Hypothyroidism causes.
\\n\\n
IntechOpen was founded by scientists, for scientists, in order to make book publishing accessible around the globe. Over the last two decades, this has driven Open Access (OA) book publishing whilst levelling the playing field for global academics. Through our innovative publishing model and the support of the research community, we have now published over 5,700 Open Access books and are visited online by over three million academics every month. These researchers are increasingly working in broad technology-based subjects, driving multidisciplinary academic endeavours into human health, environment, and technology.
\\n\\nBy listening to our community, and in order to serve these rapidly growing areas which lie at the core of IntechOpen's expertise, we are launching a portfolio of Open Science journals:
\\n\\nAll three journals will publish under an Open Access model and embrace Open Science policies to help support the changing needs of academics in these fast-moving research areas. There will be direct links to preprint servers and data repositories, allowing full reproducibility and rapid dissemination of published papers to help accelerate the pace of research. Each journal has renowned Editors in Chief who will work alongside a global Editorial Board, delivering robust single-blind peer review. Supported by our internal editorial teams, this will ensure our authors will receive a quick, user-friendly, and personalised publishing experience.
\\n\\n"By launching our journals portfolio we are introducing new, dedicated homes for interdisciplinary technology-focused researchers to publish their work, whilst embracing Open Science and creating a unique global home for academics to disseminate their work. We are taking a leap toward Open Science continuing and expanding our fundamental commitment to openly sharing scientific research across the world, making it available for the benefit of all." Dr. Sara Uhac, IntechOpen CEO
\\n\\n"Our aim is to promote and create better science for a better world by increasing access to information and the latest scientific developments to all scientists, innovators, entrepreneurs and students and give them the opportunity to learn, observe and contribute to knowledge creation. Open Science promotes a swifter path from research to innovation to produce new products and services." Alex Lazinica, IntechOpen founder
\\n\\nIn conclusion, Natalia Reinic Babic, Head of Journal Publishing and Open Science at IntechOpen adds:
\\n\\n“On behalf of the journal team I’d like to thank all our Editors in Chief, Editorial Boards, internal supporting teams, and our scientific community for their continuous support in making this portfolio a reality - we couldn’t have done it without you! With your support in place, we are confident these journals will become as impactful and successful as our book publishing program and bring us closer to a more open (science) future.”
\\n\\nWe invite you to visit the journals homepage and learn more about the journal’s Editorial Boards, scope and vision as all three journals are now open for submissions.
\\n\\nFeel free to share this news on social media and help us mark this memorable moment!
\\n\\n\\n"}]',published:!0,mainMedia:{caption:"",originalUrl:"/media/original/237"}},components:[{type:"htmlEditorComponent",content:'
After years of being acknowledged as the world's leading publisher of Open Access books, today, we are proud to announce we’ve successfully launched a portfolio of Open Science journals covering rapidly expanding areas of interdisciplinary research.
\n\n\n\nIntechOpen was founded by scientists, for scientists, in order to make book publishing accessible around the globe. Over the last two decades, this has driven Open Access (OA) book publishing whilst levelling the playing field for global academics. Through our innovative publishing model and the support of the research community, we have now published over 5,700 Open Access books and are visited online by over three million academics every month. These researchers are increasingly working in broad technology-based subjects, driving multidisciplinary academic endeavours into human health, environment, and technology.
\n\nBy listening to our community, and in order to serve these rapidly growing areas which lie at the core of IntechOpen's expertise, we are launching a portfolio of Open Science journals:
\n\nAll three journals will publish under an Open Access model and embrace Open Science policies to help support the changing needs of academics in these fast-moving research areas. There will be direct links to preprint servers and data repositories, allowing full reproducibility and rapid dissemination of published papers to help accelerate the pace of research. Each journal has renowned Editors in Chief who will work alongside a global Editorial Board, delivering robust single-blind peer review. Supported by our internal editorial teams, this will ensure our authors will receive a quick, user-friendly, and personalised publishing experience.
\n\n"By launching our journals portfolio we are introducing new, dedicated homes for interdisciplinary technology-focused researchers to publish their work, whilst embracing Open Science and creating a unique global home for academics to disseminate their work. We are taking a leap toward Open Science continuing and expanding our fundamental commitment to openly sharing scientific research across the world, making it available for the benefit of all." Dr. Sara Uhac, IntechOpen CEO
\n\n"Our aim is to promote and create better science for a better world by increasing access to information and the latest scientific developments to all scientists, innovators, entrepreneurs and students and give them the opportunity to learn, observe and contribute to knowledge creation. Open Science promotes a swifter path from research to innovation to produce new products and services." Alex Lazinica, IntechOpen founder
\n\nIn conclusion, Natalia Reinic Babic, Head of Journal Publishing and Open Science at IntechOpen adds:
\n\n“On behalf of the journal team I’d like to thank all our Editors in Chief, Editorial Boards, internal supporting teams, and our scientific community for their continuous support in making this portfolio a reality - we couldn’t have done it without you! With your support in place, we are confident these journals will become as impactful and successful as our book publishing program and bring us closer to a more open (science) future.”
\n\nWe invite you to visit the journals homepage and learn more about the journal’s Editorial Boards, scope and vision as all three journals are now open for submissions.
\n\nFeel free to share this news on social media and help us mark this memorable moment!
\n\n\n'}],latestNews:[{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"},{slug:"introducing-intechopen-book-series-a-new-publishing-format-for-oa-books-20210915",title:"Introducing IntechOpen Book Series - A New Publishing Format for OA Books"}]},book:{item:{type:"book",id:"7125",leadTitle:null,fullTitle:"Iron Deficiency Anemia",title:"Iron Deficiency Anemia",subtitle:null,reviewType:"peer-reviewed",abstract:"Iron deficiency (ID) and iron deficiency anemia (IDA) are prevalent conditions all over the world. The groups at highest risk are children, pre-menopausal women and socially disadvantaged people. Diagnose of ID using a full blood examination and iron studies can be difficulted by concomitant inflammation. Management of ID involves identification and treatment of its cause, as well as effective iron replacement. Patients who fail to respond to iron replacement will performed an endoscopy to exclude internal bleeding. Both enteral and parenteral iron are effective at replacing iron. For adult patients, we recommend trialling daily oral iron (30-100 mg of iron) as the first-line therapy. Patients who fail to respond to oral iron replacement can be safely managed with intravenous iron.",isbn:"978-1-78985-444-2",printIsbn:"978-1-78985-443-5",pdfIsbn:"978-1-83880-642-2",doi:"10.5772/intechopen.73922",price:119,priceEur:129,priceUsd:155,slug:"iron-deficiency-anemia",numberOfPages:124,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"25d82a6ea6c9d80b195bb40aad06be49",bookSignature:"Luis Rodrigo",publishedDate:"May 10th 2019",coverURL:"https://cdn.intechopen.com/books/images_new/7125.jpg",numberOfDownloads:9328,numberOfWosCitations:3,numberOfCrossrefCitations:6,numberOfCrossrefCitationsByBook:0,numberOfDimensionsCitations:14,numberOfDimensionsCitationsByBook:0,hasAltmetrics:1,numberOfTotalCitations:23,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"March 1st 2018",dateEndSecondStepPublish:"April 25th 2018",dateEndThirdStepPublish:"June 24th 2018",dateEndFourthStepPublish:"September 12th 2018",dateEndFifthStepPublish:"November 11th 2018",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"73208",title:"Prof.",name:"Luis",middleName:null,surname:"Rodrigo",slug:"luis-rodrigo",fullName:"Luis Rodrigo",profilePictureURL:"https://mts.intechopen.com/storage/users/73208/images/system/73208.jpg",biography:"Dr. Luis Rodrigo, MD, is a Professor Emeritus of Medicine, at the University of Oviedo, Spain. He has been Chief of Gastroenterology Service at HUCA Hospital, Oviedo, for more than forty years. He obtained a Ph.D. in 1975 and has developed a long teaching and research career. Dr. Rodrigo has published 716 scientific papers, 435 written in English and the rest in Spanish. He has participated as the main investigator in forty-five clinical trials and has directed forty doctoral theses. He has contributed actively to the formation of around 100 specialists in gastroenterology working in his hospital and other hospitals in Spain and abroad. He has written around thirty-five book chapters and edited twenty-six books in his specialty and related diseases.",institutionString:"University of Oviedo",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"5",totalChapterViews:"0",totalEditedBooks:"17",institution:{name:"University of Oviedo",institutionURL:null,country:{name:"Spain"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"183",title:"Hematology",slug:"hematology"}],chapters:[{id:"63604",title:"Iron-Deficiency Anemia",doi:"10.5772/intechopen.80940",slug:"iron-deficiency-anemia",totalDownloads:1913,totalCrossrefCites:2,totalDimensionsCites:3,hasAltmetrics:0,abstract:"Iron is an important element in living systems as it participates in a series of metabolic processes including DNA synthesis and oxygen and electron transport. Iron deficiency is the most common cause of anemia globally being an important healthcare problem. If left untreated, iron-deficiency anemia (IDA) can cause significant morbidity and often is the result of a more serious underlying condition. Correcting iron deficiency and replenishing iron reserves are important objectives of a well-conducted treatment, but diagnosis should prompt further investigation to establish the cause for potential reversal. Age, tolerance, preferred route of administration, and severity of anemia are some of the patient’s characteristics which require an individualized approach.",signatures:"Claudia Burz, Andrei Cismaru, Vlad Pop and Anca Bojan",downloadPdfUrl:"/chapter/pdf-download/63604",previewPdfUrl:"/chapter/pdf-preview/63604",authors:[null],corrections:null},{id:"62708",title:"Iron Deficiency and Iron Deficiency Anemia in Children",doi:"10.5772/intechopen.79790",slug:"iron-deficiency-and-iron-deficiency-anemia-in-children",totalDownloads:2161,totalCrossrefCites:2,totalDimensionsCites:3,hasAltmetrics:1,abstract:"Iron deficiency anemia is considered the most common and widespread nutritional form of anemia in childhood. Red cells are hypochromic and microcytic with low mean corpuscular volume (MCV), low mean corpuscular hemoglobin (MCH) and low reticulocyte hemoglobin content (CHr). Red blood cell distribution width (RDW) is increased. Serum iron is reduced, transferrin is increased and serum ferritin is decreased. Prematurity, decreased dietary source, malabsorption and blood loss represent the most common causes of iron deficiency. Recommended oral dose of elemental iron is 2–6 mg/kg/day; when normal hemoglobin values are reached, treatment must be generally continued for 3 months in order to replenish iron stores. Rarely intravenous therapy is required. The pediatricians and other health care providers should strive to prevent and eliminate iron deficiency and iron-deficiency anemia.",signatures:"Roberto Miniero, Valentina Talarico, Maria Concetta Galati, Laura\nGiancotti, Paola Saracco and Giuseppe Raiola",downloadPdfUrl:"/chapter/pdf-download/62708",previewPdfUrl:"/chapter/pdf-preview/62708",authors:[null],corrections:null},{id:"62047",title:"Effect of Iron Deficiency on the Increased Blood Divalent Metal Concentrations",doi:"10.5772/intechopen.78958",slug:"effect-of-iron-deficiency-on-the-increased-blood-divalent-metal-concentrations",totalDownloads:1039,totalCrossrefCites:1,totalDimensionsCites:4,hasAltmetrics:0,abstract:"The apical divalent metal transporter 1 (DMT1) and the iron exporter ferroportin 1 (FPN1) are responsible for the absorption of iron and other divalent metals (manganese, lead, and cadmium). Thus, an iron-deficient diet can lead to excess absorption of manganese, lead, and cadmium, and high blood concentrations of these metals. Relative to males, females of childbearing age have higher blood concentrations of manganese because of their lower blood concentrations of ferritin. Moreover, relative to premenopausal women, menopausal women have lower blood manganese levels because their higher concentrations of ferritin. There is also a significant increase in the whole blood manganese level throughout pregnancy due to the upregulation of iron absorption at this time. Several previous studies reported a temporal relationship between iron deficiency and increased blood lead concentrations in children. However, this association does not occur in postmenarcheal or postmenopausal women because estrogen promotes bone mineralization and redistributes blood lead into the bone, overshadowing the effect of ferritin on blood lead level. Although blood cadmium concentrations are higher in females of childbearing age because of their lower ferritin concentrations, there is no association of blood cadmium and iron levels in infants and postmenopausal women.",signatures:"Yangho Kim",downloadPdfUrl:"/chapter/pdf-download/62047",previewPdfUrl:"/chapter/pdf-preview/62047",authors:[{id:"26425",title:"Dr.",name:"Yangho",surname:"Kim",slug:"yangho-kim",fullName:"Yangho Kim"}],corrections:null},{id:"62922",title:"Vegetal Sources of Iron",doi:"10.5772/intechopen.79834",slug:"vegetal-sources-of-iron",totalDownloads:1424,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:1,abstract:"Iron deficiency anemia is a global public health problem. According to the World Health Organization, anemia affects 1620 million of people worldwide, which corresponds to 28% of the population. Fifty percent of the anemia cases are attributed to low iron intake. Among the main sources of iron from vegetable origin are legumes, such as beans, lentils, soybeans, lupin, some vegetables such as spinach, and some dehydrated fruits. Non-hemic iron is mainly from legumes and is the most important source of this mineral in the diet of developing countries’ population, but its bioavailability is very variable. Consequently, the fortification of foods with high and cheap iron sources is a practical way to prevent its deficiency. Some studies have shown that the roots of some legumes, especially nitrogen fixers, accumulate a significant amount of iron mainly in the nodule proteins. The purpose of this chapter is to present the current knowledge of novel sources of plant-based hemic iron with a high bioavailability to be used in food fortification.",signatures:"Elia Hermila Valdes-Miramontes, Ramon Rodriguez-Macias and\nMario Ruiz-Lopez",downloadPdfUrl:"/chapter/pdf-download/62922",previewPdfUrl:"/chapter/pdf-preview/62922",authors:[null],corrections:null},{id:"62609",title:"Heart Failure and Iron Deficiency",doi:"10.5772/intechopen.79358",slug:"heart-failure-and-iron-deficiency",totalDownloads:1019,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Heart failure (HF) is a major public health problem because it is one of the most common causes of morbidity and mortality in Western countries, with a prevalence of 1–2% in the adult population, rising to ≥10% in those age >70 years. In addition to the “classic” co-morbidities, such as COPD, arterial hypertension, diabetes, renal failure, etc., there are other conditions frequently found in patients with heart failure that many times are underestimated. One example are anemia and iron deficiency (ID). ID, regardless of anemia impair exercise tolerance, symptoms and quality of life, with a strong negative prognostic impact on hospitalization and mortality rate. Despite strong evidence of high prevalence of ID in these patients and current guidelines recommendations, the diagnosis of ID and its monitoring over time still have low priority for physicians in clinical practice. Consequently ID is under-treated; furthermore current therapies, in particular i.v. iron as ferric carboxymaltose, though effective, turn out to be poorly managed by clinicians. ID should be considered more in real world HF healthcare settings to improve patients’ quality of life and outcome.",signatures:"Francesco Fedele, Alessandra Cinque, Massimo Mancone, Viviana\nMaestrini and Carmen Caira",downloadPdfUrl:"/chapter/pdf-download/62609",previewPdfUrl:"/chapter/pdf-preview/62609",authors:[null],corrections:null},{id:"66374",title:"Neurocognitive Dysfunctions in Iron Deficiency Patients",doi:"10.5772/intechopen.82620",slug:"neurocognitive-dysfunctions-in-iron-deficiency-patients",totalDownloads:1774,totalCrossrefCites:1,totalDimensionsCites:4,hasAltmetrics:1,abstract:"In this chapter, the authors described the actuality of the investigations of neurocognitive dysfunctions in patients with iron deficiency. In infants, the incidence of iron deficiency is 73%; the probability of its transition to iron deficiency anemia is very high. The development of myelin at an early age reduces the production of myelin, and the formation of g-aminobutyric acid worsens the metabolism of dopamine in the striatal brain, which leads to slowing of motor function and behavioral problems in the child. Children with iron deficiency conditions are prone to developmental delays, reduced school performance, and behavioral disorders. In older adults, cognitive dysfunctions depend on complications of the vascular nature, complicated by comorbid iron deficiency. Concomitant pathology also influences iron homeostasis. The regulating mechanisms of iron deficiency, as the same cognitive deficiency, despite the age involve more than 200 proteins from iron homeostasis, appropriate cofactors: derivatives of vitamin B, copper, manganese, zinc ions, enzymes, cell growth factors, etc. All these partners could influence separately or together to the development of iron deficiency and a complication of it neurocognitive dysfunctions. The combination of iron deficiency anemia and iron deficiency with comorbid pathology often exacerbates cognitive problems and requires a weighted approach to the choice of therapeutic correction tactics.",signatures:"Elena Zhukovskaya, Alexander Karelin and Alexander Rumyantsev",downloadPdfUrl:"/chapter/pdf-download/66374",previewPdfUrl:"/chapter/pdf-preview/66374",authors:[null],corrections:null}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},subseries:null,tags:null},relatedBooks:[{type:"book",id:"932",title:"Acute Pancreatitis",subtitle:null,isOpenForSubmission:!1,hash:"b9e4aebaf0e8a2dd617fe38a5d3b2bff",slug:"acute-pancreatitis",bookSignature:"Luis Rodrigo",coverURL:"https://cdn.intechopen.com/books/images_new/932.jpg",editedByType:"Edited by",editors:[{id:"73208",title:"Prof.",name:"Luis",surname:"Rodrigo",slug:"luis-rodrigo",fullName:"Luis 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Ersen Balcioglu",coverURL:"https://cdn.intechopen.com/books/images_new/7615.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"198122",title:"Dr.",name:"Hayri Baytan",middleName:null,surname:"Ozmen",slug:"hayri-baytan-ozmen",fullName:"Hayri Baytan Ozmen"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"313776",title:"Dr.",name:"Chatarina",middleName:null,surname:"Niken",fullName:"Chatarina Niken",slug:"chatarina-niken",email:"chatarinaniken@yahoo.com",position:null,institution:null}]}},chapter:{id:"71109",slug:"the-mechanism-of-misalignment-of-saw-cutting-crack-of-concrete-pavement",signatures:"Chatarina Niken",dateSubmitted:"October 18th 2019",dateReviewed:"January 11th 2020",datePrePublished:"February 14th 2020",datePublished:"September 23rd 2020",book:{id:"7615",title:"Fracture Mechanics Applications",subtitle:null,fullTitle:"Fracture Mechanics Applications",slug:"fracture-mechanics-applications",publishedDate:"September 23rd 2020",bookSignature:"Hayri Baytan Ozmen and H. Ersen Balcioglu",coverURL:"https://cdn.intechopen.com/books/images_new/7615.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"198122",title:"Dr.",name:"Hayri Baytan",middleName:null,surname:"Ozmen",slug:"hayri-baytan-ozmen",fullName:"Hayri Baytan Ozmen"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"313776",title:"Dr.",name:"Chatarina",middleName:null,surname:"Niken",fullName:"Chatarina Niken",slug:"chatarina-niken",email:"chatarinaniken@yahoo.com",position:null,institution:null}]},book:{id:"7615",title:"Fracture Mechanics Applications",subtitle:null,fullTitle:"Fracture Mechanics Applications",slug:"fracture-mechanics-applications",publishedDate:"September 23rd 2020",bookSignature:"Hayri Baytan Ozmen and H. Ersen Balcioglu",coverURL:"https://cdn.intechopen.com/books/images_new/7615.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"198122",title:"Dr.",name:"Hayri Baytan",middleName:null,surname:"Ozmen",slug:"hayri-baytan-ozmen",fullName:"Hayri Baytan Ozmen"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}}},ofsBook:{item:{type:"book",id:"11839",leadTitle:null,title:"Assisted Reproductive Technologies - Current Practices and New Perspectives",subtitle:null,reviewType:"peer-reviewed",abstract:"
\r\n\tThis book is intended for professionals dealing with diagnostics and treatment of infertility and aims to provide comprehensive information on the current state of assisted reproductive technologies and their directions of development.
\r\n\tAssisted Reproductive Technologies (ART) is a key technology for treating infertility, which occurs in 10-15% of the general population in reproductive age. This has been one of the most tumultuously developing interdisciplinary technologies in medicine in recent decades. Thanks to in vitro methods, more than 5 million children were born in the whole world. For 40 years, the success rates of this treatment have increased many times, respectively in the first years from less than 10% to more than 50% in present days (in some groups of patients). The reason for this rapid increase is the introduction of new drugs and stimulation protocols, improvement of embryo culture media, and the use of new types of laboratory equipment that improve the conditions for embryo development. Last but not least, the introduction of modern genetic methods, as well as new gamete and tissue freezing techniques, has improved the methods' diagnostic and therapeutic capabilities.
The thyroid gland is a butterfly-shaped organ formed by a right and left lobe connected at the midline by a thin structure called isthmus. Located in the neck, the thyroid covers the anterior side of the trachea underneath the larynx at the vertebral levels of C5 to T1 (Figure 1A). The average size of a thyroid gland is of 5 cm height and 5 cm wide and it weighs between 20 and 30 grams in adults (Figure 1B), being a little more heavy in women. Is a highly vascular organ, receiving blood supply from two main sources, the superior thyroid artery, branch of the external carotid artery irrigates the superior half of the thyroid in more than 95% of the population, the inferior half is irrigated by the inferior thyroid artery that branches from the thyrocervical trunk which is a branch of the subclavian artery. Furthermore, the thyroid gland has extensive lymphatic drainage that involves multiple levels of lymphatic nodes, including the prelaryngeal, pre and paratracheal, retropharyngeal, retroesophageal and the internal jugular nodes [1].
Thyroid gland: A) butterfly-shaped, located in the anterior side of the trachea underneath the larynx; B) formed by a right and left lobes connected at the midline by a thin structure called isthmus.
The thyroid gland is the first endocrine organ that develops during fetal development [2]. It begins to develop during the fourth week of gestation as an epithelial diverticulum arising from the endoderm of the foregut near the base of the primitive tongue, it progressively extending downward starting from week fifth as the fetus develops [2, 3]. It reaches its final shape and size at the end of the seventh week of gestation [2].
The normal thyroid gland is composed of numerous follicles surrounded by a fibrous capsule that forms septa that divide the parenchyma in multiple lobules. These septa contain nerves and blood vessels that irrigate each lobule. Each lobule contain from 20 to 40 round follicles of 200 μm of diameter on average, these are coated by simple cuboidal epithelium that varies from plane to low according to the current functional activity, when more active the follicle is, taller the follicular epithelium will be. The follicular cells have small, dark and uniform nuclei that are localized at the center of the cell and some of them have an abundant granular and eosinophil cytoplasm, a variant known as Hürthle cells. The follicles contain colloid, a viscous material composed predominantly by the precursor protein of the thyroglobulin (Figure 2). The normal thyroid gland contains up to 3 months of thyroglobulin stored in the colloids. Alternating, the parafollicular cells or the C cells, derived from the neural crest through the ultimobranchial body, are found in a higher concentration in the middle and superior portions of the lobes. These cells synthesize and secrete calcitonin, thus participating on calcium homeostasis [4].
Normal thyroid gland histology.
Described in 1850, hypothyroidism was the first disorder of endocrine deficiency ever reported [5]. Hypothyroidism is the result of low levels of thyroid circulating hormones. Due to the wide variety of clinical presentations and the lack of specific symptoms, the definition of hypothyroidism is mainly biochemical [6]. Therefore, hormonal levels in overt hypothyroidism are: TSH (Thyroid Stimulating Hormone) >4.8 UI/l, FT4 < 13 pmol/l, and in subclinical hypothyroidism are: TSH >4.8 UI/l, FT4: 13–23 pmol/l [7]. Recent research suggests that the superior reference values for serum TSH varies among different age groups [8]. Nevertheless, up to this present day there is no exact definition of a cut point for serum TSH values regarding age in our population [9, 10, 11, 12]. According to the moment of clinical presentation, hypothyroidism is divided in congenital or acquired, according to the level of endocrine dysfunction is divided in primary or secondary or central and according to the severity of hypothyroidism is divided in severe or clinic hypothyroidism or in mild or subclinical hypothyroidism [13].
The prevalence of overt hypothyroidism in the general population varies between 0.3% and 3.7% in the US and between 0.2% and 5.3% in Europe, according to the used definition [6, 10, 11, 12, 13, 14, 15]. The National Health and Nutrition Examination Survey found that the prevalence of overt hypothyroidism between people older than 12 years old in the United States is of 0.3% and of subclinical hypothyroidism is of 4.3% [12]. The difference in iodine status affects the prevalence of hypothyroidism, which occurs in population with a relatively high intake of iodine as well as in populations with deficient intake of iodine. The most common cause of thyroid dysfunction is iodine deficiency and it is estimated that 2 thousand millions of people have an insufficient iodine intake [16]. Hypothyroidism is more common in women and the incidence increases with age (>65 years old) and in Caucasian individuals, although data regarding ethnical difference are scarce [6]. Female gender and older age individuals are related to an increase of TSH and prevalence of anti-thyroid antibodies [12]. Among women in reproductive age (12–49 year old), the prevalence of hypothyroidism is of 3.1%. While women older than 80 years old or more, have 5 times more probabilities to suffer from hypothyroidism, compared to the 12–49 year old women population. Hypothyroidism is more frequent among women born with low height and of low body mass index at childhood. However, in countries with good iodine supply, autoimmune disorders are the most common causes of hypothyroidism [12].
It is estimated that the heritability of serum levels of TSH and of free thyroxin levels is of 65% and of 23–65% respectively [17, 18]. The results of studies of genome association of all the genome, up to this present day have now explained only but a small proportion of the variability in thyroid function and only three studies have focused on hypothyroidism [19]. The loci that are more consistently implicated in hypothyroidism include genes related to autoimmunity and regulating genes specific to thyroid. The majority of these loci are also related to serum concentrations of TSH within the reference rank [19, 20, 21, 22, 23]. Monogenetic disorders that cause congenital hypothyroidism are rare and include TSH resistance (due to an inactivating mutation on the TSH receptor), thyroid digenesis and thyroid dyshormonogenesis.
To understand better hypothyroidism and its consequences it is important to remember the normal physiology of the thyroid gland. The main function of the thyroid follicular cells is the synthesis of thyroid hormones, tetraiodothyronine or (T4; 3,5,3′,5′-L-tetraiodothyronine) and triiodothyronine (T3; 3,5,3′-L-triiodothyronine). Iodine is essential for thyroid hormone synthesis. Food and water are the main sources for iodine intake, with a daily supply that ranges from 50 to 300 μg being absorbed in the small intestine. Both thyroid hormones are synthesized by the iodination and condensation of two tyrosine molecules and differ by an iodine atom. The production and release of thyroid hormones is stimulated by the hypothalamus-pituitary axis. The thyrotropin-releasing hormone (TRH) released from the hypothalamus stimulates the anterior pituitary gland to release thyrotropin, also called TSH (Figure 3) [24]. In response to the stimuli of TSH, the thyroid follicular cells produce thyroglobulin, an inactive protein that is then released from the apical surface into the follicle as a colloid [4]. TSH is released into the bloodstream and it then binds to the thyroid stimulating hormone receptor (TSH-R) in the basolateral surface of the follicular cell of the thyroid gland. The TSH-R is a G-protein coupled receptor and its triggering yields to the activation of the Adenylate Cyclase and of increased levels of intracellular cAMP. An increased cAMP activates the protein kinase A (PKA). PKA phosphorylates different proteins in order to change their functions. The thyroid hormone biosynthesis is made by steps, regulated by enzymes that are stimulated by TSH, these steps are: 1) thyroglobulin synthesis (TG): the thyrocites in the thyroid follicles produce a protein called thyroglobulin. Thyroglobulin does not contain iodine and is a precursor protein storaged in the follicle lumen. Thyroglobulin is produced in the rough endoplasmic reticulum, then the Golgi apparatus packs it up in vesicles and then it enters the follicle lumen by exocytosis. 2) Iodine uptake and transport: the phosphorylation of the kinase A protein increases the activity of the sodium/iodide basolateral symporter protein (Na+/I- symporter), driven by the Na + -K + -ATPase to get iodine out of the bloodstream to the thyrocites. Iodine diffuses from the basolateral surface to the apical surface of the cell, where it transports to the colloid through the pendrin transporter; 3) thyroglobulin iodination: the protein kinase A also phosphorylates and activates the thyroid peroxidase enzyme (TPO). The TPO has three main functions: oxidation, organification and coupling reaction. 4) Oxidation: the TPO uses hydrogen peroxide in order to oxidate iodide (I-) to iodine (I2). NADPH oxidase, an apical enzyme generates hydrogen peroxide for the TPO; 5) Organization: the TPO attaches the remainders of tyrosine from the thyroglobulin with the I2. It generates monoiodityrosine (MIT) and diiodotyrosine (DIT) (Figure 4). MIT has only one remaining tyrosine with iodine and DIT has two remaining tyrosine with iodine; 6) mono and diiodotyrosine attachment; the TPO combines the remainers of iodated tyrosine to produce T3 and T4 [4]. MIT and DIT combine to form T3 and two DIT molecules form T4; 5) Storing: thyroid hormones are attached to TG and are storage in the follicular lumen; and 6) secretion: the iodized thyroglobulin returns to the follicular cell, where the degradation of lysosomic proteases releases T3 and T4 in the fenestrated capillaries. Thyroid hormones travel through the bloodstream united to a binding protein called thyroxin [24]. The thyroxine-binding globuline (TBG), transthyretin (TTR) and albumin are proteins capable to bind to the thyroid hormone, thus becoming able to transport it through the bloodstream to their target sites [25].
Normal thyroid physiology.
Thyroid hormone formation.
Thyroid hormones are important for a variety of functions in the body, including development, growth and increase the basal metabolic rate (BMR) affecting circulation, corporal temperature, gluconeogenesis, lipolysis, proteolysis and glucose absorption [26]. It also increases systolic volume and heart rate, which increases cardiac output. In young populations it boosts growth and leads to bony maturation and the fusion of bone growth plates. It is essential for the maturity of the central nervous system (CNS) during fetal development [24]. All of these biochemical events that make the thyroid gland produce hormones is regulated by a negative feedback system in which high levels of thyroid hormones, especially T3, inhibit the release of TSH from the anterior pituitary gland [24]. The counterforces of TRH and T3 allow our body to keep thyroid hormones levels relatively stable in healthy individuals [24]. Although, when alterations occur within this delicate system, severe and even fatal conditions can happen [27]. The most common cause of hypothyroidism is the incapacity of the thyroid gland to produce enough thyroid hormones, nevertheless, with less frequency the hypothalamus and the pituitary can also cause thyroid dysfunction. The half-life of a T4 molecule ranges from 6 to 12 days, in regards to T3 its half-life is of 24 hours, therefore, T4 is significantly more abundant (approximately 100–125 nmol/day) and T3 is found in less quantity, nevertheless T3 is two to tenfold more bioactive [4, 24], to counteract this difference target tissues contain 5′-iodinase, which converts T4 into T3 peripherally through deiodination 5′ [4]. The levels of T3 and T4, mostly T3, establish a negative feedback on the production of TRH and TSH. Alterations on the structure and function of any of these organs or axis can result in hypothyroidism. A decline in the production of T4 results in an increased secretion of TSH by the pituitary, which in turn causes hypertrophy and hyperplasia of the thyroid parenchyma, thus leading to an increase in the production of T3 [4].
Hypothyroidism has numerous etiologies, some of them are originated on the thyroid itself and some others are of extrathyroid origin, with variable manifestations. Table 1 resumes the principal causes of hypothyroidism. Hypothyroidism can be classified on primary hypothyroidism, secondary (central), tertiary and peripheral. Primary hypothyroidism occurs when the thyroid gland is unable to produce adequate amounts of thyroid hormones. Secondary hypothyroidism occurs when the function of the thyroid gland is normal and the pathology is on the pituitary gland due to a deficiency of TSH. In tertiary hypothyroidism, the pathology is found in the hypothalamus, due to a deficiency of TRH. Central hypothyroidism (secondary and tertiary) and peripheral hypothyroidism are less frequent and represent less than 1% of all cases [28].
1. Primary hypothyroidism | 2. Secondary hypothyroidism | 3. Tertiary hypothyroidism | 4. Euthyroid disease syndrome |
---|---|---|---|
a. Biosynthetic defects: | a. Pituitary destruction | a. Hypothalamic destruction | |
Innate errors of metabolism | |||
b. Development abnormalities | i. Neoplasms | i. Neoplasms | |
c. Thyroid destruction | ii. Infarct | ii. Granuloma | |
ii. Radiation | b. Isolated deficiency of TSH | ||
iii. Autoimmune thyroiditis | |||
d. Thyroid tissue replacement | |||
i. Neoplasms | |||
ii. Fibrosis | |||
e. Drug interference in the production and/or secretion of hormones |
Hypothyroidism causes.
Thyroid autoimmune disease is the principal cause of primary hypothyroidism in the United States and in the geographical regions with enough iodine intake [10]. Hashimoto’s thyroiditis (HT) is the most frequent etiology in the United States and has a strong association with the development of malignant neoplasms like papillary thyroid carcinoma (PTC) and lymphoma [29].
There are other causes of hypothyroidism induced by drugs, like amiodarone, thalidomide, tyrosine kinase inhibitors (sunitinib, imatinib), staduvine, interpheron, rifampicin, ethionamide, phenobarbital, phenytoin, carbamazepine, interleukin-2 and lithium. Therapy with radioactive iodine, thyroid surgery and radiotherapy to the head and neck area may be causes of hypothyroidism. Contrary to the previous, smoking and moderate alcohol consumption are related to a reduced risk of hypothyroidism [10].
Post-partum thyroiditis affects nearly 10% of women and generally occurs between 8 and 20 weeks after birth. Only few women will require hormonal treatment. However, some women have a higher risk of permanent hypothyroidism or recurrent thyroiditis postpartum in future pregnancies. The use of radioactive iodine in the treatment of Graves-Basedow disease generally results in permanent hypothyroidism in approximately 80–90% of patients between 8 and 20 weeks after treatment [10]. Treatment with radiation on the head and neck area can also induce hypothyroidism. A relatively infrequent cause of primary hypothyroidism is sub-acute granulomatous thyroiditis (Quervain’s disease), it often arises in middle aged women and it tends to be an auto limited disease. Finally, Down syndrome and Turner syndrome patients have a higher risk of hypothyroidism [10].
Secondary and tertiary hypothyroidism, also known as central hypothyroidism, is caused by a defect in the hypothalamus-pituitary axis. Causes include: pituitary tumors, tumors that compress the hypothalamus, Sheehan syndrome, resistance to TRH, TSH deficiency, lymphocytic hypophysitis, cerebral radiotherapy, drugs like dopamine, prednisone or opioids [10]. A new class of drugs against cancer, like the anti-CTLA-4 (ipilimumab) and anti-PD-L1/PD1 therapies (pembrolizumab and nivolumab) have been associated with primary or secondary hypothyroidism [30, 31]. In previous years, the use of immune check point inhibitors (ICPi) has improved the treatment and prognosis of different types of cancer. The ICPi are monoclonal antibodies associated with adverse effects pertaining the immune system. Thyroid dysfunction (thyrotoxicosis or hypothyroidism) are among the most common adverse consequences. These monoclonal antibodies inhibit immune checkpoints that are present in the surface of the T cells to assure immune auto-tolerance, which results in an increased T cell capacity to attack cancerous cells. The pathogenesis of the thyroid disorders associated to the use of ICPi is not fully understood. Data from observational studies suggest that thyroid dysfunction induced by ICPi is due to a destructive thyroiditis that can evolve to hypothyroidism. On the other hand, it is proposed that thyroid manifestations in patients with immunotherapy may represent an autoimmune phenomenon. Nevertheless, little is known about thyroid antibodies status during the course of the disease [30, 31].
Consumptive hypothyroidism is caused by an aberrant expression of the enzyme type 3 iodothyronine deiodinase (D3), which inactive thyroid hormones in tumoral tissues. Even when rare, this overexpression can induce severe hypothyroidism. High concentrations of D3 was first described in a newborn with infantile hepatic hemangioma [32], but it can also occur in patients with vascular tumors and tumors of the gastrointestinal stroma [33].
Classic signs and symptoms of hypothyroidism are bradycardia, weight gain even when reducing food intake, cold intolerance, dry skin, sweat decrease, constipation, alopecia, hyporeflexia, slow talking and lethargy. Nonetheless, is important to keep high suspicion of hypothyroidism because signs and symptoms can be mild and non-specific. Chronic hypothyroidism also increases total cholesterol and low density lipoprotein and decreases high density lipoproteins, which increases the risk of cardiovascular mortality. Depression is also a common symptom of hypothyroidism and, therefore, it can be found in the medical history of patients that committed suicide [10].
A decrease in thyroid function is observed in subclinical hypothyroidism, defined by high levels of TSH and normal levels of free thyroid hormones [34]. Primary hypothyroidism is the most prevalent thyroid dysfunction in elderly population and subclinical hypothyroidism is found nearly in 20% of elderly people [10, 11]. Subclinical thyroid disease during pregnancy can be related to adverse results, including a lower than normal intellectual quotient in the offspring of the pregnant women. It is unknown if the treatment with levothyroxine in women identified with subclinical hypothyroidism or hypothyroxinemia during pregnancy improves cognitive function in their offspring [35].
Thyroid hormones are extremely important for the correct development of the central nervous system in the fetus. To ensure an adequate availability of thyroid hormones, human chorionic gonadotropin-β (hCG-β) coming from the placenta directly stimulates the maternal thyroid, which increases the production of T3 and T4 during the first trimester. After the first trimester the fetal thyroid converts in the principal source of hormonal thyroid. The placenta also expresses type 3 iodothyronine deiodinase, an enzyme that breaks down T4 into an inverse inactive T3 (rT3), as a protection against excessively high levels of thyroid hormones, however, regardless of this protection, abundant thyroid hormones cross to the fetus [36, 37].
Decreased levels of fetal thyroid hormones during the crucial period of neurologic development drives to severe mental retard, also called cretinism. Therefore, congenital hypothyroidism (CHT) is a pediatric condition that has to be treated with urgency. Other clinical features include musculoskeletal abnormalities, macroglossia and coarse facial features. This condition is irreversible if is not diagnosed early. Even when is not associated to mortality, CHT can be found on fetal and pediatric autopsy for other reasons and must be considered as a differential diagnosis with mental retardation. However, the natural history of CHT has drastically changed in previous years due to newborn screening (NS) programs that consist in detecting this disease in all apparently healthy newborns [36, 37]. In Mexico, the program of NS formally began in 1988 with the emission of the “technical norm 321.4” and in the present its realization is a mandatory action for all health centers that provide child and maternal care, according to the Norma Oficial Mexicana 007-SSA2–1993.5. (Mexican Official Norm 007-SSA2–1993.5) [11, 38].
The main causes that produce CHT are: a) aberrant or incomplete migration of the thyroid bud, which causes the formation of an ectopic gland without lateral lobes, this is also known as a thyroid nodule; b) deficient growth or differentiation that brings about thyroid agenesis or atyriosis, and c) defects on the biosynthesis of thyroid hormones or dyshormonogenesis with or without goiter. The first two entities are grouped under the name of thyroid dysgenesis, which are sporadic and have predominance for the female gender [36, 37, 38]. Female predominance is a characteristic particularly interesting in the epidemiology of CHT; although, it is not known if women are more susceptible to develop CHT or if female fetuses with CHT have higher uterine survival compared to masculine fetuses [36]. The molecular mechanisms implicated on thyroid cellular differentiation are not exactly known, yet, some mutations have been described in genes involved in thyroid growth and development, like TTF1, TTF2, PAX8 and TSHR among others [39, 40].
Endocrine disorders can be difficult to diagnose based only on morphological features because endocrine manifestations are caused primarily by a hormonal imbalance. Nonetheless, anatomical findings, like organomegaly or nodules may suggest anomalies that should encourage further investigation through laboratory tests or microscopic evaluation. Thyroid gland disorders have a wide variety of clinical presentations and can affect many organs and systems.
Autoimmune chronic thyroiditis affects from 3 to 5 more times women than men, generally at a median age or older, as well as in children. HT is the most common autoimmune disease of the thyroid and is the main cause of autoimmune hypothyroidism. This disease was first described by Hakaru Hashimoto in 1912 as a “lymphomatous stroma” [40]. The global occurrence of HT is estimated to be between 0.3 and 1.5 cases for each 1000 individuals per year; predominantly in the female gender; it has a male-female ratio of 5:20 between the 30 and 50 year old population [41, 42]. There are two different clinical variants: the diffuse form and the nodular form. The nodular form is composed by a heterogeneous thyroid parenchyma that presents fibrosis, sclerosis and calcifications and is mainly associated to neoplasms, particularly PTC (Figure 5A). It is characterized by a lymphoid infiltrate capable to destroy the gland (Figure 5B and C), inducing fibrosis and hypothyroidism as a consequence [29]. Chronic inflammation of the thyroid parenchyma is regulated by an infiltrate of predominantly T lymphocytes [13]. The role of autoimmunity is backed by histological findings of diffuse lymphocytic thyroid infiltration and by specific circulating antibodies in almost all patients. Increased levels of anti-TPO antibodies are found in 95% of cases and anti-thyroglobulin antibodies are found in 60% of cases, these being higher in the atrophic form than in the goiter form of the disease [13]. Treatment is almost always non-surgical, surgery is indicated in cases of glandular enlargement with compressive symptoms, non-satisfactory pharmacological treatment and suspicion of neoplasm degeneration in one or more nodules. The association between HT and PTC, first described by Dailey et al. in 1955 [42, 43], is a controversial matter (Figure 5D and E).
Thyroid gland: A) product of a hemythyroidectomy with Hashimoto’s thyroiditis associated to the presence of a solitary nodule; B) reactive lymphoid infiltrate with lymphoid folliculae with a germinal centers in the thyroid parenchyma (asterisk); C) Hürthle cells (asterisk); D) papillary thyroid carcinoma; E) neoplastic cells with nucleomegaly, open cromatine and nuclear clefts; F) biopsy with fine needle aspiration shows groups of cells with oxyphilic changes (Hürthle cells) and reactive lymphocytes compatible with Hashimoto’s thyroiditis.
Even when there are no established guidelines for thyroid disease detection, the American Thyroid Association recommends to start detection at 35 years old and to continue screening each 5 years. Population with high risk of hypothyroidism include: women older than 60 years old, pregnant women, people with a history of head and neck radiation, patients with autoimmune disease, diabetes type 1, positive antibodies against thyroid peroxidase, and people with family history of hypothyroidism [44]. Table 2 resumes the guidelines for hypothyroidism screening.
Patients with 4 or more of the following symptoms | Patients with a history of | Pregnant patients with a history of |
---|---|---|
Fatigue | Sudden and unexplained thyroid growth | Family history of thyroid disease |
Sleepiness | Dementia | Thyroid disease during pregnancy |
Cold intolerance | Psychiatric diseases | Type 1 diabetes or autoinmune disease |
Goiter | Genetic syndromes | |
Dry skin | Neck radiation | Complicated pregnancy |
Weight gain | Use of drugs that affect | Recurrent miscarriage |
Constipation | thyroid function | Menstrual irregularities |
Dermatologic disease | Presence of anti-thyroid | |
Hyperlipidemia | peroxidase antibodies | |
Cardiovascular diseases | ||
Autoimmune disease | ||
Hypercholesterolemia | ||
Infertility or menstrual | ||
irregularities |
Guidelines for plasma TSH measurement and referral to a specialist in cases of hypothyroidism.
The drug of choice in the treatment of hypothyroidism is the replacement of the thyroid hormones [6, 35, 45].
Hypothyroidism may have a higher risk of morbidity and mortality. It can eventually lead to coma or even death. In children, the lack of treatment can provoke severe mental retardation. One of the main causes of death in adults is cardiac failure. With treatment, the majority of patients have a good prognosis and symptoms normally revert within a few weeks or months [46].
Even when is not common, in terminal stages, hypothyroidism, also known as myxedematous coma, is a medical emergency. First described by Sir William Gull in 1873, myxedematous coma has an estimated incidence of 0.22 per million per year [46]. It affects more frequently women older than 60 years old with a large history of hypothyroidism and it tends to occur during cold weather settings. Other triggering factors include infection, cerebrovascular attack, myocardial infarction, traumatism, pregnancy and the use of drugs containing lithium and amiodarone [46].
This affection is associated with a progressive deceleration of physical and mental skills as the disease advances. Initially, symptoms can simulate depression or early dementia, with fatigue, apathy, forgetfulness as the predominant complaints. If not treated, patients can develop severe hypothermia, urinary retention, respiratory depression, bradycardia, hypotension and arrhythmias that include cardiac blocks and torsade de pointes. Torsade de pointes is a non-frequent ventricular tachycardia that is found in a large QT syndrome, caused by an enlargement of the repolarization phase of the action potential. It exists a diffuse deposit of mucopolysaccharides that eventually leads to airway obstruction by affecting tongue and larynx, cardiac tamponade as a result of pericardial effusion and edema without skin and subcutaneous foveae. Electrolyte abnormalities are also produced, specifically hyponatremia and coagulopathies, including the acquired von Willebrand disease, which is associated with an increased mortality [11]. Altered mental state worsens from lethargy to stupor to coma, which increases the risk of aspiration pneumonia, urinary tract infection and sepsis. Mortality in patients with myxedematous coma is estimated to be around 20–25%, which represents a significant improvement respect previous reports of 60–70% due to a better acknowledge and treatment of this disease. Survival rates are worse in elderly patients and in those with severe and or persistent hypothermia, bradycardia, hypotension, lower coma Glasgow score and multiorganic disease. The most common immediate causes of death are sepsis, gastrointestinal hemorrhage secondary to coagulopathy and respiratory insufficiency [10].
Even when advances have been made regarding cause detection, knowledge of clinical implications, diagnosis and treatment of hypothyroidism, there are still many questions left without answers regarding diagnosis and treatment. Several risk factors have been identified for abnormal TSH concentrations, concentrations of free thyroxin and thyroid disease, but only a small proportion of these variability is explained. At the moment hypothyroidism diagnosis is based on reference ranks for TSH and free thyroxin. Due to the arbitrary nature of cut points that define mild and overt hypothyroidism, an alternative classification system has been proposed based on thyroid function tests.
Cancer is a complex, severe class of diseases that involves a group of cells that exhibit abnormal and uncontrolled division and proliferation. It is one of the primary health concerns which accounts for the second major cause of death globally. As per the recent statistics of the world health organization (WHO), in 2020, around 10 million people succumbed to death due to cancer. However, every year the number of incidences is increasing day by day. According to WHO, around 0.3 million new cases are diagnosed each year among the age group of 0–19 years. Cancer can affect a person of any age; however, with age, the risk increases. Globally, steady increases in cancer cases every year are taking a toll on the health care system [1, 2, 3, 4, 5]. To combat cancer, identification of potential drugs and potential drugs combination is essential. Potential research has been carried out to counter such problems by addressing novel drug design and discovery approaches. In medicinal chemistry, heterocyclic rings have played a significant role in the search for potential therapeutic agents. Various drugs are currently in use and in development that widely addresses such problems. However, due to changes in cancer forms and mutations, current therapy faces challenges of poor selectivity and specificity towards certain types of cancer cells, which narrows down their effectiveness. Generally, cancer cells act by disrupting and disturbing the cell signaling pathways; therefore, it is crucial to design novel target-based heterocyclic anticancer compounds with high efficacy and fewer side effects, which will provide a solid backup to the present chemotherapeutic regime [6, 7, 8, 9, 10].
Benzimidazole is a bicyclic nitrogen bearing aromatic heterocyclic ring, structurally it consists of benzene ring fused with imidazole ring at the 4th and 5th position of the ring. Chemically it appears as white crystals, amphoteric in nature, resembles the structure of purine. It is synthesized by different reported methods. However, condensation of 1,2-diamino benzene with carbonyl compounds to give benzimidazole is the conventional method which was used widely for its preparation. In 1858, it was synthesized by Heinrich Debus, a German chemist from glyoxal, ammonia and formaldehyde, that’s why it was also known as glyoxalin. Benzimidazole ring is one of bioactive heterocyclic scaffold exhibiting wide range of biological activities. The ▬NH group present at second position of the ring is both highly acidic and weak base in nature, it also has ability to form stable salts [11, 12, 13, 14, 15, 16].
With time benzimidazole ring emerged as an important multifaceted heterocyclic system due to its wide range of pharmacological activity such as antibacterial [17], antiparasitic [18], antifungal [19], anti-inflammatory [20], analgesics [21], antiviral [22], antitubercular [23], anticoagulant [24], antihistaminic [25], antioxidant [26], antiulcer [27] and anticancer [28, 29, 30, 31]. Some of the benzimidazole based marketed drugs are listed in with their indication and marketed name in Figure 1. Adding to this benzimidazole scaffold have also displayed a significant role in synthesis of organic intermediates. In light of the application of benzimidazole earlier various authors have reported many review articles. Due to the diverse therapeutic potential, benzimidazole have attracted lot of researchers to explore more in the field of drug discovery to synthesize novel and potent compounds with a broad spectrum of biological activities. Owing to this, with time efforts have been made to create libraries of these potent compounds. In cancer treatment benzimidazole based drugs played a significant role, various targeted therapies are designed and developed as Kinase inhibitors such as EGFR, VEGFR and PI3K inhibitors here, in this chapter we have included some potent benzimidazole based kinase inhibitors.
Examples of benzimidazole based drugs in clinical use.
Benzimidazole based compounds have got much attention due to exhibiting significant cytotoxic activity. In last one decade a lot of benzimidazole based anticancer drugs have received status of US FDA global approval. Recently, Binimetinib, Selumetinib and Abemaciclib got approval for treatment of various mutated forms of cancer. Here, we have discussed some of benzimidazole based anticancer drugs which are recently approved, under development and in pipeline.
Binimetinib (
Benzimidazole based clinically approved anticancer agents.
Drug | Clinical trial number | Clinical trial study | Date of study | Current status and study phase |
---|---|---|---|---|
Binimetinib | NCT04965818 | Phase 1b/2 study of Futibatinib in combination with Binimetinib in patients with advanced KRAS mutant cancer | Last update on September 27, 2021 | Recruiting Phase 1b/2 |
NCT03170206 | Study of CDK4/6 inhibitor Palbociclib in combination with the Binimetinib for patients with advanced KRAS mutant NSCLC | Last update on June 10, 2021 | Recruiting Phase 1 | |
Bendamustine | NCT04217317 | CPI-613 in combination with Bendamustine in patients with relapsed or refractory T-cell Non-Hodgkin lymphoma | Last update on August 30,2021 | Recruiting Phase 2 |
NCT04510636 | Study of Pembrolizumab with Bendamustine in Hodgkin lymphoma | Last update on August 30,2021 | Not yet Recruiting Phase 2 | |
Selumetinib | NCT02768766 | Intermittent Selumetinib for uveal melanoma | Last update on March 19, 2021 | Recruiting Phase 1 |
NCT05101148 | Phase I study to assess the effect of food on the PK and gastrointestinal toxicity of Selumetinib in adolescent children with Neurofibromatosis Type 1 related plexiform neurofibromas | Last update on November 1, 2021 | Recruiting Phase 1 | |
Abemaciclib | NCT04003896 | A study to evaluate Abemaciclib in advanced biliary tract carcinoma who failed prior first line therapy. | Last update on | Active, Not recruiting Phase 2 |
NCT04040205 | Abemaciclib for bone and soft tissue sarcoma with cyclin dependent kinase (CDK) pathway attention | February 15, 2021 | Recruiting Phase 2 | |
Veliparib | NCT02723864 | Veliparib and VX-970 in combination with cisplatin in people with refractory solid tumors | Last update on February 5, 2021 | Active, Not recruiting Phase 1 |
NCT01434316 | Veliparib and Dinaciclib in treating patients with advanced solid tumors | July 20, 2021 | Recruiting Phase 1 | |
Dovitinib | NCT01635907 | Dovitinib in neuroendocrine tumors | Last update on April 14, 2020 | Completed Phase 2 |
Pracinostat | NCT03848754 | Pracinostat and Gemtuzumab ozogamicin in patients with relapsed or refractory acute myeloid leukemia | Last update on October 18, 2021 | Active, not recruiting Phase 1 |
Galeterone | NCT04098081 | Galeterone with Gemcitabine for patients with metastatic pancreatic adenocarcinoma | Last update on March 10, 2021 | Recruiting Phase 2 |
Nazartinib | NCT02335944 | Study and safety and efficacy of Nazartinib in combination with cMET inhibitor INC280 in NSCLC patients with EGFR mutation | Last update on October 4, 2021 | Active, not recruiting Phase 1/2 |
NCT02108964 | A phase I/II, multicentre, open label study of Nazartinib, administered orally in adult patients with EGFR mutated solid malignancies | Last update on August 13, 2021 | Active, Not recruiting Phase 1/2 |
Benzimidazole based anticancer drugs in clinical development.
Bendamustine (
Selumetinib (
Abemaciclib (
Veliparib (
Dovitinib (
Pracinostat (7) is chemically (E)-3-(2-butyl-1-(2-(diethyl amino) ethyl)-1H-benzoimidazol-5-yl)-N-hydroxyacrylamide, it is orally available, investigational drug exhibiting potential antitumor activity [49, 50]. Pracinostat is a small molecule next generation histone diacetylases (HDAC) inhibitor indicated acute myeloid leukemia [51]. In some recent study Pracinostat was found to suppresses growth and metastasis of breast cancer by inactivating the IL-6/STAT3 signaling pathway [52].
Galeterone (
Nazartinib (
Commonly the mechanism behind action of anticancer agents involve DNA intercalation, gene regulation, microtubule inhibition, transcription regulation, DNA synthesis inhibition, enzyme inhibition and so on. Nowadays in cancer treatment, target therapy emerged as one of the acknowledged strategies. Most of the available anticancer drugs acts by targeting structural proteins, tyrosine kinases, phosphoinositide 3 kinase and protein kinases for example Binimetinib acts by inhibiting mitogen activated kinase as discussed in earlier section. In this section we have included some recent examples of benzimidazole based enzyme inhibitors as potent anticancer agents.
Akhter et al. have reported a novel series of benzimidazole based oxadiazole derivatives as potential EGFR inhibitors. The target compound
Srour et al. have reported a novel series of thiazole benzimidazole derivatives as potent inhibitor of EGFR tyrosine kinase. Target compound
Akhter et al. have reported as series of pyrazole benzimidazole derivatives as potential inhibitors of EGFR. Target compound
Examples of benzimidazole derivatives as potent EGFR inhibitors.
Abdullaziz et al. have reported a novel series of 2-furybenzimidazole derivatives as potent inhibitors of VEGFR-2 kinase. Target compound
Lien et al. have reported novel 2-aminobenzimidazole derivative
Recently Yuan et al. have designed and synthesized a new series of benzimidazole derivatives as potent and selective inhibitor of VEGFR-2 kinase. Target compound
Examples of benzimidazole derivatives as potent VEGFR-2 inhibitors.
Meguid et al. have reported a novel series of benzimidazole derivatives as potent dual inhibitors of EGFR and VEGFR-2 kinases. Target compound
Kassab et al. have reported novel quinazoline bearing benzimidazole derivatives as potential inhibitors of EGFR and VEGFR-2 kinases. Target compound 22 displayed excellent inhibitory activity against EGFR kinase with an IC50 value of 127.4 μM, whereas it displayed an IC50 value of 185.7 μM against VEGFR-2 kinase. Further, cytotoxicity study of compound against MCF7 cancer cell line demonstrated good potency with IC50 value of 12.0 μM [66] (Figure 5).
Examples of benzimidazole derivatives as potent EGFR/VEGFR dual inhibitors.
GSK2636771 (
Jin et al. have reported novel benzimidazole derivatives as potent PI3K inhibitor. Target compound 24 was found most potent against PI3Kα with 36% and 86% inhibition compare to reference drug Alpelisib, which showed an inhibition of 110% and 109% at 50 nM and 500 nM respectively. Further, molecular docking analysis of target compound 24 demonstrated strong binding with six strong hydrogen bond with GLN-859, SER-854 and VAL-851 amino acid residues. Further, HUMO-LUMO calculation which is studied by using Gaussian 09 software target compound 24 showed presence of thiazole core and amide bonds which played an important role in its biological activity [69].
Recently a novel series of benzimidazole based dehydroabietic acid derivatives were reported Yang et al. as potent PI3Kα inhibitors. Target compound
Chanrasekhar et al. have reported a novel series of benzimidazole derivatives as potent PI3K inhibitors Target compound
Wu et al. have reported a novel series of triazine substituted benzimidazole derivatives a potent dual inhibitor of PI3K and mTOR, most of the compounds from the series displayed potent inhibitory activity with IC50 below 33 nM. Target compound
Shin et al. have reported a novel series of benzimidazole derivatives a potent inhibitor of PI3Kδ. Target compound
He et al. has reported benzimidazole-isoquinolinone derivatives which inhibits the cell growth via inhibiting PI3K/mTOR/Akt pathway. Target compound
Wu et al. have reported triazine bearing benzimidazole derivatives a potent inhibitor of PI3K and mTOR. Target compound
Examples of benzimidazole derivatives as potent PI3K inhibitors.
Ibrahim et al. have reported a novel series of flavopiridol-benzimidazole as potent inhibitor potent inhibitor of CDK2 and CDK9 kinase. Target compound
Examples of benzimidazole derivative as potent CDK inhibitor.
Pankaj et al. have reported a novel hybrid derivatives of benzimidazole-thiazolidinedione as potent cytotoxic agents. Target compound
Sivaramakarthikeyan et al. have reported novel hybrid derivatives of benzimidazole and pyrazole as potent anticancer agents. Compound 35 and 36 have demonstrated potent anticancer activity against selected human pancreatic cancer cell lines namely SW1990 and AsPC1 with an IC50 value in range of 30.9–61.8 μM respectively. Molecular docking study of both compound showed significant binding with the active site of B-cell lymphoma [78].
Mantu et al. have reported a novel series of benzimidazole-quinoline hybrid derivatives as potent anticancer agent. Target compound 37 exhibited potent antitumor activity against renal cancer cell line A498 and breast cancer cell line MDA-MB-468 with percentage growth inhibition of 52.92% and 56.54% respectively. Compound 37 also exhibited potent antitumor activity against leukemia cell line RPMI-8226 and non-small cell lung cancer cell line NCI-H23 with total growth inhibition of 35% [79].
Sharma et al. have reported benzimidazole-thiazolidinedione hybrid derivatives as potent anticancer agents. Target compound 38 and 39 displayed potent anticancer activity against cancer cell line with an IC50 value of in range of 0.13-10.24 μM against prostate cancer cell line PC-3, breast cancer (MDAMB-231), cervical cancer (HeLa), lung cancer (A549), and bone cancer (HT1080) cell lines. Both hybrid derivative 38 and 39 demonstrated significant inhibition of A549 cells migration through disruption of F-actin assembly, further treatment with 38 and 39 also showed increase in level of ROS in A549 cells by collapsing the mitochondrial membrane potential [80].
Bistrovic et al. have reported novel hybrid derivatives of benzimidazole-1,2,3-triazole as potent anticancer agents. Target compound 40 and 41 demonstrated excellent inhibitory activity with IC50 value of 0.05 and 6.18 against A549 cancer cell line and an IC50 value of 17.53 and 8.80 against HeLa cancer cell line respectively. Furthermore, apoptosis detection study by annexin assay of compound
Examples of benzimidazole containing hybrid derivatives as potent anticancer agents.
Many benzimidazole-containing compounds as anticancer agents are studied and available, involving various mechanisms in inhibiting mutated cancerous cells, in which kinases inhibitors play a significant role. However, in targeted therapy, benzimidazole-based derivatives are still widely explored. Due to the challenge of target specificity and poor selectivity, very few compounds have been approved to treat mutated cancers. The search for a novel benzimidazole-based next generation kinase inhibitor is going to subside such challenges. Benzimidazole-based target therapies such as enzyme inhibitors have gained a lot of attraction; owing to this, recently US FDA has approved EGFR inhibitor Abemaciclib and MEK inhibitor Binimetinib and Selumetinib as potent anticancer compounds against mutated forms of cancer. Apart from this, many benzimidazole-containing compounds are in the developmental phase as EGFR, VEGFR-2, CDK and PI3K inhibitors. However, some of the compounds demonstrated excellent kinase inhibitory activity but failed to provide a strong safety profile; these compounds will pave a path as lead compounds; further modifications, designing, and developing such compounds will give potent compounds with maximum efficiency and minimal side effects. The presented chapter mainly focuses on benzimidazole-based kinase inhibitors and their advances; the pivotal information catered here can be regarded as noteworthy and crucial by medicinal chemists for drug design, discovery and development of novel, potent and safe, target-based anticancer agents.
Authors wishes to acknowledge Jamia Hamdard (deemed-to-be-University) for providing support for conducting this study.
Authors declare “no conflict of interest.”
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He also obtained an MSc in Molecular and Genetic Medicine, and a Ph.D. in Clinical Immunology and Human Genetics from the University of Sheffield, UK. He also completed a short-term fellowship in Pediatric Clinical Immunology and Bone Marrow Transplantation at Newcastle General Hospital, England. Dr. Rezaei is a Full Professor of Immunology and Vice Dean of International Affairs and Research, at the School of Medicine, Tehran University of Medical Sciences, and the co-founder and head of the Research Center for Immunodeficiencies. He is also the founding president of the Universal Scientific Education and Research Network (USERN). Dr. Rezaei has directed more than 100 research projects and has designed and participated in several international collaborative projects. He is an editor, editorial assistant, or editorial board member of more than forty international journals. He has edited more than 50 international books, presented more than 500 lectures/posters in congresses/meetings, and published more than 1,100 scientific papers in international journals.",institutionString:"Tehran University of Medical Sciences",institution:{name:"Tehran University of Medical Sciences",country:{name:"Iran"}}},{id:"180733",title:"Dr.",name:"Jean",middleName:null,surname:"Engohang-Ndong",slug:"jean-engohang-ndong",fullName:"Jean Engohang-Ndong",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/180733/images/system/180733.png",biography:"Dr. Jean Engohang-Ndong was born and raised in Gabon. After obtaining his Associate Degree of Science at the University of Science and Technology of Masuku, Gabon, he continued his education in France where he obtained his BS, MS, and Ph.D. in Medical Microbiology. He worked as a post-doctoral fellow at the Public Health Research Institute (PHRI), Newark, NJ for four years before accepting a three-year faculty position at Brigham Young University-Hawaii. Dr. Engohang-Ndong is a tenured faculty member with the academic rank of Full Professor at Kent State University, Ohio, where he teaches a wide range of biological science courses and pursues his research in medical and environmental microbiology. Recently, he expanded his research interest to epidemiology and biostatistics of chronic diseases in Gabon.",institutionString:"Kent State University",institution:{name:"Kent State University",country:{name:"United States of America"}}},{id:"188773",title:"Prof.",name:"Emmanuel",middleName:null,surname:"Drouet",slug:"emmanuel-drouet",fullName:"Emmanuel Drouet",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/188773/images/system/188773.png",biography:"Emmanuel Drouet, PharmD, is a Professor of Virology at the Faculty of Pharmacy, the University Grenoble-Alpes, France. As a head scientist at the Institute of Structural Biology in Grenoble, Dr. Drouet’s research investigates persisting viruses in humans (RNA and DNA viruses) and the balance with our host immune system. He focuses on these viruses’ effects on humans (both their impact on pathology and their symbiotic relationships in humans). He has an excellent track record in the herpesvirus field, and his group is engaged in clinical research in the field of Epstein-Barr virus diseases. He is the editor of the online Encyclopedia of Environment and he coordinates the Universal Health Coverage education program for the BioHealth Computing Schools of the European Institute of Science.",institutionString:null,institution:{name:"Grenoble Alpes University",country:{name:"France"}}},{id:"131400",title:"Prof.",name:"Alfonso J.",middleName:null,surname:"Rodriguez-Morales",slug:"alfonso-j.-rodriguez-morales",fullName:"Alfonso J. Rodriguez-Morales",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/131400/images/system/131400.png",biography:"Dr. Rodriguez-Morales is an expert in tropical and emerging diseases, particularly zoonotic and vector-borne diseases (especially arboviral diseases). He is the president of the Travel Medicine Committee of the Pan-American Infectious Diseases Association (API), as well as the president of the Colombian Association of Infectious Diseases (ACIN). He is a member of the Committee on Tropical Medicine, Zoonoses, and Travel Medicine of ACIN. He is a vice-president of the Latin American Society for Travel Medicine (SLAMVI) and a Member of the Council of the International Society for Infectious Diseases (ISID). Since 2014, he has been recognized as a Senior Researcher, at the Ministry of Science of Colombia. He is a professor at the Faculty of Medicine of the Fundacion Universitaria Autonoma de las Americas, in Pereira, Risaralda, Colombia. He is an External Professor, Master in Research on Tropical Medicine and International Health, Universitat de Barcelona, Spain. He is also a professor at the Master in Clinical Epidemiology and Biostatistics, Universidad Científica del Sur, Lima, Peru. In 2021 he has been awarded the “Raul Isturiz Award” Medal of the API. Also, in 2021, he was awarded with the “Jose Felix Patiño” Asclepius Staff Medal of the Colombian Medical College, due to his scientific contributions to COVID-19 during the pandemic. He is currently the Editor in Chief of the journal Travel Medicine and Infectious Diseases. His Scopus H index is 47 (Google Scholar H index, 68).",institutionString:"Institución Universitaria Visión de las Américas, Colombia",institution:null},{id:"332819",title:"Dr.",name:"Chukwudi Michael",middleName:"Michael",surname:"Egbuche",slug:"chukwudi-michael-egbuche",fullName:"Chukwudi Michael Egbuche",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/332819/images/14624_n.jpg",biography:"I an Dr. Chukwudi Michael Egbuche. I am a Senior Lecturer in the Department of Parasitology and Entomology, Nnamdi Azikiwe University, Awka.",institutionString:null,institution:{name:"Nnamdi Azikiwe University",country:{name:"Nigeria"}}},{id:"284232",title:"Mr.",name:"Nikunj",middleName:"U",surname:"Tandel",slug:"nikunj-tandel",fullName:"Nikunj Tandel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/284232/images/8275_n.jpg",biography:'Mr. Nikunj Tandel has completed his Master\'s degree in Biotechnology from VIT University, India in the year of 2012. He is having 8 years of research experience especially in the field of malaria epidemiology, immunology, and nanoparticle-based drug delivery system against the infectious diseases, autoimmune disorders and cancer. He has worked for the NIH funded-International Center of Excellence in Malaria Research project "Center for the study of complex malaria in India (CSCMi)" in collaboration with New York University. The preliminary objectives of the study are to understand and develop the evidence-based tools and interventions for the control and prevention of malaria in different sites of the INDIA. Alongside, with the help of next-generation genomics study, the team has studied the antimalarial drug resistance in India. Further, he has extended his research in the development of Humanized mice for the study of liver-stage malaria and identification of molecular marker(s) for the Artemisinin resistance. At present, his research focuses on understanding the role of B cells in the activation of CD8+ T cells in malaria. Received the CSIR-SRF (Senior Research Fellow) award-2018, FIMSA (Federation of Immunological Societies of Asia-Oceania) Travel Bursary award to attend the IUIS-IIS-FIMSA Immunology course-2019',institutionString:"Nirma University",institution:{name:"Nirma University",country:{name:"India"}}},{id:"334383",title:"Ph.D.",name:"Simone",middleName:"Ulrich",surname:"Ulrich Picoli",slug:"simone-ulrich-picoli",fullName:"Simone Ulrich Picoli",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/334383/images/15919_n.jpg",biography:"Graduated in Pharmacy from Universidade Luterana do Brasil (1999), Master in Agricultural and Environmental Microbiology from Federal University of Rio Grande do Sul (2002), Specialization in Clinical Microbiology from Universidade de São Paulo, USP (2007) and PhD in Sciences in Gastroenterology and Hepatology (2012). She is currently an Adjunct Professor at Feevale University in Medicine and Biomedicine courses and a permanent professor of the Academic Master\\'s Degree in Virology. She has experience in the field of Microbiology, with an emphasis on Bacteriology, working mainly on the following topics: bacteriophages, bacterial resistance, clinical microbiology and food microbiology.",institutionString:null,institution:{name:"Universidade Feevale",country:{name:"Brazil"}}},{id:"229220",title:"Dr.",name:"Amjad",middleName:"Islam",surname:"Aqib",slug:"amjad-aqib",fullName:"Amjad Aqib",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/229220/images/system/229220.png",biography:"Dr. Amjad Islam Aqib obtained a DVM and MSc (Hons) from University of Agriculture Faisalabad (UAF), Pakistan, and a PhD from the University of Veterinary and Animal Sciences Lahore, Pakistan. Dr. Aqib joined the Department of Clinical Medicine and Surgery at UAF for one year as an assistant professor where he developed a research laboratory designated for pathogenic bacteria. Since 2018, he has been Assistant Professor/Officer in-charge, Department of Medicine, Manager Research Operations and Development-ORIC, and President One Health Club at Cholistan University of Veterinary and Animal Sciences, Bahawalpur, Pakistan. He has nearly 100 publications to his credit. His research interests include epidemiological patterns and molecular analysis of antimicrobial resistance and modulation and vaccine development against animal pathogens of public health concern.",institutionString:"Cholistan University of Veterinary and Animal Sciences",institution:null},{id:"62900",title:"Prof.",name:"Fethi",middleName:null,surname:"Derbel",slug:"fethi-derbel",fullName:"Fethi Derbel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/62900/images/system/62900.jpeg",biography:"Professor Fethi Derbel was born in 1960 in Tunisia. He received his medical degree from the Sousse Faculty of Medicine at Sousse, University of Sousse, Tunisia. He completed his surgical residency in General Surgery at the University Hospital Farhat Hached of Sousse and was a member of the Unit of Liver Transplantation in the University of Rennes, France. He then worked in the Department of Surgery at the Sahloul University Hospital in Sousse. Professor Derbel is presently working at the Clinique les Oliviers, Sousse, Tunisia. His hospital activities are mostly concerned with laparoscopic, colorectal, pancreatic, hepatobiliary, and gastric surgery. He is also very interested in hernia surgery and performs ventral hernia repairs and inguinal hernia repairs. He has been a member of the GREPA and Tunisian Hernia Society (THS). During his residency, he managed patients suffering from diabetic foot, and he was very interested in this pathology. For this reason, he decided to coordinate a book project dealing with the diabetic foot. Professor Derbel has published many articles in journals and collaborates intensively with IntechOpen Access Publisher as an editor.",institutionString:"Clinique les Oliviers",institution:null},{id:"300144",title:"Dr.",name:"Meriem",middleName:null,surname:"Braiki",slug:"meriem-braiki",fullName:"Meriem Braiki",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/300144/images/system/300144.jpg",biography:"Dr. Meriem Braiki is a specialist in pediatric surgeon from Tunisia. She was born in 1985. She received her medical degree from the University of Medicine at Sousse, Tunisia. She achieved her surgical residency training periods in Pediatric Surgery departments at University Hospitals in Monastir, Tunis and France.\r\nShe is currently working at the Pediatric surgery department, Sidi Bouzid Hospital, Tunisia. Her hospital activities are mostly concerned with laparoscopic, parietal, urological and digestive surgery. She has published several articles in diffrent journals.",institutionString:"Sidi Bouzid Regional Hospital",institution:null},{id:"229481",title:"Dr.",name:"Erika M.",middleName:"Martins",surname:"de Carvalho",slug:"erika-m.-de-carvalho",fullName:"Erika M. de Carvalho",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/229481/images/6397_n.jpg",biography:null,institutionString:null,institution:{name:"Oswaldo Cruz Foundation",country:{name:"Brazil"}}},{id:"186537",title:"Prof.",name:"Tonay",middleName:null,surname:"Inceboz",slug:"tonay-inceboz",fullName:"Tonay Inceboz",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/186537/images/system/186537.jfif",biography:"I was graduated from Ege University of Medical Faculty (Turkey) in 1988 and completed his Med. PhD degree in Medical Parasitology at the same university. I became an Associate Professor in 2008 and Professor in 2014. I am currently working as a Professor at the Department of Medical Parasitology at Dokuz Eylul University, Izmir, Turkey.\n\nI have given many lectures, presentations in different academic meetings. I have more than 60 articles in peer-reviewed journals, 18 book chapters, 1 book editorship.\n\nMy research interests are Echinococcus granulosus, Echinococcus multilocularis (diagnosis, life cycle, in vitro and in vivo cultivation), and Trichomonas vaginalis (diagnosis, PCR, and in vitro cultivation).",institutionString:"Dokuz Eylül University",institution:{name:"Dokuz Eylül University",country:{name:"Turkey"}}},{id:"71812",title:"Prof.",name:"Hanem Fathy",middleName:"Fathy",surname:"Khater",slug:"hanem-fathy-khater",fullName:"Hanem Fathy Khater",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/71812/images/1167_n.jpg",biography:"Prof. Khater is a Professor of Parasitology at Benha University, Egypt. She studied for her doctoral degree, at the Department of Entomology, College of Agriculture, Food and Natural Resources, University of Missouri, Columbia, USA. She has completed her Ph.D. degrees in Parasitology in Egypt, from where she got the award for “the best scientific Ph.D. dissertation”. She worked at the School of Biological Sciences, Bristol, England, the UK in controlling insects of medical and veterinary importance as a grant from Newton Mosharafa, the British Council. Her research is focused on searching of pesticides against mosquitoes, house flies, lice, green bottle fly, camel nasal botfly, soft and hard ticks, mites, and the diamondback moth as well as control of several parasites using safe and natural materials to avoid drug resistances and environmental contamination.",institutionString:null,institution:{name:"Banha University",country:{name:"Egypt"}}},{id:"99780",title:"Prof.",name:"Omolade",middleName:"Olayinka",surname:"Okwa",slug:"omolade-okwa",fullName:"Omolade Okwa",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/99780/images/system/99780.jpg",biography:"Omolade Olayinka Okwa is presently a Professor of Parasitology at Lagos State University, Nigeria. She has a PhD in Parasitology (1997), an MSc in Cellular Parasitology (1992), and a BSc (Hons) Zoology (1990) all from the University of Ibadan, Nigeria. She teaches parasitology at the undergraduate and postgraduate levels. She was a recipient of a Commonwealth fellowship supported by British Council tenable at the Centre for Entomology and Parasitology (CAEP), Keele University, United Kingdom between 2004 and 2005. She was awarded an Honorary Visiting Research Fellow at the same university from 2005 to 2007. \nShe has been an external examiner to the Department of Veterinary Microbiology and Parasitology, University of Ibadan, MSc programme between 2010 and 2012. She is a member of the Nigerian Society of Experimental Biology (NISEB), Parasitology and Public Health Society of Nigeria (PPSN), Science Association of Nigeria (SAN), Zoological Society of Nigeria (ZSN), and is Vice Chairperson of the Organisation of Women in Science (OWSG), LASU chapter. She served as Head of Department of Zoology and Environmental Biology, Lagos State University from 2007 to 2010 and 2014 to 2016. She is a reviewer for several local and international journals such as Unilag Journal of Science, Libyan Journal of Medicine, Journal of Medicine and Medical Sciences, and Annual Research and Review in Science. \nShe has authored 45 scientific research publications in local and international journals, 8 scientific reviews, 4 books, and 3 book chapters, which includes the books “Malaria Parasites” and “Malaria” which are IntechOpen access publications.",institutionString:"Lagos State University",institution:{name:"Lagos State University",country:{name:"Nigeria"}}},{id:"273100",title:"Dr.",name:"Vijay",middleName:null,surname:"Gayam",slug:"vijay-gayam",fullName:"Vijay Gayam",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/273100/images/system/273100.jpeg",biography:"Dr. Vijay Bhaskar Reddy Gayam is currently practicing as an internist at Interfaith Medical Center in Brooklyn, New York, USA. He is also a Clinical Assistant Professor at the SUNY Downstate University Hospital and Adjunct Professor of Medicine at the American University of Antigua. He is a holder of an M.B.B.S. degree bestowed to him by Osmania Medical College and received his M.D. at Interfaith Medical Center. His career goals thus far have heavily focused on direct patient care, medical education, and clinical research. He currently serves in two leadership capacities; Assistant Program Director of Medicine at Interfaith Medical Center and as a Councilor for the American\r\nFederation for Medical Research. As a true academician and researcher, he has more than 50 papers indexed in international peer-reviewed journals. He has also presented numerous papers in multiple national and international scientific conferences. His areas of research interest include general internal medicine, gastroenterology and hepatology. He serves as an editor, editorial board member and reviewer for multiple international journals. His research on Hepatitis C has been very successful and has led to multiple research awards, including the 'Equity in Prevention and Treatment Award” from the New York Department of Health Viral Hepatitis Symposium (2018) and the 'Presidential Poster Award” awarded to him by the American College of Gastroenterology (2018). He was also awarded 'Outstanding Clinician in General Medicine” by Venus International Foundation for his extensive research expertise and services, perform over and above the standard expected in the advancement of healthcare, patient safety and quality of care.",institutionString:"Interfaith Medical Center",institution:{name:"Interfaith Medical Center",country:{name:"United States of America"}}},{id:"93517",title:"Dr.",name:"Clement",middleName:"Adebajo",surname:"Meseko",slug:"clement-meseko",fullName:"Clement Meseko",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/93517/images/system/93517.jpg",biography:"Dr. Clement Meseko obtained DVM and PhD degree in Veterinary Medicine and Virology respectively. He has worked for over 20 years in both private and public sectors including the academia, contributing to knowledge and control of infectious disease. Through the application of epidemiological skill, classical and molecular virological skills, he investigates viruses of economic and public health importance for the mitigation of the negative impact on people, animal and the environment in the context of Onehealth. \r\nDr. Meseko’s field experience on animal and zoonotic diseases and pathogen dynamics at the human-animal interface over the years shaped his carrier in research and scientific inquiries. He has been part of the investigation of Highly Pathogenic Avian Influenza incursions in sub Saharan Africa and monitors swine Influenza (Pandemic influenza Virus) agro-ecology and potential for interspecies transmission. He has authored and reviewed a number of journal articles and book chapters.",institutionString:"National Veterinary Research Institute",institution:{name:"National Veterinary Research Institute",country:{name:"Nigeria"}}},{id:"158026",title:"Prof.",name:"Shailendra K.",middleName:null,surname:"Saxena",slug:"shailendra-k.-saxena",fullName:"Shailendra K. Saxena",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRET3QAO/Profile_Picture_2022-05-10T10:10:26.jpeg",biography:"Professor Dr. Shailendra K. Saxena is a vice dean and professor at King George's Medical University, Lucknow, India. His research interests involve understanding the molecular mechanisms of host defense during human viral infections and developing new predictive, preventive, and therapeutic strategies for them using Japanese encephalitis virus (JEV), HIV, and emerging viruses as a model via stem cell and cell culture technologies. His research work has been published in various high-impact factor journals (Science, PNAS, Nature Medicine) with a high number of citations. He has received many awards and honors in India and abroad including various Young Scientist Awards, BBSRC India Partnering Award, and Dr. JC Bose National Award of Department of Biotechnology, Min. of Science and Technology, Govt. of India. Dr. Saxena is a fellow of various international societies/academies including the Royal College of Pathologists, United Kingdom; Royal Society of Medicine, London; Royal Society of Biology, United Kingdom; Royal Society of Chemistry, London; and Academy of Translational Medicine Professionals, Austria. He was named a Global Leader in Science by The Scientist. 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