Effects of cortisol on different systems.
\\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:"intechopen-supports-asapbio-s-new-initiative-publish-your-reviews-20220729",title:"IntechOpen Supports ASAPbio’s New Initiative Publish Your Reviews"},{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"}]},book:{item:{type:"book",id:"947",leadTitle:null,fullTitle:"Cardiac Arrhythmias - New Considerations",title:"Cardiac Arrhythmias",subtitle:"New Considerations",reviewType:"peer-reviewed",abstract:"The most intimate mechanisms of cardiac arrhythmias are still quite unknown to scientists. Genetic studies on ionic alterations, the electrocardiographic features of cardiac rhythm and an arsenal of diagnostic tests have done more in the last five years than in all the history of cardiology. Similarly, therapy to prevent or cure such diseases is growing rapidly day by day. In this book the reader will be able to see with brighter light some of these intimate mechanisms of production, as well as cutting-edge therapies to date. Genetic studies, electrophysiological and electrocardiographyc features, ion channel alterations, heart diseases still unknown , and even the relationship between the psychic sphere and the heart have been exposed in this book. It deserves to be read!",isbn:null,printIsbn:"978-953-51-0126-0",pdfIsbn:"978-953-51-6837-9",doi:"10.5772/1454",price:159,priceEur:175,priceUsd:205,slug:"cardiac-arrhythmias-new-considerations",numberOfPages:546,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"450b96aa2d0bc75977a827e0fc5bae13",bookSignature:"Francisco R. 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The future body, in addition to increasing its cellular mass, progressively acquires functional capabilities that would permit it to live and grow out of the mother’s womb [1, 2]. Two clear periods can be distinguished during pregnancy in the future mother. During the first period, a marked increase in insulin level and sensitivity occurs in the mother, with parallel increases in placenta size, amniotic volume, protein content and fat stores; however, the foetus weight gain is small in comparison with that of the mother [1–3]. During the second period, a physiological increase in insulin resistance and insulin degradation takes place in the mother, in parallel to the exponential foetal growth that partially or totally blocks the gain rhythm of maternal stores. This metabolic situation assures the availability of glucose for the maternal and foetal brains and mammary gland, reducing the uptake of glucose by other maternal tissues [1–3]. When glucose homeostasis is not physiologically balanced, changes and adaptation take place during pregnancy, predisposing the individual to degenerative diseases later in life [4–8]. In some non-diabetic women, an alteration in carbohydrate metabolism occurs during pregnancy; thus, although fasting glycaemia is normal, after a carbohydrate load, the glycaemia increases over normal values. This situation is rather more frequent at the end of pregnancy and is known as gestational diabetes (GD) [1, 9].
\nSeveral homeorhetic adjustments are required to assure adequate foetal anabolism, which in turn can also be affected by genetic and nutritional factors [1, 2, 10–15]. Maternal glucocorticoids, among others, clearly affect metabolites and foetal corticoids that compete with other anabolic and growth mediators as insulin and insulin-like growth factor-1 (IGF-1) [2, 16–18]. Thus, a hormonal balance seems to be of critical importance to guarantee suitable foetal and postnatal development [4, 5, 16–19]. Glucocorticoids are central hormones engaged in correct foetal growth and maturation [16, 17]; however, their excess induces intrauterine growth delay, clearly affecting glucose homeostasis and brain development and functions [20–22]. As discussed above, palliative mechanisms are available to reduce the negative effects of excess active corticoids [20–22].
\nStore capability of body steroid hormones is limited; thus, they are synthesized from cholesterol, mainly in liver and endocrine glands. The placenta, although it produces steroid hormones, is unable to synthesize cholesterol, being, thus obliged, to take it from maternal plasma low-density and high-density lipoprotein (LDL and HDL, respectively) particles [23].
\nCholesterol (27 carbons, 27C), the common precursor of all steroid hormones, is converted in placenta to pregnenolone (27C) from which progesterone (21C) is derived. Progesterone is the precursor of several steroid hormones: (a) adrenal cortex hormones (mineralocorticoids and glucocorticoids); (b) male sex hormones (androgens) (19C); and (c) female sexual hormones (oestrogens) (18C).
\nThe adrenal cortex contains 11-, 17- and 21-hydroxylases. When hydroxylation takes place in C21, the 17-hydroxylase action is arrested and mineralocorticoids (e.g. aldosterone) are synthesized in the glomerular zone. When hydroxylation takes place in C17, glucocorticoids and sex hormones are formed in the fascicular and the reticular zones, respectively [16]. The final step production of glucocorticoids and mineralocorticoids is catalysed by two mitochondrial cytochromes P450, CYP11B1 (11b-hydroxylase or P45011b) and CYP11B2 (aldosterone synthase or P450aldo) [24]. The synthesis of steroid hormones is summarized in Figure 1.
\nSteroid hormone synthesis. Notice that role of different hydroxylases. ACTH, adrenocorticotropic hormone; StAR, steroidogenic acute regulatory protein. *Androstenedione and *testosterone can be transformed in oestrone and oestradiol, respectively by the aromatase action. The **Dehydroepiandrosterone sulphate produces oestradiol, while the **17-OH-dehydroepiandrosterone, oestriol. Modified from Pascual-Leone Pascual and Goya Suárez [
The fascicular zone produces cortisol (hydrocortisone) and, in much lower amounts, cortisone. Glucocorticoid synthesis and release is controlled by hypothalamus corticotropin-releasing hormone (CRH) and by the adrenocorticotropic hormone (ACTH) of the anterior hypophysis lobule [16, 25] (Figures 1 and 2). ACTH induces glucocorticoids releasing (and minor amounts of other cortical hormones), helping to maintain adrenal cortical structure and function and to assure cholesterol availability for hormonal synthesis. ACTH production and secretion are under negative feedback control but increased by adrenal medulla catecholamines [16, 21, 25].
\nSteroid hormones are fat soluble, and thus, they easily cross biological membranes, having crucial effects on cellular differentiation and organization. Cortisol binds amply to cortisol binding globulin (CBG), limiting the level and activity of free cortisol [16, 22, 26, 27].
\nSteroid hormone and catecholamine location in the adrenal gland. The activating and negative feedback implicated mechanisms are shown. CRH, corticotropin-releasing hormone, ACTH, adrenocorticotropic hormone. Red lines, inhibition; Green lines, activation. Modified from Nelson and Cox [
Metabolism | \nIncreases glycaemia Increases amino acids use Increases urea | \n\n |
Heart and circulation | \nIncreases heart contraction strength Increases peripheral vasoconstriction Induce angiotensinogen formation | \n\n |
Stomach | \nIncreases gastric juices | \nGastric ulcer | \n
Kidneys | \nMaintains glomerular flux Delays water elimination | \nSimilar effects as aldosterone | \n
Brain | \n\n | Hypothalamus inhibition | \n
Immune system | \n\n | Anti-allergic and anti-inflammatory | \n
Effects of cortisol on different systems.
Glucocorticoids interact on receptors located on skeletal, smooth, and cardiac muscles, brain, stomach, kidney, liver, lung, adipose and lymphatic cells. Those hormones bind to both mineralocorticoid and glucocorticoid receptors (MR and GR, respectively), members of the nuclear receptor’s superfamily. GR are expressed since the embryonic stage [28]. GR are expressed in pancreas, liver, visceral adipose tissue, skeletal muscle and in brain areas such as hippocampus and amygdaline nuclei, where they regulate memory and behaviour [17, 22]. There are GR and MR gene polymorphisms that could explain individual response to corticoids [29]. Optimum glucocorticoid concentrations in blood and tissues are needed to assure correct homeostasis. These levels are highly variable and affected by factors such as gender and circadian cycle, thus explaining difficulties on reference value establishment. Due to space limitations in this review, the particular effects of glucocorticoids on different systems and the effects of high cortisol actions are summarized in Table 1.
\nDuring alarm reaction, catecholamines stimulate hypothalamus, which releases hormones to guarantee adequate plasma glucose levels. These hormones become maximal 4 hours after alarm [16, 21]. Thus, glucocorticoids also help in the alarm reaction. Nowadays, stress response is accepted to be undoubtedly associated with
When stress becomes chronic, a high glucocorticoids release to plasma is kept. These high levels downregulate the GR expression in hippocampus. Thus, the correct feedback exerted by the hypophysis-pituitary axis (HPA) blocking is shunned, which results in lasting high glucocorticoids concentrations [26, 30, 31]. There exist three known mechanisms regulating the entrance of glucocorticoids to the brain [16]: (1) CBG, a molecule that determines the free cortisol levels in humans, and thus cortisol which is available to bind GR [16]. In response to very high free cortisol levels, the CBG transport capacity is saturated and the cortisol levels increased substantially. Thus, the situation is compatible with cortisol resistance or low response to cortisol [32]; (2) glycoprotein P carriers of blood–brain barrier limit, despite glucocorticoid fat solubility, the entrance of cortisol to the brain; and (3) isoenzymes (dehydrogenases or reductases) transform cortisone in active cortisol, which is available to bind GR. Conversely, the 11 β-hydroxysteroid dehydrogenase 2 (11 β-HSD 2) transforms in the kidneys cortisol into inactive cortisone (Figure 1). The presence of high renal levels avoid corticoids from interacting on MR. This enzyme is also available at high levels during development in the brain and placenta to protect the body against deleterious effects of high cortisol levels (e.g. cerebellar malformation [33], high HPA activity in adult life [34] and increased incidence of diseases related to corticoids hypersensitivity [22].
\nThe human foetal adrenal gland has double weight than the foetal kidneys and after delivery its size decreases from 8 to 5 g in 5 weeks. It has three areas: foetal area, definitive area and medulla. The foetal area is integrated by vast cells presenting steroid synthesis characteristics. This area occupies approximately the 80% of the total adrenal gland at the end of pregnancy. It secretes two main substances: dehydroepiandrosterone sulphate (DHAS), synthesized in the foetal area, and cortisol, synthesized in the definitive area [16, 21]. DHAS is synthesized from acetate or from cholesterol (Figure 1). It can be also formed by direct conversion from other steroid sulphates, beginning from cholesterol sulphate. The DHAS production increases as the pregnancy goes by. Its production is kept high during the first week after delivery, and then decreases, reflecting the foetal area’s atrophy. After delivery, at the age of 1 year, total involution of the foetal area is observed [3, 35].
\nThe step from DHAS to 16-α-hydroxydehydroepiandrosterone (16-α-OH-DHAS) is scarce in the foetal adrenal gland, but it can be observed in the foetal liver. Afterwards, both substances are used as substrates in the placenta for the oestrogens’ synthesis: DHAS produces oestradiol and 16-α-OH-DHAS produces oestriol (see Figure 1 footnote). In the definitive area, cortisol can be synthesized from maternal progesterone or de
The definitive area secretes deoxycorticosterone and aldosterone. These secretions begin at 10–20 weeks and increase until the end of pregnancy. There is great cortisol transference from mother to foetus through the placenta. Most of this cortisol can be found in the foetus as corticosterone. Corticosterone levels in foetus are 5–10 times higher than in the mother’s blood. Cortisol is also transferred from foetus to mother. Cortisol can be formed from cortisone in foetus, as some tissues as kidney, lung, amniotic membrane and liver have the 11-hydroxysteroid dehydrogenase (11-HSD) [16].
\nBoth the foetal and the definitive areas of the adrenal gland are stimulated by ACTH and α-melanocyte stimulating hormone (MSH). Both hormones are secreted by the foetal pituitary gland [16, 35]. As possible stimulators of the adrenal gland, angiotensin, prolactin, growth hormone (GH) and epidermal growth factor have also been suggested. Progesterone and deoxycorticosterone secretions decrease as pregnancy goes by, suggesting that the enzymatic systems for their transformation into aldosterone and cortisol become active, as these hormones levels increase at the end of pregnancy.
\nWith respect to the medulla secretions, it is known that the corticosterone synthesized
Glucose is recognized as the major energy porter of human metabolism [37–39]. Glycaemia is determined by carbohydrate intake and absorption, by the glycolysis and gluconeogenesis. Figure 3 summarizes an integrated hormonal mechanism contributing to glycaemia balance. When glycaemia is reduced, mechanisms are produced to avoid hypoglycaemic shock, inducing appetite and compensatory mechanisms, as the lack of stimulation by β-cell to produce insulin and the stimulation of glucagon by α-2 pancreatic cells. When glycaemia increases, insulin promotes the intracellular cross of glucose through expression of receptors and carriers. In addition, a general enzyme activity occurs in liver, skeletal muscle, adipose tissue, etc., increasing the protein synthesis, lipogenesis and glycogenesis [25].
Integrative scheme of hormone response to hypoglycaemia and hyperglycaemia. ACTH, adrenocorticotropic hormone, GH, growth hormone. Red lines, inhibition; green lines, activation; Dot white lines, no effect. Red lines bearing a cross: missing the inhibitory mechanism; green lines bearing a cross: missing the stimulating mechanism. Modified from Sibernagl and Despopoulos [
Hypoglycaemia and a high level of amino acids are two major stimuli for glucagon release. However, fasting, general adrenergic excitation and a decrease in the fatty acid concentrations also lead to glucagon release. On the other hand, hyperglycaemia inhibits glucagon release. The main role of glucagon is raising the glycaemia [24] by increasing glycogenolysis (that is intensified by an increased lipolysis) and diminishing glycolysis. Somatostatin is secreted by the α-cells of the pancreas and inhibits GH, thyroid-stimulating hormone (TSH), gastrin, insulin and glucagon release. All these effects result in a hypoglycaemic action. Glycaemia is registered by glycoreceptors inducing compensation by modifying insulin and glucagon release. Nevertheless, this action is completed by cortisol action and the effect of catecholamines (Figure 3).
\nThe pancreas is an endocrine and exocrine gland, which plays a major role in our economy. It contributes to the macronutrient digestion by producing enzymes while its endocrine function is critical to glucose homeostasis [1]. In humans, it appears first in gestation at 5–6 weeks, and at 11 weeks the islets can be observed. Insulin production is functional at week 20 [3, 40], and at this time, four cell types can be observed: α-cells producing glucagon, β-cells producing insulin, δ-cells producing somatostatin and PP-cells producing pancreatic polypeptide. As it occurs in adult life, at birth the most abundant cells are the β-cells and the least the PP-cells. The pancreas is an active organ at the end of the first trimester and plays a key role since the fourth month of pregnancy. IGF-1 is fundamental to pancreatic cell specialization, growth, islet maturation and thus to insulin production.
\nThere is a pancreatic plasticity that allows pancreas response to high insulin-demand situations. β-Cell adaptation to different situations (nutrient lack or excess) depends on the equilibrium between cell division, growth and apoptosis death [7]. The foetal β-cell area increases during pregnancy without changing the cell size. However, there is an increase in the number of small islets, but not of the number of β-cells in each islet [41].
\nIGF-1 is a low-molecular weight peptide hormone, expressed by all the adult and foetal tissues since early life stages. Similar to proinsulin, IGF-1 consists of one single polypeptide chain containing three disulphide bridges inside. Both IGF-1 and proinsulin have identical hydrophobic areas [42]. IGF-1 and its binding proteins (IGFBPs) are powerful stimulators of cellular division and have a very important role in the regulation of foetal growth [18]. After birth, the liver is the main source of IGF-1 and its IGFBPs. Nutritional factors such as protein intake, energy and micronutrients such as zinc regulate IGF-1 synthesis. Hormones such as GH, sexual steroids, thyroid hormones and insulin regulate the expression of IGF-1 and IGFBPs [43, 44].
\nLiver IGF-1 production | \nAnti-insulinaemic effect acumulación de nutrientes | \n|
Without relevant effects | \nStimulate liver IGF-1 and glycogenesis Stimulate fetal growth | \n
Effects of placental GH and placental lactogen in both maternal and foetal circulations.
GH, Growth hormone; IGF-1, insulin-like growth factor-1.
During gestation, pituitary GH production is scarce, while IGF-1 concentration increases, reaching the highest level at the end of pregnancy. This increment is associated with a high placental GH synthesis. Placental and pituitary GHs have similar structures, but different genes codify their production [45–47]. The main regulators of IGF-1 during pregnancy are both the placental GH and the human placental lactogen (hPL) [47]. Placental GH is secreted to maternal circulation, stimulating the synthesis of IGF-1 in the maternal liver. hPL is the most abundant peptide hormone secreted by the placenta. It circulates in both maternal and foetal blood, playing different roles. Table 2 summarizes some of the major roles of both placental hormones.
\nIGF-1 stimulates cartilage growth, DNA, RNA and protein synthesis, and anabolic processes. IGF-1 is a key mediator of hippocampal neurogenesis. GH is expressed in the hippocampus where a high stress regulates it [48]. During pregnancy, IGF-1 stimulates cell division, maternal tissues’ growth and anabolic processes resulting in increasing the adipose tissue, liver glycogen reservoir and mammary gland development. IGF-1 has effects that are similar to those of insulin on muscle and placenta, stimulating amino acid and glucose transport and inhibiting lipolysis in the adipose tissue. IGF-1 has also a main role in growth, as the correlation between its concentration and child growth speed shows [49]. In fact, it is the growth factor that best correlates with foetal growth during gestation. The protein-energetic malnutrition and preeclampsia associated with intrauterine growth retardation (IUGR) are two pathologic statuses where IUGR is associated with IGF-1 and IGFBP concentrations. Hypoglycaemia promotes adrenaline release, which stimulates hypothalamus GH release and inhibits insulin production by β-pancreatic cells (Figure 3). As indicated, placental GH induces liver IGF-1 production, palliating, at least in part, the negative effects of hypoglycaemia.
\nHormonal equilibrium and adjustment are needed for an adequate anabolism and development [16, 17, 19, 37, 50]. This equilibrium is under nutritional and genetic regulation [7, 50]. Maternal glucocorticoids have relevant effects on the foetal metabolites and corticoid levels. They have opposite effects to those of other anabolic and growth mediators such as insulin or IGF-1 [38, 44]. Glucocorticoids are key hormones for adequate foetal development and maturation [16, 17], but at high concentrations they induce IUGR with a great affectation of glucose homeostasis, brain development and maturation and thus, all the processes regulated by this complex organ. Fortunately there are mechanisms regulating the concentration of active corticoids [7, 16], palliating, at least in part, the negative effects of the excess amount of these hormones.
\nFifty years ago, it was assessed that children with marasmic malnutrition presented low insulinaemia and a high cortisol/insulin ratio [51]. However, these children kept a normal glucose tolerance [51] suggesting an increased insulin resistance. In animal models, the tissue-insulin hypersensitivity induced by protein-energy malnutrition was confirmed [52, 53]. This disagrees with the thrifty phenotype theory [4–6], which supposes less glucose consumed by peripheral tissues because of an insulin resistance status, allowing an adequate glucose transfer to the brain even in nutritional restriction conditions.
\nInsulin and lipoprotein programming during pregnancy. Foetal malnutrition influencing growth and pancreas capacities. Notice that the glucose and nutrient availability affect glucocorticoid concentrations and the flux of new cells originating lower pancreatic cell growth and less insulin production. This fact is counterbalanced by increasing insulin sensitivity and cholesterol synthesis. High food amount availabilities would induce adaptive mechanisms addressing glucose intolerance, diabetes mellitus, and/or dyslipidaemia and coronary heart disease (CHD) in this “programmed” body later in life. *Non-definitive evidence. Modified from Sánchez-Muniz et al. [
Inadequate nutrition in human foetuses negatively affects pancreatic development, leading to a smaller β-cell population [54] or a decreased ability for insulin production [55]. This situation makes pancreas unable to adequately respond to some metabolic and stress conditions in adult life. Foetal effects of this programming are less known, but it seems that malnutrition, placental insufficiency and GD alter the islets development in the perinatal period, increasing the risk of suffering diabetes in the future (Figure 4). There is no agreement on the results obtained as malnutrition effects on insulin secretion ability have been associated with alterations in the secretion mechanism or hormone biosynthesis, or other factors such as the amount of hormone in each islet and the insulin availability by modifying the expression of the insulin production and translation genes [56].
\nIt is well known that pancreatic β-cells release adequate amounts of insulin as a response to nutrients, hormones and nervous stimuli in order to keep glucose levels in a narrow range and assure optimum tissue functioning [38, 39, 57]. Glycaemia is the main insulin-secretion regulator [38, 39, 57] (Figure 3). In the foetus, insulin synthesis is regulated by glucose, and it has been described a slight foetal β-cell immaturity in the face of glucose. This seems paradoxical as glucose is the main metabolic substrate in the foetus [38, 58]. The “thrifty phenotype” hypothesis proposed by Hales and Barker [5] suggests that type 2 diabetes is due to the action of unknown factors that reduce foetal growth, islet β cell ontogeny and insulin sensitivity during the prenatal period. This hypothesis supposes a foetal programming where the HPA axis is involved under hormonal and nutritional regulation. This programming is induced as an adaptation mechanism of the future being to its limited environment in order to guarantee its own survival and is more prevalent in low birthweight individuals [7].
\nHowever, there are different studies in neonates showing that even in adequate
The hormonal imbalance associated with hypercortisolaemia, hyperinsulinaemia and reduced levels of GH and testosterone is a typical fact of the metabolic syndrome [40, 60]. However, this association has never been suggested in neonates and thus studied by our research group.
\nOur group has defined reference values for insulin resistance/sensitivity markers in neonates [59]. These ranges were obtained considering strict criteria at birth, as only term, normoweight, appropriate for gestational age, and without foetal distress (Apgar test evaluation) neonates whose mothers had normal glucose tolerance (O’Sullivan test evaluation) were studied [61]. The insulin resistance/sensitivity was calculated by the following indexes: quantitative insulin sensitivity check index (QUICKI), using the formula: 1/[(log Insulin)(μUI/mL) + (log Glucose)(mg/dL)]; homeostatic model assessment-insulin resistance (HOMA-IR), calculated as: Glucose (mmol/L) × Insulin (μUI/mL)/22.5.
\nTaking these criteria into account, the following
The following
The main reason that led us to perform this study was the current increase in obesity and type 2 diabetes mellitus, especially in young populations. The early diagnosis of the insulin sensitivity affection will allow us to apply corrective and therapeutic measures in order to reduce the chronicity of the insulin resistance and its clinical posterior manifestations.
\nTaking into account the reference values for neonates [59], the cut-off point for high insulin concentrations (percentile 75, P75) was set up at 6.4 μUI/mL for females and at 4.8 μUI/mL for males. In the case of cortisol, the cut-off point for high levels (percentile 75, P75) was set up at 9.7 μg/dL for females and 9.4 μg/dL for males.
\nTable 3 shows the general characteristics of the studied population.
\n\n | \n | ||
---|---|---|---|
Age (years) | \n30.33 ± 5.24 | \n16 | \n40 | \n
Glucose (mg/dL) | \n83.63 ± 6.72 | \n64.0 | \n101.0 | \n
Gestational age (weeks) | \n39.85 ± 1.10 | \n37 | \n42 | \n
Weight (g) | \n3301 ± 331 | \n2520 | \n3990 | \n
Length (cm) | \n50.0 ± 1.38 | \n44.0 | \n53.0 | \n
BMI (kg/m2) | \n13.19 ± 1.12 | \n10.08 | \n15.80 | \n
Ponderal index (kg/m3) | \n26.41 ± 2.39 | \n20.16 | \n33.22 | \n
Cephalic perimeter (cm) | \n34.19 ± 1.35 | \n30.0 | \n37.0 | \n
Thoracic perimeter (cm) | \n33.66 ± 1.43 | \n30.0 | \n39.0 | \n
Apgar 1 | \n8.99 ± 0.72 | \n7 | \n10 | \n
Apgar 2 | \n9.95 ± 0.29 | \n9 | \n10 | \n
Glucose (mg/dL) | \n78.23 ± 38.39 | \n18 | \n233 | \n
Insulin (μIU/mL) | \n6.57 ± 8.58 | \n0.2 | \n67.50 | \n
Cortisol (μg/dL) | \n7.54 ± 3.55 | \n2.78 | \n24.15 | \n
GH (ng/mL) | \n15.84 ± 10.19 | \n0.6 | \n73.1 | \n
IGF-1 (ng/mL) | \n57.7 ± 26.31 | \n5.0 | \n232.5 | \n
QUICKI | \n0.43 ± 0.12 | \n0.26 | \n1.18 | \n
HOMA-IR | \n1.53 ± 2.78 | \n0.02 | \n16.73 | \n
Glucose/insulin | \n29.26 ± 43.90 | \n0.79 | \n370.0 | \n
Insulin/cortisol | \n0.99 ± 1.40 | \n0.02 | \n11.05 | \n
Characteristics of the studied population: term, normoweight neonates without foetal distress.
Data are means ± standard deviations; BMI, body mass index; GH, growth hormone; IGF-1, insulin-like growth factor 1; QUICKI, quantitative insulin sensitivity check index; HOMA-IR, homeostatic model assessment-insulin resistance.
Of the 178 neonates studied, 98 were females and 80 males. All of them were Caucasic, singleton, term, normoweight and without foetal distress. The study was performed in accordance with the Declaration of Helsinki and approved by the Management and Ethical Committee of the Merida Hospital. From the 178 mothers, 156 were screened for GD by the O’Sullivan test [61] between weeks 24 and 28 of pregnancy, and 33% had impaired glucose tolerance (IGT). There were 22 mothers who could not be screened.
\n\n | |||
---|---|---|---|
Age (years) | \n30.16 ± 5.25 | \n31.14 ± 5.12 | \nNS | \n
Glucose (mg/dL) | \n83.20 ± 6.47 | \n84.13 ± 7.10 | \nNS | \n
Gestational age (weeks) | \n39.47 ± 1.16 | \n39.47 ± 1.17 | \nNS | \n
Birthweight (g) | \n3328 ± 290 | \n3372 ± 297 | \nNS | \n
Length (cm) | \n50.09 ± 1.31 | \n50.19 ± 1.35 | \nNS | \n
BMI (kg/m2) | \n13.27 ± 1.06 | \n13.38 ± 0.94 | \nNS | \n
Ponderal index (kg/m3) | \n26.51 ± 2.37 | \n26.67 ± 2.05 | \nNS | \n
Cephalic perimeter (cm) | \n34.47 ± 1.23 | \n34.13 ± 1.21 | \nNS | \n
Thoracic perimeter (cm) | \n33.80 ± 1.32 | \n33.69 ± 1.38 | \nNS | \n
Apgar 1 | \n8.96 ± 0.83 | \n9.03 ± 0.56 | \nNS | \n
Apgar 2 | \n9.93 ± 0.35 | \n9.97 ± 0.18 | \nNS | \n
Glucose (mg/dL) | \n68.40 ± 28.62 | \n99.09 ± 48.50 | \n<0.001 | \n
Insulin (μIU/mL) | \n2.84 ± 1.48 | \n14.61 ± 11.62 | \nND | \n
Cortisol (μg/dL) | \n7.39 ± 3.38 | \n7.98 ± 3.91 | \nNS | \n
GH (ng/mL) | \n16.76 ± 10.41 | \n13.28 ± 9.07 | \n0.027 | \n
IGF-1 (ng/mL) | \n55.71 ± 22.85 | \n63.64 ± 32.05 | \nNS | \n
QUICKI | \n0.47 ± 0.13 | \n0.36 ± 0.08 | \n<0.001 | \n
HOMA-IR | \n0.49 ± 0.33 | \n3.99 ± 4.17 | \n<0.001 | \n
Glucose/insulin | \n37.37 ± 37.02 | \n8.61 ± 4.39 | \n<0.001 | \n
Insulin/cortisol | \n0.47 ± 0.34 | \n2.22 ± 2.08 | \n<0.001 | \n
Characteristics of the studied population according to the insulin concentration.
Data are means ± standard deviations; BMI, body mass index; GH, growth hormone; IGF-1, insulin-like growth factor-1; QUICKI, quantitative insulin sensitivity check index; HOMA-IR, homeostatic model assessment-IR; P: percentile; NS, not significant; ND, not determined.
The general anthropometric data found were quite similar to those shown in previous studies [62, 63] with mean values of normality, clearly suggesting the absence of maternal-placental malnutrition. The mean values found in hormonal markers agree with those used as reference values in neonates [59]. Glycaemia in neonates is quite variable even in populations where distress and other factors are well controlled [59, 64]. HOMA-IR and QUICKI are usually studied in adults [65, 66], but this occurred sparingly in neonates [59, 67] and more often in low birthweight populations [68]. The data obtained in this study show that HOMA-IR values are lower than those found in low birthweight neonates [68] suggesting less insulin resistance. In addition, QUICKI was much lower and HOMA-IR much higher than those found in youths suffering or not suffering from obesity and/or metabolic syndrome [66].
\n\nNon-significant differences were found between anthropometric characteristics of neonates belonging to both insulin levels (Table 4).
\n\n | |||
---|---|---|---|
Age (years) | \n30.6 ± 5.24 | \n30.10 ± 5.18 | \nNS | \n
Glucose (mg/dL) | \n83.74 ± 6.85 | \n82.78 ± 6.12 | \nNS | \n
Gestational age (weeks) | \n39.4 ± 1.16 | \n39.80 ± 1.12 | \n0.067 | \n
Birthweight (g) | \n3338 ± 287 | \n3358 ± 312 | \nNS | \n
Length (cm) | \n50.07 ± 1.37 | \n50.28 ± 1.13 | \nNS | \n
BMI (kg/m2) | \n13.31 ± 1.04 | \n13.27 ± 0.97 | \nNS | \n
Ponderal index (kg/m3) | \n26.62 ± 2.36 | \n26.40 ± 1.93 | \nNS | \n
Cephalic perimeter (cm) | \n34.36 ± 1.15 | \n34.31 ± 1.45 | \nNS | \n
Thoracic perimeter (cm) | \n33.75 ± 1.25 | \n33.79 ± 1.55 | \nNS | \n
Apgar 1 | \n8.99 ± 0.76 | \n8.98 ± 0.76 | \nNS | \n
Apgar 2 | \n9.94 ± 0.32 | \n9.93 ± 0.26 | \nNS | \n
Glucose (mg/dL) | \n75.33 ± 36.69 | \n88.66 ± 44.63 | \n0.087 | \n
Insulin (μIU/mL) | \n6.39 ± 8.49 | \n7.62 ± 9.38 | \nNS | \n
Cortisol (μg/dL) | \n6.04 ± 1.67 | \n12.74 ± 3.33 | \nND | \n
GH (ng/mL) | \n16.92 ± 10.26 | \n11.43 ± 8.41 | \n0.001 | \n
IGF-1 (ng/mL) | \n58.27 ± 24.32 | \n58.24 ± 32.73 | \nNS | \n
QUICKI | \n0.44 ± 0.11 | \n0.43 ± 0.15 | \nNS | \n
HOMA-IR | \n1.55 ± 2.87 | \n1.89 ± 3.01 | \nNS | \n
Glucose/insulin | \n25.46 ± 26.58 | \n36.49 ± 42.63 | \nNS | \n
Insulin/cortisol | \n1.16 ± 1.58 | \n0.65 ± 0.91 | \n0.011 | \n
Characteristics of the studied population according to cortisol concentrations.
Data are means ± standard deviations; BMI, body mass index; GH, growth hormone; IGF-1, insulin-like growth factor-1; QUICKI, quantitative insulin sensitivity check index; HOMA-IR,: homeostatic model assessment-insulin resistance; P, percentile; NS, not significant; ND, not determined.
Of the 178 neonates studied, 58 (30 females and 28 males) were hyperinsulinaemic (insulin concentrations >P75). From these 58 hyperinsulinaemic neonates, 86% showed HOMA-IR values ≥P75 taking in account the reference values for neonatal population [63]. As indicated by Gesteiro et al. [67], the increased neonatal insulinaemia was not able to normalize neonatal glycaemia in the >P75 neonates as those newborns presented significantly higher cord-blood insulin levels. Despite the fact that all studied infants were full-term normoweights, about one-third show very high insulin levels (≥15 μIU/mL). No clear reasons are available; however, foetal insulin levels increase under hyperglycaemia and GD [69]. Furthermore, of the 58 hyperinsulinaemic neonates, 25 (43%) were born from mothers presenting IGT and 28 (48%) from mothers without IGT. Thus, neonatal insulin sensitivity/resistance markers could be clearly affected by maternal IGT. This factor effect will be discussed later in this review.
\n\nTable 5 shows the characteristics of the studied population according to their cortisol levels. In the case of cortisol, from the 178 neonates studied, 20 females and 21 males were hypercortisolaemics as presented cortisol levels ≥ P75.
\nPotential mechanisms implicated in glucocorticoid hormone regulation. Three possibilities are suggested. Note that glucocorticoid sensitivity in the HPA axis and tissues can be independently regulated and the former determines the serum free cortisol levels. Combination of their directions influences net peripheral action of this hormone. The glucocorticoid resistance would be a consequence of glucocorticoid receptors saturation. Modified from Chrousos and Kino [
There is a lot of available information about foetal programming and glucocorticoids in low birthweight newborns [16, 17]. However, the present study was done in control neonates where scarce information is available. Cortisol levels at birth were not affected by foetal distress as all of them had a high score in the Apgar test (>7 at the first minute and >9 at the fifth minute). Cortisol levels are highly dependent on stress and type of delivery [70, 71]. As our neonates were strictly selected, other factors, such as low cortisol sensitivity which is different from these factors, should be considered. Figure 5 shows a model comparison where cortisol and other hormone levels appear clearly related to cortisol resistance. Thus, it can be accepted that high cortisol level at birth would be also associated with low response control of cortisol.
\nWe also find that neonates presenting high cortisolaemia had lower GH (P = 0.001) and an insulin/cortisol ratio (P < 0.05) than those neonates with low–normal cortisol levels.
\n\nThis study finds for the first time in the bibliography that the conjunction of high levels of insulin and cortisol together was present in nearly 9% of term, normoweight without foetal-distress neonates, and was associated with low GH concentrations, impaired neonatal insulin sensitivity and high glycaemia at birth.
\n\nTable 6 resumes the anthropometric, hormonal and insulin resistance/sensitivity in neonates attending to their insulin and cortisol levels together. It can be observed that neonates presenting both high insulin and cortisol concentrations showed a slightly higher birthweight without differences in length, body mass index (BMI), ponderal index, cephalic or thoracic perimeters. Although fat was not analysed in these neonates, it can be speculated that as variation in length was lower than in weight, neonates presenting higher levels of both cortisol and insulin tended to accumulate more fat, as it is known that in adults, the troncular fat accumulation is associated with plasma lipids increase [72] and insulin resistance severity in adults [72, 73]. Nonetheless, data in adolescents are controversial and limited [74].
\nValues of GH (ANOVA, P = 0.009), glucose, insulin, cortisol, QUICKI, HOMA-IR and the glucose/insulin and insulin/cortisol ratios (all P < 0.001) were significantly different between the four groups. When insulin was elevated regardless of cortisol levels, neonates showed higher glucose, IGF-1, HOMA-IR and insulin/cortisol index, but lower QUICKI and glucose/insulin ratio (at least P < 0.05). Neonates with hypercortisolaemia but not hyperinsulinaemia showed lower values of GH (at least P < 0.05) than those with non-elevated levels of both hormones.
\n\nIn agreement with our results, where higher IGF-1 correspond to higher birthweight, other groups have found that IGF-1 levels are related to higher birthweight, supporting the premise that IGF-1 plays a major role in promoting the foetal growth [75], but also in keeping the hormonal balance.
\n\n | | \n||||
---|---|---|---|---|---|
Age (years) | \n30.09 ± 5.13 | \n31.71 ± 5.35 | \n30.63 ± 5.77 | \n29.35 ± 4.26 | \n0.16 | \n
Glucose (mg/dL) | \n83.48 ± 6.61 | \n84.32 ± 7.41 | \n82.05 ± 6.09 | \n83.75 ± 6.22 | \n0.57 | \n
Gestational age (weeks) | \n39.41 ± 1.10 | \n39.26 ± 1.29 | \n39.79 ± 1.29 | \n39.82 ± 0.88 | \n0.15 | \n
Birthweight (g) | \n3332 ± 296 | \n3350 ± 269 | \n3303 ± 275 | \n3437 ± 353 | \n0.15 | \n
Length (cm) | \n50.07 ± 1.39 | \n50.08 ± 1.37 | \n50.15 ± 1.04 | \n50.47 ± 1.27 | \n0.35 | \n
BMI (kg/m2) | \n13.29 ± 1.09 | \n13.36 ± 0.93 | \n13.13 ± 0.96 | \n13.47 ± 0.99 | \n0.56 | \n
Ponderal Index (kg/m3) | \n26.59 ± 2.47 | \n26.70 ± 2.13 | \n26.20 ± 2.02 | \n26.68 ± 1.83 | \n0.89 | \n
Cephalic perimeter (cm) | \n34.45 ± 1.09 | \n34.09 ± 1.26 | \n34.39 ± 1.69 | \n34.21 ± 1.18 | \n0.88 | \n
Thoracic perimeter (cm) | \n33.80 ± 1.20 | \n33.66 ± 1.38 | \n33.82 ± 1.71 | \n33.75 ± 1.42 | \n0.93 | \n
Apgar 1 | \n8.96 ± 0.87 | \n9.05 ± 0.38 | \n8.96 ± 0.69 | \n9.00 ± 0.87 | \n0.84 | \n
Apgar 2 | \n9.93 ± 0.36 | \n9.98 ± 0.15 | \n9.92 ± 0.28 | \n9.94 ± 0.24 | \n0.88 | \n
Glucose (mg/dL) | \n64.06 ± 19.08a | \n100.81 ± 51.81b | \n85.67 ± 48.59c | \n92.88 ± 39.42bc | \n<0.001 | \n
Insulin (μIU/mL) | \n2.92 ± 1.45a | \n14.26 ± 11.96b | \n2.41 ± 1.45a | \n14.98 ± 10.90b | \n<0.001 | \n
Cortisol (<g/dL) | \n5.99 ± 1.66a | \n6.15 ± 1.73a | \n12.61 ± 2.95b | \n12.92 ± 3.89b | \n<0.001 | \n
GH (ng/mL) | \n17.61 ± 10.65a | \n15.32 ± 9.23 ab | \n12.67 ± 7.89b | \n9.56 ± 9.06b | \n0.009 | \n
IGF-1 (ng/mL) | \n56.60 ± 24.19a | \n62.10 ± 24.48ab | \n50.41 ± 14.23a | \n69.49 ± 46.77b | \n0.083 | \n
QUICKI | \n0.46 ± 0.12a | \n0.37 ± 0.08 b | \n0.48 ± 0.17 a | \n0.35 ± 0.06 b | \n<0.001 | \n
HOMA-IR | \n0.47 ± 0.29 a | \n4.00 ± 4.28b | \n0.54 ± 0.46 a | \n3.80 ± 3.97b | \n<0.001 | \n
Glucose/insulin | \n32.79 ± 41.83 a | \n8.87 ± 4.49b | \n56.60 ± 61.54c | \n8.10 ± 4.10 b | \n<0.001 | \n
Insulin/cortisol | \n0.54 ± 0.34a | \n2.55 ± 2.26b | \n0.19 ± 0.11a | \n1.30 ± 1.13c | \n<0.001 | \n
Comparison of the different groups of neonates according to their insulin and cortisol levels.
Data are means ± standard deviations; Different letters for the same parameter are significantly different. BMI, body mass index; GH, growth hormone; IGF-1, insulin-like growth factor-1; QUICKI, quantitative insulin sensitivity check index; HOMA-IR, homeostatic model assessment-insulin resistance.
Pancreatic β-cells are very sensitive to substrate and hormone changes during the foetal stage. An inadequate environment
Regulation of insulin secretion by IGF-1 and GH. Notice the inverse relationship between IGF-1 and GH. IGF-1, insulin-like growth factor-1; GH, growth hormone. Modified from Yakar et al. [
Neonates presenting hyperinsulinaemia together with hypercortisolaemeia showed low insulin sensitivity and high insuline resistance according to their QUICKY and HOMA-IR values, while neonates with no elevation of both hormones showed QUICKI and HOMA-IR values >P50 and <P50 of the reference population, respectively [59]. Nevertheless, the conjunction of high levels of both hormones does not significantly affect QUICKI and HOMA-IR values with respect to those shown by the neonates presenting only high insulin concentrations. The ROC curve (Figure 7) shows that the conjunction of both high insulin and cortisol is a strong predictor for neonates presenting high HOMA-IR and low QUICKI values.
\nROC curves. Predictive value of both high insulin and cortisol concentrations. GH, growth hormone; QUICKI, quantitative insulin sensitivity check index; HOMA-IR, homeostatic model assessment-insulin resistance; IGF-1, insulin-like growth factor-1. Area under curve: GH = 0.207, QUICKI = 0.205, HOMA-IR = 0.882 (all P < 0.001).
Table 7 shows neonatal results after considering two factors: the association of high cortisol-high insulin levels and the presence of IGT during pregnancy. The gestational age did not differ in neonates with high cortisol-high insulin levels whose mother presented or not IGT with respect to those described in a neonatal control population [59].
\nNeonatal weight and length were significantly affected (P = 0.006 and 0.016, respectively) by the joint effect of high cortisol–high insulin levels but not by IGT. BMI, ponderal index, cephalic and thoracic perimeters, and the Apgar at 1 and 5 min did not change by any of the two studied factors or by their interaction. The maternal glycaemia appeared higher in IGT mothers (P < 0.001) (Table 7).
\n\nNeonatal cortisolaemia and insulinaemia were significantly affected by maternal IGT and by the interaction of IGT and high cortisol-high insulin levels (all P < 0.001). Neonatal glycaemia increased while GH decreased in children with high insulin–cortisol at birth (P < 0001), but was not affected by IGT presence. IGF-1 was affected by the cortisol–insulin joint (P = 0.031) and by IGT (P = 0.037). The insulin/cortisol ratio was significantly modified by the joint effect of high cortisol–high insulin (P < 0.001), maternal IGT (P = 0.012), as well as the interaction of the two factors (P < 0.001) (Table 7).
\n\n | |||||||
---|---|---|---|---|---|---|---|
\n | No IGT (N = 96) | \nIGT (N = 45) | \nNo IGT (N = 9) | \nIGT (N = 6) | \nInteraction | \nIGT | \nHigh insulin– high cortisol | \n
Age (years) | \n29.86 ± 4.95 | \n32.22 ± 5.09 | \n28.44 ± 3.09 | \n30.33 ± 5.24 | \n0.76 | \n0.160 | \n0.54 | \n
Glucose (mg/dL) | \n81.97 ± 6.04 | \n86.84 ± 7.03 | \n80.22 ± 4.44 | \n88.83 ± 5.56 | \n0.28 | \n<0.001 | \n0.80 | \n
Gestational age (weeks) | \n39.49 ± 1.14 | \n39.24 ± 1.30 | \n40.11 ± 0.60 | \n40.00 ± 0.00 | \n0.93 | \n0.66 | \n0.17 | \n
Birthweight (g) | \n3336 ± 286 | \n3297 ± 272 | \n3432 ± 402 | \n3488 ± 329 | \n0.26 | \n0.88 | \n0.006 | \n
Length (cm) | \n50.16 ± 1.37 | \n49.82 ± 1.29 | \n50.39 ± 0.99 | \n50.83 ± 1.72 | \n0.17 | \n0.86 | \n0.016 | \n
BMI (kg/m2) | \n13.26 ± 1.02 | \n13.29 ± 1.05 | \n13.49 ± 1.26 | \n13.47 ± 0.66 | \n0.70 | \n0.99 | \n0.14 | \n
Ponderal index (kg/m3) | \n26.47 ± 2.30 | \n26.70 ± 2.40 | \n26.77 ± 2.32 | \n26.52 ± 1.35 | \n0.98 | \n0.97 | \n0.54 | \n
Cephalic perimeter (cm) | \n34.30 ± 1.35 | \n34.44 ± 1.13 | \n34.42 ± 1.28 | \n34.20 ± 1.15 | \n0.39 | \n0.51 | \n0.51 | \n
Thoracic perimeter(cm) | \n33.75 ± 1.36 | \n33.85 ± 1.25 | \n34.00 ± 1.90 | \n33.40 ± 0.89 | \n0.78 | \n0.33 | \n0.77 | \n
Apgar1 | \n8.84 ± 0.89 | \n9.22 ± 0.42 | \n8.78 ± 1.09 | \n9.33 ± 0.52 | \n0.76 | \n0.082 | \n0.93 | \n
Apgar2 | \n9.90 ± 0.40 | \n10.0 ± 0.0 | \n9.89 ± 0.33 | \n10.0 ± 0.0 | \n0.99 | \n0.29 | \n0.99 | \n
Glucose (mg/dL) | \n73.92 ± 37.33 | \n79.98 ± 37.77 | \n100.89 ± 48.60 | \n78.33 ± 18.01 | \n0.20 | \n0.065 | \n<0.001 | \n
Insulin (μIU/mL) | \n4.62 ± 5.81 | \n8.96 ± 11.82 | \n18.03 ± 13.95 | \n11.32 ± 4.19 | \n0.012 | \n0.029 | \n<0.001 | \n
Cortisol (μg/dL) | \n7.03 ± 2.89 | \n7.22 ± 3.49 | \n10.35 ± 0.41 | \n16.35 ± 4.62 | \n<0.001 | \n<0.001 | \n<0.001 | \n
GH (ng/mL) | \n17.09 ± 9.40 | \n14.89 ± 12.32 | \n8.44 ± 6.81 | \n8.20 ± 5.04 | \n0.82 | \n0.78 | \n0.020 | \n
IGF-1 (ng/mL) | \n55.87 ± 23.49 | \n58.76 ± 23.32 | \n55.06 ± 16.31 | \n88.58 ± 72.03 | \n0.14 | \n0.037 | \n0.031 | \n
QUICKI | \n0.46 ± 0.14 | \n0.40 ± 0.09 | \n0.35 ± 0.07 | \n0.36 ± 0.06 | \n0.52 | \n0.73 | \n0.001 | \n
HOMA-IR | \n1.12 ± 2.44 | \n2.17 ± 3.42 | \n5.00 ± 5.08 | \n2.10 ± 0.68 | \n0.002 | \n0.003 | \n<0.001 | \n
Glucose/insulin | \n35.80 ± 42.38 | \n18.39 ± 14.29 | \n7.97 ± 4.81 | \n7.93 ± 3.86 | \n0.58 | \n0.54 | \n0.032 | \n
Insulin/cortisol | \n0.80 ± 1.19 | \n1.57 ± 2.11 | \n1.75 ± 1.37 | \n0.76 ± 0.46 | \n0.001 | \n0.012 | \n<0.001 | \n
Effects of high insulin and cortisol levels in neonates and impaired glucose tolerance (IGT) in mothers on anthropometric, foetal distress and insulin sensitivity/resistance markers.
Data are means ± standard deviations; BMI, body mass index; GH, growth hormone; IGF-1, insulin-like growth factor-1; QUICKI, quantitative insulin sensitivity check index; HOMA-IR, homeostatic model assessment-insulin resistance.
With respect to insulin resistance/sensitivity markers, the glucose/insulin ratio and the QUICKI were not affected by IGT but appeared lower in neonates with high cortisol-high insulin levels (P = 0.032 and <0.001, respectively). HOMA-IR was higher in neonates with high cortisol-high insulin (P < 0.001) and affected by maternal IGT (P = 0.003) and by the interaction of two factors (P = 0.002).
\nWith respect to maternal IGT prevalence, we found that one of two mothers of hyperinsulinaemic children suffered from IGT, while one out of four mothers showed IGT in those groups with insulin below P75. According to Herrera and Ramos Álvarez [19] during the last third of gestation, maternal levels of hPL, oestrogens and progesterone, increase in parallel to the placental mass. These hormones show anti-insulinaemic action, which together with the placenta availability to degrade insulin increases the maternal insulin needs. In fact, during late gestation an increase in the pancreatic β-cell sensibility to the insulintropic stimuli, and also an accelerated insulin turnover have been described. Maternal insulin level effects were partially arrested by insulin resistance. The increased insulinaemia capacitates the future mother to efficiently balance the intense metabolite extraction by the foetus–placenta unity, despite the tendency of insulin resistance occurring in the mother [2, 19].
\n\nGD is responsible for very high glycaemia that can induce important alterations in foetus size, glucose and insulin production [1, 9]. These premises encouraged us to study whether maternal pregnancy IGT presence could affect the values of insulin resistance (HOMA-IR) or insulin sensitivity (QUICKI) markers in neonates already showing high insulin and high cortisol levels at birth.
\nResults suggest that neonatal insulin-cortisol levels influence the anthropometric parameters and the insulin resistance/sensitivity markers more than IGT presence. Nonetheless, the effect of IGT on insulin was different in the two study groups, as the level of this hormone decreased remarkably in neonates with high cortisol-high insulin levels. It can be hypothesized that mothers presenting IGT should have high glucose concentrations. This increase would induce, in turn, a neonatal insulin increase in order to avoid the negative effects of glucose excess [1, 9].
\nIt seems interesting to notice that neonates presenting high cortisol-high insulin at birth, whose mothers were presenting IGT showed higher weight and length but the lowest GH and the highest IGF-1 values. Again, the inverse relationship between IGF-1 and GH seems a palliative mechanism against insulin resistance, a highly negative fact for the foetus physiology. Thus, in addition to its role in foetal growth [75], IGF-1 seems crucial in keeping hormonal balance [79]. It also seems relevant that the presence of maternal IGT and high insulin–high cortisol levels at birth reduced the negative effects on glucose, insulin and HOMA-IR but increased cortisol and IGF-1 levels with respect to their non-IGT but high insulin–high cortisol level counterparts. These findings seem paradoxical, as they suggest that the increased maternal glycaemic response to carbohydrate intake would allow the mitigation of the negative effects of reduced GH and increased cortisol levels in the neonates. More studies are needed to understand this interesting metabolic maternal-neonatal interaction.
\nUnfortunatly complete information of the diet consumed through the whole pregnancy was available in only 31 mothers whose neonates fulfil the selection criteria. Nonetheless, some relevant results were observed when comparing results from neonates whose mothers followed an adequate or unadequate diet according to the MDA (Table 8).
\n\n | |||
---|---|---|---|
Age (years) | \n28.18 ± 5.42 | \n31.90 ± 5.17 | \n0.078 | \n
Glucose (mg/dL) | \n80.44 ± 6.46 | \n84.24 ± 7.36 | \nNS | \n
Weight (g) | \n3140 ± 419 | \n3309 ± 275 | \nNS | \n
Length (cm) | \n49.68 ± 0.46 | \n50.20 ± 1.27 | \nNS | \n
BMI (kg/m2) | \n12.72 ± 1.66 | \n13.13 ± 1.02 | \nNS | \n
Ponderal index (kg/m3) | \n25.61 ± 3.33 | \n26.18 ± 2.26 | \nNS | \n
Glucose (mg/dL) | \n93.91 ± 31.28 | \n70.70 ± 14.84 | \n0.044 | \n
Insulin (μIU/mL) | \n12.46 ± 10.69 | \n3.98 ± 3.24 | \n0.040 | \n
Cortisol (μg/dL) | \n8.93 ± 3.46 | \n7.14 ± 2.56 | \nNS | \n
GH (ng/mL) | \n17.20 ± 13.01 | \n17.49 ± 9.25 | \nNS | \n
IGF-1 (ng/mL) | \n58.41 ± 32.02 | \n57.55 ± 28.11 | \nNS | \n
HOMA-IR | \n3.69 ± 5.25 | \n0.73 ± 0.67 | \n0.038 | \n
QUICKI | \n0.39 ± 0.07 | \n0.45 ± 0.14 | \nNS | \n
Glucose/insulin | \n17.49 ± 10.61 | \n40.30 ± 41.71 | \nNS | \n
Insulin/cortisol | \n1.94 ± 2.98 | \n0.60 ± 0.47 | \n0.057 | \n
Effects of maternal adherence to mediterranean diet (MDA) during pregnancy on different neonatal parameters.
Data are means ± standard deviations; BMI, body mass index; GH, growth hormone; IGF-1: insulin-like growth factor-1; QUICKI, quantitative insulin sensitivity check index; HOMA-IR, homeostatic model assessment-insulin resistance; NS, not significant.
Thus, the conjoint presence of high cortisolaemia–high insulinaemia at birth was clearly associated with pregnancy diet characteristics. In no case, neonatal hyperinsulinaemia or neonatal hyperinsulinaemia
Thus, in the absence of known factors (reduced gestational age, reduced neonatal body weight, foetal distress) that would suggest limited and stressed gestation, pregnancy diet characteristics (MDA) clearly affect glycaemic hormone balance, and thus insulin sensitivity/resistance at birth.
\n\nThe results of this chapter show the importance of analysing insulin and cortisol cord-blood concentrations even in term, normoweight neonates. Results show for the first time on the international bibliography that about 9% of term, normoweight, without foetal-distress neonates, showed increased values (≥P75 of reference values) for both cord-blood insulin and cortisol.
\nThe insulinaemia affected the insulin sensitivity/resistance markers more than cortisolaemia in the different neonate groups classified according to cortisol and insulin levels. In those neonates, GH values appear decreased, a fact that in addition to the join presence of high cortisol-high insulin induces decreases in insulin sensitivity in those neonates without affecting body weight as they were normoweight. IGT was more prevalent in mothers whose neonates were hyperinsulinaemic at birth. In addition, a follow-up study of this neonatal population is needed in order to assess the importance of the present findings. Mothers with adequate MDA score diet delivered newborns presenting healthier insulin and cortisol profiles. This finding suggests the benefits of following an adequate diet through gestation. It will allow the design of future interventions aimed to decrease the metabolic syndrome risk later in life.
\nWork suppported by the Spanish Project AGL 2014-53207-C2-2-R. We acknowledge the mothers and neonates that participated in the Merida Study. The help and assessments of Gynaecology and Obstetrics, Paediatrics and Hospital Laboratory are also acknowledged.
\nConsidered the second most commonly performed operation after cesarean section worldwide, hysterectomy may be classified as abdominal (laparotomy, laparoscopy, or robotic assistance) and vaginal (via an incision through the superior part of the vagina).
The most common indications for hysterectomy are benign conditions such as uterine fibroids, endometriosis, genital prolapse, pelvic pain, heavy menstrual bleeding, but the technique is also used for gynecological malignancy (usually ovarian, uterine, or cervical) and risk-reducing surgery (in cases of BRCA 1 or 2 mutations or Lynch syndrome) [1, 2, 3, 4].
Actually, there are three types of hysterectomy—total hysterectomy (the uterus and cervix are removed), subtotal or partial hysterectomy (the uterus is removed, but the cervix is left in place), and total hysterectomy with bilateral salpingo-oophorectomy (uterus, fallopian tubes, ovaries, and cervix are removed) [1, 2, 3, 4]. The term radical hysterectomy (removal of the uterus, cervix, parametrium, vaginal cuff, and fallopian tubes) is used to describe a wide range of procedures universally applicable to cervical cancer. However, the degree of radicality clearly depends on preoperative estimation of tumor location, surgical margins and the risk of occult lymphatic spread. Moreover, the ovaries may or may not be removed according to the patient age [1, 2, 3, 4]. In addition, supracervical hysterectomy is sometimes preferred to diminish the intraoperative complications and surgical times, as well as to limit the possibility of lower urinary tract issues and maintain normal sexual function [1, 2, 3, 4].
The best route for hysterectomy is multifactorial, depending not only on the surgeon’s skills and patient safety (minimally invasive procedures as vaginal, laparoscopic, laparoscopic-assisted, and robotic-assisted hysterectomies) but also on economic reasons [1, 2, 3, 4].
Hemorrhage after hysterectomy is recognized as an occasional life-threatening complication in modern gynecological surgery, assuming appropriate medical and surgical management [2, 3, 4, 5, 6, 7, 8, 9].
Classified as “reactionary” (postoperative bleeding within the first 24 hours following surgery) and secondary (bleeding occurring in the interval 3–22 days after surgery), unexpected hemorrhage may arise regardless of the route or subtype of hysterectomy [5, 6, 9]. Early recognition and prompt intervention (reoperation or arterial embolization) to arrest bleeding are essential strategies for the suitable outcome of the patient [2, 3, 4, 5, 6, 7, 8, 9, 10].
While the role of risk factors for “reactionary” hemorrhage is emerging and critical for a correct assessment of the patient, operative laparoscopy is still ideal to treat hemorrhage after vaginal hysterectomy, laparoscopic hysterectomy, laparoscopic-assisted vaginal hysterectomy, and laparotomy being necessary only in selected cases [2, 3, 4, 6, 9].
Secondary hemorrhage presents with varying degrees of severity and tends to be more common after laparoscopic hysterectomy, especially total laparoscopic hysterectomy than after the other hysterectomy approaches [5, 9]. Factors potentially responsible are vaginal vault infection, vault hematoma, a poor surgical technique including excessive thermal injury by electrocoagulation, and early resumption of physical activity, large uterus size, excessive use of an energy source for the uterine artery, and culdotomy [2, 3, 4, 5, 7, 9, 10].
Ultimately, the management of secondary hemorrhage is challenging and involves diverse approaches based on the exact cause of bleeding, comprising vaginal packing with or without vault suturing, laparoscopic coagulation of the uterine artery if the source of bleeding could not be identified vaginally or arterial embolization [6, 9, 10].
Because of elective gynecologic surgery, we encourage selective patients to donate their own blood before surgery [6, 11]. Several definitions are actually used:
autologous blood transfusion, when is done with the patient’s own blood; blood is stored and can be transfused during surgery;
homologous transfusion or transfusion from another woman;
parachute pack or umbrella pack is a useful tool for pelvic bleeding after pelvic exenteration;
peanut dissector; this tool is indicated for blunt pressure dissection of small places;
total blood volume; estimated blood volume of total body weight is 8% or 4.5–5.0 liters in the average women. When intraoperative blood loss exceeds 15% of the blood volume, blood transfusion must be taken into consideration in combating hypovolemic shock. About 15% of an adult blood volume can be calculated by amplification a patient’s weight in kg 10 times. The usual method of performing abdominal hysterectomy involved the use of clamps or forceps on vessels.
The present chapter will give an overview on different aspects of bleeding after hysterectomy such as incidence rate, risk factors, mechanisms, and management techniques aiming to expand our knowledge and skills in recognizing and treating this unexpected potentially serious complication. Furthermore, we intend to offer a guide toward standardizing treatment practice across bleeding issues following hysterectomy considering clear recommendations and algorithms.
Postoperative hemorrhage represents a significant potential complication of contemporary gynecological surgery. Despite normal hemostasis, appropriate/suitable surgical technique and close monitoring, postoperative bleeding may occur, leading to the different clinical and operative scenarios and challenging even the most experienced operative team [2, 3, 4, 9, 11, 12].
Based on their timing to surgery, two main subtypes of postoperative hemorrhage are actually recognized [5, 6, 7, 8, 9]:
Although the incidence of postoperative hemorrhage basically varies according to surgery, the difference between abdominal, laparoscopic, and vaginal hysterectomy remains statistically insignificant [5, 6, 7]. Indeed, some authors postulate that postoperative bleeding occurs more frequently after abdominal and laparoscopic than after vaginal hysterectomy, but overall, the incidence of hemorrhagic events after a hysterectomy varies from 0.2 to 3.1%, irrespective of surgical route [5, 6, 7, 8, 10, 13, 14].
On the other hand, the true frequency of delayed bleeding complications is still unknown, although the consequences can be particularly significant in women undergoing outpatient surgery [5, 6, 7, 8, 10, 13, 14]. Paul et al. reported an overall cumulative incidence of secondary hemorrhage after a total laparoscopic hysterectomy of 1.3% [5]. Although secondary hemorrhage is rare, it is more often reported after total laparoscopic hysterectomy than after other hysterectomy approaches [5, 6, 7, 8, 10, 13, 14].
Table 1 summarizes data on the incidence of postoperative hemorrhage reported by several authors.
Authors | Type of study, no of cases | Incidence postoperative hemorrhage |
---|---|---|
Makinen et al. [15] |
|
|
Wilke et al. [13] |
|
|
Holub and Jabor [7] |
|
|
Erian et al. [6] | 719 patients between November 1990 and March 2007: 476 VH, 243 LH |
|
Paul et al. [5] |
|
|
Incidence of postoperative hemorrhage in gynecological surgery.*
AH, abdominal hysterectomy; LH, laparoscopic hysterectomy; VH, vaginal hysterectomy; L-AVH, laparoscopic-assisted vaginal hysterectomy.
Hemorrhage is responsible for about half of the postoperative complications following gynecological surgery, ranging from persistent venous oozing to massive blood loss from injury to retroperitoneal vessels [5, 6, 7, 12, 13].
Main bleeding sites comprise the anterior abdominal wall (both the suprapubic and the umbilical incision), the vaginal cuff (after laparoscopic hysterectomy and laparoscopic-assisted vaginal hysterectomy), and intraabdominal bleeding. Abdominal wall vessel injury occurs with increasing frequency, as the practice of laparoscopic surgery becomes wider and trocars become sharper [2, 3, 4, 7, 9].
The source of bleeding in secondary hemorrhage can be the uterine vessels or descending cervical/vaginal vessels; occasionally, uterine artery pseudoaneurysm can cause delayed heavy vaginal bleeding after laparoscopic hysterectomy [2, 3, 4, 7, 9]; additionally, the technique of vaginal vault closure may also contribute to the occurrence of secondary hemorrhage [5, 9].
Postoperative hemorrhage can result from failure to control vascular injury during surgery. Accurate clamp placement, gentle handling of tissues, and the accuracy of dissection are all important and contribute to maximum efficiency with minimum blood loss and minimum tissue damage when abdominal hysterectomy is performed [9].
The electrosurgical instrument can be used for a precise incision of the abdominal wall with minimal tissue injury. By holding the electrode close to the tissue or touching the metal clamp and pressing the coagulation button, superficial coagulation can be achieved [2, 3, 4, 9].
Intra- and post-operative bleeding generally develops in younger women or those with a more vascular pelvis who underwent a hysterectomy, especially laparoscopic hysterectomy in the presence of fibroids [6, 16].
Possible rationales for secondary hemorrhage comprise a bleeding vessel missed at the end of the procedure, effects of pneumoperitoneum, Trendelenburg position, low intraoperative pressure, wearing off the effect of vasopressin, subacute infection, postoperative analgesia, as well as bleeding disorders [2, 3, 4, 5, 7, 9].
Other potential factors accounting for delayed postsurgical bleeding are vaginal vault infection, vault hematoma, poor surgical technique with excessive thermal injury by electrocoagulation, and early resumption of physical activity [5, 7, 9]. A large-sized uterus, high vascularity, large-sized vessels, excessive use of an energy source for the uterine artery, and culdotomy also play a role in this hemorrhagic event [5, 7, 9].
Most of the complications during or after hysterectomy are preventable or treatable. Other complications may exist as medical conditions before hysterectomy but are worsened during surgery, especially if not managed as part of holistic woman’s care.
Complications after surgery include [2, 3, 4, 9, 12]:
In Romania, the mortality rate following a hysterectomy is very low.
Contemporary management of surgical interventions includes postoperative bleeding and the possibility of blood transfusion with risks of HIV transmission (in 1.9 million cases), the transmission of hepatitis B (one in every 180.000 cases), or a febrile reaction to transfusion (1% cases) [2]. Most experts recommend acute normovolemic hemodilution and cell salvage in women undergoing hysterectomy section who will not accept blood products.
Hypovolemic shock can occur after major bleeding as a direct result of uncontrolled hemorrhage. Depending on the total blood volume lost, hypovolemic shock may be divided into four classes: I (< 75 mL or 15%), II (750–1500 mL, or 15–30%), III (1500–2000 mL or 30–40%) and IV (>2000 mL or > 40%) [6].
The clinical manifestations of class I hypovolemia are not measurable and compensatory mechanisms restore plasma volume within a day. In class II hypovolemia, tachycardia is the most frequent clinical finding as a result of inadequate circulatory volume. The distinction between class I and II hypovolemic shock is made by recording blood pressure and pulse in the standing, sitting, or reclining position. Postural hypotension is observed as result of cardiac failure. Compensatory mechanisms begin to fail with the class III hypovolemic shock. This results in an increase in the arterial and venous oxygen difference with classic signs including worked tachycardia, tachypnea, oliguria, and cold skin. With the class IV hypovolemic shock, a patient’s survival depends on rapid transfusion of blood and immediate surgical intervention before cardiovascular collapse and death or organ system failure.
After initial resuscitative measures are instituted, it is highly recommended for patients to be carried out in a critical care unit. Use of sympathomimetic agents after sufficient hydration and vasodilator is normally preferred in the management of patients with hemorrhagic shock who have arterial pressure higher than 70 mm Hg.
Once restoration of the intravascular volume has been completed, it is important to reassess the patient’s response to blood transfusion when managing women with severe blood loss, especially in those patients who have pulmonary edema, myocardial infarction, or congestive heart failure [12].
Transfusion for patients with hemoglobin of 8–10 mg/dL is no longer recommended.
When major surgery is anticipated and transfusion is massive, platelets in addition to packed cell transfusion are required. It is recommended that cryoprecipitate be reserved for patients with deficiencies in von Willebrand factor, factor VIII, and fibrinogen factor XIII.
Recognized as an uncommon complication of hysterectomy, postoperative hemorrhage represents a true challenge in routine practice [8]; irrespective of the procedure, a close follow-up of the patient in a high-dependency unit is indicated in order to exclude recurrence of bleeding [6, 7].
The key to successful management is timely intervention meaning prompt diagnosis, urgent resuscitation if necessary and rapid decision for either arterial embolization or reoperation according to the severity of bleeding and the hemodynamic stability of the patient. Both techniques are highly effective to control bleeding; nevertheless, if the patient is hemodynamically unstable or of the interval since surgery is under 24 hours suggesting rapid hemorrhage, the emergency return to the operating theater to arrest the bleeding is preferred [6, 7, 9].
Current options for managing hemorrhage include [6, 7, 9]:
every patient should be carefully monitored postoperatively for signs of bleeding (hypotension, tachycardia, tachypnea, abdominal distension);
ultrasound can confirm intraperitoneal bleeding; more ways to determine intraabdominal hemorrhage include abdominal and pelvic CT scan; a routine coagulation profile should be done immediately for the patient with a rapid pulse, low blood pressure, and/or low urine output. The surgeon must take charge of the problem and execute the technical steps necessary to treat hemorrhagic shock in the operating room. Intraperitoneal bleeding can be hidden by incisional pain and analgesic medications. Despite adequate dissection, a small vessel may bleed or the suture may cut through tissue. Skeletonized vessels and small sutures should be used for significantly reducing the incidence of postoperative hemorrhage. Venous bleeding can be more life-threatening than arterial hemorrhage which can be clearly seen and controlled with fast small sutures or clamps.
the presence of unexpected drop in hematocrit or hemoglobin postoperatively.
A simplified algorithm to describe steps after gynecological surgery and potential post-surgery bleeding is provided in Figure 1.
A simplified algorithm of post-surgery bleeding approach.
A closer look at the holistic management of postoperative blood should also underpin the following [9]:
to assess blood value and coagulation mechanisms;
to identify changes in the coagulation components, and to initiate replacement therapy in order to achieve adequate hemostasis. In assessing the patient’s coagulation status, it is very important to avoid such a situation known as the trauma triad of death consisting of—hypothermia, metabolic acidosis, and coagulopathy. In some patients with benign disease, blood transfusion is rarely indicated. Experience has shown that blood transfusion may be significant in women with malignant disease;
to establish the therapeutic strategy by measuring the level of prothrombin time < 14 sec, activated partial thromboplastin time (aptt) < 40 sec, fibrinogen >100 mg/dL, platelets >80 × 103 mL.
In hemodynamically unstable women (rapid pulse, falling blood pressure, with or without renal impairment) or if the bleeding occurs shortly in post-surgery (the so-called reactionary hemorrhage), it is desirable to return to the operating room [5, 6, 7, 8, 9].
A preoperative abdominal and pelvic ultrasound or CT scan is routinely required to visualize the source of bleeding as being intra- or retro-peritoneal, as well as adequate local examination without or under anesthesia. Moreover, the operative procedure should be mentally revised to identify any potential bleeding issue [9].
Surgical revision for postoperative bleeding may be performed transvaginally, laparoscopically, or both [5, 6, 7, 8, 9, 13, 14].
Postoperative hemorrhage from the vaginal vault recurrently originates from the vaginal artery in the lateral vaginal fornix or from one of its branches, since the lateral vaginal angle which includes the vaginal artery may not be accurately protected or turn into disligated [9, 13, 14]. Excessive vaginal bleeding needs to be objectively measured; since the vagina is a distensible organ, clots obstructing the vaginal introitus may lead to a large amount of blood accumulating and distending the vagina, subsequently covering the true significance of hemorrhage [9, 13, 14]. Vaginal bleeding can be controlled by clamping and ligating the bleeding point as well as by delayed-absorbable transfixion suturing of the vaginal mucosa and paravaginal tissue [9, 13, 14]. If such techniques are not enough or bleeding vessels have retracted, other tactics should be intended [8].
When no noticeable vaginal source, bleeding after abdominal or vaginal hysterectomy is traditionally treated by laparotomy or laparoscopy [7, 9]. While laparotomy is recommended in cases of intraperitoneal bleeding or unsuccessful conservative transvaginal treatment, operative laparoscopy is clearly indicated if the source of bleeding cannot be identified by the means of vaginal examination and/or if an intraabdominal bleeding source is suspected [7, 9, 13].
Post-surgery bleeding requires laparotomy in two situations.
Firstly, if the surgical hemostasis cannot be achieved transvaginally, laparotomy may be necessary [9].
Secondly, if the patient underwent an abdominal hysterectomy, the incision should be reopened, succeeding the following steps (i) clots and blood evacuation from the abdomen and pelvic area; (ii) searching of the potential bleeding sites, commencing with the most expected places; (iii) ligating, suturing, or clipping of the identified bleeding sites; (iv) verifying the ureteral integrity as high risk of ureteral damage during reoperation; and (v) closing second time after a completely dry abdomen and pelvis [9].
The laparoscopic approach to postoperative bleeding following laparoscopic hysterectomy, vaginal hysterectomy, or laparoscopic-assisted vaginal hysterectomy is an attractive alternative to the abdominal surgical approach in the majority of patients [6, 7, 9, 13]. The procedure can be used to adequately evaluate the pelvis and the abdominal wall, which is occasionally the source of hemorrhage after laparoscopic hysterectomy. Moreover, whether the bleeding is from the abdominal wall, the surgical pedicles, or the vaginal cuff, it can be managed laparoscopically [8, 9]. Evidently, hemostasis can be more easily obtained in laparoscopic surgery because of magnification, close inspection, routine use of suction irrigation, and bipolar coagulation [7, 9]. Besides, bipolar coagulation, a Foley catheter introduced in the port-site bleeding, or a collagen-fibrin agent can be used to achieve local hemostasis during laparoscopy [7, 9].
Following laparoscopic irrigation/suction using Ringer’s solution to clear the operative field, a combination of laparoscopic suturing using absorbable suture material and laparoscopic bipolar coagulation is commonly recommended [6, 8, 9]. Also, electrosurgery is effective in controlling bleeding during laparoscopic surgery. Furthermore, different forms of fibrin adhesive are tested in gynecologic open surgery in order to stop oozing hemorrhages after primary hemostatic treatment with a high efficacy rate (98%) [6]. Holub and Kliment reported successful treatment of hemorrhage from damaged tissue near important pelvic structures using the laparoscope to apply collagen fleece combined with fibrin glue [7, 17].
To avoid further risk of injury to the abdominal wall and to improve the recovery time from surgery,
Conversely, if the patient is reasonably stable and there is not abrupt early bleeding (based on the volume of blood in the abdomen or retroperitoneal space as estimated by ultrasound and the time from surgery), it seems realistic to try to identify the bleeding artery and embolize it by transcatheter interventional radiological techniques [2, 3, 4, 9, 10].
Arterial embolization remains an important minimally invasive option for the management of delayed postoperative hemorrhage [2, 3, 4, 8, 9, 18]. Transcatheter arterial embolization has been shown to be an effective tool for the management of postoperative hemorrhage after gynecologic laparoscopy, but also after abdominal and vaginal hysterectomy [8, 9]. Selective angiographic arterial embolization is a quite simple and safe procedure with a clinical success rate up to 90% in routine practice and usually a low complication rate less than 10%, including a mild postembolization syndrome with pain, fever, high leucocyte count related to vascular thrombosis and tissue necrosis [8, 9]. Bladder necrosis, vesicovaginal fistula, neuropathies as well as renal toxicity are uncommon, isolated side effects [9].
Arterial embolization technique comprises the following main steps—(i) identification of the site of bleeding by angiofluoroscopy if more than 2–3 mL/min bleeding rate; (ii) percutaneous catheterization of the femoral artery or, uncommonly, brachial artery under local anesthesia with retrograde direct access to the hypogastric artery; (iii) canulation of the hypogastric artery or specific collateral vessel if appropriate; (iv) injection of the embolization material under angiographic observation (metal coins, autologous clot, small pieces of gelfoam, small silastic spheres, subcutaneous tissue, or other hemostatic materials; (v) repeat angiography to demonstrate the occlusion of the bleeding vessel; (vi) remove of the catheter followed by careful monitoring for further bleeding [8, 9, 10].
Although second surgery is often the initial choice for postoperative hemorrhage, for a patient who is hemodynamically stable but is experiencing postoperative hemorrhage, transcatheter arterial embolization is a welcome alternative to a second surgery [8, 9]. However, if rapid access to interventional radiology is not available or if transcatheter arterial embolization is unsuccessful, laparoscopy can still be considered [8, 9]. Besides, a potential advantage of surgical management of postoperative hemorrhage over transcatheter arterial embolization is the ability to evacuate the hemoperitoneum, which may decrease postoperative pain, the risk of infection, and the risk of ileus [8, 9].
It is typical to expect some bleeding after hysterectomy in the 6–8 weeks following the procedure; the discharge may be red, brown, or pink. Bleeding should steadily decrease in the days and weeks following the surgery and should never be excessive at any point of recovery [18]. The exception is menstruation in women who have undergone a subtotal hysterectomy [18, 19]. In case of bleeding after hysterectomy, it is more likely to be of some pathologic cause instead of menstruation which needs to be ruled out [19].
However, a sudden and significant increase in bleeding during recovery should be considered abnormal. Points of concern comprise but are not limited to—bright red vaginal bleeding (indicating active bleed), temperature over 100.4°F, severe nausea or vomiting, increasing pelvic pain, a local complication such as redness, swelling, or drainage at the incision site as well as difficulty in urinating or pain with urination suggesting either an infection or a neurogenic bladder [18].
Delayed vaginal hemorrhage after laparoscopic supracervical hysterectomy usually requires emergent reoperation. Several studies have described continued cyclical bleeding from the cervical stump after supracervical hysterectomy in 0–25% of cases [20].
Effective interventions addressing hemorrhage after hysterectomy are needed to reduce women’s mortality worldwide.
Prior to hysterectomy, these women should be offered specific counseling and have a prospective plan for the management of their disease, developed by gynecologists of how their condition and hysterectomy interact. Prehysterectomy counseling services starting for all women planning this surgical intervention are a key part of hospital services and should be an integral part of the local health services network. They could be provided by general practitioners or specialist clinicians or surgeons, all of whom should be suitably trained or may require different management or specialized services before hysterectomy. There are special circumstances as congenital or acquired coagulation disorders that should be considered to evaluate by a thorough history and lab tests.
Professional interpretation services for women who do not speak English.
It is not clear how much the specific medical terminology is conveyed to the patient. Healthcare providers have to invest in technology, security, specialists, and translators to ensure healthcare becomes world-class. Medical tourism is growing each year. Romania provides the highest quality healthcare at the lowest price. Also, the cost of hysterectomy in Romania is lower than the same treatment in UK or UE. In developed countries as the USA, UE countries or Canada patients have to wait a long time for major surgeries. The cost involved in treating a patient depends upon factors like—type of hysterectomy needed, hospital and physician selected for it, and duration of staying.
Communication and referrals among professionals.
Good communication among professionals is essential. Referral between specialties involved should be rapid. They can use a variety of communication methods including—mobile phone, email, fax, Whatsapp, Instagram, Tik Tok, Facebook, etc. In many cases, junior trainees in the front line did not have proper support and need to have clear guidelines about when to seek senior help.
Women with serious medical conditions
They require immediate and appropriate multidisciplinary specialist care; women will require referral to tertiary or specialist medical centers for their preexisting medical or mental conditions before hysterectomy. Conditions that require prehysterectomy counseling and advice include—epilepsy, diabetes, asthma, congenital or known acquired cardiac disease, autoimmune disorders, renal and liver disease, obesity (BMI > 30), severe mental illness, or psychiatric conditions that require a change of medication, HIV infection. Women with potential serious underlying preexisting medical on mental health conditions should be immediately referred to appropriate specialist centers of expertise as soon as their symptoms develop.
Clinical training
All clinical staff must undertake regular training for the identification and management of serious disease conditions or potential emergencies or signs and symptoms of potentially life-threatening conditions, circulatory failure, severe hypertension or major hemorrhage, pyrexia >38°C, tachycardia >100 bpm, breathlessness. The local clinicians may be excellent at the management of severely ill women but must also accept written, documented, and audited courses. There should be a well-trained team of doctors for recording and charting investigations performed, obtaining quick results, ensuring that abnormal results are followed up promptly and have resulted in a better outcome.
Identifying and managing very sick women with critical illness before, during or after hysterectomy
In very acute situations, a team approach can be very healthful. The management of patients with an acute severe illness with circulatory failure, arterial hypertension, and major hemorrhage requires a team approach and help from the anesthetic and critical care services. There are some healthcare professionals who failed to manage crisis situations outside their immediate area of expertise; therefore, it is crucial to recognize their limitations and to know when and whom to call for another opinion once the patient was admitted to the hospital.
Coagulation factors, hematocrit, serum calcium, glucose, and electrolytes could be assessed every 120 minutes or after 10 U of transfusion; these lab tests are very helpful for the diagnosis of postoperative bleeding.
RCOG guidelines of the responsibilities of the consultant on call should be followed.
Bilateral hypogastric artery ligation can reduce blood loss to a minimum during hysterectomy [9].
Hypotensive anesthesia is also a safe and effective technique in reducing the circulation to the operative field [9].
Serious incident and women death reporting
Health professionals, senior or junior, must recognize an act on the signs and symptoms of potentially life-threatening conditions.
The evaluation of such a report must include clinicians from relevant disciplines (including anesthetics) who were not involved with the deaths. This report is recommended to be a requirement in the future.
The identification and act on women’s death should be reviewed as a serious incident and disseminated to all health professionals, junior or senior. Women’s deaths are generally underreported because of incorrect classification of cause.
Fatal hemorrhage can result from laceration of the external iliac vein or the hypogastric vein where they join together which are at risk of injury when the surgeon dissects between the distal common iliac artery, the psoas muscle, and the area of lumbosacral nerve trunks [9]. These vessels cannot be clamped and ligated with clips or sutures [9].
Dissection around the aorta and vena cava done with inadequate exposure performed in order to remove lymph nodes around them can result in serious hemorrhage. Bleeding usually can be avoided by placing a finger over the laceration and a vascular needle is used to close the laceration from side to side. The same technique may be used for common and external iliac veins [9].
Also, bleeding can occur by dissecting pararectal space and presacral space as well as obturator fossa [9].
Pathology
Patient death autopsy must be improved and require more expertise.
In Romania, the number of women death after hysterectomy (death rate) is very small and many of the autopsies reviewed were considered adequate. When an autopsy is needed, the body can be taken to another area for more expert examination. Despite evaluation by many examiners in the different specialties, the final diagnosis could not be resolved because of inadequate clinical data, poor autopsy quality, or the unmanageable nature of some death.
The lack of routine observation in the postoperative period or a failure to appreciate blood loss or recognition of abnormal vital signs such as oxygen saturation and respiratory rate can lead to death after hysterectomy. The patient should be evaluated before hysterectomy for risk factors and the medical conditions of the women should be diagnosed by a careful history and lab tests in order to decrease the possibility of hemorrhage.
The risks of blood transfusion, the transmission of HIV or hepatitis B should be discussed before surgical procedure.
The peace of surgical intervention should be governed by good exposure of the tissue, accuracy of dissection, and clamping or suturing the vessels in a precise manner. The skills and experiences of the surgeon without wasting time with unnecessary hesitation or indecision will reduce the risk of uncontrolled hemorrhage after a hysterectomy.
The surgeon should control the life-threatening hemorrhage by judgment, knowledge, and technical skills. The patient’s medical history for vital signs, blood loss volume, and levels of coagulation factors will determine how quickly blood transfusion is initiated. Careful postoperative clinical evaluation of the patient by the surgeon and surgical team with abdominal or pelvic ultrasound or CT scanning will help to prevent or minimize significant blood loss after hysterectomy and localize the site of bleeding.
No funding was received for this chapter.
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Spontaneous mutation, the natural process that develops new allele copies of a gene was the only source of genetic diversity until the 20th century. Besides, mutations can also be induced artificially using physical or chemical mutagens. Chemical mutations received popularity due to its efficiency in creating gene mutations contrary to chromosomal changes. Mutation has played a vital role in the improvement of crop productivity and quality, resultantly > 3,000 varieties of 175 plant species have been developed either through direct or indirect induced mutation breeding approaches worldwide. The advances in plant breeding also achieved through molecular marker technology. The in vitro mutagenesis, heavy-ion beam, and space mutation breeding are being efficiently used to create genetic variability to improve various complicated traits in crop plants. In mutation breeding, TILLING (Targeting Induced Local Lesions in Genomes), a more advanced molecular technique is being used to identify specific sequential genomic changes in mutant plants. Therefore, the mutation breeding in combination with molecular techniques could be an efficient tool in plant breeding programs. This chapter will discuss and review the mutation breeding application for the improvement of crop productivity and environmental stresses.",book:{id:"9743",slug:"genetic-variation",title:"Genetic Variation",fullTitle:"Genetic Variation"},signatures:"Arain Saima Mir, Meer Maria, Sajjad Muhammad and Sial Mahboob Ali",authors:[{id:"329068",title:"Dr.",name:"Arain Saima Mir",middleName:null,surname:"Saima Mir",slug:"arain-saima-mir-saima-mir",fullName:"Arain Saima Mir Saima Mir"},{id:"330046",title:"Ms.",name:"Meer",middleName:null,surname:"Maria",slug:"meer-maria",fullName:"Meer Maria"},{id:"330047",title:"Dr.",name:"Sajjad",middleName:null,surname:"Muhammad",slug:"sajjad-muhammad",fullName:"Sajjad Muhammad"},{id:"330048",title:"Dr.",name:"Sial",middleName:null,surname:"Mahboob Ali",slug:"sial-mahboob-ali",fullName:"Sial Mahboob Ali"}]},{id:"65713",title:"Introductory Chapter: Population Genetics - The Evolution Process as a Genetic Function",slug:"introductory-chapter-population-genetics-the-evolution-process-as-a-genetic-function",totalDownloads:2402,totalCrossrefCites:0,totalDimensionsCites:0,abstract:null,book:{id:"6974",slug:"integrated-view-of-population-genetics",title:"Integrated View of Population Genetics",fullTitle:"Integrated View of Population Genetics"},signatures:"Rafael Trindade Maia and Magnólia de Araújo Campos",authors:[{id:"212393",title:"Prof.",name:"Rafael",middleName:"Trindade",surname:"Maia",slug:"rafael-maia",fullName:"Rafael Maia"}]},{id:"71577",title:"Single Nucleotide Polymorphisms (SNPs) in Plant Genetics and Breeding",slug:"single-nucleotide-polymorphisms-snps-in-plant-genetics-and-breeding",totalDownloads:1556,totalCrossrefCites:9,totalDimensionsCites:11,abstract:"Recent advances in genome technology revealed various single nucleotide polymorphisms (SNPs), the most common form of DNA sequence variation between alleles, in several plant species. The discovery and application of SNPs increased our knowledge about genetic diversity and a better understanding on crop improvement. Natural breeding process which takes an agelong time during collecting, cultivating, and domestication has been accelerated by detecting dozens of SNPs on various species using advanced biotechnological techniques such as next-generation sequencing. This will result in the improvement of economically important traits. Therefore, we would like to focus on the discovery, current technologies, and applications of SNPs in breeding. The chapter covers the following topics: (1) introduction, (2) application of SNPs, (3) techniques to detect SNPs, (4) importance of SNPs for crop improvement, and (5) conclusion.",book:{id:"7947",slug:"the-recent-topics-in-genetic-polymorphisms",title:"The Recent Topics in Genetic Polymorphisms",fullTitle:"The Recent Topics in Genetic Polymorphisms"},signatures:"Hande Morgil, Yusuf Can Gercek and Isil Tulum",authors:null},{id:"71702",title:"Single-Nucleotide Polymorphisms in Inflammatory Bowel Disease",slug:"single-nucleotide-polymorphisms-in-inflammatory-bowel-disease",totalDownloads:1032,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"Inflammatory bowel disease (IBD) mainly includes ulcerative colitis (UC) and Crohn’s disease (CD). Both conditions are characterized by chronic inflammation of the gastrointestinal tract, with alternating periods of relapse and remission. Both forms of IBD involve an uncontrolled inflammatory process in the intestines, leading to worsening quality of life and requiring long-term medical and/or surgical intervention. Epidemiological and clinical studies suggest that the pathogenesis of inflammatory bowel disease is strongly linked to genetic predisposition. CD and UC are considered polygenic diseases in which familial clustering is observed in 5–10% of patients. Among genetic factors associated with IBD development, it has been found that many single nucleotide polymorphisms are associated with susceptibility to IBD progression. SNP can affect the production or function of a protein and thus affect the development of the disease. However, although the overall role of genes involved in the development of IBD is already in most cases known, as of today it is unclear how the SNPs in these genes affect cellular function, or how such changed cellular functions would contribute to the development of IBD. In the present work several selected polymorphisms in genes involved in IBD development are discussed.",book:{id:"7947",slug:"the-recent-topics-in-genetic-polymorphisms",title:"The Recent Topics in Genetic Polymorphisms",fullTitle:"The Recent Topics in Genetic Polymorphisms"},signatures:"Ewa Dudzińska",authors:null}],onlineFirstChaptersFilter:{topicId:"61",limit:6,offset:0},onlineFirstChaptersCollection:[{id:"82120",title:"Perspective Chapter: Nutraceutical Diversity of Eco-Friendly Jute and Allied Fibre (JAF) Crops in Bangladesh",slug:"perspective-chapter-nutraceutical-diversity-of-eco-friendly-jute-and-allied-fibre-jaf-crops-in-bangl",totalDownloads:26,totalDimensionsCites:0,doi:"10.5772/intechopen.102664",abstract:"The animal meats contain harmful fat and cholesterol contents but plants are the important sources of secondary metabolites that play important role against diseases, and showed less side effects. Jute, Kenaf and Mesta are self-pollinated annual herbaceous plants used to produce fibre contents. These plants are also used for nutritional purposes. Jute leaves contain vitamins, minerals, energies, macromolecules, phytochemicals, micronutrients, amino acids, anti-oxidants essential to promote human health. Only two species of jute (C. capsularis and C. olitorius) are commercially cultivated for fibre content. Olitorius leaves are sweet but capsularis leaves are bitter in taste. The young twigs and leaves of olitroius jute are used as delicious vegetable, and some capsularis cultivars released in Bangladesh can be used as leafy vegetables at young stage. C. olitorius is known as Molokhia and used as green leafy vegetable (GLV) in African and Eastern countries as a viscous soup. Hibiscus (Kenaf and Mesta) plants have antioxidants, anticancer, antibacterial and anti-cholesterol qualities. These plants produce multi-coloured lovely flowers used to grace our environment. Kenaf (H. Cannabinus) seeds contain essential amino acids and used as feed meals for the birds in different countries. Mesta or Roselle (H. sabdariffa) leaves and calyces have both vegetable and medicinal values.",book:{id:"11355",title:"Population Genetics",coverURL:"https://cdn.intechopen.com/books/images_new/11355.jpg"},signatures:"Mohammad Mia Mukul"},{id:"81118",title:"Status of World’s Unique Animal Genetic Resource of Ladakh",slug:"status-of-world-s-unique-animal-genetic-resource-of-ladakh",totalDownloads:27,totalDimensionsCites:0,doi:"10.5772/intechopen.103767",abstract:"Ladakh is the only typical cold arid zone of our country with extreme climate and hostile condition, the area makes its flora and fauna a unique one and distinct from rest of the country. Around 60% of the farmers of Ladakh are Pastoralist and 40% of the farmers are agriculturist and the majority of the economic income comes from animal rearing in Ladakh. It has some of the world’s best animal genetic resource in the form of Changthangi Pashmina goats, Changthangi Sheep, Malra Goat, Malluk and Purig Sheep, Semi domesticated Yak and its crosses, Bactrian (Double Humped Camel) Zanskari horse, Ladakhi Cattle and Changthangi Dog. All these livestock contributes a lot to the income of the farmers of Ladakh especially the Changthang nomads who are completely dependent on livestock rearing. The livestock in Changthang is reared on extensive system on high altitude pastureland. During the past few decades these unique germplasms are facing several threats for its eco-friendly existence with the human populations. These threats and constraints are figured with possible recommendation and solution in the present study. Ladakh has been deprived of basic research facilities in animal science sector for so many years due to which this unique genetic resources are declining in terms of numbers as well as in production. Another reason is shifting of Ladakh economy from agro pastoralist to tourism business. If necessary steps are not taken immediately a time will reach that all this precious animal will be lost forever. The present article describes the present status and critical issues pertaining to animal genetic resource of Ladakh.",book:{id:"11355",title:"Population Genetics",coverURL:"https://cdn.intechopen.com/books/images_new/11355.jpg"},signatures:"Feroz Din Sheikh"},{id:"81549",title:"Genetic Diversity and Evolution of Yunnan Chicken Breeds of China",slug:"genetic-diversity-and-evolution-of-yunnan-chicken-breeds-of-china",totalDownloads:36,totalDimensionsCites:0,doi:"10.5772/intechopen.102915",abstract:"Chickens are the first type of bird that was domesticated and spread widely in the world to cover the growing demand for animal protein from meat and eggs, and it was cultivated from a wild ancestor known Red junglefowl (Gallus gallus). Yunnan Province is considered the most diverse in culture and biology among all the provinces of China. There are a total of more than 24 chicken breeds in Yunnan Province. These chickens are characterized by good quality of their meat and eggs, a good immune system against diseases, and the ability to adapt to various environmental and administrative conditions. Yunnan Province is one of the centers of domestication and evolutionary of chickens in the world. There are many studies that have been conducted to evaluate and study the genetic diversity and evolutionary relationship within and among chicken breeds in Yunnan Province and their relationship with wild chicken species and other chicken breeds using phenotypic markers, protein polymorphisms, SNPs marker, microsatellite marker, and mitochondrial DNA marker. However, there is no review that summarizes these studies, and most of these studies were authored in the Chinese language. Therefore, we have reviewed all studies that have been conducted on Yunnan chicken breeds diversity in Yunnan Province.",book:{id:"11355",title:"Population Genetics",coverURL:"https://cdn.intechopen.com/books/images_new/11355.jpg"},signatures:"Mohammed Alsoufi and Ge Changrong"}],onlineFirstChaptersTotal:3},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:8,limit:8,total:0},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:90,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:107,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:33,numberOfPublishedChapters:330,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:14,numberOfPublishedChapters:145,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:9,numberOfPublishedChapters:139,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:122,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:112,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:21,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:10,numberOfOpenTopics:1,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!0},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:5,numberOfUpcomingTopics:0,issn:"2753-6580",doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. 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",coverUrl:"https://cdn.intechopen.com/series/covers/3.jpg",latestPublicationDate:"August 4th, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:9,editor:{id:"419588",title:"Ph.D.",name:"Sergio",middleName:"Alexandre",surname:"Gehrke",slug:"sergio-gehrke",fullName:"Sergio Gehrke",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000038WgMKQA0/Profile_Picture_2022-06-02T11:44:20.jpg",biography:"Dr. Sergio Alexandre Gehrke is a doctorate holder in two fields. The first is a Ph.D. in Cellular and Molecular Biology from the Pontificia Catholic University, Porto Alegre, Brazil, in 2010 and the other is an International Ph.D. in Bioengineering from the Universidad Miguel Hernandez, Elche/Alicante, Spain, obtained in 2020. In 2018, he completed a postdoctoral fellowship in Materials Engineering in the NUCLEMAT of the Pontificia Catholic University, Porto Alegre, Brazil. He is currently the Director of the Postgraduate Program in Implantology of the Bioface/UCAM/PgO (Montevideo, Uruguay), Director of the Cathedra of Biotechnology of the Catholic University of Murcia (Murcia, Spain), an Extraordinary Full Professor of the Catholic University of Murcia (Murcia, Spain) as well as the Director of the private center of research Biotecnos – Technology and Science (Montevideo, Uruguay). Applied biomaterials, cellular and molecular biology, and dental implants are among his research interests. He has published several original papers in renowned journals. In addition, he is also a Collaborating Professor in several Postgraduate programs at different universities all over the world.",institutionString:null,institution:{name:"Universidad Católica San Antonio de Murcia",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null},subseries:{paginationCount:3,paginationItems:[{id:"86",title:"Business and Management",coverUrl:"https://cdn.intechopen.com/series_topics/covers/86.jpg",isOpenForSubmission:!0,annualVolume:11970,editor:{id:"128342",title:"Prof.",name:"Vito",middleName:null,surname:"Bobek",slug:"vito-bobek",fullName:"Vito Bobek",profilePictureURL:"https://mts.intechopen.com/storage/users/128342/images/system/128342.jpg",biography:"Dr. Vito Bobek works as an international management professor at the University of Applied Sciences FH Joanneum, Graz, Austria. He has published more than 400 works in his academic career and visited twenty-two universities worldwide as a visiting professor. Dr. Bobek is a member of the editorial boards of six international journals and a member of the Strategic Council of the Minister of Foreign Affairs of the Republic of Slovenia. He has a long history in academia, consulting, and entrepreneurship. His own consulting firm, Palemid, has managed twenty significant projects, such as Cooperation Program Interreg V-A (Slovenia-Austria) and Capacity Building for the Serbian Chamber of Enforcement Agents. He has also participated in many international projects in Italy, Germany, Great Britain, the United States, Spain, Turkey, France, Romania, Croatia, Montenegro, Malaysia, and China. Dr. Bobek is also a co-founder of the Academy of Regional Management in Slovenia.",institutionString:"Universities of Applied Sciences FH Joanneum, Austria",institution:{name:"Universities of Applied Sciences Joanneum",institutionURL:null,country:{name:"Austria"}}},editorTwo:{id:"293992",title:"Dr.",name:"Tatjana",middleName:null,surname:"Horvat",slug:"tatjana-horvat",fullName:"Tatjana Horvat",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002hXb0hQAC/Profile_Picture_1642419002203",biography:"Tatjana Horvat works as a professor for accountant and auditing at the University of Primorska, Slovenia. She is a Certified State Internal Auditor (licensed by Ministry of Finance RS) and Certified Internal Auditor for Business Sector and Certified accountant (licensed by Slovenian Institute of Auditors). At the Ministry of Justice of Slovenia, she is a member of examination boards for court expert candidates and judicial appraisers in the following areas: economy/finance, valuation of companies, banking, and forensic investigation of economic operations/accounting. At the leading business newspaper Finance in Slovenia (Swedish ownership), she is the editor and head of the area for business, finance, tax-related articles, and educational programs.",institutionString:null,institution:{name:"University of Primorska",institutionURL:null,country:{name:"Slovenia"}}},editorThree:null},{id:"87",title:"Economics",coverUrl:"https://cdn.intechopen.com/series_topics/covers/87.jpg",isOpenForSubmission:!0,annualVolume:11971,editor:{id:"327730",title:"Prof.",name:"Jaime",middleName:null,surname:"Ortiz",slug:"jaime-ortiz",fullName:"Jaime Ortiz",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00002zaOKZQA2/Profile_Picture_1642145584421",biography:"Dr. Jaime Ortiz holds degrees from Chile, the Netherlands, and the United States. He has held tenured faculty, distinguished professorship, and executive leadership appointments in several universities around the world. Dr. Ortiz has previously worked for international organizations and non-government entities in economic and business matters, and he has university-wide globalization engagement in more than thirty-six countries. He has advised, among others, the United Nations Development Program, Inter-American Development Bank, Organization of American States, Pre-investment Organization of Latin America and the Caribbean, Technical Cooperation of the Suisse Government, and the World Bank. Dr. Ortiz is the author, co-author, or editor of books, book chapters, textbooks, research monographs and technical reports, and refereed journal articles. He is listed in Who’s Who in the World, Who’s Who in America, Who’s Who in Finance and Business, Who’s Who in Business Higher Education, Who’s Who in American Education, and Who’s Who Directory of Economists. Dr. Ortiz has been a Fulbright Scholar and an MSI Leadership Fellow with the W.K. Kellogg Foundation. His teaching interests revolve around global economies and markets while his research focuses on topics related to development and growth, global business decisions, and the economics of technical innovation.",institutionString:null,institution:{name:"University of Houston",institutionURL:null,country:{name:"United States of America"}}},editorTwo:null,editorThree:null},{id:"88",title:"Marketing",coverUrl:"https://cdn.intechopen.com/series_topics/covers/88.jpg",isOpenForSubmission:!0,annualVolume:11972,editor:{id:"203609",title:"Associate Prof.",name:"Hanna",middleName:null,surname:"Gorska-Warsewicz",slug:"hanna-gorska-warsewicz",fullName:"Hanna Gorska-Warsewicz",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSD9pQAG/Profile_Picture_2022-06-14T11:58:32.jpeg",biography:"Hanna Górska-Warsewicz, Ph.D. is Associate Professor at Warsaw University of Life Sciences and Head of Department of Food Market and Consumption Research. She specializes in the subject of brands, brand equity, and brand management in production, service, and trade enterprises. She combines this subject with marketing and marketing management in both theoretical and practical aspects. Prof. Hanna Górska-Warsewicz also analyzes brands in the context of trademarks, legal regulations and the protection of intangible. She is an author or co-author of over 200 publications in this field, including 8 books. She works with the business sector and has participated in projects for the Ministry of Agriculture and Rural Development and the Ministry of Education and Science in Poland.",institutionString:null,institution:{name:"Warsaw University of Life Sciences",institutionURL:null,country:{name:"Poland"}}},editorTwo:null,editorThree:null}]},overviewPageOFChapters:{paginationCount:47,paginationItems:[{id:"82938",title:"Trauma from Occlusion: Practical Management Guidelines",doi:"10.5772/intechopen.105960",signatures:"Prashanth Shetty, Shweta Hegde, Shubham Chelkar, Rahul Chaturvedi, Shruti Pochhi, Aakanksha Shrivastava, Dudala Lakshmi, Shreya Mukherjee, Pankaj Bajaj and Shahzada Asif Raza",slug:"trauma-from-occlusion-practical-management-guidelines",totalDownloads:8,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Dental Trauma",coverURL:"https://cdn.intechopen.com/books/images_new/11567.jpg",subseries:{id:"2",title:"Prosthodontics and Implant Dentistry"}}},{id:"82654",title:"Atraumatic Restorative Treatment: More than a Minimally Invasive Approach?",doi:"10.5772/intechopen.105623",signatures:"Manal A. Ablal",slug:"atraumatic-restorative-treatment-more-than-a-minimally-invasive-approach",totalDownloads:3,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Dental Caries - The Selection of Restoration Methods and Restorative Materials",coverURL:"https://cdn.intechopen.com/books/images_new/11565.jpg",subseries:{id:"1",title:"Oral Health"}}},{id:"82608",title:"Early Management of Dental Trauma in the Era of COVID-19",doi:"10.5772/intechopen.105992",signatures:"Khairul Bariah Chi Adam, Haszelini Hassan, Pram Kumar Subramaniam, Izzati Nabilah Ismail, Nor Adilah Harun and Naziyah Shaban Mustafa",slug:"early-management-of-dental-trauma-in-the-era-of-covid-19",totalDownloads:2,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Dental Trauma",coverURL:"https://cdn.intechopen.com/books/images_new/11567.jpg",subseries:{id:"2",title:"Prosthodontics and Implant Dentistry"}}},{id:"82767",title:"Teeth Avulsion",doi:"10.5772/intechopen.105846",signatures:"Manal Abdalla Eltahir, Randa Fath Elrahman Ibrahim and Hanan Alharbi",slug:"teeth-avulsion",totalDownloads:20,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Dental Trauma",coverURL:"https://cdn.intechopen.com/books/images_new/11567.jpg",subseries:{id:"2",title:"Prosthodontics and Implant Dentistry"}}}]},overviewPagePublishedBooks:{paginationCount:9,paginationItems:[{type:"book",id:"6668",title:"Dental Caries",subtitle:"Diagnosis, Prevention and Management",coverURL:"https://cdn.intechopen.com/books/images_new/6668.jpg",slug:"dental-caries-diagnosis-prevention-and-management",publishedDate:"September 19th 2018",editedByType:"Edited by",bookSignature:"Zühre Akarslan",hash:"b0f7667770a391f772726c3013c1b9ba",volumeInSeries:1,fullTitle:"Dental Caries - Diagnosis, Prevention and Management",editors:[{id:"171887",title:"Prof.",name:"Zühre",middleName:null,surname:"Akarslan",slug:"zuhre-akarslan",fullName:"Zühre Akarslan",profilePictureURL:"https://mts.intechopen.com/storage/users/171887/images/system/171887.jpg",biography:"Zühre Akarslan was born in 1977 in Cyprus. She graduated from Gazi University Faculty of Dentistry, Ankara, Turkey in 2000. \r\nLater she received her Ph.D. degree from the Oral Diagnosis and Radiology Department; which was recently renamed as Oral and Dentomaxillofacial Radiology, from the same university. \r\nShe is working as a full-time Associate Professor and is a lecturer and an academic researcher. \r\nHer expertise areas are dental caries, cancer, dental fear and anxiety, gag reflex in dentistry, oral medicine, and dentomaxillofacial radiology.",institutionString:"Gazi University",institution:{name:"Gazi University",institutionURL:null,country:{name:"Turkey"}}}]},{type:"book",id:"7139",title:"Current Approaches in Orthodontics",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/7139.jpg",slug:"current-approaches-in-orthodontics",publishedDate:"April 10th 2019",editedByType:"Edited by",bookSignature:"Belma Işık Aslan and Fatma Deniz Uzuner",hash:"2c77384eeb748cf05a898d65b9dcb48a",volumeInSeries:2,fullTitle:"Current Approaches in Orthodontics",editors:[{id:"42847",title:"Dr.",name:"Belma",middleName:null,surname:"Işik Aslan",slug:"belma-isik-aslan",fullName:"Belma Işik Aslan",profilePictureURL:"https://mts.intechopen.com/storage/users/42847/images/system/42847.jpg",biography:"Dr. Belma IşIk Aslan was born in 1976 in Ankara-TURKEY. After graduating from TED Ankara College in 1994, she attended to Gazi University, Faculty of Dentistry in Ankara. She completed her PhD in orthodontic education at Gazi University between 1999-2005. Dr. Işık Aslan stayed at the Providence Hospital Craniofacial Institude and Reconstructive Surgery in Michigan, USA for three months as an observer. She worked as a specialist doctor at Gazi University, Dentistry Faculty, Department of Orthodontics between 2005-2014. She was appointed as associate professor in January, 2014 and as professor in 2021. Dr. Işık Aslan still works as an instructor at the same faculty. She has published a total of 35 articles, 10 book chapters, 39 conference proceedings both internationally and nationally. Also she was the academic editor of the international book 'Current Advances in Orthodontics'. She is a member of the Turkish Orthodontic Society and Turkish Cleft Lip and Palate Society. She is married and has 2 children. Her knowledge of English is at an advanced level.",institutionString:"Gazi University Dentistry Faculty Department of Orthodontics",institution:null}]},{type:"book",id:"7572",title:"Trauma in Dentistry",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/7572.jpg",slug:"trauma-in-dentistry",publishedDate:"July 3rd 2019",editedByType:"Edited by",bookSignature:"Serdar Gözler",hash:"7cb94732cfb315f8d1e70ebf500eb8a9",volumeInSeries:3,fullTitle:"Trauma in Dentistry",editors:[{id:"204606",title:"Dr.",name:"Serdar",middleName:null,surname:"Gözler",slug:"serdar-gozler",fullName:"Serdar Gözler",profilePictureURL:"https://mts.intechopen.com/storage/users/204606/images/system/204606.jpeg",biography:"Dr. Serdar Gözler has completed his undergraduate studies at the Marmara University Faculty of Dentistry in 1978, followed by an assistantship in the Prosthesis Department of Dicle University Faculty of Dentistry. Starting his PhD work on non-resilient overdentures with Assoc. Prof. Hüsnü Yavuzyılmaz, he continued his studies with Prof. Dr. Gürbüz Öztürk of Istanbul University Faculty of Dentistry Department of Prosthodontics, this time on Gnatology. He attended training programs on occlusion, neurology, neurophysiology, EMG, radiology and biostatistics. In 1982, he presented his PhD thesis \\Gerber and Lauritzen Occlusion Analysis Techniques: Diagnosis Values,\\ at Istanbul University School of Dentistry, Department of Prosthodontics. As he was also working with Prof. Senih Çalıkkocaoğlu on The Physiology of Chewing at the same time, Gözler has written a chapter in Çalıkkocaoğlu\\'s book \\Complete Prostheses\\ entitled \\The Place of Neuromuscular Mechanism in Prosthetic Dentistry.\\ The book was published five times since by the Istanbul University Publications. Having presented in various conferences about occlusion analysis until 1998, Dr. Gözler has also decided to use the T-Scan II occlusion analysis method. Having been personally trained by Dr. Robert Kerstein on this method, Dr. Gözler has been lecturing on the T-Scan Occlusion Analysis Method in conferences both in Turkey and abroad. Dr. Gözler has various articles and presentations on Digital Occlusion Analysis methods. He is now Head of the TMD Clinic at Prosthodontic Department of Faculty of Dentistry , Istanbul Aydın University , Turkey.",institutionString:"Istanbul Aydin University",institution:{name:"Istanbul Aydın University",institutionURL:null,country:{name:"Turkey"}}}]},{type:"book",id:"7060",title:"Gingival Disease",subtitle:"A Professional Approach for Treatment and Prevention",coverURL:"https://cdn.intechopen.com/books/images_new/7060.jpg",slug:"gingival-disease-a-professional-approach-for-treatment-and-prevention",publishedDate:"October 23rd 2019",editedByType:"Edited by",bookSignature:"Alaa Eddin Omar Al Ostwani",hash:"b81d39988cba3a3cf746c1616912cf41",volumeInSeries:4,fullTitle:"Gingival Disease - A Professional Approach for Treatment and Prevention",editors:[{id:"240870",title:"Ph.D.",name:"Alaa Eddin Omar",middleName:null,surname:"Al Ostwani",slug:"alaa-eddin-omar-al-ostwani",fullName:"Alaa Eddin Omar Al Ostwani",profilePictureURL:"https://mts.intechopen.com/storage/users/240870/images/system/240870.jpeg",biography:"Dr. Al Ostwani Alaa Eddin Omar received his Master in dentistry from Damascus University in 2010, and his Ph.D. in Pediatric Dentistry from Damascus University in 2014. Dr. Al Ostwani is an assistant professor and faculty member at IUST University since 2014. \nDuring his academic experience, he has received several awards including the scientific research award from the Union of Arab Universities, the Syrian gold medal and the international gold medal for invention and creativity. Dr. Al Ostwani is a Member of the International Association of Dental Traumatology and the Syrian Society for Research and Preventive Dentistry since 2017. He is also a Member of the Reviewer Board of International Journal of Dental Medicine (IJDM), and the Indian Journal of Conservative and Endodontics since 2016.",institutionString:"International University for Science and Technology.",institution:{name:"Islamic University of Science and Technology",institutionURL:null,country:{name:"India"}}}]}]},openForSubmissionBooks:{paginationCount:2,paginationItems:[{id:"12141",title:"Leadership - Advancing Great Leadership Practices and Good Leaders",coverURL:"https://cdn.intechopen.com/books/images_new/12141.jpg",hash:"85f77453916f1d80d80d88ee4fd2f2d1",secondStepPassed:!0,currentStepOfPublishingProcess:3,submissionDeadline:"July 1st 2022",isOpenForSubmission:!0,editors:[{id:"420133",title:"Dr.",name:"Joseph",surname:"Crawford",slug:"joseph-crawford",fullName:"Joseph Crawford"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null},{id:"12139",title:"Global Market and Trade",coverURL:"https://cdn.intechopen.com/books/images_new/12139.jpg",hash:"fa34af07c3a9657fa670404202f8cba5",secondStepPassed:!0,currentStepOfPublishingProcess:3,submissionDeadline:"July 21st 2022",isOpenForSubmission:!0,editors:[{id:"243649",title:"Dr.Ing.",name:"Ireneusz",surname:"Miciuła",slug:"ireneusz-miciula",fullName:"Ireneusz Miciuła"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null}]},onlineFirstChapters:{paginationCount:9,paginationItems:[{id:"82936",title:"Soil Degradation Processes Linked to Long-Term Forest-Type Damage",doi:"10.5772/intechopen.106390",signatures:"Pavel Samec, Aleš Kučera and Gabriela Tomášová",slug:"soil-degradation-processes-linked-to-long-term-forest-type-damage",totalDownloads:2,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Forest Degradation Under Global Change",coverURL:"https://cdn.intechopen.com/books/images_new/11457.jpg",subseries:{id:"94",title:"Climate Change and Environmental Sustainability"}}},{id:"82777",title:"Sustainability and Social Investment: Community Microhydropower Systems in the Dominican Republic",doi:"10.5772/intechopen.105995",signatures:"Michela Izzo, Alberto Sánchez and Rafael Fonseca",slug:"sustainability-and-social-investment-community-microhydropower-systems-in-the-dominican-republic",totalDownloads:4,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Globalization and Sustainability - Recent Advances, New Perspectives and Emerging Issues",coverURL:"https://cdn.intechopen.com/books/images_new/11476.jpg",subseries:{id:"91",title:"Sustainable Economy and Fair Society"}}},{id:"82387",title:"Kept Promises? 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He previously worked as a post-doctoral fellow at the Ben-Gurion University of Negev, Israel; University of the Free State, South Africa; and Central University of Technology Bloemfontein, South Africa. He obtained his Ph.D. in Organic Chemistry from Nagaoka University of Technology, Japan. He has published more than seventy-four journal articles and attended several national and international conferences as speaker and chair. Dr. Kendrekar has received many international awards. He has several funded projects, namely, anti-malaria drug development, MRSA, and SARS-CoV-2 activity of curcumin and its formulations. He has filed four patents in collaboration with the University of Central Lancashire and Mayo Clinic Infectious Diseases. His present research includes organic synthesis, drug discovery and development, biochemistry, nanoscience, and nanotechnology.",institutionString:"Visiting Scientist at Lipid Nanostructures Laboratory, Centre for Smart Materials, School of Natural Sciences, University of Central Lancashire",institution:null},{id:"428125",title:"Dr.",name:"Vinayak",middleName:null,surname:"Adimule",slug:"vinayak-adimule",fullName:"Vinayak Adimule",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/428125/images/system/428125.jpg",biography:"Dr. Vinayak Adimule, MSc, Ph.D., is a professor and dean of R&D, Angadi Institute of Technology and Management, India. He has 15 years of research experience as a senior research scientist and associate research scientist in R&D organizations. He has published more than fifty research articles as well as several book chapters. He has two Indian patents and two international patents to his credit. Dr. Adimule has attended, chaired, and presented papers at national and international conferences. He is a guest editor for Topics in Catalysis and other journals. He is also an editorial board member, life member, and associate member for many international societies and research institutions. His research interests include nanoelectronics, material chemistry, artificial intelligence, sensors and actuators, bio-nanomaterials, and medicinal chemistry.",institutionString:"Angadi Institute of Technology and Management",institution:null},{id:"284317",title:"Prof.",name:"Kantharaju",middleName:null,surname:"Kamanna",slug:"kantharaju-kamanna",fullName:"Kantharaju Kamanna",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/284317/images/21050_n.jpg",biography:"Prof. K. Kantharaju has received Bachelor of science (PCM), master of science (Organic Chemistry) and Doctor of Philosophy in Chemistry from Bangalore University. He worked as a Executive Research & Development @ Cadila Pharmaceuticals Ltd, Ahmedabad. He received DBT-postdoc fellow @ Molecular Biophysics Unit, Indian Institute of Science, Bangalore under the supervision of Prof. P. Balaram, later he moved to NIH-postdoc researcher at Drexel University College of Medicine, Philadelphia, USA, after his return from postdoc joined NITK-Surthakal as a Adhoc faculty at department of chemistry. Since from August 2013 working as a Associate Professor, and in 2016 promoted to Profeesor in the School of Basic Sciences: Department of Chemistry and having 20 years of teaching and research experiences.",institutionString:null,institution:{name:"Rani Channamma University, Belagavi",country:{name:"India"}}},{id:"158492",title:"Prof.",name:"Yusuf",middleName:null,surname:"Tutar",slug:"yusuf-tutar",fullName:"Yusuf Tutar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/158492/images/system/158492.jpeg",biography:"Prof. Dr. Yusuf Tutar conducts his research at the Hamidiye Faculty of Pharmacy, Department of Basic Pharmaceutical Sciences, Division of Biochemistry, University of Health Sciences, Turkey. He is also a faculty member in the Molecular Oncology Program. He obtained his MSc and Ph.D. at Oregon State University and Texas Tech University, respectively. He pursued his postdoctoral studies at Rutgers University Medical School and the National Institutes of Health (NIH/NIDDK), USA. His research focuses on biochemistry, biophysics, genetics, molecular biology, and molecular medicine with specialization in the fields of drug design, protein structure-function, protein folding, prions, microRNA, pseudogenes, molecular cancer, epigenetics, metabolites, proteomics, genomics, protein expression, and characterization by spectroscopic and calorimetric methods.",institutionString:"University of Health Sciences",institution:null},{id:"180528",title:"Dr.",name:"Hiroyuki",middleName:null,surname:"Kagechika",slug:"hiroyuki-kagechika",fullName:"Hiroyuki Kagechika",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/180528/images/system/180528.jpg",biography:"Hiroyuki Kagechika received his bachelor’s degree and Ph.D. in Pharmaceutical Sciences from the University of Tokyo, Japan, where he served as an associate professor until 2004. He is currently a professor at the Institute of Biomaterials and Bioengineering (IBB), Tokyo Medical and Dental University (TMDU). From 2010 to 2012, he was the dean of the Graduate School of Biomedical Science. Since 2012, he has served as the vice dean of the Graduate School of Medical and Dental Sciences. He has been the director of the IBB since 2020. Dr. Kagechika’s major research interests are the medicinal chemistry of retinoids, vitamins D/K, and nuclear receptors. He has developed various compounds including a drug for acute promyelocytic leukemia.",institutionString:"Tokyo Medical and Dental University",institution:{name:"Tokyo Medical and Dental University",country:{name:"Japan"}}},{id:"94311",title:"Prof.",name:"Martins",middleName:"Ochubiojo",surname:"Ochubiojo Emeje",slug:"martins-ochubiojo-emeje",fullName:"Martins Ochubiojo Emeje",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/94311/images/system/94311.jpeg",biography:"Martins Emeje obtained a BPharm with distinction from Ahmadu Bello University, Nigeria, and an MPharm and Ph.D. from the University of Nigeria (UNN), where he received the best Ph.D. award and was enlisted as UNN’s “Face of Research.” He established the first nanomedicine center in Nigeria and was the pioneer head of the intellectual property and technology transfer as well as the technology innovation and support center. Prof. Emeje’s several international fellowships include the prestigious Raman fellowship. He has published more than 150 articles and patents. He is also the head of R&D at NIPRD and holds a visiting professor position at Nnamdi Azikiwe University, Nigeria. He has a postgraduate certificate in Project Management from Walden University, Minnesota, as well as a professional teaching certificate and a World Bank certification in Public Procurement. Prof. Emeje was a national chairman of academic pharmacists in Nigeria and the 2021 winner of the May & Baker Nigeria Plc–sponsored prize for professional service in research and innovation.",institutionString:"National Institute for Pharmaceutical Research and Development",institution:{name:"National Institute for Pharmaceutical Research and Development",country:{name:"Nigeria"}}},{id:"436430",title:"Associate Prof.",name:"Mesut",middleName:null,surname:"Işık",slug:"mesut-isik",fullName:"Mesut Işık",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/436430/images/19686_n.jpg",biography:null,institutionString:null,institution:{name:"Bilecik University",country:{name:"Turkey"}}},{id:"268659",title:"Ms.",name:"Xianquan",middleName:null,surname:"Zhan",slug:"xianquan-zhan",fullName:"Xianquan Zhan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/268659/images/8143_n.jpg",biography:"Dr. Zhan received his undergraduate and graduate training in the fields of preventive medicine and epidemiology and statistics at the West China University of Medical Sciences in China during 1989 to 1999. He received his post-doctoral training in oncology and cancer proteomics for two years at the Cancer Research Institute of Human Medical University in China. In 2001, he went to the University of Tennessee Health Science Center (UTHSC) in USA, where he was a post-doctoral researcher and focused on mass spectrometry and cancer proteomics. Then, he was appointed as an Assistant Professor of Neurology, UTHSC in 2005. He moved to the Cleveland Clinic in USA as a Project Scientist/Staff in 2006 where he focused on the studies of eye disease proteomics and biomarkers. He returned to UTHSC as an Assistant Professor of Neurology in the end of 2007, engaging in proteomics and biomarker studies of lung diseases and brain tumors, and initiating the studies of predictive, preventive, and personalized medicine (PPPM) in cancer. In 2010, he was promoted to Associate Professor of Neurology, UTHSC. Currently, he is a Professor at Xiangya Hospital of Central South University in China, Fellow of Royal Society of Medicine (FRSM), the European EPMA National Representative in China, Regular Member of American Association for the Advancement of Science (AAAS), European Cooperation of Science and Technology (e-COST) grant evaluator, Associate Editors of BMC Genomics, BMC Medical Genomics, EPMA Journal, and Frontiers in Endocrinology, Executive Editor-in-Chief of Med One. He has\npublished 116 peer-reviewed research articles, 16 book chapters, 2 books, and 2 US patents. His current main research interest focuses on the studies of cancer proteomics and biomarkers, and the use of modern omics techniques and systems biology for PPPM in cancer, and on the development and use of 2DE-LC/MS for the large-scale study of human proteoforms.",institutionString:null,institution:{name:"Xiangya Hospital Central South University",country:{name:"China"}}},{id:"40482",title:null,name:"Rizwan",middleName:null,surname:"Ahmad",slug:"rizwan-ahmad",fullName:"Rizwan Ahmad",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/40482/images/system/40482.jpeg",biography:"Dr. Rizwan Ahmad is a University Professor and Coordinator, Quality and Development, College of Medicine, Imam Abdulrahman bin Faisal University, Saudi Arabia. Previously, he was Associate Professor of Human Function, Oman Medical College, Oman, and SBS University, Dehradun. Dr. Ahmad completed his education at Aligarh Muslim University, Aligarh. He has published several articles in peer-reviewed journals, chapters, and edited books. His area of specialization is free radical biochemistry and autoimmune diseases.",institutionString:"Imam Abdulrahman Bin Faisal University",institution:{name:"Imam Abdulrahman Bin Faisal University",country:{name:"Saudi Arabia"}}},{id:"41865",title:"Prof.",name:"Farid A.",middleName:null,surname:"Badria",slug:"farid-a.-badria",fullName:"Farid A. Badria",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/41865/images/system/41865.jpg",biography:"Farid A. Badria, Ph.D., is the recipient of several awards, including The World Academy of Sciences (TWAS) Prize for Public Understanding of Science; the World Intellectual Property Organization (WIPO) Gold Medal for best invention; Outstanding Arab Scholar, Kuwait; and the Khwarizmi International Award, Iran. He has 250 publications, 12 books, 20 patents, and several marketed pharmaceutical products to his credit. He continues to lead research projects on developing new therapies for liver, skin disorders, and cancer. Dr. Badria was listed among the world’s top 2% of scientists in medicinal and biomolecular chemistry in 2019 and 2020. He is a member of the Arab Development Fund, Kuwait; International Cell Research Organization–United Nations Educational, Scientific and Cultural Organization (ICRO–UNESCO), Chile; and UNESCO Biotechnology France",institutionString:"Mansoura University",institution:{name:"Mansoura University",country:{name:"Egypt"}}},{id:"329385",title:"Dr.",name:"Rajesh K.",middleName:"Kumar",surname:"Singh",slug:"rajesh-k.-singh",fullName:"Rajesh K. Singh",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/329385/images/system/329385.png",biography:"Dr. Singh received a BPharm (2003) and MPharm (2005) from Panjab University, Chandigarh, India, and a Ph.D. (2013) from Punjab Technical University (PTU), Jalandhar, India. He has more than sixteen years of teaching experience and has supervised numerous postgraduate and Ph.D. students. He has to his credit more than seventy papers in SCI- and SCOPUS-indexed journals, fifty-five conference proceedings, four books, six Best Paper Awards, and five projects from different government agencies. He is currently an editorial board member of eight international journals and a reviewer for more than fifty scientific journals. He received Top Reviewer and Excellent Peer Reviewer Awards from Publons in 2016 and 2017, respectively. He is also on the panel of The International Reviewer for reviewing research proposals for grants from the Royal Society. He also serves as a Publons Academy mentor and Bentham brand ambassador.",institutionString:"Punjab Technical University",institution:{name:"Punjab Technical University",country:{name:"India"}}},{id:"142388",title:"Dr.",name:"Thiago",middleName:"Gomes",surname:"Gomes Heck",slug:"thiago-gomes-heck",fullName:"Thiago Gomes Heck",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/142388/images/7259_n.jpg",biography:null,institutionString:null,institution:{name:"Universidade Regional do Noroeste do Estado do Rio Grande do Sul",country:{name:"Brazil"}}},{id:"336273",title:"Assistant Prof.",name:"Janja",middleName:null,surname:"Zupan",slug:"janja-zupan",fullName:"Janja Zupan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/336273/images/14853_n.jpeg",biography:"Janja Zupan graduated in 2005 at the Department of Clinical Biochemistry (superviser prof. dr. Janja Marc) in the field of genetics of osteoporosis. Since November 2009 she is working as a Teaching Assistant at the Faculty of Pharmacy, Department of Clinical Biochemistry. In 2011 she completed part of her research and PhD work at Institute of Genetics and Molecular Medicine, University of Edinburgh. She finished her PhD entitled The influence of the proinflammatory cytokines on the RANK/RANKL/OPG in bone tissue of osteoporotic and osteoarthritic patients in 2012. From 2014-2016 she worked at the Institute of Biomedical Sciences, University of Aberdeen as a postdoctoral research fellow on UK Arthritis research project where she gained knowledge in mesenchymal stem cells and regenerative medicine. She returned back to University of Ljubljana, Faculty of Pharmacy in 2016. She is currently leading project entitled Mesenchymal stem cells-the keepers of tissue endogenous regenerative capacity facing up to aging of the musculoskeletal system funded by Slovenian Research Agency.",institutionString:null,institution:{name:"University of Ljubljana",country:{name:"Slovenia"}}},{id:"357453",title:"Dr.",name:"Radheshyam",middleName:null,surname:"Maurya",slug:"radheshyam-maurya",fullName:"Radheshyam Maurya",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/357453/images/16535_n.jpg",biography:null,institutionString:null,institution:{name:"University of Hyderabad",country:{name:"India"}}},{id:"418340",title:"Dr.",name:"Jyotirmoi",middleName:null,surname:"Aich",slug:"jyotirmoi-aich",fullName:"Jyotirmoi Aich",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000038Ugi5QAC/Profile_Picture_2022-04-15T07:48:28.png",biography:"Biotechnologist with 15 years of research including 6 years of teaching experience. Demonstrated record of scientific achievements through consistent publication record (H index = 13, with 874 citations) in high impact journals such as Nature Communications, Oncotarget, Annals of Oncology, PNAS, and AJRCCM, etc. Strong research professional with a post-doctorate from ACTREC where I gained experimental oncology experience in clinical settings and a doctorate from IGIB where I gained expertise in asthma pathophysiology. A well-trained biotechnologist with diverse experience on the bench across different research themes ranging from asthma to cancer and other infectious diseases. An individual with a strong commitment and innovative mindset. 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With 16+ years of trans-disciplinary research experience in Drug Design, development, and pre-clinical validation; 20+ research article publications in journals of repute, 9+ years of teaching experience, trained with cross-disciplinary education, Dr. Basu is a life-long learner and always thrives for new challenges.\r\nHer research area is the design and synthesis of small molecule partial agonists of PPAR-γ in lung cancer. She is also using artificial intelligence and deep learning methods to understand the exosomal miRNA’s role in cancer metastasis. Dr. Basu is the recipient of many awards including the Early Career Research Award from the Department of Science and Technology, Govt. of India. She is a reviewer of many journals like Molecular Biology Reports, Frontiers in Oncology, RSC Advances, PLOS ONE, Journal of Biomolecular Structure & Dynamics, Journal of Molecular Graphics and Modelling, etc. She has edited and authored/co-authored 21 journal papers, 3 book chapters, and 15 abstracts. She is a Board of Studies member at her university. She is a life member of 'The Cytometry Society”-in India and 'All India Cell Biology Society”- in India.",institutionString:"Dr. D.Y. Patil Vidyapeeth, Pune",institution:{name:"Dr. D.Y. Patil Vidyapeeth, Pune",country:{name:"India"}}},{id:"354817",title:"Dr.",name:"Anubhab",middleName:null,surname:"Mukherjee",slug:"anubhab-mukherjee",fullName:"Anubhab Mukherjee",position:null,profilePictureURL:"https://intech-files.s3.amazonaws.com/0033Y0000365PbRQAU/ProfilePicture%202022-04-15%2005%3A11%3A18.480",biography:"A former member of Laboratory of Nanomedicine, Brigham and Women’s Hospital, Harvard University, Boston, USA, Dr. Anubhab Mukherjee is an ardent votary of science who strives to make an impact in the lives of those afflicted with cancer and other chronic/acute ailments. He completed his Ph.D. from CSIR-Indian Institute of Chemical Technology, Hyderabad, India, having been skilled with RNAi, liposomal drug delivery, preclinical cell and animal studies. He pursued post-doctoral research at College of Pharmacy, Health Science Center, Texas A & M University and was involved in another postdoctoral research at Department of Translational Neurosciences and Neurotherapeutics, John Wayne Cancer Institute, Santa Monica, California. In 2015, he worked in Harvard-MIT Health Sciences & Technology as a visiting scientist. He has substantial experience in nanotechnology-based formulation development and successfully served various Indian organizations to develop pharmaceuticals and nutraceutical products. He is an inventor in many US patents and an author in many peer-reviewed articles, book chapters and books published in various media of international repute. Dr. Mukherjee is currently serving as Principal Scientist, R&D at Esperer Onco Nutrition (EON) Pvt. Ltd. and heads the Hyderabad R&D center of the organization.",institutionString:"Esperer Onco Nutrition Pvt Ltd.",institution:null},{id:"319365",title:"Assistant Prof.",name:"Manash K.",middleName:null,surname:"Paul",slug:"manash-k.-paul",fullName:"Manash K. Paul",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/319365/images/system/319365.png",biography:"Manash K. Paul is a Principal Investigator and Scientist at the University of California Los Angeles. He has contributed significantly to the fields of stem cell biology, regenerative medicine, and lung cancer. His research focuses on various signaling processes involved in maintaining stem cell homeostasis during the injury-repair process, deciphering lung stem cell niche, pulmonary disease modeling, immuno-oncology, and drug discovery. He is currently investigating the role of extracellular vesicles in premalignant lung cell migration and detecting the metastatic phenotype of lung cancer via machine-learning-based analyses of exosomal signatures. Dr. Paul has published in more than fifty peer-reviewed international journals and is highly cited. He is the recipient of many awards, including the UCLA Vice Chancellor’s award, a senior member of the Institute of Electrical and Electronics Engineers (IEEE), and an editorial board member for several international journals.",institutionString:"University of California Los Angeles",institution:{name:"University of California Los Angeles",country:{name:"United States of America"}}},{id:"311457",title:"Dr.",name:"Júlia",middleName:null,surname:"Scherer Santos",slug:"julia-scherer-santos",fullName:"Júlia Scherer Santos",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/311457/images/system/311457.jpg",biography:"Dr. Júlia Scherer Santos works in the areas of cosmetology, nanotechnology, pharmaceutical technology, beauty, and aesthetics. Dr. Santos also has experience as a professor of graduate courses. Graduated in Pharmacy, specialization in Cosmetology and Cosmeceuticals applied to aesthetics, specialization in Aesthetic and Cosmetic Health, and a doctorate in Pharmaceutical Nanotechnology. Teaching experience in Pharmacy and Aesthetics and Cosmetics courses. She works mainly on the following subjects: nanotechnology, cosmetology, pharmaceutical technology, aesthetics.",institutionString:"Universidade Federal de Juiz de Fora",institution:{name:"Universidade Federal de Juiz de Fora",country:{name:"Brazil"}}},{id:"219081",title:"Dr.",name:"Abdulsamed",middleName:null,surname:"Kükürt",slug:"abdulsamed-kukurt",fullName:"Abdulsamed Kükürt",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/219081/images/system/219081.png",biography:"Dr. Kükürt graduated from Uludağ University in Turkey. He started his academic career as a Research Assistant in the Department of Biochemistry at Kafkas University. In 2019, he completed his Ph.D. program in the Department of Biochemistry at the Institute of Health Sciences. He is currently working at the Department of Biochemistry, Kafkas University. He has 27 published research articles in academic journals, 11 book chapters, and 37 papers. He took part in 10 academic projects. He served as a reviewer for many articles. He still serves as a member of the review board in many academic journals. He is currently working on the protective activity of phenolic compounds in disorders associated with oxidative stress and inflammation.",institutionString:null,institution:{name:"Kafkas University",country:{name:"Turkey"}}},{id:"178366",title:"Dr.",name:"Volkan",middleName:null,surname:"Gelen",slug:"volkan-gelen",fullName:"Volkan Gelen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/178366/images/system/178366.jpg",biography:"Volkan Gelen is a Physiology specialist who received his veterinary degree from Kafkas University in 2011. Between 2011-2015, he worked as an assistant at Atatürk University, Faculty of Veterinary Medicine, Department of Physiology. In 2016, he joined Kafkas University, Faculty of Veterinary Medicine, Department of Physiology as an assistant professor. Dr. Gelen has been engaged in various academic activities at Kafkas University since 2016. There he completed 5 projects and has 3 ongoing projects. He has 60 articles published in scientific journals and 20 poster presentations in scientific congresses. His research interests include physiology, endocrine system, cancer, diabetes, cardiovascular system diseases, and isolated organ bath system studies.",institutionString:"Kafkas University",institution:{name:"Kafkas University",country:{name:"Turkey"}}},{id:"418963",title:"Dr.",name:"Augustine Ododo",middleName:"Augustine",surname:"Osagie",slug:"augustine-ododo-osagie",fullName:"Augustine Ododo Osagie",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/418963/images/16900_n.jpg",biography:"Born into the family of Osagie, a prince of the Benin Kingdom. I am currently an academic in the Department of Medical Biochemistry, University of Benin. Part of the duties are to teach undergraduate students and conduct academic research.",institutionString:null,institution:{name:"University of Benin",country:{name:"Nigeria"}}},{id:"192992",title:"Prof.",name:"Shagufta",middleName:null,surname:"Perveen",slug:"shagufta-perveen",fullName:"Shagufta Perveen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/192992/images/system/192992.png",biography:"Prof. Shagufta Perveen is a Distinguish Professor in the Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia. Dr. Perveen has acted as the principal investigator of major research projects funded by the research unit of King Saud University. She has more than ninety original research papers in peer-reviewed journals of international repute to her credit. She is a fellow member of the Royal Society of Chemistry UK and the American Chemical Society of the United States.",institutionString:"King Saud University",institution:{name:"King Saud University",country:{name:"Saudi Arabia"}}},{id:"49848",title:"Dr.",name:"Wen-Long",middleName:null,surname:"Hu",slug:"wen-long-hu",fullName:"Wen-Long Hu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/49848/images/system/49848.jpg",biography:"Wen-Long Hu is Chief of the Division of Acupuncture, Department of Chinese Medicine at Kaohsiung Chang Gung Memorial Hospital, as well as an adjunct associate professor at Fooyin University and Kaohsiung Medical University. Wen-Long is President of Taiwan Traditional Chinese Medicine Medical Association. He has 28 years of experience in clinical practice in laser acupuncture therapy and 34 years in acupuncture. He is an invited speaker for lectures and workshops in laser acupuncture at many symposiums held by medical associations. He owns the patent for herbal preparation and producing, and for the supercritical fluid-treated needle. Dr. Hu has published three books, 12 book chapters, and more than 30 papers in reputed journals, besides serving as an editorial board member of repute.",institutionString:"Kaohsiung Chang Gung Memorial Hospital",institution:{name:"Kaohsiung Chang Gung Memorial Hospital",country:{name:"Taiwan"}}},{id:"298472",title:"Prof.",name:"Andrey V.",middleName:null,surname:"Grechko",slug:"andrey-v.-grechko",fullName:"Andrey V. Grechko",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/298472/images/system/298472.png",biography:"Andrey Vyacheslavovich Grechko, Ph.D., Professor, is a Corresponding Member of the Russian Academy of Sciences. He graduated from the Semashko Moscow Medical Institute (Semashko National Research Institute of Public Health) with a degree in Medicine (1998), the Clinical Department of Dermatovenerology (2000), and received a second higher education in Psychology (2009). Professor A.V. Grechko held the position of Сhief Physician of the Central Clinical Hospital in Moscow. He worked as a professor at the faculty and was engaged in scientific research at the Medical University. Starting in 2013, he has been the initiator of the creation of the Federal Scientific and Clinical Center for Intensive Care and Rehabilitology, Moscow, Russian Federation, where he also serves as Director since 2015. He has many years of experience in research and teaching in various fields of medicine, is an author/co-author of more than 200 scientific publications, 13 patents, 15 medical books/chapters, including Chapter in Book «Metabolomics», IntechOpen, 2020 «Metabolomic Discovery of Microbiota Dysfunction as the Cause of Pathology».",institutionString:"Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology",institution:null},{id:"199461",title:"Prof.",name:"Natalia V.",middleName:null,surname:"Beloborodova",slug:"natalia-v.-beloborodova",fullName:"Natalia V. Beloborodova",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/199461/images/system/199461.jpg",biography:'Natalia Vladimirovna Beloborodova was educated at the Pirogov Russian National Research Medical University, with a degree in pediatrics in 1980, a Ph.D. in 1987, and a specialization in Clinical Microbiology from First Moscow State Medical University in 2004. She has been a Professor since 1996. Currently, she is the Head of the Laboratory of Metabolism, a division of the Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology, Moscow, Russian Federation. N.V. Beloborodova has many years of clinical experience in the field of intensive care and surgery. She studies infectious complications and sepsis. She initiated a series of interdisciplinary clinical and experimental studies based on the concept of integrating human metabolism and its microbiota. Her scientific achievements are widely known: she is the recipient of the Marie E. Coates Award \\"Best lecturer-scientist\\" Gustafsson Fund, Karolinska Institutes, Stockholm, Sweden, and the International Sepsis Forum Award, Pasteur Institute, Paris, France (2014), etc. Professor N.V. Beloborodova wrote 210 papers, five books, 10 chapters and has edited four books.',institutionString:"Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology",institution:null},{id:"354260",title:"Ph.D.",name:"Tércio Elyan",middleName:"Azevedo",surname:"Azevedo Martins",slug:"tercio-elyan-azevedo-martins",fullName:"Tércio Elyan Azevedo Martins",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/354260/images/16241_n.jpg",biography:"Graduated in Pharmacy from the Federal University of Ceará with the modality in Industrial Pharmacy, Specialist in Production and Control of Medicines from the University of São Paulo (USP), Master in Pharmaceuticals and Medicines from the University of São Paulo (USP) and Doctor of Science in the program of Pharmaceuticals and Medicines by the University of São Paulo. Professor at Universidade Paulista (UNIP) in the areas of chemistry, cosmetology and trichology. Assistant Coordinator of the Higher Course in Aesthetic and Cosmetic Technology at Universidade Paulista Campus Chácara Santo Antônio. Experience in the Pharmacy area, with emphasis on Pharmacotechnics, Pharmaceutical Technology, Research and Development of Cosmetics, acting mainly on topics such as cosmetology, antioxidant activity, aesthetics, photoprotection, cyclodextrin and thermal analysis.",institutionString:null,institution:{name:"University of Sao Paulo",country:{name:"Brazil"}}},{id:"334285",title:"Ph.D. Student",name:"Sameer",middleName:"Kumar",surname:"Jagirdar",slug:"sameer-jagirdar",fullName:"Sameer Jagirdar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/334285/images/14691_n.jpg",biography:"I\\'m a graduate student at the center for biosystems science and engineering at the Indian Institute of Science, Bangalore, India. I am interested in studying host-pathogen interactions at the biomaterial interface.",institutionString:null,institution:{name:"Indian Institute of Science Bangalore",country:{name:"India"}}},{id:"329248",title:"Dr.",name:"Md. Faheem",middleName:null,surname:"Haider",slug:"md.-faheem-haider",fullName:"Md. Faheem Haider",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/329248/images/system/329248.jpg",biography:"Dr. Md. Faheem Haider completed his BPharm in 2012 at Integral University, Lucknow, India. In 2014, he completed his MPharm with specialization in Pharmaceutics at Babasaheb Bhimrao Ambedkar University, Lucknow, India. He received his Ph.D. degree from Jamia Hamdard University, New Delhi, India, in 2018. He was selected for the GPAT six times and his best All India Rank was 34. Currently, he is an assistant professor at Integral University. Previously he was an assistant professor at IIMT University, Meerut, India. He has experience teaching DPharm, Pharm.D, BPharm, and MPharm students. He has more than five publications in reputed journals to his credit. Dr. Faheem’s research area is the development and characterization of nanoformulation for the delivery of drugs to various organs.",institutionString:"Integral University",institution:{name:"Integral University",country:{name:"India"}}},{id:"329795",title:"Dr.",name:"Mohd Aftab",middleName:"Aftab",surname:"Siddiqui",slug:"mohd-aftab-siddiqui",fullName:"Mohd Aftab Siddiqui",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/329795/images/system/329795.png",biography:"Dr. Mohd Aftab Siddiqui is an assistant professor in the Faculty of Pharmacy, Integral University, Lucknow, India, where he obtained a Ph.D. in Pharmacology in 2020. He also obtained a BPharm and MPharm from the same university in 2013 and 2015, respectively. His area of research is the pharmacological screening of herbal drugs/natural products in liver cancer and cardiac diseases. He is a member of many professional bodies and has guided many MPharm and PharmD research projects. Dr. Siddiqui has many national and international publications and one German patent to his credit.",institutionString:"Integral University",institution:null}]}},subseries:{item:{id:"7",type:"subseries",title:"Bioinformatics and Medical Informatics",keywords:"Biomedical Data, Drug Discovery, Clinical Diagnostics, Decoding Human Genome, AI in Personalized Medicine, Disease-prevention Strategies, Big Data Analysis in Medicine",scope:"Bioinformatics aims to help understand the functioning of the mechanisms of living organisms through the construction and use of quantitative tools. The applications of this research cover many related fields, such as biotechnology and medicine, where, for example, Bioinformatics contributes to faster drug design, DNA analysis in forensics, and DNA sequence analysis in the field of personalized medicine. Personalized medicine is a type of medical care in which treatment is customized individually for each patient. Personalized medicine enables more effective therapy, reduces the costs of therapy and clinical trials, and also minimizes the risk of side effects. Nevertheless, advances in personalized medicine would not have been possible without bioinformatics, which can analyze the human genome and other vast amounts of biomedical data, especially in genetics. The rapid growth of information technology enabled the development of new tools to decode human genomes, large-scale studies of genetic variations and medical informatics. The considerable development of technology, including the computing power of computers, is also conducive to the development of bioinformatics, including personalized medicine. In an era of rapidly growing data volumes and ever lower costs of generating, storing and computing data, personalized medicine holds great promises. Modern computational methods used as bioinformatics tools can integrate multi-scale, multi-modal and longitudinal patient data to create even more effective and safer therapy and disease prevention methods. Main aspects of the topic are: Applying bioinformatics in drug discovery and development; Bioinformatics in clinical diagnostics (genetic variants that act as markers for a condition or a disease); Blockchain and Artificial Intelligence/Machine Learning in personalized medicine; Customize disease-prevention strategies in personalized medicine; Big data analysis in personalized medicine; Translating stratification algorithms into clinical practice of personalized medicine.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/7.jpg",hasOnlineFirst:!0,hasPublishedBooks:!0,annualVolume:11403,editor:{id:"351533",title:"Dr.",name:"Slawomir",middleName:null,surname:"Wilczynski",slug:"slawomir-wilczynski",fullName:"Slawomir Wilczynski",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000035U1loQAC/Profile_Picture_1630074514792",biography:"Professor Sławomir Wilczyński, Head of the Chair of Department of Basic Biomedical Sciences, Faculty of Pharmaceutical Sciences, Medical University of Silesia in Katowice, Poland. His research interests are focused on modern imaging methods used in medicine and pharmacy, including in particular hyperspectral imaging, dynamic thermovision analysis, high-resolution ultrasound, as well as other techniques such as EPR, NMR and hemispheric directional reflectance. Author of over 100 scientific works, patents and industrial designs. Expert of the Polish National Center for Research and Development, Member of the Investment Committee in the Bridge Alfa NCBiR program, expert of the Polish Ministry of Funds and Regional Policy, Polish Medical Research Agency. Editor-in-chief of the journal in the field of aesthetic medicine and dermatology - Aesthetica.",institutionString:null,institution:{name:"Medical University of Silesia",institutionURL:null,country:{name:"Poland"}}},editorTwo:null,editorThree:null,series:{id:"7",title:"Biomedical Engineering",doi:"10.5772/intechopen.71985",issn:"2631-5343"},editorialBoard:[{id:"5886",title:"Dr.",name:"Alexandros",middleName:"T.",surname:"Tzallas",slug:"alexandros-tzallas",fullName:"Alexandros Tzallas",profilePictureURL:"https://mts.intechopen.com/storage/users/5886/images/system/5886.png",institutionString:"University of Ioannina, Greece & Imperial College London",institution:{name:"University of Ioannina",institutionURL:null,country:{name:"Greece"}}},{id:"257388",title:"Distinguished Prof.",name:"Lulu",middleName:null,surname:"Wang",slug:"lulu-wang",fullName:"Lulu Wang",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRX6kQAG/Profile_Picture_1630329584194",institutionString:"Shenzhen Technology University",institution:{name:"Shenzhen Technology University",institutionURL:null,country:{name:"China"}}},{id:"225387",title:"Prof.",name:"Reda R.",middleName:"R.",surname:"Gharieb",slug:"reda-r.-gharieb",fullName:"Reda R. 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Chapters exploring biomaterial approaches such as polymer synthesis and characterization, drug and gene vector design, biocompatibility, immunology and toxicology, and self-assembly at the nanoscale, are welcome. Finally, the tissue engineering subcategory will support topics such as the fundamentals of stem cells and progenitor cells and their proliferation, differentiation, bioreactors for three-dimensional culture and studies of phenotypic changes, stem and progenitor cells, both short and long term, ex vivo and in vivo implantation both in preclinical models and also in clinical trials.",annualVolume:11405,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/9.jpg",editor:{id:"126286",title:"Dr.",name:"Luis",middleName:"Jesús",surname:"Villarreal-Gómez",fullName:"Luis Villarreal-Gómez",profilePictureURL:"https://mts.intechopen.com/storage/users/126286/images/system/126286.jpg",institutionString:null,institution:{name:"Autonomous University of Baja California",institutionURL:null,country:{name:"Mexico"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"35539",title:"Dr.",name:"Cecilia",middleName:null,surname:"Cristea",fullName:"Cecilia Cristea",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYQ65QAG/Profile_Picture_1621007741527",institutionString:null,institution:{name:"Iuliu Hațieganu University of Medicine and Pharmacy",institutionURL:null,country:{name:"Romania"}}},{id:"40735",title:"Dr.",name:"Gil",middleName:"Alberto Batista",surname:"Gonçalves",fullName:"Gil Gonçalves",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYRLGQA4/Profile_Picture_1628492612759",institutionString:null,institution:{name:"University of Aveiro",institutionURL:null,country:{name:"Portugal"}}},{id:"211725",title:"Associate Prof.",name:"Johann F.",middleName:null,surname:"Osma",fullName:"Johann F. 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