Pituitary glandular cell types and function.
\\n\\n
Dr. Pletser’s experience includes 30 years of working with the European Space Agency as a Senior Physicist/Engineer and coordinating their parabolic flight campaigns, and he is the Guinness World Record holder for the most number of aircraft flown (12) in parabolas, personally logging more than 7,300 parabolas.
\\n\\nSeeing the 5,000th book published makes us at the same time proud, happy, humble, and grateful. This is a great opportunity to stop and celebrate what we have done so far, but is also an opportunity to engage even more, grow, and succeed. It wouldn't be possible to get here without the synergy of team members’ hard work and authors and editors who devote time and their expertise into Open Access book publishing with us.
\\n\\nOver these years, we have gone from pioneering the scientific Open Access book publishing field to being the world’s largest Open Access book publisher. Nonetheless, our vision has remained the same: to meet the challenges of making relevant knowledge available to the worldwide community under the Open Access model.
\\n\\nWe are excited about the present, and we look forward to sharing many more successes in the future.
\\n\\nThank you all for being part of the journey. 5,000 times thank you!
\\n\\nNow with 5,000 titles available Open Access, which one will you read next?
\\n\\nRead, share and download for free: https://www.intechopen.com/books
\\n\\n\\n\\n
\\n"}]',published:!0,mainMedia:null},components:[{type:"htmlEditorComponent",content:'
Preparation of Space Experiments edited by international leading expert Dr. Vladimir Pletser, Director of Space Training Operations at Blue Abyss is the 5,000th Open Access book published by IntechOpen and our milestone publication!
\n\n"This book presents some of the current trends in space microgravity research. The eleven chapters introduce various facets of space research in physical sciences, human physiology and technology developed using the microgravity environment not only to improve our fundamental understanding in these domains but also to adapt this new knowledge for application on earth." says the editor. Listen what else Dr. Pletser has to say...
\n\n\n\nDr. Pletser’s experience includes 30 years of working with the European Space Agency as a Senior Physicist/Engineer and coordinating their parabolic flight campaigns, and he is the Guinness World Record holder for the most number of aircraft flown (12) in parabolas, personally logging more than 7,300 parabolas.
\n\nSeeing the 5,000th book published makes us at the same time proud, happy, humble, and grateful. This is a great opportunity to stop and celebrate what we have done so far, but is also an opportunity to engage even more, grow, and succeed. It wouldn't be possible to get here without the synergy of team members’ hard work and authors and editors who devote time and their expertise into Open Access book publishing with us.
\n\nOver these years, we have gone from pioneering the scientific Open Access book publishing field to being the world’s largest Open Access book publisher. Nonetheless, our vision has remained the same: to meet the challenges of making relevant knowledge available to the worldwide community under the Open Access model.
\n\nWe are excited about the present, and we look forward to sharing many more successes in the future.
\n\nThank you all for being part of the journey. 5,000 times thank you!
\n\nNow with 5,000 titles available Open Access, which one will you read next?
\n\nRead, share and download for free: https://www.intechopen.com/books
\n\n\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:"1310",leadTitle:null,fullTitle:"Topics in Cancer Survivorship",title:"Topics in Cancer Survivorship",subtitle:null,reviewType:"peer-reviewed",abstract:"Cancer is now the leading cause of death in the world. In the U.S., one in two men and one in three women will be diagnosed with a non-skin cancer in their lifetime. Cancer patients are living longer than ever before. For instance, when detected early, the five-year survival for breast cancer is 98%, and it is about 84% in patients with regional disease. However, the diagnosis and treatment of cancer is very distressing. Cancer patients frequently suffer from pain, disfigurement, depression, fatigue, physical dysfunctions, frequent visits to doctors and hospitals, multiple tests and procedures with the possibility of treatment complications, and the financial impact of the diagnosis on their life. This book presents a number of ways that can help cancer patients to look, feel and become healthier, take care of specific symptoms such as hair loss, arm swelling, and shortness of breath, and improve their intimacy, sexuality, and fertility.",isbn:null,printIsbn:"978-953-307-894-6",pdfIsbn:"978-953-51-6754-9",doi:"10.5772/1779",price:119,priceEur:129,priceUsd:155,slug:"topics-in-cancer-survivorship",numberOfPages:292,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"6ea3485c7d116f29327e36b78c5e9e6f",bookSignature:"Ravinder Mohan",publishedDate:"January 27th 2012",coverURL:"https://cdn.intechopen.com/books/images_new/1310.jpg",numberOfDownloads:41381,numberOfWosCitations:14,numberOfCrossrefCitations:7,numberOfCrossrefCitationsByBook:1,numberOfDimensionsCitations:18,numberOfDimensionsCitationsByBook:1,hasAltmetrics:0,numberOfTotalCitations:39,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"November 17th 2010",dateEndSecondStepPublish:"December 15th 2010",dateEndThirdStepPublish:"April 21st 2011",dateEndFourthStepPublish:"May 21st 2011",dateEndFifthStepPublish:"July 20th 2011",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"58197",title:"Prof.",name:"Ravinder",middleName:null,surname:"Mohan",slug:"ravinder-mohan",fullName:"Ravinder Mohan",profilePictureURL:"https://mts.intechopen.com/storage/users/58197/images/3669_n.jpg",biography:"Ravinder Mohan, MD, PhD teaches and practices family medicine in Virginia and also works as a hospitalist physician. He became interested in research on health-related quality of life in Belgium, where he followed clinical outcomes in heart surgery patients. He later used similar methods in Virginia, to evaluate the quality of life of patients who had knee arthritis, and subsequently of patients before and after treatment of localized prostate cancer. \nDr. Mohan’s research has been published in over 35 high-impact factor peer-reviewed journals and he has also contributed to chapters in five books.",institutionString:null,position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"2",totalChapterViews:"0",totalEditedBooks:"3",institution:null}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"1075",title:"Breast Oncology",slug:"breast-oncology"}],chapters:[{id:"26732",title:"Living With and Beyond Cancer: New Challenges",doi:"10.5772/24959",slug:"living-with-and-beyond-cancer-new-challenges",totalDownloads:1755,totalCrossrefCites:0,totalDimensionsCites:1,hasAltmetrics:0,abstract:null,signatures:"Neel Bhuva, Sonia P. 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\r\n\tTicks are obliged to blood-feeding external parasites of mammals, birds, and reptiles. They are globally important vectors of pathogens that impact both human and animal health. The number of known tick-borne pathogens has increased dramatically since the 1980s; species of Theileria, Babesia, and Anaplasma are tick-borne parasites that are prevalent throughout the world, particularly in the tropical and subtropical regions. Associated diseases of Theileriosis, Babesiosis, and Anaplasmosis, respectively, represent a major threat to livestock production in many countries. These infections occur on all continents, whereas their distribution changes continuously due to the migration and transportation of vectors and animals and the increased globalization of live animals. Thus, the expanding geographic ranges of vectors and pathogens, increasing abundance of ticks and tick-transmitted infectious agents, are raising global public health concerns.
\r\n\r\n\t
\r\n\tThis book intends to provide the reader with a comprehensive overview of the current state-of-the-art on Theileriosis, Babesiosis, and Anaplasmosis, both in humans and domestic animals. Particularly this book aims to permit the researchers to enter into a critical focus on the biology of the parasites, eco-epidemiology of the diseases, clinical manifestations, risk factors, immunology, surveillance, diagnosis, identification, and management of risks as well as the potential economic impact on animal production.
Pituitary adenomas (PA) are benign tumors which account for being the second most common intracranial tumors after meningiomas [1]. The incidence of PA is 4.36 per 100,000 and can affect all age groups [1]. However, PA is uncommon in the 1st decade of life with a prevalence of 1–10% when compared to all brain tumors in that age group [2]. The overall chance of developing a pituitary adenoma increases with age, and the non-secretory type is most common after 40 years old [2, 3]. Presentation is highly dependent on the whether the tumor is capable to disrupt hormone homeostasis. Secretory adenomas, also called “functional” adenomas, tend to present early in the clinical course of disease. Conversely, non-secreting adenomas, also called non-functional” adenomas, typically present after reaching a critical size, leading to compression of surrounding neuronal and/or vascular structures.
The first step in the management of a patient with a pituitary adenoma is to distinguish the lesion between a secreting and a non-secreting one. The secreting-type subclassification is based on the specific hormone release by the tumor. Despite advancements in pharmacologic and radiotherapeutic management, surgery is still considered the main modality of treatment for most pituitary adenomas.
The pituitary gland is located in the hypophyseal fossa, which is a depression in body of the sphenoid bone located in the middle cranial fossa. Anteriorly, this space is limited by the tuberculum sellae, posteriorly by the dorsum sellae, laterally by the medial wall of the cavernous sinus on each side which extends from the anterior clinoid process and superior orbital fissure anteriorly to the posterior clinoid process posteriorly (Figure 1A). The chiasmatic sulcus is a shallow depression running between tuberculum sellae and the limbus sphenoidale where the optic chiasm spans between two optic nerves. The anterior tip of the chiasmatic sulcus, or limbus sphenoidale, is the limit between the anterior and middle cranial fossae. The pituitary gland is an intradural extra-arachnoidal structure with an ovoid shape composed of two lobes: a larger anterior lobe and a smaller posterior one. The pituitary stalk (aka the infundibulum) provides the pathway for ascending neural connections arising from superior surface of the posterior lobe to the hypothalamus. Due to the lack of a robust blood-brain barrier, the pituitary gland exhibits intense enhancement on contrasted magnetic resonance imaging (MRI). The larger anterior pituitary gland is composed of 3 parts:
Pars distalis (anterior): the largest of the 3 parts, responsible for the bulk of hormone production.
Pars tuberalis: an upward extension of glandular cell sheaths that connects the pars distalis to the pituitary stalk.
Pars intermedia: epithelial cells that sheath and separate the pars distalis from the pars tuberalis.
Intracranial view showing sellar and parasellar areas anatomy. A: Superior view of cranial base. Hypophyseal fossa, or sellae turcica, bounded anteriorly by tuberculum sellae, posteriorly by the dorsum sellae, laterally by the medial wall of the cavernous sinus on each side which extends form anterior clinoid process and superior orbital fissure (SOF) anteriorly to posterior clinoid process posteriorly. Anterior tip of chiasmatic sulcus called limbus sphenoidale (marked by asterisk) which is the junction between anterior and middle cranial fossa. Anterior optic strut separates optic canal superomedially from SOF inferolatearlly and maxillary strut separates SOF from foramen rotundum. Middle clinoid process (MCP), which present in 50% of population, is a projection from lateral margin of sellae turcica. It corresponds transsphenoidally to medial opticocarotid recess. B: Superior view showing the roof hypophyseal fossa and cavernous sinus. Diaphragm sellae roof the superior surface of pituitary gland with the exception of a small opening that allows the stalk to pass from the gland to the hypothalamus. It is continuous with the dura covering the planum sphenoidale anteriorly and the dorsum sellae and clivus posteriorly. The roof of cavernous sinus formed by the oculomotor triangle (blue highlighted triangle) and clinoidal triangle. Oculomotor nerve (CNIII) enter the cavernous sinus at the middle of oculomotor triangle. The roof of left cavernous sinus is opened to show the contents of the cavernous sinus. Only the ICA and abducens nerve (CN VI) are running inside the sinus. CNIII, trochlear (CNIV), ophthalmic, and maxillary nerve are running in the lateral wall of cavernous sinus. CN VI enters the cavernous sinus by passing under Gruber’s ligament (aka petrosphenoidal ligament) which spans from the petrous apex to the posterior clinoid process and form the roof of Dorello’s canal. In this specimen, Gruber’s ligament is duplicated. ACP, anterior clinoid process; CAV. ICA, cavernous segment of ICA; MCP, middle clinoid process; PCP, posterior clinoid process; ON, optic nerve; PETR. ICA, petrous segment of ICA.
Five types of endocrine cells are contained inside the anterior lobe that secrete 6 different hormones (Table 1). The secretion of hormones is under either stimulatory control from hypothalamus or inhibitory control through feed-back mechanisms. Prolactin is the only pituitary hormone that is under inhibitory control from hypothalamus by prolactin releasing inhibitory factor, mainly dopamine.
Anterior lobe | |||||
---|---|---|---|---|---|
Pituitary cell | Hormone produced | Control | Staining | Target organ | Effects |
Corticotrophs | ACTH | ⨁CRH | Basophile | Adrenal gland | Cortisol secretion |
Thyrotrophs | TSH | ⨁TRH | Basophile | Thyroid gland | T3 & T4 secretion |
Gonadotrophs | LH, FSH | ⨁GnRH | Basophile | Gonads | ♂: Testosterone ♀: Estradiol |
Somatotrophs | GH | ⨁GHRH ⊝Somatostatin | Acidophile | Epiphyses of long bones Liver | Bones: Chondrocyte proliferation Liver: IGF-1 release |
Lactotrophs | PRL* | ⊝PIF | Acidophile | Mammillary gland | Lactation |
Antidiuretic hormone (ADH) | Kidneys | Fluid retention, vasoconstriction | |||
Oxytocin | Uterine smooth muscle Mammary gland | Uterine contraction Milk ejection into lactation ducts |
Pituitary glandular cell types and function.
Prolactin is the only hormone that is under direct inhibition from hypothalamus.
ACTH, adrenocorticotropic hormone; FSH, follicle-stimulating hormone; GH, growth hormone; GHRH, growth hormone releasing hormone; LH, luteinizing hormone; PRL, prolactin; TSH, thyroid-stimulating hormone.
The roof of the sellae is formed by a structure known as the diaphragm sellae, which covers the entire superior surface of pituitary gland with the exception of a small opening that allows the stalk to pass from the gland to the hypothalamus. It is formed by a dual layer of dura that is continuous with the dura covering the planum sphenoidale anteriorly and the dorsum sellae and clivus posteriorly (Figure 1B).
Two layers of dura cover the sellar anterior wall and the floor, namely: the inner (meningeal) layer, and the outer (periosteal) layer. These dural layers run adherent to each other on the anterior and floor of the hypophyseal fossa. Laterally, these 2 dural layers split, as the outer layer continues laterally and form the anterior wall of the cavernous sinus, and the inner layer adheres to lateral wall of pituitary gland to form the medial wall of cavernous sinus (Figure 2). Inferior and superior intercavernous sinuses are venous channels that connect the bilateral cavernous sinuses to each other. These venous channels run in the space between the two dural layers in superior and inferior aspects of the hypophyseal fossa (Figure 2). In extended transsphenoidal approaches, it is important to coagulate those venous channels before dural opening to avoid significant venous bleeding.
Transsphenoidal endoscopic stepwise dissection of sellar floor. (A) Sellar floor bone over the right side anterior wall of cavernous sinus and pituitary gland has been removed and kept intact on the left side. Important landmarks can be appreciated on the sellar floor. Optic nerve, cavernous and paraclival ICA segments prominences can be seen. Lateral opticocarotid recess (LOR) seen superolateral to carotid prominence and inferior to optic nerve prominence (ON Prom.), and it corresponds to optic strut. Limbus sphenoidale spans between optic chiasm/chiasmatic sulcus and planum sphenoidale. (B) Bone over sellar floor removed completely. Periosteal layer of dura (PoL) has been peeled from the meningeal layer (MenL) on the right half of the gland and kept on the left. The anterior wall of cavernous sinus formed by PoL after separating form MenL on the lateral aspect of the pituitary gland and MenL remains stuck to the gland forming the medial wall of cavernous sinus. Note the ligament (marked by “*”) that anchor the medial wall of cavernous sinus. Also, those 2 layers separate at superior and inferior aspects of pituitary gland to form superior intercavernous sinus (Sup. InterCavS.) and inferior intercavernous sinus (Inf. InterCavS.), respectively, which are venous channels connecting the bilateral cavernous sinuses. Inferior hypophyseal artery (IHA) is a branch from meningohypophyseal trunk in majority of cases and supply the pituitary gland with blood. (C) Dura over sellae and suprasellar area has been removed to show the superior hypophyseal artery (SHA) which is a direct branch from supraclinoidal segment of ICA to supply the stalk and gland in addition to optic chiasm and nerves. The arrow heads pointing to diaphragma sellae. Note the opening in the diaphragm through which the stalk ascends from the gland to hypothalamus.
The floor of the sellae forms the posterior wall of sphenoidal sinus, which offers a shortcut in approaching the sellar region. The sphenoidal sinus can be classified based on the degree of pneumatization: conchal, presellar, and sellar. The sellar type is the most common and it is found in 80% of population, representing of a fully pneumatized sphenoid sinus. The conchal type is present in 3% of the population, and it represents a non-pneumatized form. It is common to see this type in the pediatric age population as aeration begins at 10 months of age and rapidly progresses between ages 3 and 6 years—eventually achieving final pneumatization around the 3rd decade of life. The presellar type is an intermediate classification between the conchal and sellar types in which partial pneumatization is observed.
During the endonasal transsphenoidal approach to the sellar and suprasellar regions important structures can be identified as bony prominences on the posterior wall of sphenoidal sinus depending on the degree of aeration. These include the cavernous carotid artery prominences, optic nerves prominences, pituitary gland prominence, and paraclival carotids segments prominences. The lateral optic carotid recess is a depression seen between internal carotid artery (ICA) and the optic nerve prominences. This structure correlates with the optic strut/anterior clinoid process when viewed transcranially (Figure 2).
The pituitary gland receives its blood supply from bilateral superior and inferior hypophyseal arteries. Superior hypophyseal artery (SHA) is a direct branch from the supraclinoidal segment of the ICA. In addition to supplying the pituitary gland and stalk, the SHA also supplies the optic nerve and chiasm. The inferior hypophyseal artery (IHA) branches from the cavernous segment of the ICA, but can also branch from the meningohypophyseal trunk. The IHA supplies the pituitary gland and to some extent the stalk (Figure 2). Truong et al. [4] found that the bilateral coagulation of IHA has minimal effect on adenohypophysis and neurohypophysis functions due to presence of rich intraarterial anastomosis between SHAs. However, injury to SHA branches supplying the visual apparatus may result in visual field defects or vision loss due to paucity of anastomosis in the optic nerves or chiasm.
Multiple classification systems have been adopted to classify pituitary adenomas. They can be classified either based on functioning status (i.e. secretory and non- secretory) or on the size of the adenoma (i.e. >1 cm in diameter macroadenoma, <1 cm diameter microadenoma). Other classification systems include pathological findings under light microscopy with hematoxylin and eosin stains (basophilic, acidophilic, or chromophobic), or growth characteristics found on imaging studies (e.g. modified Hardy’s classification for suprasellar extension and Knosp classification for parasellar/cavernous sinus extension).
The functional classification is the most widely used. It classifies pituitary adenomas on the hormone secretion status and the resultant endocrinologic manifestation. Functioning adenomas may secrete PRL, GH, ACTH, TSH, or FSH/LH, and patients usually present with endocrinologic manifestations of endogenous effect of the hyper-secreted hormone. Non-functioning adenomas usually present with mass effect on surrounding neuronal or vascular structures or with pituitary dysfunction due to compression on normal glandular tissue.
Pituitary adenomas may present with multiple different manifestations. These include: hormonal hypersecretory signs and symptoms, pituitary dysfunction, mass effect on surrounding neuronal structures, or may present acutely with headache and altered mental status due to pituitary apoplexy. However, asymptomatic pituitary adenomas discovered incidentally on brain MRI are not uncommon. It was found that 10% of general adult population may have asymptomatic pituitary adenoma (pituitary incidentalomas) [5].
One of the most common clinical presentation of pituitary adenomas is hormonal disturbances. Hypersecretion of one of the pituitary hormones will result in distinctive clinical syndrome that is related to endogenous effect of the hormone (Table 2).
Adenoma type | Incidence* | Hormone in excess | Clinical manifestation |
---|---|---|---|
Prolactinoma | 40–57% | PRL | Male: decrease libido, impotence. Female: amenorrhea-galactorrhea syndrome Either sex: infertility, osteoporosis, headache, visual changes |
GH cell (somatotroph) adenoma | 11% | GH | Acromegaly |
Corticotroph adenoma | 2% | ACTH | Cushing’s disease |
Thyrotroph adenoma | Rare | TSH | Hyperthyroidism |
Gonadotroph adenoma | Rare | LH, FSH | Mostly present as non-secretory adenoma; rarely may cause menstrual abnormalities, ovarian hyperstimulation syndrome, and in males may cause testicular enlargement, hypogonadism |
Functional pituitary adenomas clinical presentation.
Incidence of all pituitary adenomas [41].
Pituitary dysfunction is generally caused by the adenoma compression over normal secretory glandular tissue or the pituitary stalk. Usually, significant tumor growth (size >1 cm) and pituitary compression is needed to cause pituitary dysfunction. GH is the first hormone to be affected, followed by LH and FSH, then TSH and lastly ACTH. Single hormonal dysfunction due to pituitary compression is extremely rare. Pituitary stalk compression may result in hyperprolactinemia due to the loss of inhibitory control from hypothalamus which manifest as a moderate elevation in prolactin level (usually <150 μg/l).
Pituitary macroadenomas may extend to the suprasellar region causing compression to the optic nerves and chiasm. Visual impairment is seen in about 40–60% of patients upon presentation and the classical presentation is bitemporal hemianopsia. In addition, suprasellar mass growth may result in hypothalamic compression with subsequent disturbances in eating, emotion or sleep pattern. Rarely, 3rd ventricle extension may result in obstructive hydrocephalus. Parasellar extension into cavernous sinus is usually asymptomatic, however, oculomotor, abducens and trigeminal nerves compressive symptoms may occur. Additional parasellar extension may compress the mesial temporal lobe which can result in seizures.
Pituitary apoplexy is defined as sudden onset of intense headache associated with visual field defects, ophthalmoplegia, and/or altered mental status [6]. Pituitary apoplexy is clinically observed in 1–7% of pituitary adenomas [6, 7]. The accepted pathophysiology is tumor outgrowth of the vascular blood supply resulting in hemorrhagic infarction of the tumor mass [8]. Headache is the most common symptom which is usually felt over frontal or retro-orbital areas. However, visual field defects, cranial nerves palsy, and meningeal irritation signs and symptoms are not uncommon. Approximately 80% of patients have anterior pituitary hormonal dysfunction with ACTH deficiency being the most critical one.
There is evidence suggesting that the risk of pituitary apoplexy is higher in functional pituitary adenomas (e.g. GH-secreting adenomas and prolactinomas). However, there is contradicting data demonstrating a higher risk in non-functional ones [7]. Multiple risk factors for pituitary apoplexy have been identified including; sudden changes in blood pressure, (e.g. major surgeries), coagulative disorders and anticoagulation usage, radiotherapy, estrogen-based oral contraceptive pills, and head trauma [6, 7, 9].
Prolactinoma is the most common type in secretary pituitary adenoma with an incidence of 50% of all pituitary adenomas. It is typically commonly seen in women aged 20–50 years old. As stated previously, prolactin is under continuous inhibition from dopamine, a PIF, secreted from hypothalamus through the pituitary stalk. Stalk dysfunction, either by compression or hypothalamic lesion, will result in loss of prolactin inhibition with subsequent prolactin elevation. Prolactinomas arise from monoclonal expansion of pituitary lactotrophs, however, 5–10% of prolactinomas can co-secrete GH resulting in superimposed gigantism/acromegaly [10]. As the disruption of hormone homeostasis causes subtle symptoms in some prolactinoma patients, it is the most likely tumor to become large enough to cause clinical manifestations of mass effect compared to other secreting tumors.
Hyperprolactinemia symptoms in males include decreased libido, sexual dysfunction and oligozoospermia (due to secondary hypogonadism). In perimenopause females, amenorrhea-galactorrhea syndrome is usually seen, which is a triad of galactorrhea, amenorrhea and infertility. In children and adolescents, growth arrest, pubertal delay and primary amenorrhea are frequently seen. Symptoms may also be due to mass effect which may cause headache, vision field deficits, cranial nerve palsy, seizure, and hydrocephalus.
Diagnosis of prolactinoma requires both: radiological evidence of adenoma and sustained hyperprolactinemia. Normal PRL levels in women are <25 μg/l and in men are <20 μg/l. Single random measurement of PRL at any time of the day is adequate for evaluation of hyperprolactinemia. The differential diagnosis of hyperprolactinemia is wide (Table 3), but PRL level is seldom >100 μg/l in these conditions. Pituitary stalk compression (Stalk Effect) can also cause hyperprolactinemia (e.g. PRL level up to 150 μg/l) [11, 12].
Head trauma |
Convulsions |
Medication (antipsychotics, antiemetics, verapamil) |
Chest wall stimulation, strenuous exercises, heavy meals. |
Craniopharyngioma, granulomatous disease of the hypothalamus, acromegaly |
Primary hypothyroidism |
Pregnancy and breast feeding |
Differential diagnosis of hyperprolactinemia.
In PRL-secreting adenomas, PRL level usually correlates with tumor size as levels above 250 μg/l are commonly seen in macroadenomas [12]. In the setting of low PRL level in patients with clinical presentation strongly suggestive of a prolactinoma, “hook effect” should be suspected. Hook effect occurs due to the impairment of immune-complex formation in the presence of high levels of PRL. To overcome this phenomenon, serial dilution of the sample with repetition of the immunoassay is needed.
After ruling-out other causes of hyperprolactinemia, diagnosis confirmation of prolactinoma is made by gadolinium-enhanced brain MRI.
Management of prolactinomas depends on several factors: tumor size, patient symptoms and preferences, and PRL level. All patients with macroadenoma require treatment, however, mildly symptomatic microadenoma patients (e.g. premenopausal woman with normal menstrual cycles and galactorrhea, or postmenopausal woman with tolerable galactorrhea) can be followed-up with serial PRL level measurement and brain MRI. Since only 5–10% of microadenomas will enlarge in size [13], management of microadenomas should not be based on size control alone. Prolactinomas respond very well to medical therapy, and dopamine agonists are the first line of management (e.g. bromocriptine or cabergoline) (Table 4).
Dopamine agonist | Bromocriptine | Cabergoline |
---|---|---|
Mode of action | Ergot-derivate D1 and D2 receptors agonist | Non-ergot-derivate Selective D2 agonist |
starting dosage | 1.25 mg/day | 0.5 mg/week |
Desired dosage | 1.25 mg increment weekly until 2.5 mg × 3/day is reached | 0.5 mg increment monthly until maximum dose of 3 mg/week is reached |
Side effects | Gastrointestinal (GI) upset, postural hypotension, peripheral vasodilation, mood disturbances | GI upset, headache, dizziness, hypotension, cardiac valve fibrosis (mitral valve most commonly affected) |
Response rate [14] | Microadenoma: normalize PRL in 82%, gonadal function restoration in 90% Macroadenoma: 80% will reduce in size | Microadenoma: 70% effective in bromocriptine resistant patients with fewer side effects rate Macroadenoma: higher tumor size control compared to bromocriptine |
Bromocriptine and cabergoline specifications.
Bromocriptine is a non-selective dopamine receptor agonist. It is the first line of management for microadenoma patients seeking fertility restoration and it is effective in 90% of patients and PRL level normalization can be achieved in 82% of patients [14]. If pregnancy has been achieved, bromocriptine can be stopped safely without a risk of abortion or congenital malformation. In child-bearing age women with microadenomas, risk of microadenoma progression is low and prolactin level monitoring is not necessary [15].
Macroadenomas always need management. Bromocriptine should be the drug of choice for patients who need fertility restoration. Pregnant women with macroadenoma without extrasellar extension can be followed similarly as microadenoma patients. However, if the suprasellar extension was detected before pregnancy, tumor debulking is advisable as the risk of macroadenoma growth during pregnancy is up to 35% [15, 16]. In these patients, it is also prudent to have a visual field assessment every 3 months till delivery.
Surgical management of prolactinoma is indicated in patients who are non-responders to dopaminergic therapy, with intolerable adverse effects from medical therapy (e.g. bromocriptine), CSF fistulas under DA, cystic tumors with intramural hemorrhage, or progressive neurological deficits [11, 17]. Stable visual field defect is not considered an indication for surgery as most patients will have tumor shrinkage on medical therapy with improvement on visual symptoms.
When to consider a prolactinoma as being medication resistant?
Failure to normalize serum prolactin levels after having received a daily dose of 15 mg of Bromocriptine for 3 months (25% of patients).
Failure to normalize serum prolactin levels after having received a weekly dose of 1.5–3.0 mg of Cabergoline for 3 months (10–15% of patients).
Seventy-percent of bromocriptine resistant patients will respond on cabergoline. Around 10–16% of prolactinoma patients will need surgical management [11]. Most patients will have a reduction of PRL levels 2–3 weeks after dopamine agonist initiation, which generally precedes the tumor size reduction. Periodic PRL measurements and pituitary MRI every 6–12 months is advised. After 2 years of continuous therapy, if prolactin levels have been normalized and >50% reduction of tumor size has been achieved, medication dose can be reduced. Typically, a low-dose of dopamine agonist after 2 years of tumor control will usually keep prolactin within normal range and prevent tumor recurrence [18].
Acromegaly is a rare disorder resulting from exposure to high levels of GH which is associated with significant morbidity and mortality. The most common cause of acromegaly is pituitary adenomas which may be either pure-GH secreting adenoma (60%) or mixed cell adenoma. In children before epiphyseal plate closure, GH secreting adenoma results in gigantism. It has an annual prevalence of 4 new cases per million inhabitants, with male and female being equally affected [19]. Other rare causes of acromegaly include growth hormone releasing hormone (GHRH) secretion from hypothalamus (e.g. hamartoma or glioma) or ectopic GHRH secreting tumors (e.g. primary bronchial carcinoid or pancreatic cancers).
The majority of acromegaly cases are due to GH-secreting pituitary adenomas. Similar to other subtypes of pituitary adenomas, GH-secreting adenomas may present with mass effect symptoms and/or with signs and symptoms of the endogenous effect of the over secreted hormone (i.e. GH).
Acromegaly dysmorphic features include enlarged hands and feet, facial bone enlargement that results in frontal bossing, prognathism, maxillary widening with the resultant of teeth separation and jaw malocclusion. The pathophysiology of bone changes is due to GH/IGF-1 effects on the periosteum of bones that results in new bone formation and bone remodeling. In the extremities, these effects will result in osteophyte formation over the digits with cartilage hypertrophy. Radiological hand findings include joint spaces widening, enthesopathy, diaphysis broadening and soft tissue hypertrophy. Due to these changes, two-thirds of patients will have degenerative arthropathy with large joints more commonly affected. In fact, arthropathy is the most common symptom referred by patients with acromegaly on presentation and the leading cause of morbidity. The axial skeleton can be affected by the same mechanism resulting in excessive kyphotic angulation of the thoracic spine with a compensatory hyperlordotic angulation of lumber vertebrae. These factors contribute to the fact that approximately half of these patients have low back pain. Neurogenic claudication is not uncommon due to ligamentum flavum hypertrophy with the resultant spinal canal stenosis. Patients with pure somatotroph pituitary adenoma usually have normal bone mineral density, however, acromegaly patients showed a higher incidence of vertebral compression fractures with high IGF-1 being a significant risk factor [20].
Growth Hormone and insulin like growth factor 1 can also affect visceral organs. Up to 50% of acromegaly patients have hypertension [21, 22]. The underlying cause is multifactorial. Endothelial dysfunction can be caused by GH-induced hyper-reactivity of the sympathetic nervous system [23]. In addition, high levels of GH/IGF-1 increase sodium reabsorption in renal distal tubules which results in chronic water retention/hypervolemia and increased plasma volume (up to 40%) when compared with normal individuals. Another important cause is chronic-sleep-apnea-induced hypertension as 80% of acromegaly patients have obstructive-sleep apnea induced by soft tissue hypertrophy. In addition, hypertrophic cardiomyopathy is commonly found in long standing acromegaly with diastolic dysfunction being the most common cardiac manifestation. Moreover, premature ventricular contractions can be detected in up to 50% of patients. The most common cause of mortality in acromegaly patients is due to cardiac arrhythmias or dysfunction [19].
Acromegaly has deleterious effects on both the upper and lower respiratory systems. Costal bone and subsequently chest wall changes (e.g. barrel chest) are common. Intercostal muscles also are affected by segmental degenerative fibrotic changes resulting weak inspiratory and expiratory efforts [24]. In the upper respiratory tract, acromegaly patients develop macroglossia, narrowing of pharyngeal airway space and thickening of vocal cords. These changes contribute largely to the pathogenesis of obstructive sleep apnea. One third of acromegalic patients with sleep apnea have neurogenic causes due to the effect of GH/IGF-1 on the respiratory center in the brain stem. Total lung capacity is increased in the majority of acromegalic patients due to increased alveolar volume. Narrowing of bronchi and bronchioles lead to obstructive patterns found in approximately 30% of patients, but they rarely have hypoxia due to the absence of ventilation-perfusion mismatch.
In the intestine, increased GH results in an incidence of colon polyps and cancer. Delhougne et al. [25] found in a prospective study that 45% of acromegalic patients had colonic polyps, 24% of them were of the adenomatous type. IGF-1 is unique in that it induces cellular growth and proliferation while also possessing an anti-apoptogenic effect. In 2010, The British Society of Gastroenterology (BSG) and the Association of Coloproctology for Great Britain and Ireland (ACPGBI) advised to start screening of acromegaly patients at the age of 40 with colonoscopy, 10 years earlier than the general population. Patients who were found to have adenoma at first screening
Due to its pulsatile nature of secretion, random GH measurement is not preferred. Clinical diagnosis starts by observing the typical manifestations of GH hypersecretion (Figure 3). Once it is suspected, early morning GH level and IGF-1 level are measured. It is highly advised to use sex and age adjusted levels of IGF-1 as variations in the levels may result in false negative results. The gold standard test for acromegaly diagnosis confirmation is oral-glucose tolerance test (OGTT).
Acromegaly diagnosis algorithm.
All patients with confirmed acromegaly should be screened for associated comorbidities which include hypertension, diabetes, cardiomyopathy and ECG, sleep apnea, and colonoscopy if the age above >40 years old. Patients who have acromegaly related comorbidities have two-fold increase in mortality [24]. While clinical manifestation is extremely indicative of the type of pituitary adenoma—lab values for other pituitary hormones are important screening factors for mixed adenomas (e.g. PRL co-secretion is found in 30% of patients). Standard visual field assessment should be offered to all patients who have macroadenomas abutting the visual apparatus on imaging studies.
Pituitary MRI is needed for evaluation of acromegaly of pituitary source. Because of its insidious onset, GH secreting pituitary adenomas present around 4–7 years after onset. At the time of diagnosis, around 75% of acromegaly patients have macroadenoma on MRI. It is important to note the extent of invasion to suprasellar and cavernous sinus compartments (Figure 4).
Modified Hardy’s classification for sphenoidal sinus and extrasellar extension (A), and Knosp classification of cavernous sinus invasion (B).
The goal of management in GH-secreting adenomas is to normalize GH/IGF-1 levels, remove the mass effect of adenoma from surrounding neurovascular structure, and reverse or control comorbidities that are related to high GH levels. Most of biochemical and structural changes caused by high GH status are reversible (Table 5). Treated acromegaly patients with postoperative GH <1 ng/mL have mortality rate that is similar to age-matched general population [27].
Cardiovascular changes | Outcome | Notes |
---|---|---|
Hypertrophic cardiomyopathy | Reversable | Better prognosis in patients <40 years and shorter duration of GH exposure (<5 years duration) |
Arrhythmias | Reversable | |
Hypertension | Possible reversable | Unsolid data showed possible reversibility |
Valvular hear disease | Irreversible | Mitral and aortic valves are most commonly affected |
Insulin resistance/diabetes | Reversable | Depends on the status of beta-cells function. |
Hyperlipidemia | Reversable | |
Sleep apnea | Reversible (unless significant remodeling of upper airways due to long-standing acromegaly) | Nocturnal PEEP-ventilation assisted device ma needed in treated patients with irreversible upper airway changes |
Lung volume and elasticity | Reversible | |
Arthropathy | Irreversible | Treated patients may have improvement on pain and range of motion, but not on the structural joints changes. |
Carpal tunnel syndrome | Reversible |
Reversible and irreversible biochemical and structural changes in treated acromegaly patients [22].
Surgical excision through a trans-sphenoidal route is the gold standard. Unless it is contraindicated, all patients should be offered surgical excision of the adenoma. In older reports before the year of 2000, GH normalization rate after surgical management was between 40 and 70% [28]. The most common cause of incomplete tumor excision and failure of GH normalization after surgery is extra-sellar tumor growth, specifically invasion into the cavernous sinus. Adenoma total resection will result in a biochemical cure which is defined as IGF-1 within normal range for age and gender, and suppression of GH to <1 ng/mL following OGTT [29].
Recent studies have found that the rate of medial wall invasion in GH-secreting adenomas between 70 and 89% and resection of the medial wall of the cavernous sinus resulted in higher post-operative GH normalization rate which in recent reports was found to be 67–92% [29, 30, 31, 32]. Detection of suprasellar extension or cavernous sinus invasion can be evaluated and graded on pre-operative MRI scans by using Hardy’s and Knops’ classification systems (Figure 4), This system uses CISS and VIPE sequences to evaluate cavernous sinus invasion and optic canal tumor extension [33, 34].
Treatment algorithm is summarized in (Figure 5) which is adopted from The Endocrine Society Guidelines released in 2014 [35].
Acromegaly management algorithm. SRL, somatostatin receptors ligands. *Repeat surgery is recommended for residual and resectable disease. **SRL are the first line of management in patients who are poor surgical candidates, have extensive parasellar invasion, or who had only tumor debulking.
Important points regarding the management of GH-secreting adenomas:
Surgical debulking should be offered to patients who harbor large adenomas with significant extra-sellar extension as that would increase the response to medical therapy.
All patients who had total resection of the adenoma and achieved biochemical cure should be followed-up with IGF-1 level annually.
All patients who did not achieve biochemical cure should be treated with octreotide (SRL). Pegvisomant is added to medical regimen if the response on octreotide is suboptimal.
Radiotherapy is offered for patients who had recurrent adenoma or in suboptimal response on medical therapy. All patient who received radiotherapy should be monitored for hypopituitarism as 80–100% of patients will develop it about 10 years after radiotherapy [28]. It is particularly helpful in adenoma growth control in 90% of patients and can achieve normal IGF-1 level in up to 70% of patients, however, full response takes 10 to 15 years to be seen [28, 36].
On early morning of post-operative day 1, GH level < 2 ng/ml is highly predictive of surgical biochemical cure [37].
Octreotide may result in gastrointestinal hypomotility and increase the risk of gallbladder stones, however, regular monitoring with ultrasound is not needed.
Pegvisomant reversibly elevates liver enzymes. Patients should have liver enzymes monitored every month for first 6 months and every 6 months thereafter. If liver enzymes become elevated three-times above the baseline level, Pegvisomant should be stopped.
Patients may experience excessive diuresis after surgery with immediate improvement in soft tissue edema which should be differentiated from postoperative diabetes insipidus. This phenomenon occurs due to fluid mobilization from soft tissue as GH cause significant fluid retention and plasma volume expansion. Zada et al. found that patients with a negative cumulative fluid balance at 48 hours after surgery were more than twice as likely to have a GH level of <1.5 ng/ml (55 vs. 25%, p = 0.023) [38].
Cushing disease (CD) is a clinical syndrome caused by exposure to supraphysiological levels of cortisol due to adrenocorticotropic hormone (ACTH) hypersecretion from pituitary gland. Cushing disease has an annual incidence of about 2.4 cases/million and a prevalence of 39.1 cases/million [39, 40]. The cause of 70% of endogenous CD is by pituitary adenomas. 20–30% of endogenous CD are due to ectopic-ACTH secreting tumors, 50% of them are from lung cancer.
In normal physiological conditions, ACTH secretion from the anterior pituitary gland is under stimulatory effect by corticotropin-releasing hormone (CRH) released from the paraventricular hypothalamic nucleus. CRH is delivered to pituitary corticotroph cells through hypophyseal portal venous system. ACTH release will stimulate cortisol secretion from adrenal glands. Cortisol will exert an inhibitory effect on ACTH and CRH release from pituitary gland and the hypothalamic nucleus, respectively, in a negative feedback-mechanism. Adenoma cells are not sensitive to high levels of cortisol, however, CRH levels will be suppressed.
ACTH-secreting adenomas are rare, they constitute around 6% of pituitary adenomas [41]. On diagnosis, the majority are microadenomas and only 4–10% are macroadenomas [40]. Unlike acromegaly, CD has female predominance (3:1). Unlike prolactinomas and GH-secreting adenomas, ACTH-secreting adenomas have no relationship between the size of the adenoma and the extent of hypersecretion. Mathioudakis et al. found that patients with microadenomas had more clinical signs and symptoms overall when compared to patients with macroadenomas [42].
High cortisol levels have deleterious effects on almost every organ or system in the body. The most common signs and symptoms are glucose intolerance, hypertension, plethoric rounded facies, decreased libido in both sexes, and menstrual irregularities in females [43]. Other manifestations include osteoporosis, skin thinning and easy bruising, buffalo hump, acne, and proximal muscle weakness. In the pediatric age group, CD should be suspected in children who present with rapid weight gain, growth retardation and dorsocervical fat pad. Uncontrolled CD is associated with high mortality with estimated 5 years’ survival of 50% [44]. The main causes of morbidity and mortality in untreated patient are myocardial infarction, strokes, diabetes mellitus, and infection. However, even after successful management, patients are at higher risk for lethal cardiovascular incidents up to 5 years after treatment [45].
Early recognition of CD is vital for mitigation of long-term consequences from high cortisol exposure. The first step in diagnosis relies on clinical suspicion. Exogenous corticosteroid source should be first ruled-out by a detailed history. The diagnostic work-up is summarized by 3 broad steps: detection of high cortisol level, ACTH level status, and localization of the disease origin (Figure 6). After biochemical confirmation of Cushing syndrome, ACTH level should be measured.
Diagnosis algorithm for Cushing disease.
Low-ACTH levels mean that pituitary cells are suppressed and there is no extra-pituitary ACTH secretion. In this setting, it is prudent to rule-out adrenal adenomas. If ACTH level is high, CD is confirmed and the localization of the source of ACTH secretion should be evaluated. Unlike cancer cells that secret ACTH, adenomas affecting corticotrophic pituitary cells are usually suppressed by exogenous high corticosteroids doses. High-dose dexamethasone test (e.g. 8 mg given at 9 p.m. and cortisol levels measured at 8 a.m. the next morning) will suppress ACTH secreted from pituitary adenoma but not from ectopic sources. MRI pituitary need to be ordered if high-dose dexamethasone test localize the source to pituitary gland. As mentioned earlier, 70–75% of ACTH-secreting adenomas are microadenomas. However, up to 60% of these adenomas are not detected on MRI [43, 45, 46]. To increase detection rate of the adenoma, volumetric interpolated breath-hold examination (VIBE) sequences should be added [47]. If the brain MRI is negative or high-dose dexamethasone test is unequivocal and a pituitary source is still highly suspected, inferior petrosal sinus (IPS) sampling would confirm the pituitary source and also localize the tumor within the pituitary gland to the left or right side. IPS sampling has an accuracy rate of up to 95%, however, it is an invasive procedure and requires highly experienced operators. To enhance the detection rate, bilateral simultaneous IPS sampling after CRH
Bilateral internal jugular vein catheterization (A) and selective contrast injection and sampling of bilateral inferior petrosal sinuses (B).
It is important to mention that IPS sampling is not recommended for adenoma localization in previous surgically treated patients because the venous drainage of the pituitary gland lateralizes unpredictably after initial surgery [50].
The only current treatment is surgery, and the aim should be total adenomectomy. Surgical cure and recurrence rate depends on surgeon experience, adenoma size, extra-sellar extension, and adenoma detection on preoperative MRI. The definition of postoperative biochemical remission varies in the literature but cortisol levels in the early morning after surgery <5 μg/dl within 2–7 days of adenomectomy is widely considered to have high positive predictive value of remission [51].
Remission rate in surgically treated CD is 69–93% [52, 53, 54]. Recurrence rate after successful management is between 3 and 22% of patients after 3 years [50]. However, in patients whose preoperative MRI failed to show the adenoma, remission rate drops to 50–70% [54]. Adenomectomy resection using pseudocapsule technique in which the tumor is resected with its surrounding adherent pituitary cells is associated with higher success rate, longer remission rate, and higher rate of cortisol decline in the post-operative period (Figure 8) [45, 55].
A 30-year-old female patient presented with typical features of Cushing disease. Preoperative workup revealed high cortisol level. She was investigated with MRI pituitary with contrast which showed microadenoma involving the left half of the pituitary gland (A). The patient underwent endoscopic transsphenoidal total resection by utilizing pseudocapsular technique (B). She went to complete remission 36 hours after surgery.
In cases where the adenoma is small or not visualized on MRI, several options are available which will aid in intraoperative tumor localization. Waston et al. could localize ACTH-secreting adenomas by using intraoperative ultrasound in 69% of their patients with negative preoperative MRI [56]. If intraoperative ultrasound is not available or inconclusive, sellar exploration with making multiple cuts within the pituitary gland looking for the adenoma may be warranted. However, in such cases it is very important to expose the whole pituitary gland by wide removal of sellar floor bone and wide dural opening. Additionally, it is crucial to expose the anterior and medial walls of cavernous sinuses bilaterally for adequate visualization. If the exploration was not fruitful, then a partial hypophysectomy of the side that was lateralized by IPS sampling should be considered. Total hypophysectomy (i.e. removal of the anterior pituitary gland while leaving the posterior gland attached to the stalk) may be considered in cases where IPS sampling was unable to lateralize the adenoma, or in cases where intraoperative localization of the adenoma failed.
But the question is when to consider that patient has failed the surgical management and did not achieve remission?
Determining when to consider a patient has failed surgical management is difficult. As stated, all patients should have their cortisol levels evaluated the morning after surgery. Immediate postoperative cortisol levels may fluctuate. Generally after 72 h, cortisol level is stabilized, and therefore can be a better determinant of whether that the patient did not reach the remission state [57]. However, it was found that cortisol level ≤2 μg/dl within first 24 h after surgery there is a 100% sensitivity for durable remission [58]. A serum cortisol value >5 μg/dl up to 6 weeks post-surgery is considered to have persistent disease and should be considered for repeat surgery. Ten percent of patients who had durable remission after adenomectomy will develop recurrence of the disease, therefore, all patients need regular long follow-up for recurrence monitoring [59].
Then, what if the patient failed first surgery and remission did not achieved?
If a patient failed to achieve remission after their first surgery, it is always advisable to do an exploration of the pituitary gland and resect any remnant of the adenoma. Firstly, a pituitary MRI should be repeated; if MRI shows remnant adenoma, resection is needed as soon as possible. If MRI failed to show the remnant disease, surgical exploration of the resected cavity and possible partial or total hypophysectomy should be considered.
But, what if partial or total hypophysectomy have been done in first operation?
In such cases, patient should receive medical therapy, radiotherapy, or other adjuvant therapy.
The aforementioned plan can also be adopted for recurrent disease after an initial biochemical cure. In terms of radiotherapy, stereotactic radiosurgery has the highest incidence of CD remission with rate of 70–75% according to recent reports [60, 61].
Most patients who had successful resection of the adenoma will develop hypocortisolism. This is happens due to longstanding suppression of normal corticotroph cells by high cortisol levels and it takes more than 6 months for those cells to recover. In our practice, we do the first cortisol level measurement 6 h after the surgery and we repeat it every 6 h for the first 3 days. We give replacement therapy (hydrocortisone 8 mg/m2 on early morning and 4 mg/m2 on evening) only if cortisol level < 1.8 ug/dl. Hypopituitarism occurs after adenoma resection in <5% of cases, therefore, pituitary function assessment should be usually done 2 weeks after surgery by measuring prolactin and T4 levels [45].
Lastly, Cushing’s disease patients have an increased risk of venous thromboembolism (VTE). The incidence of postoperative VTE was found to be 3.4% in one study. Excess circulating corticosteroids cause inhibition of fibrinolysis and accelerated activation of coagulation factors. Even after correction of high cortisol level, Hypercoagulability state persist for extended period and the exact time of hemostatic parameters normalization is not well studied [62]. One proposed plan is to keep the VTE chemoprophylaxis up to 30 days after surgery [62].
Non-functional, or non-secretory, adenomas constitute about 10–20% of all intracranial tumors and 15–30% of all pituitary adenomas [63]. They are the second most common pituitary adenoma after prolactinoma. However, if only macroadenomas are considered, NFPA is the most common one [64]. NFPA is unique compared to functional pituitary adenomas in different aspects. First, NFPA are usually seen in old age groups compared to functional adenomas. Second, patients present mainly with signs and symptoms of mass effect. Third, large number of patients have hypopituitarism in one or more of pituitary axes. On the other side, many of NFPA patients are detected incidentally (pituitary incidentalomas). The incidence of asymptomatic NFPA varies in the literature, but one large meta-analysis-autopsy study found the mean prevalence of pituitary incidentalomas was 10.7% [65].
The natural history of incidentally discovered NFPA remains relatively unknown. However, the risk of tumor expansion is related closely to tumor size on presentation and, to lesser extent, tumor relation to optic apparatus [66]. Microadenomas have a low chance of expansion (19%) compared to macroadenomas (25–50% of macroadenoma patients show tumor expansion on follow-up imaging) [66].
The most common presentation of NFPA is headache. It may be caused by intrasellar pressure increment and dural lining compression which are innervated by trigeminal nerve branches. Visual field defect is the second most common clinical presentation that may be seen in up to 61% of cases [64, 67]. Visual field defects are asymmetrical in 2/3 of the patients. They occur due to optic nerves and/or chiasm displacement and compression, which also may result in permanent deficit in long-standing compressions.
Tumor extension to cavernous sinus may result in ophthalmoplegia due to compression of CNIII, CNIV, and CNVI. CNIII is most commonly affected followed by CNVI and then CNIV.
Adenomas greater than >4 cm of diameter may obstruct foramen of Monro and cause obstructive hydrocephalus.
Pituitary apoplexy is another common presentation for these lesions. Pituitary apoplexy is most commonly seen in NFPA, accounting for 45–82% of pituitary apoplexy cases, and 7–9.5% of asymptomatic NFPA present initially with pituitary apoplexy [64].
Hypopituitarism is another common sequela of NFPA. 70–85% patients will have deficiency in at least one axis of pituitary cells secretion [68]. Hypopituitarism occurs in an expected sequence of hormonal loss which usually affect GH, then LF/FSH, then TSH, and lastly ACTH. Diabetes insipidus is rare in non-surgically-NFPA-treated patients, and if it is found in a patient with pituitary lesion, other lesions should be considered (e.g. craniopharyngioma, aneurysms, metastasis).
Lastly, as stated previously, NFPA may be discovered incidentally on brain MRI that was done for other causes. In one large single-center prospective study, 49% of NFPA presented incidentally and 85% of them harbored macroadenomas. Interestingly, in the same cohort, they found that half of the patients in the asymptomatic group reported some mass effects symptoms like headache and/or visual symptoms and only 35% of the incidentally discovered group (in which brain imaging done for unrelated reasons) has no symptoms at all [69].
All patients who their imaging studies showed pituitary adenoma, whether symptomatic or asymptomatic, should go thorough hormonal evaluation as recommended by The Clinical Guidelines Subcommittee of The Endocrine Society [70]. These include IGF-1 and GH, ACTH, prolactin, FSH/LH, and TSH. If ACTH and IGF-1 test are equivocal, stimulatory tests are recommended. Hypopituitarism is not uncommon and hormonal replacement therapy should be initiated in patients with hormonal deficiency. Panhypopituitarism can be seen in up to 30% of patients. Prolactin level could be elevated in 25–65% caused by pituitary stalk compression (stalk effect) [71]. Therefore, it is important to differentiate between hyperprolactinemia caused by a prolactinoma or NFPA. Prolactin level > 200 μg/L is unlikely to be caused by stalk effect.
The diagnostic approach and follow-up are different between symptomatic and asymptomatic NFPA. In symptomatic NFPA, and after doing the hormonal laboratory tests, all patients need to have ophthalmic evaluation for assessing optic apparatus function. Also, it is important to have a detailed history and physical examination to assess the patient symptoms. In asymptomatic NFPA, patients need to have complete hormonal evaluation as mentioned previously to rule-out hyper-or-hypopituitarism. Asymptomatic microadenomas can be followed-up after 1 year of diagnosis by repeating the brain imaging only. In asymptomatic macroadenomas, follow-up is after 6 months with brain MRI and hormone levels, then every year if the follow-up images and laboratories did not show tumor progression or pituitary dysfunction (Figure 9).
Simplified scheme of NFPA diagnosis and management.
Treatment of patients with NFPA starts with hormonal replacement therapy in case of hypopituitarism. It is vital to recognize and treat cortisol deficiency efficiently. The same is true for secondary hypothyroidism as patients should receive thyroxine immediately after confirming its deficiency. Both cortisol and thyroxine should be initiated before surgery, and in non-emergency surgery, it is better to replace thyroxine and wait until hypothyroidism is adequately treated.
Surgical indications for NFPA are symptomatic optic nerve or chiasm compression, cranial nerves dysfunction, and pituitary apoplexy with visual impairment (Figure 9). However, surgery is also advised in asymptomatic growing adenomas that are close to or progressively abutting optic nerves and/or chiasm on follow-up imaging studies [70].
What about patients who have hypopituitarism or headache only?
Surgery in patients with hypopituitarism alone without visual symptoms is not recommended as only 30% of patients will have improvement over pituitary function. Also, headache is a common symptom in NFPA patients, but as headache has multiple causes, there is a high chance of headache persistence after adenoma resection. Therefore, only intractable headache that is affecting patient’s daily activities should be an indication of surgery and the patient should be aware that headache relief cannot be guaranteed [71].
After surgery, patients should be evaluated for hypopituitarism 6 weeks after surgery. Also, pituitary MRI should be done 3 months after surgery to have it as a baseline for future follow-up. Gross-total resection of NFPA has a recurrence rate of 7–24%, and 47–64% of cases in partially resected ones [72].
Currently, pituitary adenomas are approached almost exclusively through transsphenoidal route because it offers a direct access to sellar and suprasellar region by removing of posterior wall of sphenoidal sinus. Also, it is associated with lower morbidity and it is considered a less invasive approach than the transcranial route. Either endoscopic and microscopic, transsphenoidal approach is adequate to remove intrasellar lesions with satisfactory outcomes. Recent advancements in surgical endoscopy have improved our ability to visualize and dissect normal anatomical structures from the adherent pathologies in a way that is nearly similar to microneurosurgery. However, in selected cases, transcranial approaches are still needed for resecting tumors extending to suprasellar or parasellar regions that could not be addressed by transsphenoidal approaches.
It is an extra-arachnoidal direct route to pituitary gland. It has the advantage of avoiding brain retraction, early optic nerves decompression with minimal manipulation, and wide operative view. Posterior wall of sphenoidal sinus, or sellar floor, can be accessed via a transnasal or translabial route. Usually, it involves the usage of microscope, endoscope, or both. Whether endoscope or microscope is used, the procedure has three-stages that are needed to reach the intrasellar space: nasal stage, sphenoidal stage, and sellar stage.
It is important to utilize an operative setup that is comfortable for whole team. Patient is typically positioned supine with 20-degrees head elevation and is positioned straight or slightly extended and fixed using Mayfield head clamp. The surgeon usually operates on the right and facing of the patient. We prefer to have the scrub nurse on the right side of the surgeon and the assistant on the left side. The screen and the navigation are positioned on the left side of the patient facing the surgeon (Figure 10). Neuronavigation is essential for dealing with tumors that extended to supra- or para-sellar regions, and recurrent tumors.
Patient positioned supine, with head slightly extended, monitors are placed to left of the patient (A). The surgeon standing on the right of the patient and the assistant on the surgeon’s left side (B).
Using 0-degree endoscopy, inferior, middle and superior turbinates are identified. Middle turbinate usually obstructs the access to sphenoidal sinus. To have unobstructed route, middle turbinate is typically displaced laterally, or resected if a wider view is needed, using a blunt dissector to create enough working space. After that, the choana is found on the inferomedial aspect of the view. Sphenoethmoidal recess is identified and sphenoid ostium is seen on the roof of the recess and the choana. Nasal septum the best landmark for midline identification.
It starts with enlarging the sphenoidal ostium lateral and inferiorly. This step is usually undertaken by using chisel or high-speed drill. Care is taken to avoid injury to sphenopalatine artery the lies in the inferolateral direction. Posterior nasal septum is coagulated and detached from the sphenoidal rostrum. Anterior wall of the sphenoidal sinus now is exposed, circumferentially with bony removal using high-speed drill and sphenoidal rostrum is removed in fragments. It is important to perform a wide removal of anterior wall of sphenoidal sinus to avoid a narrow working space. Multiple sphenoidal septa can be seen inside the sinus and may need to be drilled. Care is taken septa drilling as one or more of the septa may be attached to carotid prominences.
After a wide removal of anterior wall of sphenoidal sinus and drilling of sphenoidal septa, sellar floor will be seen. Important anatomical landmarks at sellar floor include carotids, optic nerves, pituitary prominences, and lateral opticocarotid recesses bilaterally (Figure 2). Progressive thinning of sellar floor using diamond drill and Kerrison rongeur till the dura over the pituitary gland is exposed. Lateral and superior exposure depends on the extent of the tumor. We prefer not to expose the intracavernous carotids unless the anterior wall of cavernous sinus is needed to be opened for medial wall resection or when dealing with functional adenomas.
Transsphenoidal approach is usually safe and associated with low morbidity rate [73]. The most feared intraoperative complication is ICA injury, which has a very low incidence rate. However, it is associated with significant morbidity and mortality. Consequences of a such injury include pseudoaneurysm formation and carotid cavernous fistula.
Postoperative complications include the ones related to the nose (nasal septum perforation, insomnia, epistaxis from injury to sphenopalatine artery or its branches), sphenoid sinus complications (mucocele formation, sinusitis or sphenoid bone fractures), or related to intrasellar (hemorrhage, cerebrospinal fluid (CSF) leak and tension pneumocephalus).
CSF leak incidence has decreased in recent years due to the advancements and newer techniques in harvesting vascularized nasoseptal flaps [74]. CSF leak incidence in recently published series falls between 1% and 4% [75].
The majority of patients can be treated using transsphenoidal route. However, a few of pituitary adenomas may require transcranial approaches for resecting adenoma extensions that cannot be reached by transsphenoidal route.
Common indications for transcranial surgery in pituitary adenomas include:
Lateral and significant suprasellar adenoma extensions to critical neurovascular structures.
Anatomical challenges like conchal-type sphenoidal sinus, kissing carotids, sinuses infection.
Unsuccessful previous transsphenoidal surgery.
Other uncommon indications include patients with obstructive sleep apnea who could not be weaned off CPAP or concomitant aneurysm that is in proximity to the sellar area.
Recurrent adenomas are no longer an indication for transcranial surgery [76, 77]. Also, giant adenomas (>4 cm) used to be an indication for transcranial surgery, but due to recent advancements in endoscopic approaches, large size adenomas can be effectively treated through transsphenoidal route [78].
In dealing with giant pituitary adenomas that encasing nearby neurovascular structures, both transsphenoidal and transcranial may be needed, especially when the goal of surgery is gross total excision in functional-adenoma cases.
But what approach should be the first choice, the transsphenoidal or the transcranial surgery?
The answer of this question relies on the understanding of the blood supply of pituitary adenomas. These tumors share the same blood supply of normal pituitary gland which comes from inferior and superior hypophyseal arteries. In general, pituitary adenomas have low vascular density which may explain their slow growth [77]. Attacking the adenoma through transsphenoidal route will result in acute devascularization of the remaining unresected adenoma which result in intratumoral necrosis and subsequently hemorrhage (Figure 11). Therefore, it is preferred to go transcranially first then to operate transsphenoidal [79, 80].
Preoperative MRI (A and B) and postoperative CT scan (C and D) for a senior male patient who was complaining form headache and progressive visual dysfunction. The patient was operated in outside hospital through transsphenoidal approach. Incomplete excision was done. However, the patient developed decrease in the level of consciousness and oculomotor nerve dysfunction after surgery. Brain CT scan showed excessive hemorrhage in the unresected intracranial part of the adenoma.
Transcranial approaches that commonly utilized to deal with pituitary adenomas include pterional, orbitozygomatic, bifrontal, and supraorbital approaches. The choice of the approach depends on tumor extension and the neurovascular structures that are needed to be addressed intraoperatively.
Pituitary adenomas associated with significant morbidity and require multiple modalities of treatment. Management is usually surgical except for prolactinomas. The therapeutic decision should be adjusted to adenomas type, center expertise, and patient desire. Thorough understanding of the pathophysiology and management options of PA different types is essential to achieve the therapeutic goals, which can be summarized in pituitary and neurological function restoration.
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Integrity - We are consistent and dependable, always striving for precision and accuracy in the true spirit of science.
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Therefore, this chapter deals with the philosophical systems and paradigms of scientific research, the epistemology, evaluating understanding and application of various theories and practices used in the scientific research. The key components of the scientific research paradigm are highlighted. 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Likewise, they exist in all schools. The school is inserted in a space where the conflict manifests itself daily and assumes relevance, being the result of the multiple interpersonal relationships that occur in the school context. Thus, conflict is part of school life, which implies that teachers must have the skills to manage conflict constructively. Recognizing the diversity of school conflicts, this chapter aimed to present its causes, highlighting the main ones in the classroom, in the teacher-student relationship. It is important to conflict face and resolve it with skills to manage it properly and constructively, establishing cooperative relationships, and producing integrative solutions. Harmony and appreciation should coexist in a classroom environment and conflict should not interfere, negatively, in the teaching and learning process. 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It has many different shapes as well as many various effects, both on the economy and the society at large. Among the most common causes of corruption are the political and economic environment, professional ethics and morality and, of course, habits, customs, tradition and demography. Its effects on the economy (and also on the wider society) are well researched, yet still not completely. Corruption thus inhibits economic growth and affects business operations, employment and investments. It also reduces tax revenue and the effectiveness of various financial assistance programs. The wider society is influenced by a high degree of corruption in terms of lowering of trust in the law and the rule of law, education and consequently the quality of life (access to infrastructure, health care). There also does not exist an unambiguous answer as to how to deal with corruption. Something that works in one country or in one region will not necessarily be successful in another. This chapter tries to answer at least a few questions about corruption and the causes for it, its consequences and how to deal with it successfully.",book:{id:"6487",slug:"trade-and-global-market",title:"Trade and Global Market",fullTitle:"Trade and Global Market"},signatures:"Štefan Šumah",authors:[{id:"228073",title:"Mr.",name:"Stefan",middleName:null,surname:"Sumah",slug:"stefan-sumah",fullName:"Stefan Sumah"}]},{id:"55499",title:"Human Resources Management in Nonprofit Organizations: A Case Study of Istanbul Foundation for Culture and Arts",slug:"human-resources-management-in-nonprofit-organizations-a-case-study-of-istanbul-foundation-for-cultur",totalDownloads:2399,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"The aim of this study is to investigate the efficiency and importance of human resources management in nonprofit organizations. The understanding was included to the literature as personnel management at the beginning of the twentieth century and it turned into an approach as human resources management in the 1980s. It could be observed that many organizations, which deem the human as the most critical stakeholder, adopt a traditional way of personnel management in operating human resources. The employees play a key role in the success of an organization. For this reason, subjects such as recruitment, training, development, career management, performance appraisal, occupational health, and safety are the fundamental functions of human resources management. The study examines to what extent these roles are evaluated through a case study. The subject matter of the study is the most powerful culture and art foundation in Turkey. Compared to many other nonprofit organizations, the foundation actively performs a variety of services within a year worldwide. The fact that the total number of employees might rise up to 800, including the field personnel, indicates the need of a good functioning human resources management. The human resources practices of the foundation are examined and evaluated within that scope.",book:{id:"5826",slug:"issues-of-human-resource-management",title:"Issues of Human Resource Management",fullTitle:"Issues of Human Resource Management"},signatures:"Beste Gökçe Parsehyan",authors:[{id:"189113",title:"Dr.",name:"Beste",middleName:null,surname:"Gokce Parsehyan",slug:"beste-gokce-parsehyan",fullName:"Beste Gokce Parsehyan"}]},{id:"59152",title:"Marketing Strategies for the Social Good",slug:"marketing-strategies-for-the-social-good",totalDownloads:1669,totalCrossrefCites:1,totalDimensionsCites:1,abstract:"Social network sites (SNS) have proven to be a good environment to promote and sell goods and services, but marketing is more than creating commercial strategies. Social marketing strategies can also be used to promote behavioral change and help individuals transform their lives, achieve well-being, and adopt prosocial behaviors. In this chapter, we seek to analyze with a netnographic study, how SNS are being employed by nonprofits and nongovernment organizations (NGOs) to enable citizens and consumers to participate in different programs and activities that promote social transformation and well-being. A particular interest is to identify how organizations are using behavioral economic tactics to nudge individuals and motivate them to engage in prosocial actions. By providing an understanding on how SNS can provide an adequate environment for the design of social marketing strategies, we believe our work has practical implications both for academicians and marketers who want to contribute in the transformation of consumer behavior and the achievement of well-being and social change.",book:{id:"6583",slug:"marketing",title:"Marketing",fullTitle:"Marketing"},signatures:"Alicia De La Pena",authors:[{id:"196878",title:"Dr.",name:"Alicia",middleName:null,surname:"De La Pena",slug:"alicia-de-la-pena",fullName:"Alicia De La Pena"}]}],onlineFirstChaptersFilter:{topicId:"4",limit:6,offset:0},onlineFirstChaptersCollection:[{id:"83075",title:"Practices and Challenges of Community Services at Debre Markos University, Ethiopia: A Case Study",slug:"practices-and-challenges-of-community-services-at-debre-markos-university-ethiopia-a-case-study",totalDownloads:1,totalDimensionsCites:0,doi:"10.5772/intechopen.105896",abstract:"Universities are the main actors that deliver community service in Ethiopia. Community service is among the three pillars of the university’s business along with teaching and research tasks. Employing a qualitative case study design, this research inspects the practices of community services against the ascribed principles and identifes the pitfalls of community service in Debre Markos University. Both primary and secondary data were collected. Primary data were collected through key informants interviews, semistructured interviews, and non-participant observation. Thirteen participants, five through key informant interview and eight through a semistructured interview were addressed. Participants were purposively selected from both the university and the nearby community. Lecturers, vice-presidents, and directors have participated in the interview. Articles, books, different reports, newspapers, and magazines were reviewed and used as sources of secondary data. Thematic data analysis technique was employed to analyze the primary data, and document analysis was used to analyze the data gained from secondary sources. The results show that, though community service is rendered since 2006 at Debre Markos University, there are still limitations in adhering to the principles of community service. These include shortage of budget, low level of University-Industry Linkage (UIL), less commitment of the staff, and the low level of monitoring and evaluation.",book:{id:"11602",title:"Corporate Social Responsibility",coverURL:"https://cdn.intechopen.com/books/images_new/11602.jpg"},signatures:"Adane Mengist"},{id:"83053",title:"Apologies in L2 French in Canadian Context",slug:"apologies-in-l2-french-in-canadian-context",totalDownloads:0,totalDimensionsCites:0,doi:"10.5772/intechopen.106557",abstract:"This article presents the results of an analysis of apology strategies in native and non-native French in Canadian context. The data used were obtained through a Discourse Completion Task questionnaire that was completed by a group of native French speakers (FL1) and a group of learners of French as a second language (FL2). The goal was to identify and compare pragmatic and linguistic choices made by both groups when apologizing in three different situations. Several differences and similarities emerged between the two groups regarding the use of exclamations to introduce apologies, direct apologies, indirect apologies, and supportive acts. For instance, it was found that the FL1 speakers used “expressions of regret”, “offers of apology” 15 and “requests for forgiveness” to apologize directly, while the FL2 speaking informants used 16 only “expressions of regret” and “offers of apology”. While the respondents of both groups 17 mostly chose “offers of repair” to apologize indirectly, they displayed divergent preferences 18 regarding the use of other indirect apology strategies. Differences were also documented 19 with respect to the use of intensification devices in direct apologies and the use of supportive acts. Implications of the findings for L2 French pedagogy were also discussed.",book:{id:"11480",title:"Second Language Acquisition - Learning Theories and Recent Approaches",coverURL:"https://cdn.intechopen.com/books/images_new/11480.jpg"},signatures:"Bernard Mulo Farenkia"},{id:"83049",title:"An Ethnographic Study on Sense of a Community: The “Awramba” Experience",slug:"an-ethnographic-study-on-sense-of-a-community-the-awramba-experience",totalDownloads:0,totalDimensionsCites:0,doi:"10.5772/intechopen.105953",abstract:"The study was conducted on “Awramba” Community who are living in “Amhara” region, south “Gondor” Zone, Ethiopia. The general objective of this study was to capture an understanding of sense of community in “Awramba” community. The study tried to answer the following questions: How the community was established? What are the criteria to be part of the community? What are the shared values of social practice that has survived for the test of time? What is the historical background of the “Awramba” Community? The researcher used realist ethnography method to achieve the above objective and to answer the questions. In-depth interview and observational guide techniques were applied to collect reliable data for the study. The observation and in-depth interview data were analyzed qualitatively. The study showed the following themes: Membership criteria of the community are based on adhering to the community norm. They have a strong sense of community based on shared story, cooperative work, marriage and mourning values, religious view, gender equality, commitment to be honest, and solving their problem by themselves. The emotional connection of the “Awramba” community is strengthened by their common celebration of the yearly anniversary of New Year and scheduled meeting.",book:{id:"11429",title:"Sustainability, Ecology, and Religions of the World",coverURL:"https://cdn.intechopen.com/books/images_new/11429.jpg"},signatures:"Nassir-Maru Yesuf"},{id:"83027",title:"Coping Strategies and Meta-Worry in Adolescents’ Adjustment during COVID-19 Pandemic",slug:"coping-strategies-and-meta-worry-in-adolescents-adjustment-during-covid-19-pandemic",totalDownloads:1,totalDimensionsCites:0,doi:"10.5772/intechopen.106258",abstract:"With the beginning of the COVID-19 pandemic, several limitations and stressful changes have been introduced in adolescent’s daily life. Particularly, Italian teenagers were the first among western populations to experience fears of infection, home confinement, and social restrictions due to a long lockdown period (10 weeks). This study explores the role of coping strategies (task-oriented, emotion-oriented, and avoidance coping) and meta-beliefs about worry as vulnerability factors associated with adolescents’ anxiety. A community sample of adolescents (N = 284, aged 16–18 y.o.) answered questionnaires assessing anxiety symptoms (RCMAS-2), meta-cognitive beliefs and processes about worry (MCQ-C), and coping strategies (CISS). Results show that 37% of participants report clinically elevated anxiety. Emotion-centered coping predicted higher anxiety, whereas task-centered coping resulted associated with decreased anxiety. Cognitive monitoring about their own worry contributes, but to a lesser extent, to higher levels of anxiety. The implications for the intervention are discussed, especially the need to enhance the coping skills of adolescents and mitigate the stress of the COVID-19 pandemic, which could last for a long time.",book:{id:"10671",title:"Adolescences",coverURL:"https://cdn.intechopen.com/books/images_new/10671.jpg"},signatures:"Loredana Benedetto, Ilenia Schipilliti and Massimo Ingrassia"},{id:"83023",title:"Gestational Tryptophan Fluctuation Underlying Ontogenetic Origin of Neuropsychiatric Disorders",slug:"gestational-tryptophan-fluctuation-underlying-ontogenetic-origin-of-neuropsychiatric-disorders",totalDownloads:5,totalDimensionsCites:0,doi:"10.5772/intechopen.106421",abstract:"Neuropsychiatry underlies personality development and social functioning. Borderline personality disorder exhibits high trait aggression and is associated with tryptophan hydroxylase polymorphisms. The acute tryptophan depletion reduces plasma and cerebrospinal fluid tryptophan availability and brain serotonin concentrations, leading to alterations in personality and trait-related behaviors. Tryptophan is essential for fatal neurodevelopment and immunomodulation in pregnancy. Gestational tryptophan fluctuation induced by maternal metabolic disorders or drug administrations may account for the maternal-fetal transmission determining neurogenesis and microbial development, consequentially shaping the long-standing patterns of thinking and behavior. However, it is not possible to assess the gestational tryptophan exposure effects on fetal brain and gastrointestinal system in humans for ethical reasons. The maternal–fetal microbe transmission in rodents during gestation, vaginal delivery, and breastfeeding is inevitable. Chicken embryo may be an alternative and evidence from the chicken embryo model reveals that gestational tryptophan fluctuation, i.e., exposed to excessive tryptophan or its metabolite, serotonin, attenuates aggressiveness and affects peer sociometric status. This chapter discusses the gestational tryptophan fluctuation as a risk factor of personality disorders in offspring and the prevention of personality disorders by dietary tryptophan control and medication therapy management during pregnancy.",book:{id:"11782",title:"Personality Traits - The Role in Psychopathology",coverURL:"https://cdn.intechopen.com/books/images_new/11782.jpg"},signatures:"Xiaohong Huang, Xiaohua Li and Heng-Wei Cheng"},{id:"83014",title:"Culture: A Pillar of Organizational Sustainability",slug:"culture-a-pillar-of-organizational-sustainability",totalDownloads:3,totalDimensionsCites:0,doi:"10.5772/intechopen.106523",abstract:"Sustainability is a concern that permeates all levels of society and is premised on meeting the needs of the present without compromising the ability of future generations to meet theirs. More recently, policies and research have emerged that guide organizations to align their activities with the broader sustainable development agendas, including cultural issues, not just economic, social, and environmental ones. Culture is the material and immaterial attribute of society. It incorporates social organizations, literature, religion, myths, beliefs, behaviors and entrepreneurial practices of the productive segment, use of technology, and expressive art forms on which future generations depend. Thus, cultural sustainability is a fundamental issue and is configured as the fourth pillar of sustainability, equal to social, economic, and environmental issues, which has to do with the ability to sustain or continue with cultural beliefs and practices, preserve cultural heritage as its entity, and try to answer whether any culture will exist in the future. The importance of cultural sustainability lies in its power to influence people. Their beliefs are in the decisions made by society. Thus, there can be no sustainable development without including culture.",book:{id:"11429",title:"Sustainability, Ecology, and Religions of the World",coverURL:"https://cdn.intechopen.com/books/images_new/11429.jpg"},signatures:"Clea Beatriz Macagnan and Rosane Maria Seibert"}],onlineFirstChaptersTotal:282},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:108,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:140,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:123,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:22,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:11,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. The whole process of submitting an article and editing of the submitted article goes extremely smooth and fast, the number of reads and downloads of chapters is high, and the contributions are also frequently cited.",author:{id:"55578",name:"Antonio",surname:"Jurado-Navas",institutionString:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRisIQAS/Profile_Picture_1626166543950",slug:"antonio-jurado-navas",institution:{id:"720",name:"University of Malaga",country:{id:null,name:"Spain"}}}},{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}}]},series:{item:{id:"7",title:"Biomedical Engineering",doi:"10.5772/intechopen.71985",issn:"2631-5343",scope:"Biomedical Engineering is one of the fastest-growing interdisciplinary branches of science and industry. The combination of electronics and computer science with biology and medicine has improved patient diagnosis, reduced rehabilitation time, and helped to facilitate a better quality of life. Nowadays, all medical imaging devices, medical instruments, or new laboratory techniques result from the cooperation of specialists in various fields. The series of Biomedical Engineering books covers such areas of knowledge as chemistry, physics, electronics, medicine, and biology. This series is intended for doctors, engineers, and scientists involved in biomedical engineering or those wanting to start working in this field.",coverUrl:"https://cdn.intechopen.com/series/covers/7.jpg",latestPublicationDate:"August 14th, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:12,editor:{id:"50150",title:"Prof.",name:"Robert",middleName:null,surname:"Koprowski",slug:"robert-koprowski",fullName:"Robert Koprowski",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYTYNQA4/Profile_Picture_1630478535317",biography:"Robert Koprowski, MD (1997), PhD (2003), Habilitation (2015), is an employee of the University of Silesia, Poland, Institute of Computer Science, Department of Biomedical Computer Systems. For 20 years, he has studied the analysis and processing of biomedical images, emphasizing the full automation of measurement for a large inter-individual variability of patients. Dr. Koprowski has authored more than a hundred research papers with dozens in impact factor (IF) journals and has authored or co-authored six books. Additionally, he is the author of several national and international patents in the field of biomedical devices and imaging. Since 2011, he has been a reviewer of grants and projects (including EU projects) in biomedical engineering.",institutionString:null,institution:{name:"University of Silesia",institutionURL:null,country:{name:"Poland"}}},editorTwo:null,editorThree:null},subseries:{paginationCount:3,paginationItems:[{id:"7",title:"Bioinformatics and Medical Informatics",coverUrl:"https://cdn.intechopen.com/series_topics/covers/7.jpg",isOpenForSubmission:!0,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},{id:"8",title:"Bioinspired Technology and Biomechanics",coverUrl:"https://cdn.intechopen.com/series_topics/covers/8.jpg",isOpenForSubmission:!0,editor:{id:"144937",title:"Prof.",name:"Adriano",middleName:"De Oliveira",surname:"Andrade",slug:"adriano-andrade",fullName:"Adriano Andrade",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRC8QQAW/Profile_Picture_1625219101815",biography:"Dr. Adriano de Oliveira Andrade graduated in Electrical Engineering at the Federal University of Goiás (Brazil) in 1997. He received his MSc and PhD in Biomedical Engineering respectively from the Federal University of Uberlândia (UFU, Brazil) in 2000 and from the University of Reading (UK) in 2005. He completed a one-year Post-Doctoral Fellowship awarded by the DFAIT (Foreign Affairs and International Trade Canada) at the Institute of Biomedical Engineering of the University of New Brunswick (Canada) in 2010. Currently, he is Professor in the Faculty of Electrical Engineering (UFU). He has authored and co-authored more than 200 peer-reviewed publications in Biomedical Engineering. He has been a researcher of The National Council for Scientific and Technological Development (CNPq-Brazil) since 2009. He has served as an ad-hoc consultant for CNPq, CAPES (Coordination for the Improvement of Higher Education Personnel), FINEP (Brazilian Innovation Agency), and other funding bodies on several occasions. He was the Secretary of the Brazilian Society of Biomedical Engineering (SBEB) from 2015 to 2016, President of SBEB (2017-2018) and Vice-President of SBEB (2019-2020). He was the head of the undergraduate program in Biomedical Engineering of the Federal University of Uberlândia (2015 - June/2019) and the head of the Centre for Innovation and Technology Assessment in Health (NIATS/UFU) since 2010. He is the head of the Postgraduate Program in Biomedical Engineering (UFU, July/2019 - to date). He was the secretary of the Parkinson's Disease Association of Uberlândia (2018-2019). Dr. Andrade's primary area of research is focused towards getting information from the neuromuscular system to understand its strategies of organization, adaptation and controlling in the context of motor neuron diseases. His research interests include Biomedical Signal Processing and Modelling, Assistive Technology, Rehabilitation Engineering, Neuroengineering and Parkinson's Disease.",institutionString:null,institution:{name:"Federal University of Uberlândia",institutionURL:null,country:{name:"Brazil"}}},editorTwo:null,editorThree:null},{id:"9",title:"Biotechnology - Biosensors, Biomaterials and Tissue Engineering",coverUrl:"https://cdn.intechopen.com/series_topics/covers/9.jpg",isOpenForSubmission:!0,editor:{id:"126286",title:"Dr.",name:"Luis",middleName:"Jesús",surname:"Villarreal-Gómez",slug:"luis-villarreal-gomez",fullName:"Luis Villarreal-Gómez",profilePictureURL:"https://mts.intechopen.com/storage/users/126286/images/system/126286.jpg",biography:"Dr. Luis Villarreal is a research professor from the Facultad de Ciencias de la Ingeniería y Tecnología, Universidad Autónoma de Baja California, Tijuana, Baja California, México. Dr. Villarreal is the editor in chief and founder of the Revista de Ciencias Tecnológicas (RECIT) (https://recit.uabc.mx/) and is a member of several editorial and reviewer boards for numerous international journals. He has published more than thirty international papers and reviewed more than ninety-two manuscripts. His research interests include biomaterials, nanomaterials, bioengineering, biosensors, drug delivery systems, and tissue engineering.",institutionString:null,institution:{name:"Autonomous University of Baja California",institutionURL:null,country:{name:"Mexico"}}},editorTwo:null,editorThree:null}]},overviewPageOFChapters:{paginationCount:27,paginationItems:[{id:"83092",title:"Novel Composites for Bone Tissue Engineering",doi:"10.5772/intechopen.106255",signatures:"Pugalanthipandian Sankaralingam, Poornimadevi Sakthivel and Vijayakumar Chinnaswamy Thangavel",slug:"novel-composites-for-bone-tissue-engineering",totalDownloads:0,totalCrossrefCites:null,totalDimensionsCites:0,authors:null,book:{title:"Biomimetics - Bridging the Gap",coverURL:"https://cdn.intechopen.com/books/images_new/11453.jpg",subseries:{id:"8",title:"Bioinspired Technology and Biomechanics"}}},{id:"82800",title:"Repurposing Drugs as Potential Therapeutics for the SARS-Cov-2 Viral Infection: Automatizing a Blind Molecular Docking High-throughput Pipeline",doi:"10.5772/intechopen.105792",signatures:"Aldo Herrera-Rodulfo, Mariana Andrade-Medina and Mauricio Carrillo-Tripp",slug:"repurposing-drugs-as-potential-therapeutics-for-the-sars-cov-2-viral-infection-automatizing-a-blind-",totalDownloads:7,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Molecular Docking - Recent Advances",coverURL:"https://cdn.intechopen.com/books/images_new/11451.jpg",subseries:{id:"7",title:"Bioinformatics and Medical Informatics"}}},{id:"82582",title:"Protecting Bioelectric Signals from Electromagnetic Interference in a Wireless World",doi:"10.5772/intechopen.105951",signatures:"David Marcarian",slug:"protecting-bioelectric-signals-from-electromagnetic-interference-in-a-wireless-world",totalDownloads:4,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Biosignal Processing",coverURL:"https://cdn.intechopen.com/books/images_new/11153.jpg",subseries:{id:"7",title:"Bioinformatics and Medical Informatics"}}},{id:"82586",title:"Fundamentals of Molecular Docking and Comparative Analysis of Protein–Small-Molecule Docking Approaches",doi:"10.5772/intechopen.105815",signatures:"Maden Sefika Feyza, Sezer Selin and Acuner Saliha Ece",slug:"fundamentals-of-molecular-docking-and-comparative-analysis-of-protein-small-molecule-docking-approac",totalDownloads:27,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Molecular Docking - Recent Advances",coverURL:"https://cdn.intechopen.com/books/images_new/11451.jpg",subseries:{id:"7",title:"Bioinformatics and Medical Informatics"}}}]},overviewPagePublishedBooks:{paginationCount:12,paginationItems:[{type:"book",id:"6692",title:"Medical and Biological Image Analysis",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/6692.jpg",slug:"medical-and-biological-image-analysis",publishedDate:"July 4th 2018",editedByType:"Edited by",bookSignature:"Robert Koprowski",hash:"e75f234a0fc1988d9816a94e4c724deb",volumeInSeries:1,fullTitle:"Medical and Biological Image Analysis",editors:[{id:"50150",title:"Prof.",name:"Robert",middleName:null,surname:"Koprowski",slug:"robert-koprowski",fullName:"Robert Koprowski",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYTYNQA4/Profile_Picture_1630478535317",biography:"Robert Koprowski, MD (1997), PhD (2003), Habilitation (2015), is an employee of the University of Silesia, Poland, Institute of Computer Science, Department of Biomedical Computer Systems. For 20 years, he has studied the analysis and processing of biomedical images, emphasizing the full automation of measurement for a large inter-individual variability of patients. Dr. Koprowski has authored more than a hundred research papers with dozens in impact factor (IF) journals and has authored or co-authored six books. Additionally, he is the author of several national and international patents in the field of biomedical devices and imaging. Since 2011, he has been a reviewer of grants and projects (including EU projects) in biomedical engineering.",institutionString:null,institution:{name:"University of Silesia",institutionURL:null,country:{name:"Poland"}}}]},{type:"book",id:"7218",title:"OCT",subtitle:"Applications in Ophthalmology",coverURL:"https://cdn.intechopen.com/books/images_new/7218.jpg",slug:"oct-applications-in-ophthalmology",publishedDate:"September 19th 2018",editedByType:"Edited by",bookSignature:"Michele Lanza",hash:"e3a3430cdfd6999caccac933e4613885",volumeInSeries:2,fullTitle:"OCT - Applications in Ophthalmology",editors:[{id:"240088",title:"Prof.",name:"Michele",middleName:null,surname:"Lanza",slug:"michele-lanza",fullName:"Michele Lanza",profilePictureURL:"https://mts.intechopen.com/storage/users/240088/images/system/240088.png",biography:"Michele Lanza is Associate Professor of Ophthalmology at Università della Campania, Luigi Vanvitelli, Napoli, Italy. His fields of interest are anterior segment disease, keratoconus, glaucoma, corneal dystrophies, and cataracts. His research topics include\nintraocular lens power calculation, eye modification induced by refractive surgery, glaucoma progression, and validation of new diagnostic devices in ophthalmology. \nHe has published more than 100 papers in international and Italian scientific journals, more than 60 in journals with impact factors, and chapters in international and Italian books. He has also edited two international books and authored more than 150 communications or posters for the most important international and Italian ophthalmology conferences.",institutionString:'University of Campania "Luigi Vanvitelli"',institution:{name:'University of Campania "Luigi Vanvitelli"',institutionURL:null,country:{name:"Italy"}}}]},{type:"book",id:"7560",title:"Non-Invasive Diagnostic Methods",subtitle:"Image Processing",coverURL:"https://cdn.intechopen.com/books/images_new/7560.jpg",slug:"non-invasive-diagnostic-methods-image-processing",publishedDate:"December 19th 2018",editedByType:"Edited by",bookSignature:"Mariusz Marzec and Robert Koprowski",hash:"d92fd8cf5a90a47f2b8a310837a5600e",volumeInSeries:3,fullTitle:"Non-Invasive Diagnostic Methods - Image Processing",editors:[{id:"253468",title:"Dr.",name:"Mariusz",middleName:null,surname:"Marzec",slug:"mariusz-marzec",fullName:"Mariusz Marzec",profilePictureURL:"https://mts.intechopen.com/storage/users/253468/images/system/253468.png",biography:"An assistant professor at Department of Biomedical Computer Systems, at Institute of Computer Science, Silesian University in Katowice. Scientific interests: computer analysis and processing of images, biomedical images, databases and programming languages. 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Working with large volumes of data has given him a good command of big data processing tools and NoSQL databases. He has also been a visiting scholar at the Knowledge Engineering and Discovery Research Institute, Auckland University of Technology.",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"314575",title:"Dr.",name:"Jesus",middleName:null,surname:"L. Lobo",slug:"jesus-l.-lobo",fullName:"Jesus L. Lobo",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/314575/images/system/314575.png",biography:"Dr. Jesús López is currently based in Bilbao (Spain) working at TECNALIA as Artificial Intelligence Research Scientist. In most cases, a project idea or a new research line needs to be investigated to see if it is good enough to take into production or to focus on it. That is exactly what he does, diving into Machine Learning algorithms and technologies to help TECNALIA to decide whether something is great in theory or will actually impact on the product or processes of its projects. So, he is expert at framing experiments, developing hypotheses, and proving whether they’re true or not, in order to investigate fundamental problems with a longer time horizon. He is also able to design and develop PoCs and system prototypes in simulation. He has participated in several national and internacional R&D projects.\n\nAs another relevant part of his everyday research work, he usually publishes his findings in reputed scientific refereed journals and international conferences, occasionally acting as reviewer and Programme Commitee member. Concretely, since 2018 he has published 9 JCR (8 Q1) journal papers, 9 conference papers (e.g. ECML PKDD 2021), and he has co-edited a book. He is also active in popular science writing data science stories for reputed blogs (KDNuggets, TowardsDataScience, Naukas). Besides, he has recently embarked on mentoring programmes as mentor, and has also worked as data science trainer.",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"103779",title:"Prof.",name:"Yalcin",middleName:null,surname:"Isler",slug:"yalcin-isler",fullName:"Yalcin Isler",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRyQ8QAK/Profile_Picture_1628834958734",biography:"Yalcin Isler (1971 - Burdur / Turkey) received the B.Sc. degree in the Department of Electrical and Electronics Engineering from Anadolu University, Eskisehir, Turkey, in 1993, the M.Sc. degree from the Department of Electronics and Communication Engineering, Suleyman Demirel University, Isparta, Turkey, in 1996, the Ph.D. degree from the Department of Electrical and Electronics Engineering, Dokuz Eylul University, Izmir, Turkey, in 2009, and the Competence of Associate Professorship from the Turkish Interuniversity Council in 2019.\n\nHe was Lecturer at Burdur Vocational School in Suleyman Demirel University (1993-2000, Burdur / Turkey), Software Engineer (2000-2002, Izmir / Turkey), Research Assistant in Bulent Ecevit University (2002-2003, Zonguldak / Turkey), Research Assistant in Dokuz Eylul University (2003-2010, Izmir / Turkey), Assistant Professor at the Department of Electrical and Electronics Engineering in Bulent Ecevit University (2010-2012, Zonguldak / Turkey), Assistant Professor at the Department of Biomedical Engineering in Izmir Katip Celebi University (2012-2019, Izmir / Turkey). He is an Associate Professor at the Department of Biomedical Engineering at Izmir Katip Celebi University, Izmir / Turkey, since 2019. In addition to academics, he has also founded Islerya Medical and Information Technologies Company, Izmir / Turkey, since 2017.\n\nHis main research interests cover biomedical signal processing, pattern recognition, medical device design, programming, and embedded systems. He has many scientific papers and participated in several projects in these study fields. He was an IEEE Student Member (2009-2011) and IEEE Member (2011-2014) and has been IEEE Senior Member since 2014.",institutionString:null,institution:{name:"Izmir Kâtip Çelebi University",country:{name:"Turkey"}}},{id:"339677",title:"Dr.",name:"Mrinmoy",middleName:null,surname:"Roy",slug:"mrinmoy-roy",fullName:"Mrinmoy Roy",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/339677/images/16768_n.jpg",biography:"An accomplished Sales & Marketing professional with 12 years of cross-functional experience in well-known organisations such as CIPLA, LUPIN, GLENMARK, ASTRAZENECA across different segment of Sales & Marketing, International Business, Institutional Business, Product Management, Strategic Marketing of HIV, Oncology, Derma, Respiratory, Anti-Diabetic, Nutraceutical & Stomatological Product Portfolio and Generic as well as Chronic Critical Care Portfolio. A First Class MBA in International Business & Strategic Marketing, B.Pharm, D.Pharm, Google Certified Digital Marketing Professional. Qualified PhD Candidate in Operations and Management with special focus on Artificial Intelligence and Machine Learning adoption, analysis and use in Healthcare, Hospital & Pharma Domain. Seasoned with diverse therapy area of Pharmaceutical Sales & Marketing ranging from generating revenue through generating prescriptions, launching new products, and making them big brands with continuous strategy execution at the Physician and Patients level. Moved from Sales to Marketing and Business Development for 3.5 years in South East Asian Market operating from Manila, Philippines. Came back to India and handled and developed Brands such as Gluconorm, Lupisulin, Supracal, Absolut Woman, Hemozink, Fabiflu (For COVID 19), and many more. In my previous assignment I used to develop and execute strategies on Sales & Marketing, Commercialization & Business Development for Institution and Corporate Hospital Business portfolio of Oncology Therapy Area for AstraZeneca Pharma India Ltd. Being a Research Scholar and Student of ‘Operations Research & Management: Artificial Intelligence’ I published several pioneer research papers and book chapters on the same in Internationally reputed journals and Books indexed in Scopus, Springer and Ei Compendex, Google Scholar etc. Currently, I am launching PGDM Pharmaceutical Management Program in IIHMR Bangalore and spearheading the course curriculum and structure of the same. I am interested in Collaboration for Healthcare Innovation, Pharma AI Innovation, Future trend in Marketing and Management with incubation on Healthcare, Healthcare IT startups, AI-ML Modelling and Healthcare Algorithm based training module development. I am also an affiliated member of the Institute of Management Consultant of India, looking forward to Healthcare, Healthcare IT and Innovation, Pharma and Hospital Management Consulting works.",institutionString:null,institution:{name:"Lovely Professional University",country:{name:"India"}}},{id:"310576",title:"Prof.",name:"Erick Giovani",middleName:null,surname:"Sperandio Nascimento",slug:"erick-giovani-sperandio-nascimento",fullName:"Erick Giovani Sperandio Nascimento",position:null,profilePictureURL:"https://intech-files.s3.amazonaws.com/0033Y00002pDKxDQAW/ProfilePicture%202022-06-20%2019%3A57%3A24.788",biography:"Prof. Erick Sperandio is the Lead Researcher and professor of Artificial Intelligence (AI) at SENAI CIMATEC, Bahia, Brazil, also working with Computational Modeling (CM) and HPC. He holds a PhD in Environmental Engineering in the area of Atmospheric Computational Modeling, a Master in Informatics in the field of Computational Intelligence and Graduated in Computer Science from UFES. He currently coordinates, leads and participates in R&D projects in the areas of AI, computational modeling and supercomputing applied to different areas such as Oil and Gas, Health, Advanced Manufacturing, Renewable Energies and Atmospheric Sciences, advising undergraduate, master's and doctoral students. He is the Lead Researcher at SENAI CIMATEC's Reference Center on Artificial Intelligence. In addition, he is a Certified Instructor and University Ambassador of the NVIDIA Deep Learning Institute (DLI) in the areas of Deep Learning, Computer Vision, Natural Language Processing and Recommender Systems, and Principal Investigator of the NVIDIA/CIMATEC AI Joint Lab, the first in Latin America within the NVIDIA AI Technology Center (NVAITC) worldwide program. He also works as a researcher at the Supercomputing Center for Industrial Innovation (CS2i) and at the SENAI Institute of Innovation for Automation (ISI Automação), both from SENAI CIMATEC. He is a member and vice-coordinator of the Basic Board of Scientific-Technological Advice and Evaluation, in the area of Innovation, of the Foundation for Research Support of the State of Bahia (FAPESB). He serves as Technology Transfer Coordinator and one of the Principal Investigators at the National Applied Research Center in Artificial Intelligence (CPA-IA) of SENAI CIMATEC, focusing on Industry, being one of the six CPA-IA in Brazil approved by MCTI / FAPESP / CGI.br. He also participates as one of the representatives of Brazil in the BRICS Innovation Collaboration Working Group on HPC, ICT and AI. He is the coordinator of the Work Group of the Axis 5 - Workforce and Training - of the Brazilian Strategy for Artificial Intelligence (EBIA), and member of the MCTI/EMBRAPII AI Innovation Network Training Committee. He is the coordinator, by SENAI CIMATEC, of the Artificial Intelligence Reference Network of the State of Bahia (REDE BAH.IA). He leads the working group of experts representing Brazil in the Global Partnership on Artificial Intelligence (GPAI), on the theme \"AI and the Pandemic Response\".",institutionString:"Manufacturing and Technology Integrated Campus – SENAI CIMATEC",institution:null},{id:"1063",title:"Prof.",name:"Constantin",middleName:null,surname:"Volosencu",slug:"constantin-volosencu",fullName:"Constantin Volosencu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/1063/images/system/1063.png",biography:"Prof. Dr. Constantin Voloşencu graduated as an engineer from\nPolitehnica University of Timișoara, Romania, where he also\nobtained a doctorate degree. He is currently a full professor in\nthe Department of Automation and Applied Informatics at the\nsame university. Dr. Voloşencu is the author of ten books, seven\nbook chapters, and more than 160 papers published in journals\nand conference proceedings. He has also edited twelve books and\nhas twenty-seven patents to his name. He is a manager of research grants, editor in\nchief and member of international journal editorial boards, a former plenary speaker, a member of scientific committees, and chair at international conferences. His\nresearch is in the fields of control systems, control of electric drives, fuzzy control\nsystems, neural network applications, fault detection and diagnosis, sensor network\napplications, monitoring of distributed parameter systems, and power ultrasound\napplications. He has developed automation equipment for machine tools, spooling\nmachines, high-power ultrasound processes, and more.",institutionString:'"Politechnica" University Timişoara',institution:null},{id:"221364",title:"Dr.",name:"Eneko",middleName:null,surname:"Osaba",slug:"eneko-osaba",fullName:"Eneko Osaba",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/221364/images/system/221364.jpg",biography:"Dr. Eneko Osaba works at TECNALIA as a senior researcher. He obtained his Ph.D. in Artificial Intelligence in 2015. He has participated in more than twenty-five local and European research projects, and in the publication of more than 130 papers. He has performed several stays at universities in the United Kingdom, Italy, and Malta. Dr. Osaba has served as a program committee member in more than forty international conferences and participated in organizing activities in more than ten international conferences. He is a member of the editorial board of the International Journal of Artificial Intelligence, Data in Brief, and Journal of Advanced Transportation. He is also a guest editor for the Journal of Computational Science, Neurocomputing, Swarm, and Evolutionary Computation and IEEE ITS Magazine.",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"275829",title:"Dr.",name:"Esther",middleName:null,surname:"Villar-Rodriguez",slug:"esther-villar-rodriguez",fullName:"Esther Villar-Rodriguez",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/275829/images/system/275829.jpg",biography:"Dr. Esther Villar obtained a Ph.D. in Information and Communication Technologies from the University of Alcalá, Spain, in 2015. She obtained a degree in Computer Science from the University of Deusto, Spain, in 2010, and an MSc in Computer Languages and Systems from the National University of Distance Education, Spain, in 2012. Her areas of interest and knowledge include natural language processing (NLP), detection of impersonation in social networks, semantic web, and machine learning. Dr. Esther Villar made several contributions at conferences and publishing in various journals in those fields. Currently, she is working within the OPTIMA (Optimization Modeling & Analytics) business of TECNALIA’s ICT Division as a data scientist in projects related to the prediction and optimization of management and industrial processes (resource planning, energy efficiency, etc).",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"49813",title:"Dr.",name:"Javier",middleName:null,surname:"Del Ser",slug:"javier-del-ser",fullName:"Javier Del Ser",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/49813/images/system/49813.png",biography:"Prof. Dr. Javier Del Ser received his first PhD in Telecommunication Engineering (Cum Laude) from the University of Navarra, Spain, in 2006, and a second PhD in Computational Intelligence (Summa Cum Laude) from the University of Alcala, Spain, in 2013. He is currently a principal researcher in data analytics and optimisation at TECNALIA (Spain), a visiting fellow at the Basque Center for Applied Mathematics (BCAM) and a part-time lecturer at the University of the Basque Country (UPV/EHU). His research interests gravitate on the use of descriptive, prescriptive and predictive algorithms for data mining and optimization in a diverse range of application fields such as Energy, Transport, Telecommunications, Health and Industry, among others. In these fields he has published more than 240 articles, co-supervised 8 Ph.D. theses, edited 6 books, coauthored 7 patents and participated/led more than 40 research projects. He is a Senior Member of the IEEE, and a recipient of the Biscay Talent prize for his academic career.",institutionString:"Tecnalia Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"278948",title:"Dr.",name:"Carlos Pedro",middleName:null,surname:"Gonçalves",slug:"carlos-pedro-goncalves",fullName:"Carlos Pedro Gonçalves",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRcmyQAC/Profile_Picture_1564224512145",biography:'Carlos Pedro Gonçalves (PhD) is an Associate Professor at Lusophone University of Humanities and Technologies and a researcher on Complexity Sciences, Quantum Technologies, Artificial Intelligence, Strategic Studies, Studies in Intelligence and Security, FinTech and Financial Risk Modeling. He is also a progammer with programming experience in:\n\nA) Quantum Computing using Qiskit Python module and IBM Quantum Experience Platform, with software developed on the simulation of Quantum Artificial Neural Networks and Quantum Cybersecurity;\n\nB) Artificial Intelligence and Machine learning programming in Python;\n\nC) Artificial Intelligence, Multiagent Systems Modeling and System Dynamics Modeling in Netlogo, with models developed in the areas of Chaos Theory, Econophysics, Artificial Intelligence, Classical and Quantum Complex Systems Science, with the Econophysics models having been cited worldwide and incorporated in PhD programs by different Universities.\n\nReceived an Arctic Code Vault Contributor status by GitHub, due to having developed open source software preserved in the \\"Arctic Code Vault\\" for future generations (https://archiveprogram.github.com/arctic-vault/), with the Strategy Analyzer A.I. module for decision making support (based on his PhD thesis, used in his Classes on Decision Making and in Strategic Intelligence Consulting Activities) and QNeural Python Quantum Neural Network simulator also preserved in the \\"Arctic Code Vault\\", for access to these software modules see: https://github.com/cpgoncalves. He is also a peer reviewer with outsanding review status from Elsevier journals, including Physica A, Neurocomputing and Engineering Applications of Artificial Intelligence. Science CV available at: https://www.cienciavitae.pt//pt/8E1C-A8B3-78C5 and ORCID: https://orcid.org/0000-0002-0298-3974',institutionString:"University of Lisbon",institution:{name:"Universidade Lusófona",country:{name:"Portugal"}}},{id:"241400",title:"Prof.",name:"Mohammed",middleName:null,surname:"Bsiss",slug:"mohammed-bsiss",fullName:"Mohammed Bsiss",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/241400/images/8062_n.jpg",biography:null,institutionString:null,institution:null},{id:"276128",title:"Dr.",name:"Hira",middleName:null,surname:"Fatima",slug:"hira-fatima",fullName:"Hira Fatima",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/276128/images/14420_n.jpg",biography:"Dr. Hira Fatima\nAssistant Professor\nDepartment of Mathematics\nInstitute of Applied Science\nMangalayatan University, Aligarh\nMobile: no : 8532041179\nhirafatima2014@gmal.com\n\nDr. Hira Fatima has received his Ph.D. degree in pure Mathematics from Aligarh Muslim University, Aligarh India. Currently working as an Assistant Professor in the Department of Mathematics, Institute of Applied Science, Mangalayatan University, Aligarh. She taught so many courses of Mathematics of UG and PG level. Her research Area of Expertise is Functional Analysis & Sequence Spaces. She has been working on Ideal Convergence of double sequence. She has published 17 research papers in National and International Journals including Cogent Mathematics, Filomat, Journal of Intelligent and Fuzzy Systems, Advances in Difference Equations, Journal of Mathematical Analysis, Journal of Mathematical & Computer Science etc. She has also reviewed few research papers for the and international journals. She is a member of Indian Mathematical Society.",institutionString:null,institution:null},{id:"414880",title:"Dr.",name:"Maryam",middleName:null,surname:"Vatankhah",slug:"maryam-vatankhah",fullName:"Maryam Vatankhah",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Borough of Manhattan Community College",country:{name:"United States of America"}}},{id:"414879",title:"Prof.",name:"Mohammad-Reza",middleName:null,surname:"Akbarzadeh-Totonchi",slug:"mohammad-reza-akbarzadeh-totonchi",fullName:"Mohammad-Reza Akbarzadeh-Totonchi",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Ferdowsi University of Mashhad",country:{name:"Iran"}}},{id:"414878",title:"Prof.",name:"Reza",middleName:null,surname:"Fazel-Rezai",slug:"reza-fazel-rezai",fullName:"Reza Fazel-Rezai",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"American Public University System",country:{name:"United States of America"}}},{id:"426586",title:"Dr.",name:"Oladunni A.",middleName:null,surname:"Daramola",slug:"oladunni-a.-daramola",fullName:"Oladunni A. Daramola",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Federal University of Technology",country:{name:"Nigeria"}}},{id:"357014",title:"Prof.",name:"Leon",middleName:null,surname:"Bobrowski",slug:"leon-bobrowski",fullName:"Leon Bobrowski",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Bialystok University of Technology",country:{name:"Poland"}}},{id:"302698",title:"Dr.",name:"Yao",middleName:null,surname:"Shan",slug:"yao-shan",fullName:"Yao Shan",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Dalian University of Technology",country:{name:"China"}}},{id:"354126",title:"Dr.",name:"Setiawan",middleName:null,surname:"Hadi",slug:"setiawan-hadi",fullName:"Setiawan Hadi",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Padjadjaran University",country:{name:"Indonesia"}}},{id:"125911",title:"Prof.",name:"Jia-Ching",middleName:null,surname:"Wang",slug:"jia-ching-wang",fullName:"Jia-Ching Wang",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"National Central University",country:{name:"Taiwan"}}},{id:"332603",title:"Prof.",name:"Kumar S.",middleName:null,surname:"Ray",slug:"kumar-s.-ray",fullName:"Kumar S. Ray",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Indian Statistical Institute",country:{name:"India"}}},{id:"415409",title:"Prof.",name:"Maghsoud",middleName:null,surname:"Amiri",slug:"maghsoud-amiri",fullName:"Maghsoud Amiri",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Allameh Tabataba'i University",country:{name:"Iran"}}},{id:"357085",title:"Mr.",name:"P. Mohan",middleName:null,surname:"Anand",slug:"p.-mohan-anand",fullName:"P. Mohan Anand",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Indian Institute of Technology Kanpur",country:{name:"India"}}},{id:"356696",title:"Ph.D. Student",name:"P.V.",middleName:null,surname:"Sai Charan",slug:"p.v.-sai-charan",fullName:"P.V. Sai Charan",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Indian Institute of Technology Kanpur",country:{name:"India"}}},{id:"357086",title:"Prof.",name:"Sandeep K.",middleName:null,surname:"Shukla",slug:"sandeep-k.-shukla",fullName:"Sandeep K. Shukla",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Indian Institute of Technology Kanpur",country:{name:"India"}}}]}},subseries:{item:{id:"22",type:"subseries",title:"Applied Intelligence",keywords:"Machine Learning, Intelligence Algorithms, Data Science, Artificial Intelligence, Applications on Applied Intelligence",scope:"This field is the key in the current industrial revolution (Industry 4.0), where the new models and developments are based on the knowledge generation on applied intelligence. The motor of the society is the industry and the research of this topic has to be empowered in order to increase and improve the quality of our lives.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/22.jpg",hasOnlineFirst:!0,hasPublishedBooks:!0,annualVolume:11418,editor:{id:"27170",title:"Prof.",name:"Carlos",middleName:"M.",surname:"Travieso-Gonzalez",slug:"carlos-travieso-gonzalez",fullName:"Carlos Travieso-Gonzalez",profilePictureURL:"https://mts.intechopen.com/storage/users/27170/images/system/27170.jpeg",biography:"Carlos M. Travieso-González received his MSc degree in Telecommunication Engineering at Polytechnic University of Catalonia (UPC), Spain in 1997, and his Ph.D. degree in 2002 at the University of Las Palmas de Gran Canaria (ULPGC-Spain). He is a full professor of signal processing and pattern recognition and is head of the Signals and Communications Department at ULPGC, teaching from 2001 on subjects on signal processing and learning theory. His research lines are biometrics, biomedical signals and images, data mining, classification system, signal and image processing, machine learning, and environmental intelligence. He has researched in 52 international and Spanish research projects, some of them as head researcher. He is co-author of 4 books, co-editor of 27 proceedings books, guest editor for 8 JCR-ISI international journals, and up to 24 book chapters. He has over 450 papers published in international journals and conferences (81 of them indexed on JCR – ISI - Web of Science). He has published seven patents in the Spanish Patent and Trademark Office. He has been a supervisor on 8 Ph.D. theses (11 more are under supervision), and 130 master theses. He is the founder of The IEEE IWOBI conference series and the president of its Steering Committee, as well as the founder of both the InnoEducaTIC and APPIS conference series. He is an evaluator of project proposals for the European Union (H2020), Medical Research Council (MRC, UK), Spanish Government (ANECA, Spain), Research National Agency (ANR, France), DAAD (Germany), Argentinian Government, and the Colombian Institutions. He has been a reviewer in different indexed international journals (<70) and conferences (<250) since 2001. He has been a member of the IASTED Technical Committee on Image Processing from 2007 and a member of the IASTED Technical Committee on Artificial Intelligence and Expert Systems from 2011. \n\nHe has held the general chair position for the following: ACM-APPIS (2020, 2021), IEEE-IWOBI (2019, 2020 and 2020), A PPIS (2018, 2019), IEEE-IWOBI (2014, 2015, 2017, 2018), InnoEducaTIC (2014, 2017), IEEE-INES (2013), NoLISP (2011), JRBP (2012), and IEEE-ICCST (2005)\n\nHe is an associate editor of the Computational Intelligence and Neuroscience Journal (Hindawi – Q2 JCR-ISI). 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We encourage the submission of manuscripts that provide novel and mechanistic insights that report significant advances in the fields. Topics can include but are not limited to: Biotechnology such as biotechnological products and process engineering; Biotechnologically relevant enzymes and proteins; Bioenergy and biofuels; Applied genetics and molecular biotechnology; Genomics, transcriptomics, proteomics; Applied microbial and cell physiology; Environmental biotechnology; Methods and protocols. Moreover, topics in biosensor technology, like sensors that incorporate enzymes, antibodies, nucleic acids, whole cells, tissues and organelles, and other biological or biologically inspired components will be considered, and topics exploring transducers, including those based on electrochemical and optical piezoelectric, thermal, magnetic, and micromechanical elements. Chapters exploring biomaterial approaches such as polymer synthesis and characterization, drug and gene vector design, biocompatibility, immunology and toxicology, and self-assembly at the nanoscale, are welcome. Finally, the tissue engineering subcategory will support topics such as the fundamentals of stem cells and progenitor cells and their proliferation, differentiation, bioreactors for three-dimensional culture and studies of phenotypic changes, stem and progenitor cells, both short and long term, ex vivo and in vivo implantation both in preclinical models and also in clinical trials.",annualVolume:11405,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/9.jpg",editor:{id:"126286",title:"Dr.",name:"Luis",middleName:"Jesús",surname:"Villarreal-Gómez",fullName:"Luis Villarreal-Gómez",profilePictureURL:"https://mts.intechopen.com/storage/users/126286/images/system/126286.jpg",institutionString:null,institution:{name:"Autonomous University of Baja California",institutionURL:null,country:{name:"Mexico"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"35539",title:"Dr.",name:"Cecilia",middleName:null,surname:"Cristea",fullName:"Cecilia Cristea",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYQ65QAG/Profile_Picture_1621007741527",institutionString:null,institution:{name:"Iuliu Hațieganu University of Medicine and Pharmacy",institutionURL:null,country:{name:"Romania"}}},{id:"40735",title:"Dr.",name:"Gil",middleName:"Alberto Batista",surname:"Gonçalves",fullName:"Gil Gonçalves",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYRLGQA4/Profile_Picture_1628492612759",institutionString:null,institution:{name:"University of Aveiro",institutionURL:null,country:{name:"Portugal"}}},{id:"211725",title:"Associate Prof.",name:"Johann F.",middleName:null,surname:"Osma",fullName:"Johann F. 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