologically different chronic heart diseases like the idiopathic dilated cardiomyopathy or presenting primary electrical alterations produce chagasic IgG-like enriched fractions with antibody activity. Circulating autoantibodies to cardiac beta-adrenergic and muscarinic receptors may affect cardiac function in chagasic patients. The prevalence of anti-autonomic receptors antibodies was higher in patients with chronic chagasic heart disease and other forms of heart disease than in the healthy counterparts [36].
6.2.2.2. Immune origin of the disease and the localized inflammatory response
The ‘tissue load of parasites’ is associated with the ‘severity of the lesion’ and might predict not only the characteristics of the immune response in the acute or chronic (reactivation by immunosuppression) stages of the disease of the disease but also of the localized inflammatory response. Accordingly, tissue specificity would result from the local ‘parasites persistence’ in the site of inflammation. Whole, fractionated, or recombinant parasites immunization triggers inflammatory lesions and electrocardiographic alterations. The spectrum of clinical presentations might result from both the efficacy of the immune response during the acute stage and the parasite strain involved. Individuals infected with less virulent strains and immunocompetent hosts should become asymptomatic over the chronic stage (Figure 3). The immune response so results from the net balance of the T. cruzi strain immunogenic potency and the regulatory T cells and effector lymphocyte subpopulation Th1/Th17 during the infection. The IL-17 produced during experimental T. cruzi infection regulates Th1 cells differentiation and parasite-induced myocarditis. A low regulatory T cell activity and the frequency of IL-17-producing T cells correlate with CCC severity [37], not precluding a minor participation of the self-reactive immune reactions in producing injury.
Figure 3.
Possible mechanisms involved in the immunopathogenesis of Chagas disease. Although the immune system protects man from massive infection, he is unable to completely eliminate all parasites. (A) The humoral protective and immunopathogenic immune response to T. cruzi has been intensely studied. Although many questions remain, the antibody response is always present in infected individuals and many of the antibodies have a protective capacity. Several aspects are related to the presence of autoreactive antibodies in chagasic patients and in experimental chagasic models. The presence of similarities between the epitopes of the parasite and cardiac tissue leads to the expansion of autoreactive clones. Some authors argue that some autoantibodies should be due to the existence of polyclonal activation. Other autoantibodies may be the result of the autoantigen release of damaged tissue (epitopes dispersion epiphenomenon). (B) Th1 lymphocytes have great relevance in the control of the disease. The importance of the T-dependent response is evidenced by the observations recorded in immunosuppressed patients in whom the disease worsens. In vitro studies would indicate that the NK cell-mediated immune response (ADCC and natural cytotoxicity) could participate in the in vivo response. According to some authors the antigenic persistence would be the main mechanism inducing the inflammatory immune response in the chronic stage and IL17 seems to be involved in CCC. This interpretation postulates that the sustained activation of the immunoinflammatory response is the main cause of tissue damage.
Induced immunosuppression fails to cause relevant autoimmune-mediated damage for it aggravates rather than ameliorates the disease. Adoptive lymphocytes transfer to syngeneic recipients produces inflammation indicating that the T-response can effectively control the disease. The cellular immune response is critical in controlling T. cruzi infection, and the developed vaccine so far exacerbates damage and progression of the disease. Then, the vaccine either failed in enhancing the adequate response and/or its design requires further adjusting the epitopes. Of note, despite cellular control the infection, immune response persistence and cardiac infiltrated cells may cause injury. Finally, the contribution of autoantibodies is complex as it is likely involved in further enhancing cardiovascular damage.
7. Suppressor of cytokine signaling proteins, immune regulation, and dilated cardiomyopathy
Cell-cell signaling is an essential hallmark of multicellular organisms for communicating different cell populations [38] and is particularly crucial for the immune system function. The ‘suppressor of cytokine signaling’ (SOCS) plays a critical role in the regulation of all crossroads of the cytokine-induced pathogenesis of dilated cardiomyopathy. The SOCS3 transgene induces Th2 responses, and SOCS3 gene deletion did not enhance Th1 polarization as expected but induced a negative regulator of the Treg subset with increased IL-10 and TGFβ production in mice [39, 41]. Not only SOCS3 is essential for G-CSF, IL-6, LIF, and leptin signaling, but is also an indirect regulator of IFNγ signaling and a negative regulator of IL-23 signaling, inducing IL-17-secreting T cells (Th17) polarization (Table 1).
The SOCS3 pathways are important, altering cardiac physiology by affecting molecular targets associated with myocardial changes implicated in structural pathologies. The SOCS3 proteins regulate specific cytokine pathways related to cardiac growth and enlargement and seem to be consistent with their roles critical regulators of hypertrophy, contractile dysfunction, and ventricular arrhythmias. They were, as their name suggests, first described as cytokine signaling inhibitors as observed for the Janus kinase/Signal Transducer and Activator of Transcription/Suppressor of Cytokine Signaling (JAK/STAT/SOCS) signaling pathway (JSS-SP). The remodeling by cytokine receptor signaling mediated by the JSS-SP provides a morphological basis explaining the pathogenesis of myocardial hypertrophy, fibrosis, and inflammation [41] in CCC. The inflammatory markers TNFα, and IL1-β represent potential targets in cardioprotection and therapy [42].
The SOCS3 protein is a key negative-feedback regulator of the gp130 receptor involved in signaling pertaining cardiac hypertrophy and survival. Activation of the gp130 without SOCS3 regulation leads to cardiac hypertrophy, in line with their roles as negative regulators of cardiac growth. Also, SOCS3 regulation on cardiac gp130 signaling participates in the pathogenesis of contractile dysfunction and ventricular arrhythmias. Consistently, human CCC is characterized by segmental left ventricular wall motion abnormalities (WMA), mainly in the early stages of the disease.
The failure of the SOCS3 protein, also a major negative regulator of both leptin, and insulin signaling, might participate in the pathogenesis of obesity, and associated metabolic abnormalities as found for diet-induced and genetic obesity, systemic inflammatory burden, and hyperlipidemia. In sum, the SOCS3 may be critically negative regulators of inflammation, cardiac hypertrophy, contractile dysfunction, and ventricular arrhythmias. However, our understanding of the origins of the individual pathway components and their assembly into a functional pathway has remained limited.
8. Long-lasting systemic inflammatory burden and clinical Chagas progression
The immune-inflammatory response plays a key role in cardiovascular damage [40, 41], and T. cruzi-derived molecules may sustain the TLR-mediated innate immune response inducing inflammatory cytokines and chemokines secretion. The adaptive immune response to Chagas antigens may protect the host from secondary reinfection, though damaging the CV system due to inflammation, and the associated connective repair (fibrosis).
Crossroads between “natural, and specific immunity effector cells and molecules” and “parasite persistence strategies in blood, adipose tissue, the heart, and other infected tissues” seem to contribute to cardiovascular risk. Tissue damage induces inflammatory reactions. Immune-activated pathways are the main contributors to systemic inflammation in human CCC by active crosstalk between different CVRFs, metabolic and immune-mediated innate and adaptive host-parasite interactions. The contribution of natural and specific immunity against Chagas antigens enhance systemic inflammatory burden (SIB). Certainly, the immune system is not the only source of inflammatory molecules, but other tissues also contribute to enhancing systemic inflammatory burden as the WAT which releases inflammatory cytokines.
In a recent study, the levels of IL1β, IL6, IL10, TGFβ, IL12, IL17, TNFα, and serum IFNα were different in either chronic asymptomatic or cardiac chagasic patients compared with healthy controls. The asymptomatic patients had a higher plasma TNFα concentration (eightfold) and IL10, and lower IFNα than in normal controls, suggesting a process of immune regulation. Neither the interaction with traditional CVRFs and their contribution to CVR nor control-matching for age, sex, weight, or BMI were considered in this study. The advent of noninvasive imaging techniques allows studying the relationship between inflammatory markers in subclinical atherosclerosis development. The association of many systemic diseases with an increase in the prevalence of cardiovascular diseases involves immunoinflammatory mediators related to chronic inflammation and cannot be explained by the classic CVRFs. Unlike the classical CVRFs like the lipid profile, the approaches based on the contribution of the inflammatory milieu to cardiovascular disease development have not yet allowed identifying clinically validated biomarkers regardless the evidence suggesting their association with increased morbidity, and mortality except CRP [43].
Scientific research is encouraged to delve into the important role suggested for the inflammatory response in the metabolism and control of the atherogenic potential [44]. Hypercholesterolemia and inflammation are certainly considered contributive partners in atherosclerosis.
Only lipid-related indicators like LDL- and HDL-cholesterol fractions, and triglycerides are currently recommended in predicting cardiovascular risk. Paradoxically, plasma total cholesterol level is accepted as a marker of relative CVR, though more than 50% of all cardiovascular events can occur in individuals with concentrations below the accepted normal total cholesterol level [56].
With a complete understanding of atherogenesis, the atherothrombotic markers, and the already mentioned inflammatory markers [45] are potentially available for CVR estimation.
Recent data suggest that the measurement of related inflammatory markers may improve cardiovascular risk assessment. Certain markers being evaluated include a group termed as “cellular” cytokines (e.g., IL1, IL2, IL12p40, IL15, IL17, TNF, IFN, and IFN), and “humoral” cytokines (e.g.IL4, IL5, IL6, IL10, and IL13), growth factors and angiogenic [e.g., EGF, VEGF, FGF, granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage-colony-stimulating factor (GM-CSF)], and chemokines [e.g. CCL2 (MCP1), CCL3 (MIP1), CCL11 (Eotaxin), and CXCL8 (IL8)]. The role of some of them in cardiovascular pathogenesis is described below.
8.1. Soluble ICAM1
Inflammatory stimuli trigger a dramatic increase in ICAM1 expression on the vascular surface. Later on, inflammatory cytokines induce the endothelial expression of VCAM1 which, like ICAM1, interacts with leukocyte integrins promoting the firm adhesion of leukocytes to the surface of the endothelial cells. After proteolytic cleavage, the endothelial ICAM1 molecules can be released into the circulation as soluble molecules (ICAM1s), the level of which correlates with CVRFs like smoking, hypertension, hypercholesterolemia, and hypertriglyceridemia and with acute phase reactants like the PCR, and increases in patients with coronary disease. The circulating level of the soluble forms of ICAM-1, VCAM-1, selectin, and CD44 are remarkably high during the acute T. cruzi infection, while the soluble forms of VCAM-1 and P-selectin increase in chronic infection [46, 47, 48, 49, 50, 51, 52]. As inflammation markers, the soluble forms of ICAM-1 might be notably higher in patients with DCM [53, 54, 55].
8.2. Chemotactic monocyte-1 protein
An important early step in atherosclerosis is the adhesion of monocytes to activated endothelial cells. The endothelium produces several molecules critical in the proatherogenic events like the endothelium-released MCP1 which contributes to increased monocyte recruitment, and activation of nuclear factor kappa B (NF-kB) involved in the transcription of many functional genes in the inflammatory process [64]. Recently, CCL2/MCP-1 has emerged as a critical factor in infectious and autoimmune myocarditis, is largely produced in T. cruzi-loaded mice hearts, and it promotes macrophages infiltration and parasite destruction. T. cruzi-infected CCL2(−/−) mice developed higher parasitemia, dying prematurely, and showed increased levels of TNF, IFN-gamma, and IL-10 in plasma, clinical signs of systemic inflammatory response. Cardiac density of amastigote nests was associated with leukocytes infiltrates. Other studies demonstrated that CCL2 contributes to the reduction of parasite growth by controlling the distribution, cellular composition, and the status of inflammatory infiltrates in acute T. cruzi infection [21]. More recent evidence shows that polymorphisms involved key molecules related to innate immunity, and that cell migration plays a critical role in genetic susceptibility to CCC [56, 57, 58].
8.3. Interleukin 10
Within the group of the so-called anti-inflammatory cytokines, the human IL10 is associated with an anti-atherogenic action reducing inflammation. Cytokine knockout of the Th1 inhibitor IL10 increase vascular lesions [59]. IL10 has strong regulatory properties on macrophages and T cells, and negatively regulates many cellular processes involved in atherosclerotic plaque development and stability.
A recent study revealed comparable serum cytokine levels in cardiac chagasic and asymptomatic patients though IL10 level was higher, and IFNγ level was lower in the former suggesting a greater regulatory activity in cardiac patients. Presumably, the IL10 level is ineffective to restore homeostasis. Likewise, circulating IL10 increases in patients with DCM.
8.4. Transforming growth factor beta (TGFβ)
The transforming growth factor beta is produced by different cell types including adipocytes, macrophages, endothelial cells, smooth muscle cells, platelets, and regulatory T cells. The TGFβ1 factor stimulates PAI-1 release and suppresses leptin release from the human adipose tissue. It inhibits atherogenesis modulating T-lymphocyte activity rather than modulating the prothrombotic and fibrinogenic activity, as confirmed in TGF II receptor type-KO models. It is also involved in regulating host tissue fibrosis. The oral administration of GW788388, a novel kinase inhibitor type associated with TGFß I and II receptors, remarkably increased cardiac cells’ survival time and decreased cardiac fibrosis, offering a potential alternative to the current asymptomatic Chagas treatment. However, the cost-benefit balance is uncertain since circulating TGFβ modulates the pathogenic effector immune response avoiding immune damage but exacerbating fibrosis. Recent studies indicate that the deep alterations induced by circulating TGFβ increase in patients with DCM with or without cardiac fibrosis [60, 61, 62].
8.5. Interleukin-17A
The interleukin-17A cytokine released by Th17 cells is elevated in plasma in atherogenesis mice models. Increased serum levels of IL17 and IFNγ are found in patients with coronary atherosclerosis. The proatherogenicity of IL17A results from the monocytes/macrophages recruitment into the aortic wall [63]. The differentiation of Th17 depends on IL23 and IL6 released by myeloid dendritic cells, IL1, IL6, and IL21 derived from macrophages and T lymphocytes [64]. In humans, TGFα acts as a negative regulator of IL17. For years, Chagas-associated cardiac damage has been attributed to immunological dysregulation, including an imbalance between pro- and anti-inflammatory cytokines, Th1-Th2 immune deflection, and regulatory T cell activity. Recently, IL17 produced during experimental T. cruzi infection regulated Th1 differentiation, and parasite-induced myocarditis. The decrease in IL10 and IL17 cytokines’ production in association with high levels of IFNγ, and TNFα correlates with the severity of human chagasic cardiomyopathy. This immunological imbalance might be causally related to a poor suppressor activity of the regulating T cells controlling myocardial inflammation. Finally, the derived IL17A-fibroblast and the derived -GM-CSF-macrophage axis are potential targets for the treatment of DCM and related inflammatory cardiac disorders [64].
8.6. C-reactive protein
The CRP marker level is used as a predictor of future cardiovascular events, being a good estimator of mortality risk in different contexts, particularly in metabolic syndrome in the general population. It has also been suggested as a direct stimulator of plaque formation decreasing endothelial nitric oxide synthase (eNOS) activity [65], and implicated in other deleterious effects. In vitro studies provide evidence of the proatherogenic direct effects of CRP as found in endothelial dysfunction, Also, an increase CRP serum level in chagasic patients has been associated with a greater progression towards heart failure. High hs-CRP level is associated with a higher incidence of the long-term combined endpoint of all-cause mortality and hospitalization in patients with DCM. Besides, oxidative stress molecules and hs-CRP are both associated with heart failure and damage severity in patients with DCM [66, 67].
8.7. Tumor necrosis factor alpha (TNFα)
The pleiotropic TNFα cytokine is one of the most potent mediators of inflammation. It is associated with an increased CVR. It can induce proatherogenic lipid alterations, including increased LDL-cholesterol and HDL-cholesterol [68] and promote hypercoagulability inducing tissue factor (TF) expression in endothelial tissue and suppressing anticoagulant activity through activated thrombomodulin-activated protein C [69]. It also induces endothelial dysfunction through decreasing nitric oxide and regulating adhesion molecules, an early critical step in atherogenesis. Several investigations in animal and human models provide convincing evidence on the action of TNFα as one of the major regulators of vascular homeostasis. Blocking of TNFα results in a significant decrease in Lp (a), homocysteine levels and increases in Apo AI, triglycerides, and Apo B concentration. The prolonged use of TNFα blocking agents interferes with proatherogenic action, reducing the incidence of cardiovascular events. Taken together these studies confirm a critical role of TNFα at the prothrombotic, proinflammatory and metabolic level. An association between TNFα levels with heart failure was observed in chagasic patients. Autopsies specimens confirmed the presence of cardiac inflammatory cell infiltrates showing a Th1 cytokines pattern. Chronic asymptomatic chagasic patients have TNFα plasma concentrations roughly eightfold higher than healthy controls, and TNFα may play a role in progression to heart failure, The increased level of TNFα might also be related to disease severity in chronic Chagas disease as found in patients with DCM. Interestingly TNFα blockage aggravates experimental CCC [70, 73].
8.8. Interleukin-1 (IL-1)
The IL-1 interleukin is a crucial proinflammatory mediator in acute and chronic inflammation, and also a powerful innate immune response inducer. It induces the synthesis and expression of several hundreds of secondary inflammatory mediators in different diseases [74, 75]. The inflammatory response is associated with the expression of numerous cytokines [interferon gamma, interferon alpha, tumor necrosis factor (TNF), and interleukin-3 (IL-3)], which stimulate xanthine oxidoreductase (XOR). The main circulating form of IL-1 is the IL-1β, initially synthesized as the pro IL-1β a precursor which is activated by caspase-1 cleavage in the setting of a macromolecular structure known as the inflammasome [71]. Many potential triggers of the inflammasome have been identified, including microbial agents, ischemia, damaged cells, cholesterol crystals, and TLRs ligands such as danger-associated molecular patterns (DAMPs) or pathogen-associated molecular patterns (PAMPs). The IL-1 molecule has been associated with endothelial dysfunction, hypertension, heart failure, and diabetes [75]. Recent studies indicate that XOR and XO serum levels are considerably increased in both cardiac and asymptomatic patients following T. cruzi invasion. Serum levels of IL-1β could be used in predicting the long-term outcome of patients affected by idiopathic DCM [71, 76]. Cardiac fibrosis and heart failure progression in inflammatory dilated DCM might be related to the myeloid differentiation factor-88/IL-1β signaling pathway [72, 77].
8.9. Interleukin-6
IL-6 provides a link between innate and adaptive immunity through the regulation of leukocyte activation, differentiation, and proliferation. During the acute and chronic inflammatory response, macrophages release TNFα in the presence of a variety of stimuli including atherogenic factors. In the macrophages, TNFα triggers the release of TNFα, and of more IL1B, which stimulates endothelial cells to produce IL6 and IL8. To date, both the scientific outcome of experimental studies, and the abundant clinical evidence in atherosclerosis indicate that low-intensity sustained inflammation plays a key role in atherosclerotic plaque formation, progression, and destabilization leading to clinical endpoints like myocardial infarction, sudden death, or stroke. The underlying mechanisms are still unclear, despite the intense research over the past two decades. Both IL6 and its signaling events contribute to atherosclerotic plaque development and destabilization. Increased levels of IL6 [78, 79] and CRP, an accepted CVRF, can also contribute to atherosclerosis and arterial thrombosis by activating tissue factor production, increasing adhesiveness of endothelial cells, fibrinogen and factor VIII and stimulating platelet production, and aggregation [91]. In addition, smooth muscle cells (SMC) also produce abundant IL-6. Other inflammatory factors generated by adipocytes like IL6, CRP, and TNFα are also implicated in the pathophysiology of the metabolic syndrome. The polymorphism of IL6 genes correlates with the severity of coronary artery disease, and with myocardial infarction risk [80, 81], but not with carotid atherosclerosis, which seems to be independent, These findings clearly suggest a strong association between IL6 levels, atherosclerosis, and risk of cardiovascular death. Produced locally IL6 in the endothelial vasculature and by SMC, IL6 induces ROS production, proliferation, and SMC migration. IL6 is an important autocrine and/or paracrine regulator of SMC proliferation and migration, critical steps in atherosclerosis progression. Besides, circulating IL-6 levels (in parallel with an increase in circulating CRP) increase with progression to heart failure in Chagas disease. These observations agree with the polymorphisms analyzed in patients with idiopathic dilated cardiomyopathy (IDCM) that relates to TNF, IL-6, and CRP profile. A recent study shows that a rough increase in serum IL-6 is incidental with chronic IDCM [82].
9. Conclusion
Search results illustrated that immune-activated pathways are the main contributors to systemic inflammation in human CCC due an interplay and active crosstalk between different traditional risk factors, mainly metabolic and inflammatory factors derived from immune-mediated host-parasite interactions, both innate and adaptive.
Tissue damage induces inflammatory reactions leading to dilated cardiomyopathy in genetically predisposed persons. The DCM represents an essential hallmark of CCC. Evidence suggests that the pathway of inflammation in DCM culminates in altered concentrations of various markers in peripheral blood, including oxidative stress molecules and markers of vascular and systemic inflammation. These scenarios necessarily require a means of communicating between different cell populations. Crossroads between “natural and specific immunity effector cells and molecules” and “parasite persistence strategies in blood, adipose tissue and heart and other infected tissue” would appear to contribute to cardiovascular risk. The Suppressor of Cytokine Signaling (SOCS) plays a critical role in the regulation of all crossroads of cytokine inflammatory network that induced pathogenesis of dilated cardiomyopathy and seems to play a critical role as negative regulators of inflammation, hypertrophy, contractile dysfunction and ventricular arrhythmias. However, our understanding of the origins of the individual pathway components and crossroads and their assembly into a functional pathway is limited so far. Unlike classical risk factors, approaches based on inflammatory status needs clinically validated biomarkers and its contribution to the development of cardiomyopathy in chagasic and IDCM needs additional studies, even when there is strong evidence suggesting increased morbidity and mortality associated with the systemic inflammatory burden and inflammatory cardiomyopathy.
Acknowledgments
The authors would like to thank Dr. José Milei for gently providing us with Figure 1 to illustrate our chapter.
\n',keywords:"Chagas disease, myocarditis, cardiomyopathy, inflammation, immune system, cardiovascular risk",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/62321.pdf",chapterXML:"https://mts.intechopen.com/source/xml/62321.xml",downloadPdfUrl:"/chapter/pdf-download/62321",previewPdfUrl:"/chapter/pdf-preview/62321",totalDownloads:958,totalViews:136,totalCrossrefCites:2,totalDimensionsCites:3,totalAltmetricsMentions:0,impactScore:2,impactScorePercentile:80,impactScoreQuartile:4,hasAltmetrics:0,dateSubmitted:"May 18th 2017",dateReviewed:"April 25th 2018",datePrePublished:null,datePublished:"September 12th 2018",dateFinished:"June 27th 2018",readingETA:"0",abstract:"The economic and social burden associated with Chagas disease morbidity and mortality is regrettably large in Latin America causing more deaths than does any other parasitic disease. Inflammatory dilated cardiomyopathy is, by far, the most important clinical consequence of Trypanosoma cruzi infection. The insidious persistence of this parasite determines chronic myocarditis progression. The clinical outcome is multifactorial and depends on the particular parasite strain and virulence factors, the infective load and route of infection, the parasite ability to by-pass the protective immune response, the intensity and type of immune response during the acute infective phase, and the host genetic background. From the immunological viewpoint, host control of T. cruzi has been shown to depend on both humoral and cell-mediated adaptive responses and from the innate immune system. In this review, we discuss the most relevant literature conveying information on the relevance of identifying a subset of systemic inflammatory molecules as potential markers of cardiovascular risk morbidity and mortality in patients with Chagas disease. Concurrently, a direct role for the parasite in the perpetuation of myocardial inflammation is substantiated. Ultimately, host-parasite interactions determine the course of the ongoing systemic inflammation and the perpetuation of myocardial inflammation in genetically predisposed patients.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/62321",risUrl:"/chapter/ris/62321",book:{id:"6267",slug:"chagas-disease-basic-investigations-and-challenges"},signatures:"Rodolfo A Kölliker-Frers, Matilde Otero-Losada, Gabriela Razzitte,\nMariela Calvo, Justo Carbajales and Francisco Capani",authors:[{id:"120703",title:"Dr.",name:"Francisco",middleName:null,surname:"Capani",fullName:"Francisco Capani",slug:"francisco-capani",email:"franciscocapani@hotmail.com",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/120703/images/system/120703.jpeg",institution:{name:"University of Buenos Aires",institutionURL:null,country:{name:"Argentina"}}},{id:"205589",title:"Dr.",name:"Rodolfo Alberto",middleName:null,surname:"Kölliker Frers",fullName:"Rodolfo Alberto Kölliker Frers",slug:"rodolfo-alberto-kolliker-frers",email:"rodolfo@kollikerfrers.com.ar",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"213940",title:"Dr.",name:"Justo",middleName:null,surname:"Carbajales",fullName:"Justo Carbajales",slug:"justo-carbajales",email:"justocarbajales@hotmail.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"213941",title:"Ms.",name:"Gabriela",middleName:null,surname:"Razzitte",fullName:"Gabriela Razzitte",slug:"gabriela-razzitte",email:"grazzitte@hotmail.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Cardiomyopathy genes",level:"1"},{id:"sec_3",title:"3. Anatomopathological findings of Chagas cardiomyopathy",level:"1"},{id:"sec_4",title:"4. Clinical expression of the acute phase of Chagas disease",level:"1"},{id:"sec_5",title:"5. Clinical expression of the chronic phase of Chagas disease",level:"1"},{id:"sec_5_2",title:"5.1. Clinical asymptomatic expression of the chronic phase",level:"2"},{id:"sec_6_2",title:"5.2. Clinical symptomatic expression of the chronic phase",level:"2"},{id:"sec_8",title:"6. Factors that define blood inflammatory outcome in Chagas disease",level:"1"},{id:"sec_8_2",title:"6.1. Factors that promote parasite evasion and persistence",level:"2"},{id:"sec_8_3",title:"6.1.1. Parasitemia and sustained antigen stimulation",level:"3"},{id:"sec_9_3",title:"6.1.2. Cruzi virulence and immunomodulatory factors",level:"3"},{id:"sec_10_3",title:"6.1.3. White adipose tissue is an immune active endocrine organ",level:"3"},{id:"sec_12_2",title:"6.2. Host-protective and pathogenic anti-T. cruzi immune-mediated-response",level:"2"},{id:"sec_12_3",title:"6.2.1. The innate immune system",level:"3"},{id:"sec_12_4",title:"6.2.1.1. Toll-like receptors agonists expressed by T. cruzi activate inflammatory pathways",level:"4"},{id:"sec_13_4",title:"6.2.1.2. Toll-like receptors and resistance to infection",level:"4"},{id:"sec_14_4",title:"6.2.1.3. Cardiac toll-like receptors increase in ischemia/reperfusion-induced cardiac hypertrophy",level:"4"},{id:"sec_16_3",title:"6.2.2. The adaptive immune system",level:"3"},{id:"sec_16_4",title:"6.2.2.1. Autoimmunity",level:"4"},{id:"sec_16_5",title:"6.2.2.1.1. Evidence derived from the autoreactive immune response",level:"5"},{id:"sec_17_5",title:"6.2.2.1.2. Evidence derived from molecular mimicry and the formation of cardioactive autoantibodies",level:"5"},{id:"sec_19_4",title:"6.2.2.2. Immune origin of the disease and the localized inflammatory response",level:"4"},{id:"sec_23",title:"7. Suppressor of cytokine signaling proteins, immune regulation, and dilated cardiomyopathy",level:"1"},{id:"sec_24",title:"8. Long-lasting systemic inflammatory burden and clinical Chagas progression",level:"1"},{id:"sec_24_2",title:"8.1. Soluble ICAM1",level:"2"},{id:"sec_25_2",title:"8.2. Chemotactic monocyte-1 protein",level:"2"},{id:"sec_26_2",title:"8.3. Interleukin 10",level:"2"},{id:"sec_27_2",title:"8.4. Transforming growth factor beta (TGFβ)",level:"2"},{id:"sec_28_2",title:"8.5. Interleukin-17A",level:"2"},{id:"sec_29_2",title:"8.6. C-reactive protein",level:"2"},{id:"sec_30_2",title:"8.7. Tumor necrosis factor alpha (TNFα)",level:"2"},{id:"sec_31_2",title:"8.8. Interleukin-1 (IL-1)",level:"2"},{id:"sec_32_2",title:"8.9. Interleukin-6",level:"2"},{id:"sec_34",title:"9. 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O Biologico. 2009;86:1239-1246'},{id:"B53",body:'Frade AF, Pissetti CW, Ianni BM, Saba B, et al. Genetic susceptibility to Chagas disease cardiomyopathy: Involvement of several genes of the innate immunity and chemokine-dependent migration pathways. BMC Infectious Diseases. 2013;13:587'},{id:"B54",body:'Guo Y, Cen Z, Wei B, Wu W, et al. Increased circulating interleukin 10-secreting B cells in patients with dilated cardiomyopathy. International Journal of Clinical and Experimental Pathology. 2015;8:8107-8114'},{id:"B55",body:'Rubiś P, Wiśniowska-Smiałek S, Wypasek E, Rudnicka-Sosin L, et al. 12-month patterns of serum markers of collagen synthesis, transforming growth factor and connective tissue growth factor are similar in new-onset and chronic dilated cardiomyopathy in patients both with and without cardiac fibrosis. Cytokine. 2017;96:217-227'},{id:"B56",body:'van der Aar AM, Sibiryak DS, Bakdash G, van Capel TM, et al. Vitamin D3 targets epidermal and dermal dendritic cells for induction of distinct regulatory T cells. The Journal of Allergy and Clinical Immunology. 2011;127:1532-1540.e7'},{id:"B57",body:'Wu L, Ong S, Talor MV, Barin JG, et al. Cardiac fibroblasts mediate IL-17A-driven inflammatory dilated cardiomyopathy. The Journal of Experimental Medicine. 2014;211:1449-1464'},{id:"B58",body:'Jialal I, Devaraj S, Venugopal SK. C-reactive protein: Risk marker or mediator in atherothrombosis? Hypertension. 2004;44:6-11'},{id:"B59",body:'Birjmohun RS, Bisoendial RJ, van Leuven SI, Ackermans M, et al. A single bolus infusion of C-reactive protein increases gluconeogenesis and plasma glucose concentration in humans. Metabolism. 2007;56:1576'},{id:"B60",body:'Qamirani E. C-reactive protein inhibits endothelium-dependent NO-mediated dilation in coronary arterioles by activating p38 kinase and NAD(P)H oxidase. 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Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases. Nature Reviews. Drug Discovery. 2012;11:633-652'},{id:"B70",body:'Berry CE, Hare JM. Xanthine oxidoreductase and cardiovascular disease: Molecular mechanisms and pathophysiological implications. The Journal of Physiology. 2004;555:589-606'},{id:"B71",body:'Stutz A, Golenbock DT, Lat E. Inflammasomes: Too big to miss. The Journal of Clinical Investigation. 2009;119:3502-3511'},{id:"B72",body:'Aleksova A, Beltrami AP, Carriere C, Barbati G, et al. Interleukin-1β levels predict long-term mortality and need for heart transplantation in ambulatory patients affected by idiopathic dilated cardiomyopathy. Oncotarget. 2017;8:25131-25140'},{id:"B73",body:'Blyszczuk P, Kania G, Dieterle T, Marty RR, et al. Myeloid differentiation factor-88/interleukin-1 signaling controls cardiac fibrosis and heart failure progression in inflammatory dilated cardiomyopathy. Circulation Research. 2009;105:912-920'},{id:"B74",body:'Matsuzawa Y. Adipocytokines and metabolic syndrome. Seminars in Vascular Medicine. 2005;5:34-39'},{id:"B75",body:'Yin YW, Hu AM, Sun QQ, Liu HL, et al. Association between interleukin-6 gene-174 G/C polymorphism and the risk of coronary heart disease: A meta-analysis of 20 studies including 9619 cases and 10919 controls. Gene. 2012;503:25-30'},{id:"B76",body:'Rauramaa R, Väisänen SB, Luong LA, Schmidt-Trücksäss A, et al. Stromelysin-1 and interleukin-6 gene promoter polymorphisms are determinants of asymptomatic carotid artery atherosclerosis. Arteriosclerosis, Thrombosis, and Vascular Biology. 2000;20:2657-2662'},{id:"B77",body:'Rundek T, Elkind MS, Pittman J, Boden-Albala B, et al. Carotid intima-media thickness is associated with allelic variants of stromelysin-1, interleukin-6, and hepatic lipase genes: The Northern Manhattan Prospective Cohort Study. Stroke. 2002;33:1420-1423'},{id:"B78",body:'Schuett H. How much is too much? Interleukin-6 and its signaling in atherosclerosis. Thrombosis and Haemostasis. 2009;102:215-222'},{id:"B79",body:'Tedgui A, Mallat Z. Cytokines in atherosclerosis: Pathogenic and regulatory pathways. Physiological Reviews. 2006;86:515-581'},{id:"B80",body:'López L, Arai K, Giménez E, Jiménez M, et al. Proteína C reactiva y la interleucina-6 aumentan los niveles séricos como la enfermedad de Chagas avanza hacia la insuficiencia cardiaca. Revista Española de Cardiología. 2006;59:50-56'},{id:"B81",body:'Liaquat A, Asifa GZ, Zeenat A, Javed Q. Polymorphisms of tumor necrosis factor-alpha and interleukin-6 gene and C-reactive protein profiles in patients with idiopathic dilated cardiomyopathy. Annals of Saudi Medicine. 2014;34:407-414'},{id:"B82",body:'Bironaite D, Daunoravicius D, Bombloads J, Cibiras S, et al. Molecular mechanisms behind progressing chronic inflammatory dilated cardiomyopathy. BMC Cardiovascular Disorders. 2015;15:26'}],footnotes:[],contributors:[{corresp:null,contributorFullName:"Rodolfo A Kölliker-Frers",address:null,affiliation:'
Parasitology Unit, José María Ramos Mejía Hospital, Argentina
Laboratory of Cytoarchitecture and Neuronal Plasciticy, Institute of Cardiological Research, “Prof. Dr. Alberto Taquini”, ININCA-UBA-CONICET, Argentina
Laboratory of Cytoarchitecture and Neuronal Plasciticy, Institute of Cardiological Research, “Prof. Dr. Alberto Taquini”, ININCA-UBA-CONICET, Argentina
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1. Introduction
Volatilomics indicates the qualitative and quantitative study of the volatilome, defined as the complex blend of volatile organic compounds (VOCs) originating from different biosynthetic pathways and emitted by living organisms [1]. VOCs are small molecules (below 500 Da), with hydrophobic character, low boiling points, and high vapor pressure at ambient temperature. Unconjugated volatiles can freely diffuse across membranes to be released from flowers, fruits, and vegetative tissues into the atmosphere and from roots into the soil to be perceived at short and long-distance. Therefore, plants and animals use VOCs for chemical communication with the surrounding ecosystem, and plants also use them as attractors for pollinators and defense against herbivory and biotic and abiotic stress [2, 3, 4, 5].
The study of VOCs of plants has focused not only on the qualitative and quantitative composition of the volatile fraction but on the bioactive compounds as well as flavors and fragrances [6, 7]. Similarly, the understanding of fruits’ sensorial attributes is of great interest as quality control, as well as in the determination of origin mark, and the performance of ecological studies aimed at the establishment of the relationship between the ripening stage and the incidence of fruit diseases for insect or microorganism attack [8, 9, 10].
Microorganisms produce a plethora of important microbial volatile organic compounds (mVOCs), that play an essential role in inter- and intra-kingdom connections. The study of mVOCs has allowed, for example, to detect terpenes, compounds normally associated with plants, also in fungi and bacteria [11]. Also, these compounds are related to ecological interactions between living organisms found in the soil, including the rhizosphere [12].
In addition, several studies of VOCs from animals not only have allowed decoding the signal of the animal chemical communication but also have demonstrated the potential use of that knowledge in early disease’s diagnostics. For example, recent studies have shown novel practice for the detection of biomarkers to identify the intoxication using unusual biological fluids like ear wax, being fast, economic, and noninvasive bioanalysis, with minimal sample preparation and very versatile to identify the first signals of intoxication [13, 14].
Differently to the genomes, the volatilome changes continuously across time, and its composition depends on external and internal factors, such as the environmental conditions, and/or the physiological state [15]. Therefore, the study of the volatilome is not a simple task and the researchers in this area entail multiple challenges derived from the chemical complexity of the samples and the superposition of VOCs signals as proper of the ecosystems. Thus, sensitive yet unbiased methodologies are needed to provide researchers with comprehensive and accurate representations of a plant species’ volatile metabolome.
However, current methodologies are limited in their ability to isolate, and even more critically to identify, many of the compounds present in each sample. In volatile metabolomics, the emitted metabolites are already isolated from tissues, they need to be temporarily trapped, and eventually preconcentrated, in a way that allows them to be released unadulterated for separation and identification.
A variety of technologies have been developed. In these methods, the sample of interest is enclosed in a collection chamber and the released volatiles present in the airspace surrounding the sample, headspace (HS), are trapped onto an adsorbent. And are subsequently analyzed by gas chromatography in combination with mass spectrometry (GC–MS) as the method of choice for volatilomics.
Hence, in the next sections of this chapter, we will provide an overview of the volatilome study process, including the main practical and theoretical aspects of volatiles capture, sample preparation, and the main analytical techniques employed to monitor VOCs, together with the chemoinformatics tools used for volatilome dereplication, elucidation, annotation, and interpretation of data.
2. Volatiles collection
Sample acquisition in volatilomics experiments requires consistency, therefore due to the high variability of chemical structures, concentrations levels, sample types, and physiological variations, other variables different than metabolites (addressed as meta-variables from now on) should be controlled or at least carefully monitored in order to evaluate their effect on the study outcome. Some important variables that should be taken into account include replicate number, taxonomic identification, geographic location, phenotypic or phylogenetic variant, sample weight, phenotypic characteristics, sex, developmental stage, health status, collection date, and time. Photographs should be taken. A useful reference for registering meta-variables is the ReDU Sample Information Template. (https://docs.google.com/spreadsheets/d/1v71bnUd8fiXX51zuZIUAvYETWmpwFQj-M3mu4CNsHBU/edit?usp=sharing) [16] build by the collaborative Global Natural Products Social Networking (GNPS) (https://gnps.ucsd.edu/ProteoSAFe/static/gnps-splash.jsp) [17] where researchers can add new meta-variables and share their data in an open-source and collaborative environment.
2.1 Plants
The plant volatilome is defined as the complex blend of essential oils (EOs) and VOCs fed by different biosynthetic pathways and emitted by plants, constitutively and/or after induction, as a defense strategy against biotic and abiotic stress. Plants have a vast diversity in their range of metabolites and their concentrations, as there are hundreds of thousands of metabolites in different categories. As such, there is no single analytical technique that has the capability of extracting and detecting the whole metabolome [18].
Plant volatile emissions are linked to the physiological status of the emitter, therefore special care must be taken to control the plant-growing environment as well as all variables concerning the developmental stage of the plant to limit unwanted fluctuations in metabolism that might affect collected. These include the time of day, photoperiod, temperature, humidity, water conditions, collection site altitude, plant age, climate, and soil type so that a careful experimental design is recommended. Whenever possible, growth chambers must be used for plant cultivation and volatile collection [19, 20]. EOs and VOCs can be extracted and analyzed from both fresh and dried plant materials. When using fresh material, particular attention must be paid to the health status of plants, since microbial and other infections may alter metabolites production. Plants must not show necrotic areas and be at the same developmental stage if comparative analyses are needed. Since the content of water may vary, it is a good practice to use some of the fresh material to calculate the dry matter percentage [21].
Since volatile emissions from many plant species vary with respect to the time of day, and different organs in the plant are known to produce and/or accumulate different profiles of secondary metabolites, collection strategies should consider volatile sampling over an extended period of time and from the investigated organ or entire plant, to prevent unintentional exclusion of volatile components in the sampled mixture. Also, when running VOCs analyses from living plants it must be remembered that rooted plants in pots respond differently than cuttings, and that soil in pots may contain microorganisms that can produce VOCs [22, 23]. Once a plant part is collected, at least two herbarium samples should be prepared and identified or authenticated by a taxonomist. One of these voucher specimens should be deposited in a local national herbarium. A card with details of the place, altitude, environment, and photographs should be attached to the herbarium sample, in case a recollection of the plant material is necessary. Although depositing herbarium samples is a basic step in performing phytochemical investigation, many researchers in the past neglected this step and thus were unable to reproduce their work [23, 24, 25].
2.2 Flowers
Living flowers change their volatile profile in a continuous way that depends on intrinsic and extrinsic factors. Once cut, flowers undergo rapid deterioration and loose volatiles. Flower volatiles allow discrimination between different plants and attract insects for pollination when they are released. The amount of emission is not uniform through time, with some differences between diurnal and nocturnal emission levels, and between reproduction phases. The volatile compounds emitted by flowers are mainly aliphatics, terpenoids, benzenoids, and phenylpropanoids. Flower volatiles require special methods for their isolation with preconcentration and can be obtained from the air surrounding the living or excised flower, or from the flower tissues themselves. The selected extraction technique determines the composition of the isolated volatiles mixture [26, 27].
2.3 Fruits
Fruits are very complex samples, rich in a great number of different classes of metabolites, including volatile, semi-volatile, and no volatile compounds. The flavor is one of the most important characteristics to value the quality of fruit. Volatile and semi-volatile compounds usually are responsible for aroma fruit, and their study has conducive to identify both positive and negative sensory attributes [28]. VOCs are produced in trace amounts, and although they are easily perceptible by the human nose, their sampling and monitoring can be challenging at an analytical level [29]. The volatile fraction of fruits is composed of hundreds of different chemical substances that can vary according to the type of fruit, but the emitted compounds can be grouped according to the chemical function mainly into esters, alcohols, aldehydes, ketones, lactones, and terpenoids [29]. Moreover, VOCs emitted by fruit depend on the production conditions (cultivars, state of maturity, post-harvest treatment, and storage) the sample format (whole fruit, sliced, wet, dry), and the type of analysis (in-field or in-lab). Capturing volatiles in-situ is a challenge, as small amounts of VOCs are released and diffuse in a large volume of air, which requires highly efficient sampling techniques to capture them. Solid-phase microextraction (SPME) and solid-phase extraction (SPE) are usually the most profitable techniques for the capture of fruit volatiles in-situ. Once the volatile compounds are retained in an adsorbent material, their storage and transport are facilitated. On the other hand, in laboratory capture of VOCs from fruits, can be efficiently performed by solvent or gas-based extraction techniques, such as Soxhlet, simultaneous distillation extraction, purge and trap, and headspace, among others.
2.4 Microorganisms
Analysis of mVOCs is commonly performed under controlled culture media, temperature, and agitation. Also, the percentage of humidity and exposure to UV–visible light among other growing conditions should be taken into account. In order to account for reproducibility of the experiments, laboratory tests on microorganisms must be performed using international reference strains e.g.: American Type Culture Collection (ATCC), instead of clinical or field isolations, or even strains isolated and saved in the research group for a long time. Because the emission of VOCs can vary in terms of presence or absence, and in terms of fluctuation in concentration, throughout the life span of the microorganisms (which can be from a few hours to days), it is advisable to perform analyses both in the exponential or logarithmic growth phase, as well as in the stationary phase [12, 30, 31]. During the exponential phase, the microorganism is reactivating its biosynthetic pathways after having been in a state of latency. Therefore, in this stage, there is generally a high concentration of some metabolites that are part of the first stages of the biosynthetic pathways, which can later diminish and disappear in the exponential phase. The stationary phase is achieved when the initial metabolic processes have been reached and occurs when the survival process of the species begins [32]. The metabolic changes produced in these two stages of microbial culture are fundamental to understanding and solving research questions [33, 34]. The determination of each of the culture phases is commonly done with a measurement of the absorption of light in the visible region between 500 and 650 nm for liquid growth medium. This is achieved by counting the colony-forming units (CFU) in the solid medium. The sampling time for analysis of mVOCs must coincide with those obtained in the growth curves, correctly differentiating the exponential and stationary phases.
2.5 Animals
For conducting volatile sampling from animals, the specimens could be either raised in captivity at controlled vivaria or extracted from their natural environments. Proper training in animal manipulation is an important aspect to be fulfilled before performing animal experimentation, as well as an approved permit by the Institution in charge to validates the procedures. Also, when animals are to be collected in their habitats, it is necessary to review if a Convention on International Trade in Endangered Species of Wild Fauna and Flora (CITES) permit is needed for protected species. A specialist should validate taxonomic identification and, in those cases, where sample collection involves euthanization of specimens that should be registered at a recognized Museum, and voucher numbers should be annotated and published on the research paper. In the same way, as other organisms could be sampled by different methods, almost all animals could be sampled in vivo, but in some cases, tissue extraction could be preferred for guaranteeing detection of less abundant metabolites. Some techniques applied for VOCs analysis from terrestrial arthropods [35, 36, 37, 38, 39], aquatic organisms [40, 41, 42], mammals [43, 44, 45, 46, 47, 48], birds [49, 50], reptiles [51, 52], fishes [53], and amphibians [37, 38, 54, 55, 56, 57] include headspace-adsorbent traps, polydimethylsiloxane (PDMS) patches, swabs and stir bar sorptive extraction (SBSE).
3. Volatiles extraction
Sample preparation is one of the most important steps in the analytical process. The goal of sample preparation is to efficiently isolate target analytes from potential interferences and to extract as many VOCs as possible to provide a true representation of the studied system.
Some steps of pre-treatment of the sample are necessary in order to minimize the manipulation of the sample and avoid its modification, to clean-up the sample efficiently, and to quench metabolic reactions that could cause degradation and decomposition. To date, two different types of headspace sampling, static and dynamic, are widely used for volatilomics investigation.
Static headspace sampling is a passive technique for VOCs collection, where no air is circulated for the concentration of the volatiles on a sorbent matrix [18]. As a result, the background noise is drastically reduced due to the absence of a continuous airflow that can contain impurities that could mask compounds released at trace amounts. In static headspace methods, samples are typically sealed inside a container or bag, where the volatiles are released and, in the more traditional version of the technique, the headspace is sampled directly using a gas-tight syringe and transferred to the Gas Chromatography (GC) injection port. When the analytes are present at trace level, it might be necessary to carry out static headspace methods with special techniques to concentrate volatiles during collection and reduce the dilution of the sample during desorption in the GC inlet. In such a context, SPME stands out as the most versatile strategy for volatile capture from the sample headspace in static mode. Nowadays, SPME is the leading technique in the analysis of volatiles of biological origin because it uses a fiber coated with a sorbent phase to combine extraction and pre-concentration compounds. SPME fibers are available in a wide range of coatings that allow the sampling of compounds of different polarities and volatilities. Considering that the goal of volatilomics profiling is to analyze as many metabolites as possible, the use of divinylbenzene/carboxen/polydimethylsiloxane (DVB/CAR/PDMS) fibers is the most suited to increase the number of analytes that can be trapped on the fiber because it can allow capture VOCs in a wide range of polarity and molecular weight [58].
This type of coating contains a layer of CAR particles underneath a layer of DVB particles. Because the ability of adsorbent coatings to extract a particular analyte strongly depends on the size of the pores, larger analytes will be retained in the outer DVB layer, while the smaller analytes will migrate through this layer and are retained by the inner layer of CAR. On the contrary, if the study targeted only on the most volatile fraction, PDMS/CAR would be an appropriate choice of coating, since the micropores of the CAR retain smaller analytes better than other coatings, although introducing a high degree of discrimination towards high-molecular-weight compounds.
On another hand, although other coatings, such as PDMS, polyacrylate (PA), and Carbowax (CW), are also commercially available, their use in volatilomics is quite scarce due to the higher selectivity towards certain classes of polarities [58, 59].
From a practical point of view, SPME is a versatile technique for in-field sampling as a non-destructive strategy for the study of the volatiles emitted ex-vivo, for example, by grapes. In this case, an aluminum wire cage can be used to support a polymeric film to enclose a whole cluster of grapes, and SPME fiber is introduced through a port fitted with a silicone septum (Figure 1a).
Figure 1.
Sampling handling techniques of VOC’s fruit. a) Ex-vivo sampling of volatiles from the whole cluster of grapes by SPME; b)Ex-vivo sampling of volatiles from a single grape berry by SPME. Adapted from [10] under the Creative Commons Attribution License.
Also, an interesting strategy for speeding up the volatiles’ uptake is vacuum-assisted SPME. For example, in-field sampling of volatiles from a single grape berry, a modified screw top, and a 2 mL glass vial can be used for fiber exposition. A syringe is usually used to create a negative pressure to hold the sampling device with the SPME sealed onto the sample surface (Figure 1b).
This type of coating contains a layer of CAR particles underneath a layer of DVB particles. Because the ability of adsorbent coatings to extract a particular analyte strongly depends on the size of the pores, larger analytes will be retained in the outer DVB layer, while the smaller analytes will migrate through this layer and are retained by the inner layer of Carboxen. Conversely, if the study targeted only on the most volatile fraction, PDMS/CAR would be an appropriate choice of coating, since the micropores of the CAR retain smaller analytes better than other coatings, although introducing a high degree of discrimination towards high-molecular-weight compounds.
Although SPME generally exhibits better extraction efficiency as the polarity of the compound decreases, these three coatings can provide balanced metabolome coverage as long as most polar analytes are present at reasonable concentration levels. Absorbent coatings, such as PDMS, PA, and CW, were rarely employed in profiling studies. These coatings display selectivity based on polarity, resulting in poor metabolomic coverage. The second case is dynamic headspace sampling, which offers a highly concentrated sample that can be desorbed into a solvent at volumes suitable for multiple analyses. To date, it is the most frequently used technique in all areas of plant volatile analysis. Dynamic headspace sampling collects a much larger quantity of compounds at higher concentrations because the continuous stream of air allows the sorbent to act as a filter trapping the volatiles.
Also, push and pull headspace sampling, two examples of dynamic headspace sampling, allow to avoid problems often encountered with the sealed systems used in static headspace and closed-loop stripping methods including heat, water vapor, and, in the case of plants, ethylene accumulation that can affect not only sampling efficiency but also plant physiology. Among the several methods, closed-loop stripping systems have broad utility for the collection of volatiles: volatiles are collected during continuous circulation of HS air inside closed chambers in which air circulation pumps are connected to supporting columns or coated supports [22].
As an example, SPME is a versatile technique for in-field sampling handling as a non-destructive strategy for the study of the volatiles emitted ex-vivo, for example, by the whole cluster of grapes. In this case, an aluminum wire cage can be used to support a polymeric film to enclosing a whole cluster of grapes, and SPME fiber introduced through a port fitted with silicone septa (Figure 1a) [60]. Also, an interesting strategy for speed up the volatile’s uptake is vacuum-assisted SPME. For example, in-field sampling of volatiles from a single grape berry, a modified screw top, and a 2 mL glass vial can be used for fiber exposition. A syringe is usually used to create a negative pressure to hold the sampling device with SPME sealed unto the sample surface (Figure 1b) [60].
Alternatively, to the SPME, some liquid-phase microextractions (LPME), such as the single drop microextraction (SDME) or the hollow fiber liquid-phase microextraction (HF-LPME), can also provide efficient and profitable volatiles recoveries in the headspace static mode. For example, SDME is a technique based on a few microliters of solvent, in which volatiles can be capture in a small drop of extraction solvent-exposed to the headspace of the sample [20, 59]. In the same way, to address the drawbacks of the drop instability, the extraction solvent can be deposited into the lumen of a porous fiber HF-LPME, improving the extraction kinetics by use of a bigger transference surface or by the incorporation of an acceptor solvent into the membrane pores (Supported Liquid Membrane, SLM). Although the use of hazardous organic solvents can be considered a drawback, nowadays those solvent-based extractions can be performed with environmental-friendly alternatives, such as ionic liquids, deep eutectic solvents, or supramolecular solvents, among others.
The second type of headspace sampling is the dynamic headspace (DHS) method. It encompasses strategies in which VOCs are captured in a sorbent-packed trap by passing a continuous flow of inert dry gas through the sample. In this way, the emission of VOCs speeds up by the continuous renovation of the headspace fraction. After extraction, concentrated VOCs can be desorbed from the sorbent-packed trap with a suitable solvent or via thermal desorption. Besides, DHS address some drawbacks of the static modes such as the accumulation of water vapor or highly concentrated compounds, which presence can affect extraction efficiency. Two examples of dynamic headspace sampling which allow avoiding some drawbacks of the static mode, e.g., heat and water vapor accumulation that can affect not only sampling efficiency but also plant physiology, are closed-loop stripping and push and pull methods. These systems collect VOCs in sorbent-packed traps or coated devices, via the continuous circulation of gas inside closed circuits [22].
In addition to headspace sampling techniques, some sui generis approaches can combine two methods from different groups, for example, solvent-assisted flavor evaporation (SAFE). SAFE is an exhaustive extraction technique based on the high volatility rather than the polarity of the target compounds. In this case, a crude-extract from dry sample pieces is prepared with an appropriate solvent, such as dichloromethane, and then added into the dropping funnel and passed through a specific distillation chamber. Extraction takes place at high vacuum, and low-temperature conditions (20–30°C), and VOCs are collected in a cooled extraction vessel [61]. Other techniques including in this group are simultaneous extraction-distillation (SDE) and/or liquid–liquid extraction (LLE). Nevertheless, those can be subjected to some drawbacks, like the use of hazardous solvents, as well as the requirement of high temperatures and long extraction times, with potential formation of artifacts and degradation of some compounds.
Finally, volatile compounds also can be obtained for direct collection of the secretions of odoriferous glands or via non-invasive strategies using PDMS patches or swabs [22]. These techniques are especially useful in the monitoring of VOCs from animals. For example, obtaining the animal skin volatilome on PDMS patches is an excellent option [62]. Patches could be prepared by cutting a Silicone Elastomer Sheet (Goodfellows mfr. No. 942-965-49, Coraopolis, PA) and then carefully fix it on the animal skin with Tegaderm® dressings or water block clear Band-aids®. Alternatively, this procedure could be modified by gently swabbing the skin with or without previous stress-induced secretion. PDMS patches also can be placed into an animal enclosure and used without direct contact for capturing the volatiles that emanates in the headspace.
4. Volatilome profiling: separation and detection
Currently, gas chromatography coupled to mass spectrometry (GC–MS) is the primary analytical technique for the elucidation of the volatilome profile from natural sources. In gas chromatography analytes elute according to their volatility carried by a gas, usually Helium, through a coated fused silica capillary using a temperature gradient. Separation occurs based on the differential partition between the gas phase and the coating and the eluting peaks will give a response in the detector. The sample is vaporized in the injection system before it enters the column.
Several injection systems can be used to introduce the sample onto the column. Split injection allows transferring to the column only controlled sample amounts and prevent overloading of the column, thanks to a split valve at the base of the hot injector that divides the flow between column and waste in a fixable ratio. High-concentration samples can easily overload the GC column, resulting in all active sites on the column becoming occupied and leading to additional analytes not being retained and therefore to poor chromatographic resolution. For trace analysis, the injector can be used in splitless mode, which allows the entire volume of sample vaporized in the injector to reach the column. An alternative to the split/splitless interface is the programmed temperature vaporizer (PTV). Samples are injected onto a cool (40–60°C) PTV where they are trapped and concentrated on different sorbent materials before the inlet is rapidly heated to desorb the sample onto the column.
Different selectivity and sizes of columns have been used for GC–MS–based metabolomic analysis. The most used phase is 5% phenyl, 95% methyl siloxane, which offers a sufficiently generic selectivity, optimal for metabolomic applications where analytes with a wide range of volatilities have to be separated. Capillary columns of 25 to 30 m will provide the highest resolution and are available in most phases. An important point for all capillary GC–MS work is the need to condition the column prior to running valuable samples. Sangster et al. have recommended that several quality control samples be run at the beginning of a sample batch to condition the column [63]. Care also needs to be taken to randomize the injection sequence in order not to compromise subsequent statistical analysis.
In GC–MS ionization of analytes is mainly produced by electron ionization (EI) or chemical ionization (CI), while ion separation is obtained by mass analyzers operating on different principles. In EI, analytes that elute from the GC column are vaporized into the ion source and collide with an electron beam at 70 eV. As a result of the high energy imparted by electrons to the vaporized molecules, characteristic fragmentation occurs, providing structural information. EI is very robust and highly reproducible between instruments, and spectral libraries are available that can be used to search for the identities of unknown compounds based on m/z and intensity ratios of the observed fragment ions. A disadvantage of EI is that fragmentation is usually so efficient that the intensity of the molecular ion can be extremely low or even lost. For CI, a reagent gas, such as methane or ammonia, is introduced into the source of the mass spectrometer. Protonated gas ions, produced by the collision with electrons originating from an electron beam, ionize the analytes eluting from the column after vaporization into the ion source. Significantly less energy than in EI is transferred to the analytes, and as a result, the dominant ion is usually the molecular ion.
Mass spectrometer based detectors are mainly used in metabolomic analysis and can be grouped according to the spectral information they provide, i.e., low-resolution instruments such as quadrupole mass spectrometer (qMS), ion-trap mass spectrometer (IT-MS), and high-speed time-of-flight mass spectrometer (TOF-MS) give nominal molecular weights and fragmentation of an analyte, while high-resolution instruments (high-resolution TOF-MS and hybrids) give the precise elemental composition of nominal masses. The single quadrupole mass analyzer is widely used and relatively inexpensive. The ions move along the axis of four parallel rods to which a direct current (DC) and an alternating current (AC) voltage are applied. These voltages affect the trajectory of ions traveling down the flight path between the rods in a way that only ions of a given m/z are transmitted at a given point in time. Scan speeds are rather low on quadrupole instruments, therefore considering the very high separation power of GC with peak widths of only a few seconds, it will be difficult to acquire several spectra across the width of a typical peak on a single quadrupole instrument. Time-of-flight (TOF) instruments are the most common mass analyzers in GC–MS–based metabolomics. The ions are accelerated in an electric field in which ions with the same charge will have the same kinetic energy, but different velocity depending on their mass-to-charge ratio (m/z). Successively, the ions enter a field-free region (flight tube) where they separate based on their m/z. TOF instruments are characterized by the fastest scan rate among all mass analyzers: a significant number of spectra can be acquired across each peak, leading to higher sensitivity and better spectral quality.
GC–MS has very high sensitivity and can therefore be used for the analysis of less commonly encountered samples that might only be available in trace amounts. Monodimensional GC–MS analysis provides suitable resolving-power for the analysis of relatively simple mixtures of VOCs. Nevertheless, volatilome samples can be very complex mixtures, involving a diverse plethora of chemical structures in a wide range of polarities, so that the restricted chromatographic resolution commonly limits the identification via MS to the more abundant compounds. Complex mixtures can be better resolved by employing comprehensive two-dimensional gas chromatography–mass spectrometry (GCxGC–MS), which has been defined as “…an orthogonal two-column separation, with complete transfer of a solute from the separation system 1 (column 1) to the separation system 2 (column 2), such that the separation performance from each system (column) is preserved” [64]. In GC × GC, two columns with different polarity—usually a nonpolar column in the first dimension and a moderately polar column for the second one—are run in series. Analytes eluting from the first dimension (1D) column are trapped, focused, and then rapidly injected, as a narrow band of few milliseconds, in the second dimension (2D) column, then the eluting peaks are detected by MS. The transfer process is actuated by a modulator, a thermal or valve-based focusing system. Each single modulator cycle takes a fixed time (4–8 s) and each fraction, injected online into the second column must be analyzed in a time equal to that of the successive modulation. The challenge is to avoid continuously transmitting analyte onto the second column, which would lead to a loss of resolution. A solution to this problem is to make the separation on the second column much faster than the separation on the first column. The volume of data generated is significantly larger than the one obtained in a one-dimensional analysis. However, this approach allows for better separation of the number of components in the sample. Although single qMS instruments are cheaper, can provide very low LODs via selected ion monitoring (SIM), and can provide maximum acquisition rates (20,000 amu/s) suitable for metabolic profiling, TOF has become the preferentially MS analyzers for GCxGC volatilome analysis. TOF-MS instruments are capable of full-spectrum collection rates up to 500 Hz with improved sensitivity. Besides the high-resolution mass spectrometry (HRMS) provide accurate mass data, which increases the identification confidence and allows to annotate molecular formulas for unknown compounds, being especially useful in untargeted metabolomic studies.
Metabolite identification remains a major complication. Although EI generates highly reproducible fragmentation spectra, only a relatively small percentage of metabolites can be identified by searching databases, mainly because these have traditionally been a repository of EI spectra of synthetic organic compounds. Only recently, the number of metabolite spectra started to increase. A more powerful identification method involves comparing both EI/CI spectra and retention indices obtained from analyzing a reference compound under identical analytical conditions. If commercial standards are not available, metabolite identification can be cumbersome.
Retention indexes (RI) were first introduced by Kováts [28] for isothermal analysis and then by Van den Dool [65] for temperature-programmed analysis (linear retention indices, LRIs) and are calculated vs. a homologous series of linear hydrocarbons run in the same GC conditions as samples. RI can also be automatically calculated using the Automated Mass Spectral Deconvolution and Identification System (AMDIS), freely available from the National Institute of Standards and Technology (NIST) at this site (http://www.amdis.net/).
In order to achieve the identification of unknown compounds, their background-subtracted EI spectra are searched against EI libraries (such as the NIST library) to achieve identification. Values of m/z values and relative ion intensities in a spectrum are matched against spectra in a reference library [the most used database of EI spectra is the NIST database (http://www.nist.gov/srd/nist1.htm)]. The database search will usually return a list of possible hits, ranked by the probability of the match. Although, even if a match is exceedingly high, the metabolite should still not be considered as identified.
The high variability of data obtained from the investigated matrix composition makes it hard to indicate a universal approach to quantitatively evaluate the volatilome composition. The most widely used approaches are: (a) relative percentage abundance, (b) internal standard normalized percentage abundance, and (c) “absolute” or true quantitation of one or more target components, with or without a validated method. Relative percentage abundance can be applied only to evaluate relative component ratios within the same sample. Internal standard normalized percentage abundance is the ideal approach when a group of samples is compared: raw data must first be corrected vs. analyte response factors to the detector, then normalized vs. an internal standard. Percentage abundance must be calculated vs. the sum of the areas of a fixed number of selected components, found in all the samples. The quantitation of marker components is obtained from the chromatographic area in SIM mode vs. an internal (or external) standard and calculated via a calibration curve constructed from amounts of pure standards in the selected concentration range.
Some common non-separative techniques used in the study of volatilome using mass spectrometry are selected-ion flow-tube mass spectrometry (SIFT-MS) and proton-transfer-reaction mass spectrometry (PTR-MS). These techniques are focused on the use of soft chemical ionization, allow on-line detection of VOCs with low levels of detection without the need for pre-concentration or sample preparation, which facilitates obtaining reproducible results. For example, Vendel and co-workers [66], used SIFT-MS and HS-SPME-GC–MS for the analysis of strawberry aroma. Although both techniques provided similar results in the study of the fruit ripening, the SIFT-MS analysis was about 11 times faster than HS-SPME-GC–MS. Moreover, SIFT-MS showed low detection limits, so that the postharvest analysis can be easily performed by the analysis of individual fruit. Capellin and collaborators [67] developed a similar study was using PTR-TOF-MS to study the volatilome of clones belonging to three types of apple. They concluded that PTR-TOF-MS is a very useful tool for volatilome studies once this technique allows obtaining a rapid and non-invasive fingerprint of the VOCs profile from single apple fruits.
With an alternative focus, the chromatographic system can be coupled to an olfactometer detector to identify the aroma-active compounds present in a determinate volatilome. This type of analysis allows determining the compounds which generate a positive response to the electronic noise detector, obtaining their identification by comparison of the mass spectrum, retention index, and odor descriptions with reference compounds. Using gas chromatography-olfactometry-mass spectrometry (GC-O-MS), Zhu and co-workers [68] studied the volatile profile of three cultivars of mulberries, establishing benzaldehyde, ethyl butanoate, (E)-2-nonenal, 1-hexanol, hexanal, methional, 3-mercaptohexyl acetate, and 3-mercapto-1-hexanol as the main compounds responsible for the characteristic aroma of mulberry.
5. Volatilome data processing
Once the raw data have been acquired following chromatographic separation and mass spectrometry analysis, the large amount of data generated needs to be processed following a standardized procedure that includes data conversion, pre-processing, pre-treatment, and metabolite annotation [69]. An additional step, sharing data derived from any metabolomics analysis, currently is optional for researchers but highly recommended.
5.1 Extract raw files from instruments and proceed to data conversion
Data processing starts with a set of raw data files for different samples. Usually, default vendor formats from instruments need a conversion. A useful toolkit compatible with several instruments formats is ProteoWizard (http://proteowizard.sourceforge.net/download.html) [70]. Open-source formats usually supported by many software packages are Network Common Data Form (NetCDF) [71], Extensible Markup Language (mzXML) [72], and Mass Spectrometry Markup Language (mzmL) [73]. Each file is processed to an easily accessible and more informative data table, where rows represent samples and columns represent different features from volatilome. Values from this matrix represent intensity values of peak area/height, standing for relative concentration. The data should be checked for missing values and possible outliers.
5.2 Set parameters to perform data pre-processing
Pre-processing involves setting different filters to recognize signals from noise, select masses or intensities to perform feature detection, and finally adjust the retention time shifts parameters needed to align features throughout all samples. The aim of pre-processing is to minimize the number of false positives features and to establish quantitative procedures for discarding less reliable signals with low signal-to-noise ratio, or low prevalence within a similar set of samples [74].
5.3 Choose the best method to perform data pre-treatment
Pre-treatment or data correction is one of the most important steps from data analysis because systematic and technical variation could obscure relevant biological patterns. The variation in the data resulting from a metabolomics experiment is the sum of the induced variation and the total uninduced variation [75]. Some sources of variation could be controlled by researchers through a careful experimental design. In other cases, this variation is very difficult to control. Natural variation in the metabolism of an organism can cause 5000-fold differences in signal intensities for different metabolites, or sampling could not be performed on the exact conditions for all samples, sample work-up varies naturally between batches, and analytical errors are always present. This variation could be accounted for using different classes of corrections that include centering, scaling, transformation, and normalization of raw data and several methods are available to do so (e.g., autoscaling, pareto scaling, range scaling, vast scaling, log transformation, and power transformation, normalization by sum, normalization by a reference sample). The selection of the most appropriate method depends on the hypothesis to be tested and the statistical behavior of the data matrix. Before applying pre-treatment methods, it is required to check if data is fit for analysis. For example, performing the treatment may enhance the results of a clustering method (if the hypothesis is related to comparison of similarities), while obscuring the results of a Principal Component Analysis (PCA) (if in contrast, the hypothesis is related with determining redundancy between metabolites) [75].
5.4 Metabolite annotation
The analysis by comparison with pure standards of different family of compounds is advisable, in order to compare the retention rates of the compounds. However, the characterization of a certain metabolite that there are no pure standards, its determination can be done by comparison with homologues of a certain family of compounds, which the detailed analysis of the fragmentation pattern. Metabolite annotation is still challenging despite all efforts made for establishing specialized databases with mass spectral properties of different metabolites. Annotation and identification levels for metabolites were defined by the Chemical Analysis Working Group of the Metabolomics Standards Initiative (MSI). Level 1 indicates compromise identified compounds, level 2 is used for putatively annotated compounds, level 3 is used for putatively characterized compound classes, and level 4 is used for unidentified or unclassified metabolites that still can be differentiated and quantified based upon spectral data. Dark matter, also called “unknown unknowns”, represents the majority of metabolites analyzed on a metabolomics experiment, because instruments collect much more information than it is currently possible to annotate [76]. It is estimated that an average of only 2% of the data can be annotated. This is even a most common problem in metabolomics analysis from animals because many databases are specialized in human-derived metabolites, or some molecular structures from animals have been solved but are absent from the reference databases. Analysis from non-model organisms tends to have a higher number of truly novel compounds, called “unknown unknowns” [77]. As it is impossible to collect spectra for every molecule in the universe, computer-generated (in silico) spectral prediction algorithms are also recommended during metabolite annotation such as CSI:FingerID (https://www.csi-fingerid.uni-jena.de/) and Competitive Fragmentation Modeling-ID (CFM-ID, https://cfmid.wishartlab.com/) for analyzing fragmentation patterns. For volatilome analysis NIST (https://www.mswil.com/software/spectral-libraries-and-databases/nist20/) and Wiley (https://www.mswil.com/software/spectral-libraries-and-databases/wiley-spectral-libraries/wiley-gcms-libraries/) electronic collections are the most used mass spectra databases. The Dictionary of Natural Products (DNP) (http://dnp.chemnetbase.com/faces/chemical/ChemicalSearch.xhtml;jsessionid=DBE98AD72918A1607A7E739064D0DB21), Pherobase (https://www.pherobase.com/), Human Metabolome Database (HMDB) (https://hmdb.ca/), METLIN (https://metlin.scripps.edu/landing_page.php?pgcontent=mainPage), MassBank Japan (http://www.massbank.jp/), MassBank Europe (https://massbank.eu/MassBank/), MassBank North America (https://mona.fiehnlab.ucdavis.edu/), Supernatural II (http://bioinf-applied.charite.de/supernatural_new/index.php), ChEMBL (https://www.ebi.ac.uk/chembl/), Mass Spectral and GC Data of Drugs, Poisons, Pesticides, Pollutants, and Their Metabolites (https://www.wiley.com/en-gb/Mass+Spectral+and+GC+Data+of+Drugs%2C+Poisons%2C+Pesticides%2C+Pollutants%2C+and+Their+Metabolites%2C+5th+Edition-p-9783527342877) and vocBinBase (https://bitbucket.org/fiehnlab/binbase/src/master/) are other useful resources. When compound annotation is not possible and only chemical class could be assigned to a metabolite it is recommended to employ the comprehensive, and computable chemical taxonomy from Classyfire (http://classyfire.wishartlab.com/). See [78] for a review focused on mass spectral databases for LC/MS- and GC/MS-based metabolomics. For the analysis of mVOCs, in 2014 was developed a software that allows the characterization of mass spectra obtained in microorganisms. It was updated in 2018 with more than 2000 compounds from more than 1000 species, which is called mVOC database 2.0 (http://bioinformatics.charite.de/mvoc) [79]. With this tool a more precise characterization of the different volatilome of the microbes studied at present is achieved.
6. Select the best statistical analysis for the research question and coherent with data pre-treatment
Select the univariate statistics according to the variables of interest. T-test, U-test, and analysis of variance (ANOVA) are the most common univariate statistics employed for data mining in volatilomics. As datasets usually include a large number of features, the significance level should be determined appropriately to reduce the number of false positives and false negatives. For reducing false positive, family wise error rate (FWER) correction, such as a Bonferroni correction, is a conservative approach, in which the p-values are multiplied by the number of comparisons. In contrast, for reducing false negatives, false discovery rate (FDR) correction is a highly sensitive method [80].
7. Select the best suitable multivariate statistics
Multivariate statistical methods are very powerful at summarizing large and multidimensional data generated from volatilomics. Exactly as for pre-treatment methods, multivariable analysis should be chosen carefully and selected coherently with the hypothesis of interest and methods used for data pretreatment. Unsupervised approaches and supervised approaches differ in how samples are grouped within the multivariate calculations. Unsupervised solely have access to the matrix to find features useful for grouping and categorizing the samples. Clustering methods, such as hierarchical clustering (HCA), K-means clustering, self-organizing maps, principal component analysis (PCA) are among this group. Once the data have been analyzed by unsupervised methods, supervised methods (e.g. partial least squares discriminant analysis (PLD-DA), artificial neural networks, and evolutionary algorithms) should be applied for further evaluation [81]. Supervised methods have access to qualitative or quantitative traits (e.g., specie, location, body size, tissue type) and the matrix of measurements and can classify samples. Volcano plots have also recently been used to identify significantly covarying metabolites in binary comparisons. Volcano plots show each features’ statistical significance, p-value, on the y-axis, and fold change along the x-axis [82].
7.1 Determine if network inference provide better insights about data interpretation
Correlation networks is a visualization tool that summarizes positive and negative correlations found between samples that represent different biological process [69]. Molecular networking organizes metabolite features from a volatilomics analysis into a connectivity network based on similarities in molecular fragmentation patterns obtained from mass spectrometry [82]. This analysis cluster families of molecules through vector correlations between fragment ions and enhance the interpretation of volatilome differentiation using a chemically informed visualization. Also, it enhances the annotation process with experimental and in silico databases [83]. When it is possible to combine Volatilomic and Genomic analysis, molecular networking can also be useful to prioritize features by linking observed natural products to their cognate biosynthetic gene clusters and gene cluster families [82].
7.2 Whenever possible, share data in public repositories
Current technological advances in sample collection, extraction techniques, volatile profiling, and data processing allow that the analysis of an invisible world where VOCs mediates different ecological processes could recover a more accurate picture of the complex chemical communication that occurs in nature. Different combinations of procedures need to be followed by researchers with the aim to answer specific scientific questions or hypotheses. Microextraction techniques emerge as tools for increasing extraction efficiency and at the same time facilitating faster extraction times without the environmental impact of large volume solvent wastes. Gas chromatography has played a fundamental role to detect volatile compounds often present as trace levels. Mass spectrometry has proved to be the preferred technique for the structure elucidation of new compounds and annotation of known VOCs. Current improvements in data analysis allow to extract of more biologically relevant information from a single study and to standardize procedures for evaluating hypothesis properly. All these steps are of paramount importance to evaluate both the ecological function of these compounds and the economic value in the medical, agricultural, flavor, and fragrance industry.
Acknowledgments
The authors thank the Department of Chemistry and Vicerrectoria de Investigaciones at Universidad de los Andes, Bogotá, Colombia for financial support. We wish to thank to Ministerio de Ciencia, Tecnología e Innovación (MinCiencias) for Julie Paulin Garcia Rodriguez (No 679), Mabel Gonzalez (No 757) and Gerson-Dirceu López (No 785), as well as the support to No. 44842-058-2018 and No. 80740-532-2019 projects. Also, the Faculty of Sciences of the Universidad de los Andes forgivable loan and research funds (INV-2018-2033-1259, INV-2019-2067-1747, INV-2018-2048-1338, and INV-2019-2086-1843). Scholarship granted by Fulbright to Mabel González as a Visiting Scholar at the Dorrestein Laboratory at Skaggs School of Pharmacy & Pharmaceutical Sciences, University of California, San Diego, United States.
Conflict of interest
The authors declare no conflict of interest.
Abbreviations
1D
First-Dimension
2D
Second-Dimension
AC
Alternating Current
AMDIS
Automated Mass Spectral Deconvolution and Identification System
ANOVA
Analysis of variance
ATCC
American Type Culture Collection
CAR
Carboxen
CFM-ID
Competitive Fragmentation Modeling-Id
CI
Chemical Ionization
CITES
Convention on International Trade in Endangered Species of Wild Fauna and Flora
CW
Carbowax
DC
Direct Current
SDE
Simultaneous Extraction-Distillation
DHS
Dynamic Headspace
DNP
Dictionary of Natural Products
DVB
Divinylbenzene
EI
Electron Ionization
EOs
Essential Oils
FWER
Family Wise Error Rate
FDR
False Discovery Rate
GC
Gas Chromatography
GC–MS
Gas Chromatography–Mass Spectrometry
GC-O-MS
Gas Chromatography-Olfactometry-Mass Spectrometry
GNPS
Global Natural Products Social Networking
GCxGC
Comprehensive Two-Dimensional Gas Chromatography
HCA
Hierarchical Clustering
HF-LPME
Hollow Fiber Liquid-Phase Microextraction
HMDB
Human Metabolome Database
HRMS
High-Resolution Mass Spectrometry
HS
Headspace
IT-MS
Ion-Trap Mass Spectrometer
LLE
Liquid–Liquid Extraction
LPME
Liquid-Phase Microextractions
LRI
Linear Retention Indices
MS
Mass Spectrometer
MSI
Metabolomics Standards Initiative
mVOCs
Microbial Volatile Organic Compounds
m/z
Mass-To-Charge Ratio
mzmL
Mass Spectrometry Markup Language
mzXML
Extensible Markup Language
NetCDF
Network Common Data Form
NIST
National Institute of Standards and Technology
PA
Polyacrylate
PCA
Principal Component Analysis
PDMS
Polydimethylsiloxane
PLD-DA
Partial Least Squares Discriminant Analysis
PTR-MS
Proton-Transfer-Reaction Mass Spectrometry
PTV
Programmed Temperature Vaporizer
RI
Retention indexes
qMS
Quadrupole Mass Spectrometer
SAFE
Solvent Assisted Flavor Evaporation
SBSE
Stir Bar Sorptive Extraction
SDME
Single Drop Microextraction
SIFT-MS
Selected-Ion Flow-Tube Mass Spectrometry
SIM
Selected Ion Monitoring
SLM
Supported Liquid Membrane
SPE
Solid-Phase Extraction
SPME
Solid-Phase Microextraction
TOF-MS
Time-of-Flight Mass Spectrometer
VOCs
Volatile Organic Compounds
\n',keywords:"volatile organic compounds (VOCs), microbial volatile organic compounds (mVOCs), static headspace, dynamic headspace, SPME, PDMS-patches, GC–MS, metabolomics workflow",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/76199.pdf",chapterXML:"https://mts.intechopen.com/source/xml/76199.xml",downloadPdfUrl:"/chapter/pdf-download/76199",previewPdfUrl:"/chapter/pdf-preview/76199",totalDownloads:176,totalViews:0,totalCrossrefCites:0,dateSubmitted:"October 30th 2020",dateReviewed:"March 15th 2021",datePrePublished:"July 16th 2021",datePublished:"September 1st 2021",dateFinished:"April 9th 2021",readingETA:"0",abstract:"Volatilomics studies the emission of volatile compounds from living organisms like plants, flowers, animals, fruits, and microorganisms, using metabolomics tools to characterize the analytes. This is a complex process that involves several steps like sample preparation, extraction, instrumental analysis, and data processing. In this chapter, we provide balanced coverage of the different theoretical and practical aspects of the study of the volatilome. Static and dynamic headspace techniques for volatile capture will be discussed. Then, the main techniques for volatilome profiling, separation, and detection will be addressed, emphasizing gas chromatographic separation, mass spectrometry detection, and non-separative techniques using mass spectrometry. Finally, the whole volatilome data pre-processing and multivariate statistics for data interpretation will be introduced. We hope that this chapter can provide the reader with an overview of the research process in the study of volatile organic compounds (VOCs) and serve as a guide in the development of future volatilomics studies.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/76199",risUrl:"/chapter/ris/76199",signatures:"Chiara Carazzone, Julie P.G. Rodríguez, Mabel Gonzalez and Gerson-Dirceu López",book:{id:"10220",type:"book",title:"Metabolomics",subtitle:"Methodology and Applications in Medical Sciences and Life Sciences",fullTitle:"Metabolomics - Methodology and Applications in Medical Sciences and Life Sciences",slug:"metabolomics-methodology-and-applications-in-medical-sciences-and-life-sciences",publishedDate:"September 1st 2021",bookSignature:"Xianquan Zhan",coverURL:"https://cdn.intechopen.com/books/images_new/10220.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",isbn:"978-1-83969-084-6",printIsbn:"978-1-83969-083-9",pdfIsbn:"978-1-83969-085-3",isAvailableForWebshopOrdering:!0,editors:[{id:"223233",title:"Prof.",name:"Xianquan",middleName:null,surname:"Zhan",slug:"xianquan-zhan",fullName:"Xianquan Zhan"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"337884",title:"Dr.",name:"Chiara",middleName:null,surname:"Carazzone",fullName:"Chiara Carazzone",slug:"chiara-carazzone",email:"c.carazzone@uniandes.edu.co",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"348495",title:"Dr.",name:"Julie P.G.",middleName:null,surname:"Rodriguez",fullName:"Julie P.G. Rodriguez",slug:"julie-p.g.-rodriguez",email:"jp.garciar2@uniandes.edu.co",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"348496",title:"MSc.",name:"Mabel",middleName:null,surname:"Gonzalez",fullName:"Mabel Gonzalez",slug:"mabel-gonzalez",email:"mabel.c.gonzalez@uniandes.edu.co",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"348498",title:"Dr.",name:"Gerson-Dirceu",middleName:null,surname:"López",fullName:"Gerson-Dirceu López",slug:"gerson-dirceu-lopez",email:"gd.lopez@uniandes.edu.co",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Volatiles collection",level:"1"},{id:"sec_2_2",title:"2.1 Plants",level:"2"},{id:"sec_3_2",title:"2.2 Flowers",level:"2"},{id:"sec_4_2",title:"2.3 Fruits",level:"2"},{id:"sec_5_2",title:"2.4 Microorganisms",level:"2"},{id:"sec_6_2",title:"2.5 Animals",level:"2"},{id:"sec_8",title:"3. Volatiles extraction",level:"1"},{id:"sec_9",title:"4. Volatilome profiling: separation and detection",level:"1"},{id:"sec_10",title:"5. Volatilome data processing",level:"1"},{id:"sec_10_2",title:"5.1 Extract raw files from instruments and proceed to data conversion",level:"2"},{id:"sec_11_2",title:"5.2 Set parameters to perform data pre-processing",level:"2"},{id:"sec_12_2",title:"5.3 Choose the best method to perform data pre-treatment",level:"2"},{id:"sec_13_2",title:"5.4 Metabolite annotation",level:"2"},{id:"sec_15",title:"6. Select the best statistical analysis for the research question and coherent with data pre-treatment",level:"1"},{id:"sec_16",title:"7. Select the best suitable multivariate statistics",level:"1"},{id:"sec_16_2",title:"7.1 Determine if network inference provide better insights about data interpretation",level:"2"},{id:"sec_17_2",title:"7.2 Whenever possible, share data in public repositories",level:"2"},{id:"sec_19",title:"8. Conclusions",level:"1"},{id:"sec_20",title:"Acknowledgments",level:"1"},{id:"sec_23",title:"Conflict of interest",level:"1"},{id:"sec_22",title:"Abbreviations",level:"1"}],chapterReferences:[{id:"B1",body:'Crandall SG, Gold KM, Jiménez-Gasco M del M, Filgueiras CC, Willett DS. A multi-omics approach to solving problems in plant disease ecology. PLoS One. 2020 Sep 22;15(9):e0237975. DOI: 10.1371/journal.pone.0237975'},{id:"B2",body:'Raguso RA. Start making scents: the challenge of integrating chemistry into pollination ecology. Entomol Exp Appl. 2008 Jul 19;128(1):196-207. DOI: 10.1111/j.1570-7458.2008.00683.x'},{id:"B3",body:'Raguso ROEA, Pichersky E. 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Laboratory of Advanced Analytical Techniques (LATNAP), University of los Andes, Bogotá D.C., Colombia
Laboratory of Advanced Analytical Techniques (LATNAP), University of los Andes, Bogotá D.C., Colombia
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The nanoparticles’ unique physical and chemical properties render them most appropriate for a number of specialist applications.",book:{id:"9109",slug:"engineered-nanomaterials-health-and-safety",title:"Engineered Nanomaterials",fullTitle:"Engineered Nanomaterials - Health and Safety"},signatures:"Takalani Cele",authors:[{id:"305934",title:"Dr.",name:"Takalani",middleName:null,surname:"Cele",slug:"takalani-cele",fullName:"Takalani Cele"}]},{id:"72636",title:"Nanocomposite Materials",slug:"nanocomposite-materials",totalDownloads:2139,totalCrossrefCites:5,totalDimensionsCites:11,abstract:"Nanocomposites are the heterogeneous/hybrid materials that are produced by the mixtures of polymers with inorganic solids (clays to oxides) at the nanometric scale. Their structures are found to be more complicated than that of microcomposites. They are highly influenced by the structure, composition, interfacial interactions, and components of individual property. Most popularly, nanocomposites are prepared by the process within in situ growth and polymerization of biopolymer and inorganic matrix. With the rapid estimated demand of these striking potentially advanced materials, make them very much useful in various industries ranging from small scale to large to very large manufacturing units. With a great deal to mankind with environmental friendly, these offer advanced technologies in addition to the enhanced business opportunities to several industrial sectors like automobile, construction, electronics and electrical, food packaging, and technology transfer.",book:{id:"10072",slug:"nanotechnology-and-the-environment",title:"Nanotechnology and the Environment",fullTitle:"Nanotechnology and the Environment"},signatures:"Mousumi Sen",authors:[{id:"310218",title:"Dr.",name:"Mousumi",middleName:null,surname:"Sen",slug:"mousumi-sen",fullName:"Mousumi Sen"}]},{id:"38951",title:"Carbon Nanotube Transparent Electrode",slug:"carbon-nanotube-transparent-electrode",totalDownloads:3985,totalCrossrefCites:3,totalDimensionsCites:5,abstract:null,book:{id:"3077",slug:"syntheses-and-applications-of-carbon-nanotubes-and-their-composites",title:"Syntheses and Applications of Carbon Nanotubes and Their Composites",fullTitle:"Syntheses and Applications of Carbon Nanotubes and Their Composites"},signatures:"Jing Sun and Ranran Wang",authors:[{id:"153508",title:"Prof.",name:"Jing",middleName:null,surname:"Sun",slug:"jing-sun",fullName:"Jing Sun"},{id:"153596",title:"Ms.",name:"Ranran",middleName:null,surname:"Wang",slug:"ranran-wang",fullName:"Ranran Wang"}]},{id:"49413",title:"Electrodeposition of Nanostructure Materials",slug:"electrodeposition-of-nanostructure-materials",totalDownloads:3732,totalCrossrefCites:1,totalDimensionsCites:7,abstract:"We are conducting a multi-disciplinary research work that involves development of nanostructured thin films of semiconductors for different applications. Nanotechnology is widely considered to constitute the basis of the next technological revolution, following on from the first Industrial Revolution, which began around 1750 with the introduction of the steam engine and steelmaking. Nanotechnology is defined as the design, characterization, production, and application of materials, devices and systems by controlling shape and size of the nanoscale. The nanoscale itself is at present considered to cover the range from 1 to 100 nm. All samples prepared in thin film forms and the characterization revealed their nanostructure. The major exploitation of thin films has been in microelectronics, there are numerous and growing applications in communications, optical electronics, coatings of all kinds, and in energy generation. A great many sophisticated analytical instruments and techniques, largely developed to characterize thin films, have already become indispensable in virtually every scientific endeavor irrespective of discipline. Among all these techniques, electrodeposition is the most suitable technique for nanostructured thin films from aqueous solution served as samples under investigation. The electrodeposition of metallic layers from aqueous solution is based on the discharge of metal ions present in the electrolyte at a cathodic surface (the substrate or component.) The metal ions accept an electron from the electrically conducting material at the solid- electrolyte interface and then deposit as metal atoms onto the surface. The electrons necessary for this to occur are either supplied from an externally applied potential source or are surrendered by a reducing agent present in solution (electroless reduction). The metal ions themselves derive either from metal salts added to solution, or by the anodic dissolution of the so-called sacrificial anodes, made of the same metal that is to be deposited at the cathode.",book:{id:"4718",slug:"electroplating-of-nanostructures",title:"Electroplating of Nanostructures",fullTitle:"Electroplating of Nanostructures"},signatures:"Souad A. M. Al-Bat’hi",authors:[{id:"174793",title:"Dr.",name:"Mohamad",middleName:null,surname:"Souad",slug:"mohamad-souad",fullName:"Mohamad Souad"}]},{id:"71346",title:"Application of Nanomaterials in Environmental Improvement",slug:"application-of-nanomaterials-in-environmental-improvement",totalDownloads:1691,totalCrossrefCites:0,totalDimensionsCites:13,abstract:"In recent years, researchers used many scientific studies to improve modern technologies in the field of reducing the phenomenon of pollution resulting from them. In this chapter, methods to prepare nanomaterials are described, and the main properties such as mechanical, electrical, and optical properties and their relations are determined. The investigation of nanomaterials needed high technologies that depend on a range of nanomaterials from 1 to 100 nm; these are scanning electron microscopy (SEM), transmission electron microscopy (TEM), and X-ray diffractions (XRD). The applications of nanomaterials in environmental improvement are different from one another depending on the type of devices used, for example, solar cells for producing clean energy, nanotechnologies in coatings for building exterior surfaces, and sonochemical decolorization of dyes by the effect of nanocomposite.",book:{id:"10072",slug:"nanotechnology-and-the-environment",title:"Nanotechnology and the Environment",fullTitle:"Nanotechnology and the Environment"},signatures:"Ali Salman Ali",authors:[{id:"313275",title:"Associate Prof.",name:"Ali",middleName:null,surname:"Salman",slug:"ali-salman",fullName:"Ali Salman"}]}],onlineFirstChaptersFilter:{topicId:"208",limit:6,offset:0},onlineFirstChaptersCollection:[{id:"81438",title:"Research Progress of Ionic Thermoelectric Materials for Energy Harvesting",slug:"research-progress-of-ionic-thermoelectric-materials-for-energy-harvesting",totalDownloads:24,totalDimensionsCites:0,doi:"10.5772/intechopen.101771",abstract:"Thermoelectric material is a kind of functional material that can mutually convert heat energy and electric energy. It can convert low-grade heat energy (less than 130°C) into electric energy. Compared with traditional electronic thermoelectric materials, ionic thermoelectric materials have higher performance. The Seebeck coefficient can generate 2–3 orders of magnitude higher ionic thermoelectric potential than electronic thermoelectric materials, so it has good application prospects in small thermoelectric generators and solar power generation. According to the thermoelectric conversion mechanism, ionic thermoelectric materials can be divided into ionic thermoelectric materials based on the Soret effect and thermocouple effect. They are widely used in pyrogen batteries and ionic thermoelectric capacitors. The latest two types of ionic thermoelectric materials are in this article. The research progress is explained, and the problems and challenges of ionic thermoelectric materials and the future development direction are also put forward.",book:{id:"10037",title:"Thermoelectricity - Recent Advances, New Perspectives and Applications",coverURL:"https://cdn.intechopen.com/books/images_new/10037.jpg"},signatures:"Jianwei Zhang, Ying Xiao, Bowei Lei, Gengyuan Liang and Wenshu Zhao"},{id:"77670",title:"Thermoelectric Elements with Negative Temperature Factor of Resistance",slug:"thermoelectric-elements-with-negative-temperature-factor-of-resistance",totalDownloads:72,totalDimensionsCites:0,doi:"10.5772/intechopen.98860",abstract:"The method of manufacturing of ceramic materials on the basis of ferrites of nickel and cobalt by synthesis and sintering in controllable regenerative atmosphere is presented. As the generator of regenerative atmosphere the method of conversion of carbonic gas is offered. Calculation of regenerative atmosphere for simultaneous sintering of ceramic ferrites of nickel and cobalt is carried out. It is offered, methods of the dilated nonequilibrium thermodynamics to view process of distribution of a charge and heat along a thermoelement branch. The model of a thermoelement taking into account various relaxation times of a charge and warmth is constructed.",book:{id:"10037",title:"Thermoelectricity - Recent Advances, New Perspectives and Applications",coverURL:"https://cdn.intechopen.com/books/images_new/10037.jpg"},signatures:"Yuri Bokhan"},{id:"79236",title:"Processing Techniques with Heating Conditions for Multiferroic Systems of BiFeO3, BaTiO3, PbTiO3, CaTiO3 Thin Films",slug:"processing-techniques-with-heating-conditions-for-multiferroic-systems-of-bifeo3-batio3-pbtio3-catio",totalDownloads:96,totalDimensionsCites:0,doi:"10.5772/intechopen.101122",abstract:"In this chapter, we have report a list of synthesis methods (including both synthesis steps & heating conditions) used for thin film fabrication of perovskite ABO3 (BiFeO3, BaTiO3, PbTiO3 and CaTiO3) based multiferroics (in both single-phase and composite materials). The processing of high quality multiferroic thin film have some features like epitaxial strain, physical phenomenon at atomic-level, interfacial coupling parameters to enhance device performance. Since these multiferroic thin films have ME properties such as electrical (dielectric, magnetoelectric coefficient & MC) and magnetic (ferromagnetic, magnetic susceptibility etc.) are heat sensitive, i.e. ME response at low as well as higher temperature might to enhance the device performance respect with long range ordering. The magnetoelectric coupling between ferromagnetism and ferroelectricity in multiferroic becomes suitable in the application of spintronics, memory and logic devices, and microelectronic memory or piezoelectric devices. In comparison with bulk multiferroic, the fabrication of multiferroic thin film with different structural geometries on substrate has reducible clamping effect. A brief procedure for multiferroic thin film fabrication in terms of their thermal conditions (temperature for film processing and annealing for crystallization) are described. Each synthesis methods have its own characteristic phenomenon in terms of film thickness, defects formation, crack free film, density, chip size, easier steps and availability etc. been described. A brief study towards phase structure and ME coupling for each multiferroic system of BiFeO3, BaTiO3, PbTiO3 and CaTiO3 is shown.",book:{id:"10037",title:"Thermoelectricity - Recent Advances, New Perspectives and Applications",coverURL:"https://cdn.intechopen.com/books/images_new/10037.jpg"},signatures:"Kuldeep Chand Verma and Manpreet Singh"},{id:"78034",title:"Quantum Physical Interpretation of Thermoelectric Properties of Ruthenate Pyrochlores",slug:"quantum-physical-interpretation-of-thermoelectric-properties-of-ruthenate-pyrochlores",totalDownloads:78,totalDimensionsCites:0,doi:"10.5772/intechopen.99260",abstract:"Lead- and lead-yttrium ruthenate pyrochlores were synthesized and investigated for Seebeck coefficients, electrical- and thermal conductivity. Compounds A2B2O6.5+z with 0 ≤ z < 0.5 were defect pyrochlores and p-type conductors. The thermoelectric data were analyzed using quantum physical models to identify scattering mechanisms underlying electrical (σ) and thermal conductivity (κ) and to understand the temperature dependence of the Seebeck effect (S). In the metal-like lead ruthenates with different Pb:Ru ratios, σ (T) and the electronic thermal conductivity κe (T) were governed by ‘electron impurity scattering’, the lattice thermal conductivity κL (T) by the 3-phonon resistive process (Umklapp scattering). In the lead-yttrium ruthenate solid solutions (Pb(2-x)YxRu2O(6.5±z)), a metal–insulator transition occurred at 0.2 moles of yttrium. On the metallic side (<0.2 moles Y) ‘electron impurity scattering’ prevailed. On the semiconductor/insulator side between x = 0.2 and x = 1.0 several mechanisms were equally likely. At x > 1.5 the Mott Variable Range Hopping mechanism was active. S (T) was discussed for Pb-Y-Ru pyrochlores in terms of the effect of minority carrier excitation at lower- and a broadening of the Fermi distribution at higher temperatures. The figures of merit of all of these pyrochlores were still small (≤7.3 × 10−3).",book:{id:"10037",title:"Thermoelectricity - Recent Advances, New Perspectives and Applications",coverURL:"https://cdn.intechopen.com/books/images_new/10037.jpg"},signatures:"Sepideh Akhbarifar"},{id:"77635",title:"Optimization of Thermoelectric Properties Based on Rashba Spin Splitting",slug:"optimization-of-thermoelectric-properties-based-on-rashba-spin-splitting",totalDownloads:124,totalDimensionsCites:0,doi:"10.5772/intechopen.98788",abstract:"In recent years, the application of thermoelectricity has become more and more widespread. Thermoelectric materials provide a simple and environmentally friendly solution for the direct conversion of heat to electricity. The development of higher performance thermoelectric materials and their performance optimization have become more important. Generally, to improve the ZT value, electrical conductivity, Seebeck coefficient and thermal conductivity must be globally optimized as a whole object. However, due to the strong coupling among ZT parameters in many cases, it is very challenging to break the bottleneck of ZT optimization currently. Beyond the traditional optimization methods (such as inducing defects, varying temperature), the Rashba effect is expected to effectively increase the S2σ and decrease the κ, thus enhancing thermoelectric performance, which provides a new strategy to develop new-generation thermoelectric materials. Although the Rashba effect has great potential in enhancing thermoelectric performance, the underlying mechanism of Rashba-type thermoelectric materials needs further research. In addition, how to introduce Rashba spin splitting into current thermoelectric materials is also of great significance to the optimization of thermoelectricity.",book:{id:"10037",title:"Thermoelectricity - Recent Advances, New Perspectives and Applications",coverURL:"https://cdn.intechopen.com/books/images_new/10037.jpg"},signatures:"Zhenzhen Qin"},{id:"75364",title:"Challenges in Improving Performance of Oxide Thermoelectrics Using Defect Engineering",slug:"challenges-in-improving-performance-of-oxide-thermoelectrics-using-defect-engineering",totalDownloads:214,totalDimensionsCites:0,doi:"10.5772/intechopen.96278",abstract:"Oxide thermoelectric materials are considered promising for high-temperature thermoelectric applications in terms of low cost, temperature stability, reversible reaction, and so on. Oxide materials have been intensively studied to suppress the defects and electronic charge carriers for many electronic device applications, but the studies with a high concentration of defects are limited. It desires to improve thermoelectric performance by enhancing its charge transport and lowering its lattice thermal conductivity. For this purpose, here, we modified the stoichiometry of cation and anion vacancies in two different systems to regulate the carrier concentration and explored their thermoelectric properties. Both cation and anion vacancies act as a donor of charge carriers and act as phonon scattering centers, decoupling the electrical conductivity and thermal conductivity.",book:{id:"10037",title:"Thermoelectricity - Recent Advances, New Perspectives and Applications",coverURL:"https://cdn.intechopen.com/books/images_new/10037.jpg"},signatures:"Jamil Ur Rahman, Gul Rahman and Soonil Lee"}],onlineFirstChaptersTotal:6},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:87,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:98,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:27,numberOfPublishedChapters:287,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:9,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:11,numberOfPublishedChapters:139,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:8,numberOfPublishedChapters:129,numberOfOpenTopics:0,numberOfUpcomingTopics:2,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!1},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:107,numberOfOpenTopics:3,numberOfUpcomingTopics:1,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:10,numberOfPublishedChapters:103,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:12,numberOfOpenTopics:2,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:0,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!1},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:0,numberOfPublishedChapters:10,numberOfOpenTopics:4,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. 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"}}}},{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"}}}}]},series:{item:{id:"24",title:"Sustainable Development",doi:"10.5772/intechopen.100361",issn:null,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.
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\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\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
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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\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
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\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
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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.
",coverUrl:"https://cdn.intechopen.com/series/covers/24.jpg",latestPublicationDate:"May 19th, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:0,editor:{id:"262440",title:"Prof.",name:"Usha",middleName:null,surname:"Iyer-Raniga",slug:"usha-iyer-raniga",fullName:"Usha Iyer-Raniga",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRYSXQA4/Profile_Picture_2022-02-28T13:55:36.jpeg",biography:"Usha Iyer-Raniga is a professor in the School of Property and Construction Management at RMIT University. Usha co-leads the One Planet Network’s Sustainable Buildings and Construction Programme (SBC), a United Nations 10 Year Framework of Programmes on Sustainable Consumption and Production (UN 10FYP SCP) aligned with Sustainable Development Goal 12. The work also directly impacts SDG 11 on Sustainable Cities and Communities. She completed her undergraduate degree as an architect before obtaining her Masters degree from Canada and her Doctorate in Australia. Usha has been a keynote speaker as well as an invited speaker at national and international conferences, seminars and workshops. Her teaching experience includes teaching in Asian countries. She has advised Austrade, APEC, national, state and local governments. She serves as a reviewer and a member of the scientific committee for national and international refereed journals and refereed conferences. She is on the editorial board for refereed journals and has worked on Special Issues. Usha has served and continues to serve on the Boards of several not-for-profit organisations and she has also served as panel judge for a number of awards including the Premiers Sustainability Award in Victoria and the International Green Gown Awards. Usha has published over 100 publications, including research and consulting reports. Her publications cover a wide range of scientific and technical research publications that include edited books, book chapters, refereed journals, refereed conference papers and reports for local, state and federal government clients. She has also produced podcasts for various organisations and participated in media interviews. She has received state, national and international funding worth over USD $25 million. Usha has been awarded the Quarterly Franklin Membership by London Journals Press (UK). Her biography has been included in the Marquis Who's Who in the World® 2018, 2016 (33rd Edition), along with approximately 55,000 of the most accomplished men and women from around the world, including luminaries as U.N. Secretary-General Ban Ki-moon. In 2017, Usha was awarded the Marquis Who’s Who Lifetime Achiever Award.",institutionString:null,institution:{name:"RMIT University",institutionURL:null,country:{name:"Australia"}}},editorTwo:null,editorThree:null},subseries:{paginationCount:0,paginationItems:[]},overviewPageOFChapters:{paginationCount:0,paginationItems:[]},overviewPagePublishedBooks:{paginationCount:0,paginationItems:[]},openForSubmissionBooks:{paginationCount:5,paginationItems:[{id:"11576",title:"Malaria - Recent Advances, and New Perspectives",coverURL:"https://cdn.intechopen.com/books/images_new/11576.jpg",hash:"5a01644fb0b4ce24c2f947913d154abe",secondStepPassed:!0,currentStepOfPublishingProcess:3,submissionDeadline:"April 26th 2022",isOpenForSubmission:!0,editors:[{id:"76041",title:"Prof.",name:"Pier Paolo",surname:"Piccaluga",slug:"pier-paolo-piccaluga",fullName:"Pier Paolo Piccaluga"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null},{id:"11577",title:"Tick-Borne Diseases - A Review and an Update of Knowledge on Infections in Human and Animal Population",coverURL:"https://cdn.intechopen.com/books/images_new/11577.jpg",hash:"3d72ae651ee2a04b2368bf798a3183ca",secondStepPassed:!0,currentStepOfPublishingProcess:3,submissionDeadline:"April 29th 2022",isOpenForSubmission:!0,editors:[{id:"51521",title:"Prof.",name:"Elisa",surname:"Pieragostini",slug:"elisa-pieragostini",fullName:"Elisa Pieragostini"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null},{id:"11570",title:"Influenza - New Approaches",coverURL:"https://cdn.intechopen.com/books/images_new/11570.jpg",hash:"157b379b9d7a4bf5e2cc7a742f155a44",secondStepPassed:!0,currentStepOfPublishingProcess:3,submissionDeadline:"May 10th 2022",isOpenForSubmission:!0,editors:[{id:"139889",title:"Dr.",name:"Seyyed Shamsadin",surname:"Athari",slug:"seyyed-shamsadin-athari",fullName:"Seyyed Shamsadin Athari"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null},{id:"11569",title:"Bacterial Sexually Transmitted Infections - New Findings, Diagnosis, Treatment, and Prevention",coverURL:"https://cdn.intechopen.com/books/images_new/11569.jpg",hash:"069d6142ecb0d46d14920102d48c0e9d",secondStepPassed:!1,currentStepOfPublishingProcess:2,submissionDeadline:"May 31st 2022",isOpenForSubmission:!0,editors:[{id:"189561",title:"Dr.",name:"Mihaela Laura",surname:"Vica",slug:"mihaela-laura-vica",fullName:"Mihaela Laura Vica"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null},{id:"11568",title:"Staphylococcal Infections - Recent Advances and Perspectives",coverURL:"https://cdn.intechopen.com/books/images_new/11568.jpg",hash:"92c881664d1921c7f2d0fee34b78cd08",secondStepPassed:!1,currentStepOfPublishingProcess:2,submissionDeadline:"June 1st 2022",isOpenForSubmission:!0,editors:[{id:"59719",title:"Dr.",name:"Jaime",surname:"Bustos-Martínez",slug:"jaime-bustos-martinez",fullName:"Jaime Bustos-Martínez"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null}]},onlineFirstChapters:{paginationCount:17,paginationItems:[{id:"81751",title:"NanoBioSensors: From Electrochemical Sensors Improvement to Theranostic Applications",doi:"10.5772/intechopen.102552",signatures:"Anielle C.A. 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He is the author or co-author of more than seventy papers in peer-reviewed journals and conferences as well as the co-author of several books. He serves as a reviewer for many scientific journals, international conferences, and research foundations. Since 2010, Dr. Placzek has been a reviewer of grants and projects (including EU projects) in the field of information technologies.",institutionString:"University of Silesia",institution:{name:"University of Silesia",country:{name:"Poland"}}},{id:"35000",title:"Prof.",name:"Ulrich H.P",middleName:"H.P.",surname:"Fischer",slug:"ulrich-h.p-fischer",fullName:"Ulrich H.P Fischer",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/35000/images/3052_n.jpg",biography:"Academic and Professional Background\nUlrich H. P. has Diploma and PhD degrees in Physics from the Free University Berlin, Germany. He has been working on research positions in the Heinrich-Hertz-Institute in Germany. Several international research projects has been performed with European partners from France, Netherlands, Norway and the UK. He is currently Professor of Communications Systems at the Harz University of Applied Sciences, Germany.\n\nPublications and Publishing\nHe has edited one book, a special interest book about ‘Optoelectronic Packaging’ (VDE, Berlin, Germany), and has published over 100 papers and is owner of several international patents for WDM over POF key elements.\n\nKey Research and Consulting Interests\nUlrich’s research activity has always been related to Spectroscopy and Optical Communications Technology. Specific current interests include the validation of complex instruments, and the application of VR technology to the development and testing of measurement systems. He has been reviewer for several publications of the Optical Society of America\\'s including Photonics Technology Letters and Applied Optics.\n\nPersonal Interests\nThese include motor cycling in a very relaxed manner and performing martial arts.",institutionString:null,institution:{name:"Charité",country:{name:"Germany"}}},{id:"341622",title:"Ph.D.",name:"Eduardo",middleName:null,surname:"Rojas Alvarez",slug:"eduardo-rojas-alvarez",fullName:"Eduardo Rojas Alvarez",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/341622/images/15892_n.jpg",biography:null,institutionString:null,institution:{name:"University of Cuenca",country:{name:"Ecuador"}}},{id:"215610",title:"Prof.",name:"Muhammad",middleName:null,surname:"Sarfraz",slug:"muhammad-sarfraz",fullName:"Muhammad Sarfraz",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/215610/images/system/215610.jpeg",biography:"Muhammad Sarfraz is a professor in the Department of Information Science, Kuwait University, Kuwait. His research interests include optimization, computer graphics, computer vision, image processing, machine learning, pattern recognition, soft computing, data science, and intelligent systems. Prof. Sarfraz has been a keynote/invited speaker at various platforms around the globe. He has advised/supervised more than 110 students for their MSc and Ph.D. theses. He has published more than 400 publications as books, journal articles, and conference papers. He has authored and/or edited around seventy books. Prof. Sarfraz is a member of various professional societies. He is a chair and member of international advisory committees and organizing committees of numerous international conferences. He is also an editor and editor in chief for various international journals.",institutionString:"Kuwait University",institution:{name:"Kuwait University",country:{name:"Kuwait"}}},{id:"32650",title:"Prof.",name:"Lukas",middleName:"Willem",surname:"Snyman",slug:"lukas-snyman",fullName:"Lukas Snyman",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/32650/images/4136_n.jpg",biography:"Lukas Willem Snyman received his basic education at primary and high schools in South Africa, Eastern Cape. He enrolled at today's Nelson Metropolitan University and graduated from this university with a BSc in Physics and Mathematics, B.Sc Honors in Physics, MSc in Semiconductor Physics, and a Ph.D. in Semiconductor Physics in 1987. After his studies, he chose an academic career and devoted his energy to the teaching of physics to first, second, and third-year students. After positions as a lecturer at the University of Port Elizabeth, he accepted a position as Associate Professor at the University of Pretoria, South Africa.\r\n\r\nIn 1992, he motivates the concept of 'television and computer-based education” as means to reach large student numbers with only the best of teaching expertise and publishes an article on the concept in the SA Journal of Higher Education of 1993 (and later in 2003). The University of Pretoria subsequently approved a series of test projects on the concept with outreach to Mamelodi and Eerste Rust in 1993. In 1994, the University established a 'Unit for Telematic Education ' as a support section for multiple faculties at the University of Pretoria. In subsequent years, the concept of 'telematic education” subsequently becomes well established in academic circles in South Africa, grew in popularity, and is adopted by many universities and colleges throughout South Africa as a medium of enhancing education and training, as a method to reaching out to far out communities, and as a means to enhance study from the home environment.\r\n\r\nProfessor Snyman in subsequent years pursued research in semiconductor physics, semiconductor devices, microelectronics, and optoelectronics.\r\n\r\nIn 2000 he joined the TUT as a full professor. Here served for a period as head of the Department of Electronic Engineering. Here he makes contributions to solar energy development, microwave and optoelectronic device development, silicon photonics, as well as contributions to new mobile telecommunication systems and network planning in SA.\r\n\r\nCurrently, he teaches electronics and telecommunications at the TUT to audiences ranging from first-year students to Ph.D. level.\r\n\r\nFor his research in the field of 'Silicon Photonics” since 1990, he has published (as author and co-author) about thirty internationally reviewed articles in scientific journals, contributed to more than forty international conferences, about 25 South African provisional patents (as inventor and co-inventor), 8 PCT international patent applications until now. Of these, two USA patents applications, two European Patents, two Korean patents, and ten SA patents have been granted. A further 4 USA patents, 5 European patents, 3 Korean patents, 3 Chinese patents, and 3 Japanese patents are currently under consideration.\r\n\r\nRecently he has also published an extensive scholarly chapter in an internet open access book on 'Integrating Microphotonic Systems and MOEMS into standard Silicon CMOS Integrated circuitry”.\r\n\r\nFurthermore, Professor Snyman recently steered a new initiative at the TUT by introducing a 'Laboratory for Innovative Electronic Systems ' at the Department of Electrical Engineering. The model of this laboratory or center is to primarily combine outputs as achieved by high-level research with lower-level system development and entrepreneurship in a technical university environment. Students are allocated to projects at different levels with PhDs and Master students allocated to the generation of new knowledge and new technologies, while students at the diploma and Baccalaureus level are allocated to electronic systems development with a direct and a near application for application in industry or the commercial and public sectors in South Africa.\r\n\r\nProfessor Snyman received the WIRSAM Award of 1983 and the WIRSAM Award in 1985 in South Africa for best research papers by a young scientist at two international conferences on electron microscopy in South Africa. He subsequently received the SA Microelectronics Award for the best dissertation emanating from studies executed at a South African university in the field of Physics and Microelectronics in South Africa in 1987. In October of 2011, Professor Snyman received the prestigious Institutional Award for 'Innovator of the Year” for 2010 at the Tshwane University of Technology, South Africa. This award was based on the number of patents recognized and granted by local and international institutions as well as for his contributions concerning innovation at the TUT.",institutionString:null,institution:{name:"University of South Africa",country:{name:"South Africa"}}},{id:"317279",title:"Mr.",name:"Ali",middleName:"Usama",surname:"Syed",slug:"ali-syed",fullName:"Ali Syed",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/317279/images/16024_n.png",biography:"A creative, talented, and innovative young professional who is dedicated, well organized, and capable research fellow with two years of experience in graduate-level research, published in engineering journals and book, with related expertise in Bio-robotics, equally passionate about the aesthetics of the mechanical and electronic system, obtained expertise in the use of MS Office, MATLAB, SolidWorks, LabVIEW, Proteus, Fusion 360, having a grasp on python, C++ and assembly language, possess proven ability in acquiring research grants, previous appointments with social and educational societies with experience in administration, current affiliations with IEEE and Web of Science, a confident presenter at conferences and teacher in classrooms, able to explain complex information to audiences of all levels.",institutionString:null,institution:{name:"Air University",country:{name:"Pakistan"}}},{id:"75526",title:"Ph.D.",name:"Zihni Onur",middleName:null,surname:"Uygun",slug:"zihni-onur-uygun",fullName:"Zihni Onur Uygun",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/75526/images/12_n.jpg",biography:"My undergraduate education and my Master of Science educations at Ege University and at Çanakkale Onsekiz Mart University have given me a firm foundation in Biochemistry, Analytical Chemistry, Biosensors, Bioelectronics, Physical Chemistry and Medicine. After obtaining my degree as a MSc in analytical chemistry, I started working as a research assistant in Ege University Medical Faculty in 2014. In parallel, I enrolled to the MSc program at the Department of Medical Biochemistry at Ege University to gain deeper knowledge on medical and biochemical sciences as well as clinical chemistry in 2014. In my PhD I deeply researched on biosensors and bioelectronics and finished in 2020. Now I have eleven SCI-Expanded Index published papers, 6 international book chapters, referee assignments for different SCIE journals, one international patent pending, several international awards, projects and bursaries. In parallel to my research assistant position at Ege University Medical Faculty, Department of Medical Biochemistry, in April 2016, I also founded a Start-Up Company (Denosens Biotechnology LTD) by the support of The Scientific and Technological Research Council of Turkey. Currently, I am also working as a CEO in Denosens Biotechnology. The main purposes of the company, which carries out R&D as a research center, are to develop new generation biosensors and sensors for both point-of-care diagnostics; such as glucose, lactate, cholesterol and cancer biomarker detections. My specific experimental and instrumental skills are Biochemistry, Biosensor, Analytical Chemistry, Electrochemistry, Mobile phone based point-of-care diagnostic device, POCTs and Patient interface designs, HPLC, Tandem Mass Spectrometry, Spectrophotometry, ELISA.",institutionString:null,institution:{name:"Ege University",country:{name:"Turkey"}}},{id:"246502",title:"Dr.",name:"Jaya T.",middleName:"T",surname:"Varkey",slug:"jaya-t.-varkey",fullName:"Jaya T. Varkey",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/246502/images/11160_n.jpg",biography:"Jaya T. Varkey, PhD, graduated with a degree in Chemistry from Cochin University of Science and Technology, Kerala, India. She obtained a PhD in Chemistry from the School of Chemical Sciences, Mahatma Gandhi University, Kerala, India, and completed a post-doctoral fellowship at the University of Minnesota, USA. She is a research guide at Mahatma Gandhi University and Associate Professor in Chemistry, St. Teresa’s College, Kochi, Kerala, India.\nDr. Varkey received a National Young Scientist award from the Indian Science Congress (1995), a UGC Research award (2016–2018), an Indian National Science Academy (INSA) Visiting Scientist award (2018–2019), and a Best Innovative Faculty award from the All India Association for Christian Higher Education (AIACHE) (2019). She Hashas received the Sr. Mary Cecil prize for best research paper three times. She was also awarded a start-up to develop a tea bag water filter. \nDr. Varkey has published two international books and twenty-seven international journal publications. She is an editorial board member for five international journals.",institutionString:"St. Teresa’s College",institution:null},{id:"250668",title:"Dr.",name:"Ali",middleName:null,surname:"Nabipour Chakoli",slug:"ali-nabipour-chakoli",fullName:"Ali Nabipour Chakoli",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/250668/images/system/250668.jpg",biography:"Academic Qualification:\r\n•\tPhD in Materials Physics and Chemistry, From: Sep. 2006, to: Sep. 2010, School of Materials Science and Engineering, Harbin Institute of Technology, Thesis: Structure and Shape Memory Effect of Functionalized MWCNTs/poly (L-lactide-co-ε-caprolactone) Nanocomposites. Supervisor: Prof. Wei Cai,\r\n•\tM.Sc in Applied Physics, From: 1996, to: 1998, Faculty of Physics & Nuclear Science, Amirkabir Uni. of Technology, Tehran, Iran, Thesis: Determination of Boron in Micro alloy Steels with solid state nuclear track detectors by neutron induced auto radiography, Supervisors: Dr. M. Hosseini Ashrafi and Dr. A. Hosseini.\r\n•\tB.Sc. in Applied Physics, From: 1991, to: 1996, Faculty of Physics & Nuclear Science, Amirkabir Uni. of Technology, Tehran, Iran, Thesis: Design of shielding for Am-Be neutron sources for In Vivo neutron activation analysis, Supervisor: Dr. M. Hosseini Ashrafi.\r\n\r\nResearch Experiences:\r\n1.\tNanomaterials, Carbon Nanotubes, Graphene: Synthesis, Functionalization and Characterization,\r\n2.\tMWCNTs/Polymer Composites: Fabrication and Characterization, \r\n3.\tShape Memory Polymers, Biodegradable Polymers, ORC, Collagen,\r\n4.\tMaterials Analysis and Characterizations: TEM, SEM, XPS, FT-IR, Raman, DSC, DMA, TGA, XRD, GPC, Fluoroscopy, \r\n5.\tInteraction of Radiation with Mater, Nuclear Safety and Security, NDT(RT),\r\n6.\tRadiation Detectors, Calibration (SSDL),\r\n7.\tCompleted IAEA e-learning Courses:\r\nNuclear Security (15 Modules),\r\nNuclear Safety:\r\nTSA 2: Regulatory Protection in Occupational Exposure,\r\nTips & Tricks: Radiation Protection in Radiography,\r\nSafety and Quality in Radiotherapy,\r\nCourse on Sealed Radioactive Sources,\r\nCourse on Fundamentals of Environmental Remediation,\r\nCourse on Planning for Environmental Remediation,\r\nKnowledge Management Orientation Course,\r\nFood Irradiation - Technology, Applications and Good Practices,\r\nEmployment:\r\nFrom 2010 to now: Academic staff, Nuclear Science and Technology Research Institute, Kargar Shomali, Tehran, Iran, P.O. Box: 14395-836.\r\nFrom 1997 to 2006: Expert of Materials Analysis and Characterization. Research Center of Agriculture and Medicine. Rajaeeshahr, Karaj, Iran, P. O. Box: 31585-498.",institutionString:"Atomic Energy Organization of Iran",institution:{name:"Atomic Energy Organization of Iran",country:{name:"Iran"}}},{id:"248279",title:"Dr.",name:"Monika",middleName:"Elzbieta",surname:"Machoy",slug:"monika-machoy",fullName:"Monika Machoy",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/248279/images/system/248279.jpeg",biography:"Monika Elżbieta Machoy, MD, graduated with distinction from the Faculty of Medicine and Dentistry at the Pomeranian Medical University in 2009, defended her PhD thesis with summa cum laude in 2016 and is currently employed as a researcher at the Department of Orthodontics of the Pomeranian Medical University. She expanded her professional knowledge during a one-year scholarship program at the Ernst Moritz Arndt University in Greifswald, Germany and during a three-year internship at the Technical University in Dresden, Germany. She has been a speaker at numerous orthodontic conferences, among others, American Association of Orthodontics, European Orthodontic Symposium and numerous conferences of the Polish Orthodontic Society. She conducts research focusing on the effect of orthodontic treatment on dental and periodontal tissues and the causes of pain in orthodontic patients.",institutionString:"Pomeranian Medical University",institution:{name:"Pomeranian Medical University",country:{name:"Poland"}}},{id:"252743",title:"Prof.",name:"Aswini",middleName:"Kumar",surname:"Kar",slug:"aswini-kar",fullName:"Aswini Kar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/252743/images/10381_n.jpg",biography:"uploaded in cv",institutionString:null,institution:{name:"KIIT University",country:{name:"India"}}},{id:"204256",title:"Dr.",name:"Anil",middleName:"Kumar",surname:"Kumar Sahu",slug:"anil-kumar-sahu",fullName:"Anil Kumar Sahu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/204256/images/14201_n.jpg",biography:"I have nearly 11 years of research and teaching experience. I have done my master degree from University Institute of Pharmacy, Pt. Ravi Shankar Shukla University, Raipur, Chhattisgarh India. I have published 16 review and research articles in international and national journals and published 4 chapters in IntechOpen, the world’s leading publisher of Open access books. I have presented many papers at national and international conferences. I have received research award from Indian Drug Manufacturers Association in year 2015. My research interest extends from novel lymphatic drug delivery systems, oral delivery system for herbal bioactive to formulation optimization.",institutionString:null,institution:{name:"Chhattisgarh Swami Vivekanand Technical University",country:{name:"India"}}},{id:"253468",title:"Dr.",name:"Mariusz",middleName:null,surname:"Marzec",slug:"mariusz-marzec",fullName:"Mariusz Marzec",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/253468/images/system/253468.png",biography:"An assistant professor at Department of Biomedical Computer Systems, at Institute of Computer Science, Silesian University in Katowice. Scientific interests: computer analysis and processing of images, biomedical images, databases and programming languages. He is an author and co-author of scientific publications covering analysis and processing of biomedical images and development of database systems.",institutionString:"University of Silesia",institution:null},{id:"212432",title:"Prof.",name:"Hadi",middleName:null,surname:"Mohammadi",slug:"hadi-mohammadi",fullName:"Hadi Mohammadi",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/212432/images/system/212432.jpeg",biography:"Dr. Hadi Mohammadi is a biomedical engineer with hands-on experience in the design and development of many engineering structures and medical devices through various projects that he has been involved in over the past twenty years. Dr. Mohammadi received his BSc. and MSc. degrees in Mechanical Engineering from Sharif University of Technology, Tehran, Iran, and his PhD. degree in Biomedical Engineering (biomaterials) from the University of Western Ontario. He was a postdoctoral trainee for almost four years at University of Calgary and Harvard Medical School. He is an industry innovator having created the technology to produce lifelike synthetic platforms that can be used for the simulation of almost all cardiovascular reconstructive surgeries. He’s been heavily involved in the design and development of cardiovascular devices and technology for the past 10 years. He is currently an Assistant Professor with the University of British Colombia, Canada.",institutionString:"University of British Columbia",institution:{name:"University of British Columbia",country:{name:"Canada"}}},{id:"254463",title:"Prof.",name:"Haisheng",middleName:null,surname:"Yang",slug:"haisheng-yang",fullName:"Haisheng Yang",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/254463/images/system/254463.jpeg",biography:"Haisheng Yang, Ph.D., Professor and Director of the Department of Biomedical Engineering, College of Life Science and Bioengineering, Beijing University of Technology. He received his Ph.D. degree in Mechanics/Biomechanics from Harbin Institute of Technology (jointly with University of California, Berkeley). Afterwards, he worked as a Postdoctoral Research Associate in the Purdue Musculoskeletal Biology and Mechanics Lab at the Department of Basic Medical Sciences, Purdue University, USA. He also conducted research in the Research Centre of Shriners Hospitals for Children-Canada at McGill University, Canada. Dr. Yang has over 10 years research experience in orthopaedic biomechanics and mechanobiology of bone adaptation and regeneration. He earned an award from Beijing Overseas Talents Aggregation program in 2017 and serves as Beijing Distinguished Professor.",institutionString:"Beijing University of Technology",institution:null},{id:"255757",title:"Dr.",name:"Igor",middleName:"Victorovich",surname:"Lakhno",slug:"igor-lakhno",fullName:"Igor Lakhno",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/255757/images/system/255757.jpg",biography:"Lakhno Igor Victorovich was born in 1971 in Kharkiv (Ukraine). \nMD – 1994, Kharkiv National Medical Univesity.\nOb&Gyn; – 1997, master courses in Kharkiv Medical Academy of Postgraduate Education.\nPhD – 1999, Kharkiv National Medical Univesity.\nDSc – 2019, PL Shupik National Academy of Postgraduate Education \nLakhno Igor has been graduated from an international training courses on reproductive medicine and family planning held in Debrecen University (Hungary) in 1997. Since 1998 Lakhno Igor has worked as an associate professor of the department of obstetrics and gynecology of VN Karazin National University and an associate professor of the perinatology, obstetrics and gynecology department of Kharkiv Medical Academy of Postgraduate Education. Since June 2019 he’s a professor of the department of obstetrics and gynecology of VN Karazin National University and a professor of the perinatology, obstetrics and gynecology department of Kharkiv Medical Academy of Postgraduate Education . He’s an author of about 200 printed works and there are 17 of them in Scopus or Web of Science databases. Lakhno Igor is a rewiever of Journal of Obstetrics and Gynaecology (Taylor and Francis), Informatics in Medicine Unlocked (Elsevier), The Journal of Obstetrics and Gynecology Research (Wiley), Endocrine, Metabolic & Immune Disorders-Drug Targets (Bentham Open), The Open Biomedical Engineering Journal (Bentham Open), etc. He’s defended a dissertation for DSc degree \\'Pre-eclampsia: prediction, prevention and treatment”. Lakhno Igor has participated as a speaker in several international conferences and congresses (International Conference on Biological Oscillations April 10th-14th 2016, Lancaster, UK, The 9th conference of the European Study Group on Cardiovascular Oscillations). His main scientific interests: obstetrics, women’s health, fetal medicine, cardiovascular medicine.",institutionString:"V.N. Karazin Kharkiv National University",institution:{name:"Kharkiv Medical Academy of Postgraduate Education",country:{name:"Ukraine"}}},{id:"89721",title:"Dr.",name:"Mehmet",middleName:"Cuneyt",surname:"Ozmen",slug:"mehmet-ozmen",fullName:"Mehmet Ozmen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/89721/images/7289_n.jpg",biography:null,institutionString:null,institution:{name:"Gazi University",country:{name:"Turkey"}}},{id:"243698",title:"M.D.",name:"Xiaogang",middleName:null,surname:"Wang",slug:"xiaogang-wang",fullName:"Xiaogang Wang",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/243698/images/system/243698.png",biography:"Dr. Xiaogang Wang, a faculty member of Shanxi Eye Hospital specializing in the treatment of cataract and retinal disease and a tutor for postgraduate students of Shanxi Medical University, worked in the COOL Lab as an international visiting scholar under the supervision of Dr. David Huang and Yali Jia from October 2012 through November 2013. Dr. Wang earned an MD from Shanxi Medical University and a Ph.D. from Shanghai Jiao Tong University. Dr. Wang was awarded two research project grants focused on multimodal optical coherence tomography imaging and deep learning in cataract and retinal disease, from the National Natural Science Foundation of China. He has published around 30 peer-reviewed journal papers and four book chapters and co-edited one book.",institutionString:"Shanxi Eye Hospital",institution:{name:"Shanxi Eye Hospital",country:{name:"China"}}},{id:"242893",title:"Ph.D. Student",name:"Joaquim",middleName:null,surname:"De Moura",slug:"joaquim-de-moura",fullName:"Joaquim De Moura",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/242893/images/7133_n.jpg",biography:"Joaquim de Moura received his degree in Computer Engineering in 2014 from the University of A Coruña (Spain). In 2016, he received his M.Sc degree in Computer Engineering from the same university. He is currently pursuing his Ph.D degree in Computer Science in a collaborative project between ophthalmology centers in Galicia and the University of A Coruña. His research interests include computer vision, machine learning algorithms and analysis and medical imaging processing of various kinds.",institutionString:null,institution:{name:"University of A Coruña",country:{name:"Spain"}}},{id:"267434",title:"Dr.",name:"Rohit",middleName:null,surname:"Raja",slug:"rohit-raja",fullName:"Rohit Raja",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRZkkQAG/Profile_Picture_2022-05-09T12:55:18.jpg",biography:null,institutionString:null,institution:null},{id:"294334",title:"B.Sc.",name:"Marc",middleName:null,surname:"Bruggeman",slug:"marc-bruggeman",fullName:"Marc Bruggeman",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/294334/images/8242_n.jpg",biography:"Chemical engineer graduate, with a passion for material science and specific interest in polymers - their near infinite applications intrigue me. \n\nI plan to continue my scientific career in the field of polymeric biomaterials as I am fascinated by intelligent, bioactive and biomimetic materials for use in both consumer and medical applications.",institutionString:null,institution:null},{id:"244950",title:"Dr.",name:"Salvatore",middleName:null,surname:"Di Lauro",slug:"salvatore-di-lauro",fullName:"Salvatore Di Lauro",position:null,profilePictureURL:"https://intech-files.s3.amazonaws.com/0030O00002bSF1HQAW/ProfilePicture%202021-12-20%2014%3A54%3A14.482",biography:"Name:\n\tSALVATORE DI LAURO\nAddress:\n\tHospital Clínico Universitario Valladolid\nAvda Ramón y Cajal 3\n47005, Valladolid\nSpain\nPhone number: \nFax\nE-mail:\n\t+34 983420000 ext 292\n+34 983420084\nsadilauro@live.it\nDate and place of Birth:\nID Number\nMedical Licence \nLanguages\t09-05-1985. Villaricca (Italy)\n\nY1281863H\n474707061\nItalian (native language)\nSpanish (read, written, spoken)\nEnglish (read, written, spoken)\nPortuguese (read, spoken)\nFrench (read)\n\t\t\nCurrent position (title and company)\tDate (Year)\nVitreo-Retinal consultant in ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl. National Health System.\nVitreo-Retinal consultant in ophthalmology. Instituto Oftalmologico Recoletas. Red Hospitalaria Recoletas. Private practise.\t2017-today\n\n2019-today\n\t\n\t\nEducation (High school, university and postgraduate training > 3 months)\tDate (Year)\nDegree in Medicine and Surgery. University of Neaples 'Federico II”\nResident in Opthalmology. Hospital Clinico Universitario Valladolid\nMaster in Vitreo-Retina. IOBA. University of Valladolid\nFellow of the European Board of Ophthalmology. Paris\nMaster in Research in Ophthalmology. University of Valladolid\t2003-2009\n2012-2016\n2016-2017\n2016\n2012-2013\n\t\nEmployments (company and positions)\tDate (Year)\nResident in Ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl.\nFellow in Vitreo-Retina. IOBA. University of Valladolid\nVitreo-Retinal consultant in ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl. National Health System.\nVitreo-Retinal consultant in ophthalmology. Instituto Oftalmologico Recoletas. Red Hospitalaria Recoletas. \n\t2012-2016\n2016-2017\n2017-today\n\n2019-Today\n\n\n\t\nClinical Research Experience (tasks and role)\tDate (Year)\nAssociated investigator\n\n' FIS PI20/00740: DESARROLLO DE UNA CALCULADORA DE RIESGO DE\nAPARICION DE RETINOPATIA DIABETICA BASADA EN TECNICAS DE IMAGEN MULTIMODAL EN PACIENTES DIABETICOS TIPO 1. Grant by: Ministerio de Ciencia e Innovacion \n\n' (BIO/VA23/14) Estudio clínico multicéntrico y prospectivo para validar dos\nbiomarcadores ubicados en los genes p53 y MDM2 en la predicción de los resultados funcionales de la cirugía del desprendimiento de retina regmatógeno. Grant by: Gerencia Regional de Salud de la Junta de Castilla y León.\n' Estudio multicéntrico, aleatorizado, con enmascaramiento doble, en 2 grupos\nparalelos y de 52 semanas de duración para comparar la eficacia, seguridad e inmunogenicidad de SOK583A1 respecto a Eylea® en pacientes con degeneración macular neovascular asociada a la edad' (CSOK583A12301; N.EUDRA: 2019-004838-41; FASE III). Grant by Hexal AG\n\n' Estudio de fase III, aleatorizado, doble ciego, con grupos paralelos, multicéntrico para comparar la eficacia y la seguridad de QL1205 frente a Lucentis® en pacientes con degeneración macular neovascular asociada a la edad. (EUDRACT: 2018-004486-13). Grant by Qilu Pharmaceutical Co\n\n' Estudio NEUTON: Ensayo clinico en fase IV para evaluar la eficacia de aflibercept en pacientes Naive con Edema MacUlar secundario a Oclusion de Vena CenTral de la Retina (OVCR) en regimen de tratamientO iNdividualizado Treat and Extend (TAE)”, (2014-000975-21). Grant by Fundacion Retinaplus\n\n' Evaluación de la seguridad y bioactividad de anillos de tensión capsular en conejo. Proyecto Procusens. Grant by AJL, S.A.\n\n'Estudio epidemiológico, prospectivo, multicéntrico y abierto\\npara valorar la frecuencia de la conjuntivitis adenovírica diagnosticada mediante el test AdenoPlus®\\nTest en pacientes enfermos de conjuntivitis aguda”\\n. National, multicenter study. Grant by: NICOX.\n\nEuropean multicentric trial: 'Evaluation of clinical outcomes following the use of Systane Hydration in patients with dry eye”. Study Phase 4. Grant by: Alcon Labs'\n\nVLPs Injection and Activation in a Rabbit Model of Uveal Melanoma. Grant by Aura Bioscience\n\nUpdating and characterization of a rabbit model of uveal melanoma. Grant by Aura Bioscience\n\nEnsayo clínico en fase IV para evaluar las variantes genéticas de la vía del VEGF como biomarcadores de eficacia del tratamiento con aflibercept en pacientes con degeneración macular asociada a la edad (DMAE) neovascular. Estudio BIOIMAGE. IMO-AFLI-2013-01\n\nEstudio In-Eye:Ensayo clínico en fase IV, abierto, aleatorizado, de 2 brazos,\nmulticçentrico y de 12 meses de duración, para evaluar la eficacia y seguridad de un régimen de PRN flexible individualizado de 'esperar y extender' versus un régimen PRN según criterios de estabilización mediante evaluaciones mensuales de inyecciones intravítreas de ranibizumab 0,5 mg en pacientes naive con neovascularización coriodea secunaria a la degeneración macular relacionada con la edad. CP: CRFB002AES03T\n\nTREND: Estudio Fase IIIb multicéntrico, randomizado, de 12 meses de\nseguimiento con evaluador de la agudeza visual enmascarado, para evaluar la eficacia y la seguridad de ranibizumab 0.5mg en un régimen de tratar y extender comparado con un régimen mensual, en pacientes con degeneración macular neovascular asociada a la edad. CP: CRFB002A2411 Código Eudra CT:\n2013-002626-23\n\n\n\nPublications\t\n\n2021\n\n\n\n\n2015\n\n\n\n\n2021\n\n\n\n\n\n2021\n\n\n\n\n2015\n\n\n\n\n2015\n\n\n2014\n\n\n\n\n2015-16\n\n\n\n2015\n\n\n2014\n\n\n2014\n\n\n\n\n2014\n\n\n\n\n\n\n\n2014\n\nJose Carlos Pastor; Jimena Rojas; Salvador Pastor-Idoate; Salvatore Di Lauro; Lucia Gonzalez-Buendia; Santiago Delgado-Tirado. Proliferative vitreoretinopathy: A new concept of disease pathogenesis and practical\nconsequences. Progress in Retinal and Eye Research. 51, pp. 125 - 155. 03/2016. DOI: 10.1016/j.preteyeres.2015.07.005\n\n\nLabrador-Velandia S; Alonso-Alonso ML; Di Lauro S; García-Gutierrez MT; Srivastava GK; Pastor JC; Fernandez-Bueno I. Mesenchymal stem cells provide paracrine neuroprotective resources that delay degeneration of co-cultured organotypic neuroretinal cultures.Experimental Eye Research. 185, 17/05/2019. DOI: 10.1016/j.exer.2019.05.011\n\nSalvatore Di Lauro; Maria Teresa Garcia Gutierrez; Ivan Fernandez Bueno. Quantification of pigment epithelium-derived factor (PEDF) in an ex vivo coculture of retinal pigment epithelium cells and neuroretina.\nJournal of Allbiosolution. 2019. ISSN 2605-3535\n\nSonia Labrador Velandia; Salvatore Di Lauro; Alonso-Alonso ML; Tabera Bartolomé S; Srivastava GK; Pastor JC; Fernandez-Bueno I. Biocompatibility of intravitreal injection of human mesenchymal stem cells in immunocompetent rabbits. Graefe's archive for clinical and experimental ophthalmology. 256 - 1, pp. 125 - 134. 01/2018. DOI: 10.1007/s00417-017-3842-3\n\n\nSalvatore Di Lauro, David Rodriguez-Crespo, Manuel J Gayoso, Maria T Garcia-Gutierrez, J Carlos Pastor, Girish K Srivastava, Ivan Fernandez-Bueno. A novel coculture model of porcine central neuroretina explants and retinal pigment epithelium cells. Molecular Vision. 2016 - 22, pp. 243 - 253. 01/2016.\n\nSalvatore Di Lauro. Classifications for Proliferative Vitreoretinopathy ({PVR}): An Analysis of Their Use in Publications over the Last 15 Years. Journal of Ophthalmology. 2016, pp. 1 - 6. 01/2016. DOI: 10.1155/2016/7807596\n\nSalvatore Di Lauro; Rosa Maria Coco; Rosa Maria Sanabria; Enrique Rodriguez de la Rua; Jose Carlos Pastor. Loss of Visual Acuity after Successful Surgery for Macula-On Rhegmatogenous Retinal Detachment in a Prospective Multicentre Study. Journal of Ophthalmology. 2015:821864, 2015. DOI: 10.1155/2015/821864\n\nIvan Fernandez-Bueno; Salvatore Di Lauro; Ivan Alvarez; Jose Carlos Lopez; Maria Teresa Garcia-Gutierrez; Itziar Fernandez; Eva Larra; Jose Carlos Pastor. Safety and Biocompatibility of a New High-Density Polyethylene-Based\nSpherical Integrated Porous Orbital Implant: An Experimental Study in Rabbits. Journal of Ophthalmology. 2015:904096, 2015. DOI: 10.1155/2015/904096\n\nPastor JC; Pastor-Idoate S; Rodríguez-Hernandez I; Rojas J; Fernandez I; Gonzalez-Buendia L; Di Lauro S; Gonzalez-Sarmiento R. Genetics of PVR and RD. Ophthalmologica. 232 - Suppl 1, pp. 28 - 29. 2014\n\nRodriguez-Crespo D; Di Lauro S; Singh AK; Garcia-Gutierrez MT; Garrosa M; Pastor JC; Fernandez-Bueno I; Srivastava GK. Triple-layered mixed co-culture model of RPE cells with neuroretina for evaluating the neuroprotective effects of adipose-MSCs. Cell Tissue Res. 358 - 3, pp. 705 - 716. 2014.\nDOI: 10.1007/s00441-014-1987-5\n\nCarlo De Werra; Salvatore Condurro; Salvatore Tramontano; Mario Perone; Ivana Donzelli; Salvatore Di Lauro; Massimo Di Giuseppe; Rosa Di Micco; Annalisa Pascariello; Antonio Pastore; Giorgio Diamantis; Giuseppe Galloro. Hydatid disease of the liver: thirty years of surgical experience.Chirurgia italiana. 59 - 5, pp. 611 - 636.\n(Italia): 2007. ISSN 0009-4773\n\nChapters in books\n\t\n' Salvador Pastor Idoate; Salvatore Di Lauro; Jose Carlos Pastor Jimeno. PVR: Pathogenesis, Histopathology and Classification. Proliferative Vitreoretinopathy with Small Gauge Vitrectomy. Springer, 2018. ISBN 978-3-319-78445-8\nDOI: 10.1007/978-3-319-78446-5_2. \n\n' Salvatore Di Lauro; Maria Isabel Lopez Galvez. Quistes vítreos en una mujer joven. Problemas diagnósticos en patología retinocoroidea. Sociedad Española de Retina-Vitreo. 2018.\n\n' Salvatore Di Lauro; Salvador Pastor Idoate; Jose Carlos Pastor Jimeno. iOCT in PVR management. OCT Applications in Opthalmology. pp. 1 - 8. INTECH, 2018. DOI: 10.5772/intechopen.78774.\n\n' Rosa Coco Martin; Salvatore Di Lauro; Salvador Pastor Idoate; Jose Carlos Pastor. amponadores, manipuladores y tinciones en la cirugía del traumatismo ocular.Trauma Ocular. Ponencia de la SEO 2018..\n\n' LOPEZ GALVEZ; DI LAURO; CRESPO. OCT angiografia y complicaciones retinianas de la diabetes. PONENCIA SEO 2021, CAPITULO 20. (España): 2021.\n\n' Múltiples desprendimientos neurosensoriales bilaterales en paciente joven. Enfermedades Degenerativas De Retina Y Coroides. SERV 04/2016. \n' González-Buendía L; Di Lauro S; Pastor-Idoate S; Pastor Jimeno JC. Vitreorretinopatía proliferante (VRP) e inflamación: LA INFLAMACIÓN in «INMUNOMODULADORES Y ANTIINFLAMATORIOS: MÁS ALLÁ DE LOS CORTICOIDES. 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