Receptors in parathyroid cells
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",isbn:"978-1-83969-150-8",printIsbn:"978-1-83969-149-2",pdfIsbn:"978-1-83969-151-5",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,hash:"7409b2acd5150a93004300800918b736",bookSignature:"Prof. Karmen Pažek",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/10548.jpg",keywords:"Lean Manufacturing, Agriculture, Production and Process, Costs Reduction, Lean Principles, Industry, Tools, Implementation, Sustainability, Modeling, Environment, Planning",numberOfDownloads:7,numberOfWosCitations:0,numberOfCrossrefCitations:0,numberOfDimensionsCitations:0,numberOfTotalCitations:0,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"October 20th 2020",dateEndSecondStepPublish:"November 17th 2020",dateEndThirdStepPublish:"January 16th 2021",dateEndFourthStepPublish:"April 6th 2021",dateEndFifthStepPublish:"June 5th 2021",remainingDaysToSecondStep:"2 months",secondStepPassed:!0,currentStepOfPublishingProcess:4,editedByType:null,kuFlag:!1,biosketch:"Dr. Pažek is Head of the undergraduate study program Agricultural economics and rural development and Vice-dean for education. She is the author or co-author of 61 scientific papers, 6 scientific books, and 24 book chapters.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"179642",title:"Prof.",name:"Karmen",middleName:null,surname:"Pažek",slug:"karmen-pazek",fullName:"Karmen Pažek",profilePictureURL:"https://mts.intechopen.com/storage/users/179642/images/system/179642.jpg",biography:"Karmen Pažek achieved her Ph.D. at University of Maribor, Faculty of Agriculture in 2006. She is active as Full Professor for Farm management in the Department for Agriculture Economics and Rural Development on Faculty of Agriculture and Life Sciences, University of Maribor. Her research includes development of decision support tools and systems for farm management (simulation modeling, multi-criteria decision analysis, option models, investment analysis) and economics of agricultural production. She is involved in teaching activities as thesis supervisor at postgraduate study programs and involved in national and international research projects. She is author or coauthor of 61 scientific papers (including 34 papers in journals with impact factor), 6 scientific books and 24 book chapters. Currently she is Head of the undergraduate study program Agricultural economics and rural development and Vice dean for education. \r\n\r\nAcademic activities\r\nResearch:\r\n-\tFarm management\r\n-\tDecision support, simulation, forecasting, multi criteria decision making in the area of agriculture with emphasis on field crops, farm tourism and fruit producon\r\n\r\nCurrent Research work:\r\n- Financial parameters assessment based on perfect and in-perfect information in agrifood \r\n systems \r\n- Option modeling of agrifood projects\r\n-\tEfficiency assessment in farm tourism \r\n-\tEfficiency of sugar beet production systems \r\n\r\nTeaching:\r\nUndergraduate Programmes and Courses\r\n-\tFarm management I and II\r\n-\tIntroduction to decision theory\r\n-\tOrganic fam management\r\n-\tManagement od supplementary activities\r\n-\tEconomics and management of rural tourism\r\n-\tSelected issues in agricultural entrepreneurship\r\n\r\nMaster Programmes and Courses\r\n\r\n-\tResearch methods in farm management\r\n-\tDecision theory\r\n-\tProject planning and quality management\r\n-\tOrganic fam management\r\n\r\n \r\nPhD Programme and Course\r\n\r\n-\tProject management (transferable skills)\r\n-\tSelected issues in farm management",institutionString:"University of Maribor",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"3",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"University of Maribor",institutionURL:null,country:{name:"Slovenia"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"11",title:"Engineering",slug:"engineering"}],chapters:[{id:"74769",title:"Development of Integrated Lean Six Sigma-Baldrige Framework for Manufacturing Waste Minimization: A Case of NAS Foods Plc",slug:"development-of-integrated-lean-six-sigma-baldrige-framework-for-manufacturing-waste-minimization-a-c",totalDownloads:7,totalCrossrefCites:0,authors:[null]}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"247865",firstName:"Jasna",lastName:"Bozic",middleName:null,title:"Ms.",imageUrl:"https://mts.intechopen.com/storage/users/247865/images/7225_n.jpg",email:"jasna.b@intechopen.com",biography:"As an Author Service Manager, my responsibilities include monitoring and facilitating all publishing activities for authors and editors. 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CKD-Mineral and Bone Disorder (CKD-MBD) is the clinical syndrome that develops as a systemic disorder of bone and mineral metabolism due to CKD, which is manifested by abnormalities in bone and mineral metabolism [1]. Alterations in calcium and phosphate metabolism that are frequently observed in secondary hyperparathyroidism of uremia (SHPT), particularly in patients with maintenance hemodialysis, contribute to ectopic calcification, CV disease, and the risk of death [2].
SHPT is associated with various bone diseases including osteitis fibrosa caused by excessive secretion of parathyroid hormone (PTH), osteomalacia, adynamic bone disease, and combinations thereof; these diseases are collectively called renal osteodystrophy (ROD). In addition, ectopic calcifications such as soft-tissue and vascular calcifications are observed in patients with long-standing CKD. These patients are characterized by calcification of the vascular media, which is called Mönckeberg medial calcific sclerosis, and vascular intima, which is typically triggered by abnormal calcium and phosphorous metabolism due to SHPT [3]. Calcification of the vascular media is a particularly important factor for predicting CV mortality in dialysis patients. Elevation of the serum calcium × phosphate product also increases the relative mortality risk. The abovementioned facts suggest that the pathology of CKD-MBD should be fully elucidated to prepare an appropriate treatment plan.
Small changes in extracellular fluid calcium concentration have major effects on muscle contraction and neuronal excitability, as well as numerous cellular functions such as cell division, cell adhesion, plasma membrane integrity, and coagulation. However, the changes in serum phosphate concentration are asymptomatic in normally functioning kidneys. Severe chronic depletion may cause anorexia, muscle weakness, and osteomalacia. Hyperphosphatemia is also asymptomatic, although symptoms of hypocalcemia, including tetany, can occur when concomitant hypocalcemia is present.
Parathyroid hormone (PTH), the active form of vitamin D (1,25-dihydroxyvitamin D; 1,25-(OH)2D), and fibroblast growth factor (FGF)-23, are the principal physiologic regulators of calcium and phosphate homeostasis in humans [4,5] (Figure 1). Feedback loops exist between ionized calcium (Ca2+), phosphate, 1,25-(OH)2D, FGF-23, and PTH.
Feedback loops in calcium ion (Ca2+) and phosphate (P) homeostasis [4,5], modified from a previous report [8]. Feedback loops exist between Ca2+, P, 1,25-dihydroxyvitamin D (1,25-(OH)2D), fibroblast growth factor 23 (FGF-23), and parathyroid hormone (PTH). Ca2+, 1,25-(OH)2D, and FGF-23 suppress PTH secretion, whereas P overload accelerates it. P overload does not always cause the elevation of serum phosphate, with the exception of some conditions such as chronic kidney disease.
The extracellular fluid Ca2+ concentration is the primary regulator of the rapid (in minutes) synthesis and secretion of PTH. An inverse relationship was observed between the extracellular fluid Ca2+ concentration and PTH secretion from parathyroid cells in vitro [6] (Figure 2). Hypersecretion of PTH causes hypophosphatemia due to hyperphosphaturia in normally functioning kidneys; however, it leads to hyperphosphatemia by mobilization of phosphate from skeletal tissues in CKD, particularly in hemodialysis patients.
In contrast to the rapid action of PTH, 1,25-(OH)2D contributes to long-term calcium homeostasis. 1,25-(OH)2D also elevates serum phosphate concentration by promoting incremental intestinal phosphate absorption.
Pathogenesis of secondary hyperparathyroidism of uremia (SHPT) [56], modified from a previous report [26]. The analyses of PTH secretions inhibited by extracellular calcium in vitro revealed the sigmoidal relationship of the PTH−calcium relationship. Setpoint, the calcium concentration causing half-maximal inhibition of PTH secretion, is an indicator of sensitivity of parathyroid cells to extracellular calcium by CaR. (A) The relationship in healthy subjects was fitted to a symmetrical sigmoidal curve. (B) The normal sigmoidal curve will shift upward when the secretory cell number is increased, without changing its setpoint. (C) An altered sigmoidal curve is observed in human parathyroid adenomas, refractory SHPT, by changing the setpoint to the right. In the case of severe setpoint shift, PTH secretion is persistent even at high calcium concentration: so-called ‘autonomous’ PTH secretion. An altered PTH−calcium relationship was also observed in PTH-cyclin D1 transgenic mice [4, 52]. (D) Administration of cinacalcet or activating mutation of CaR observed in autosomal dominant hypocalcemia increases the CaR sensitivity to serum calcium. Activations of CaR result in the PTH−calcium relationship curve moving to the left.
FGF-23, a member of the FGF family, is a major phosphaturic factor in the development of hypophosphatemic rickets/osteomalacia, including X-linked hypophosphatemic rickets (XLH) and oncogenic osteomalacia [7]. FGF-23 suppresses both PTH secretion and its expression in parathyroid cells [8]. PTH also stimulated FGF-23 expression and its secretion in bone [9], suggesting that a negative feedback loop exists between PTH and FGF-23 [4,5] (Figure 1).
The 3 parathyroid cell receptors that are important in calcium and phosphate homeostasis include the calcium-sensing receptor (CaR) and the FGF receptor (FGFR)-Klotho complex located on the cell surface and nuclear vitamin D receptor (VDR) (Table 1). CaR and VDR are target molecules for the treatment of hyperfunctioning parathyroid diseases in CKD patients.
\n\t\t\t\tReceptor\n\t\t\t | \n\t\t\t\n\t\t\t\tLocation\n\t\t\t | \n\t\t
1. Vitamin D receptor; VDR | \n\t\t\tcell nucleus | \n\t\t
2. Calcium-sensing receptor; CaR | \n\t\t\tcell membrane | \n\t\t
3. FGFR-Klotho complex | \n\t\t\tcell membrane | \n\t\t
Receptors in parathyroid cells
CaR contains a characteristic G protein-coupled receptor 7 membrane-spanning motif with an unusually large N-terminal extracellular domain, which was cloned in 1993 [10]. Positional cloning approaches have clarified that loss-of-function mutations in the CaR gene cause familial hypocalciuric hypercalcemia (heterozygous mutations) and neonatal severe hyperparathyroidism (homozygous mutations) [11].
Heterozygous CaR knockout mice exhibited a phenotype that was similar to that of familial hypocalciuric hypercalcemia [12]. Serum PTH levels were inappropriately elevated; however, the parathyroid glands were not enlarged in the heterozygous knockout mice. Homozygous knockout mice demonstrated markedly elevated serum calcium and PTH concentrations, retarded growth, and premature death [12]. These symptoms are similar to those of human neonatal severe hyperparathyroidism.
Synthetic allosteric modulators of CaR have been developed that act as either positive modulators (calcimimetics) or negative modulators (calcilytics). These ligands do not activate the wild-type receptor directly, but rather shift the PTH-calcium sigmoidal curves to the left or right, respectively (Figure 2).
1,25-(OH)2D is the major steroid hormone that plays a crucial role in calcium and phosphate homeostasis, and its actions are mediated by VDR. Hereditary hypocalcemic vitamin D-resistant rickets (HVDDR) is an autosomal recessive disorder that is caused by inactivating mutations in the VDR gene, resulting in target tissue insensitivity to 1,25-(OH)2D [13].
VDR knockout mice exhibit hypocalcemia, hypophosphatemia, rickets, alopecia, and hyperparathyroidism with enlarged parathyroid glands, similar to HVDDR [14,15]. Tissue-specific ablation of VDR in parathyroid tissue results in decreased parathyroid CaR expression and moderately increased basal PTH levels; however, no significant abnormalities in PTH-calcium sigmoidal curves were observed [16], suggesting limited roles of VDR in parathyroid pathophysiology.
Klotho, which is expressed in kidney and pituitary and parathyroid glands, converts FGFR1, a canonical receptor for various FGFs, into an FGF-23-specific receptor [17]. FGF-23 null mice exhibit various senescence-like phenotypes such as a short lifespan, infertility, atrophy of the lymphopoietic and reproductive organs, decreased bone mineral density, and ectopic calcification. This phenotype is similar to that of Klotho-deficient mice [18], suggesting that FGF-23 signaling is Klotho dependent.
It is widely known that the progression of CKD increases mortality risk and the incidence of CV events [19]. Hyperphosphatemia is a critical electrolyte abnormality in patients with CKD-mineral and bone disorder (CKD-MBD) [20]. Even though hemodialysis or peritoneal dialysis is given to hyperphosphatemia patients with advanced CKD, these therapies are ineffective due to insufficient phosphorus-removal ability.
FGF-23 is involved in abnormal calcium and phosphate metabolism in CKD patients as the disease progresses. A cross-sectional study of 80 CKD patients revealed decreases in estimated GFR (eGFR), serum calcium, and 1,25-(OH)2D levels as well as increases in serum P, fractional excretion of phosphate, PTH, and FGF-23 [21].
Further study of the abovementioned data revealed an increase in serum FGF-23 level (eGFR 45~60 mL/min), which is an independent predictor of the fractional excretion of phosphate, far earlier than the increase in serum phosphate levels (eGFR <30 mL/min). The increase in FGF-23 level is one of the greatest independent predictors of decreased 1,25-(OH)2D level, independent of serum phosphate and eGFR. This suggests that the increase in FGF-23 level is the main reason for the decrease in 1,25-(OH)2D level in CKD progression. Thus, the increase in FGF-23 level compensates for the increase in the serum phosphate levels caused by the decrease in nephrons associated with CKD progression by increasing the fractional excretion of phosphate. However, the increase in FGF-23 level also decreases the level of 1,25-(OH)2D, which promotes PTH secretion and accelerates the progression of SHPT.
In an experiment using human vascular smooth muscle cells, inorganic phosphate transport into the cells via type III Na-Pi co-transporter (Pit-1) increased as the extracellular phosphate concentration increased. The increase in the intracellular phosphate concentration induced the expression of marker genes of apoptosis and osteogenic/chondrogenic cells in the vascular wall cells, which resulted in calcification [22]. This finding also implies a relationship between blood vessel calcification and phosphate levels in vitro.
Maintenance hemodialysis patients often develop blood vessel calcification, which is directly proportional to the duration of dialysis, irrespective of their age; this condition is characterized by calcification of the vascular media called Mönckeberg sclerosis rather than calcification of the vascular intima. The onset of blood vessel calcification in dialysis patients is mainly caused by abnormal calcium and phosphate metabolism due to SHPT [3], which is one of the signs of CKD-MBD. Calcification of the iliac artery [23] and abdominal aorta [24] are critical predictors of CV mortality in dialysis patients.
ROD is a mineral and bone disorder that occurs as a complication of CKD, which exacerbates bone fragility and fracture [1]. The serum phosphorus concentration was significantly related to hospitalization for fracture [2]. Old age, dialysis vintage, female gender, white race, and lower body weight were significantly associated with an increased risk of fracture-related hospitalization.
In CKD patients, ROD manifests as alterations in bone morphology, such as osteitis fibrosa cystica, mild hyperparathyroid-related bone disease, osteomalacia, adynamic bone disease, and mixed uremic osteodystrophy. ROD represents histopathologic changes observed in bone and is typically characterized by changes in bone turnover, volume, and mineralization (TMV) (Table 2). The TMV classification, assessed by histomorphometry, provides a clinically relevant description of the underlying bone pathology and helps define the pathophysiology of the disease.
\n\t\t\t\tTurnover\n\t\t\t | \n\t\t\t\n\t\t\t\tMineralization\n\t\t\t | \n\t\t\t\n\t\t\t\tVolume\n\t\t\t | \n\t\t
Low | \n\t\t\tNormal | \n\t\t\tLow | \n\t\t
Normal | \n\t\t\tAbnormal | \n\t\t\tNormal | \n\t\t
High | \n\t\t\t\n\t\t\t | High | \n\t\t
TMV classification for renal osteodystrophy (ROD) [1]
TMV: bone turnover, mineralization, and volume
PTH secretion increases when the glomerular filtration rate (GFR) of CKD patients decreases to 40–50 mL/min or less [25]. Renal impairment decreases urinary phosphate excretion, gradually leading to hyperphosphatemia. Phosphate accumulation in the body reduces 1α hydroxylase activity in the kidneys and suppresses vitamin D activation, which results in decreased serum active vitamin D (1,25-(OH)2D) levels [26] (Figure 3). Hyperphosphatemia causes hypocalcemia by directly affecting the parathyroid glands; moreover, impaired vitamin D activation promotes PTH synthesis and secretion [27], which induces the proliferation of parathyroid cells and parathyroid hyperplasia. This change stimulates excessive PTH activity and allows phosphates of the bone to move into the blood, exacerbating the hyperphosphatemia. Even though hemodialysis or peritoneal dialysis is given to hyperphosphatemia patients with advanced CKD, these therapies are ineffective due to the patients’ insufficient phosphate-removal ability.
Pathogenesis of parathyroid tumorigenesis [4]. (A) A set of somatic mutations (hits) confers a growth advantage to an affected cell. Monoclonal growth renders the cells susceptible to more somatic mutations (hits), which leads to clonal evolution. (B) A uremic status such as chronic hypocalcemia, decreased levels of serum 1,25-(OH)2D, and hyperphosphatemia stimulates parathyroid cell growth and leads to multi-glandular polyclonal hyperplasia. These hyperplastic parathyroid cells are susceptible to somatic mutations (hits), resulting in monoclonal growth.
In the earliest stages of CKD, the parathyroid glands undergo multi-glandular generalized hyperplasia, presumably a true polyclonal expansion, in response to stimuli that may include chronic hypocalcemia, decreased levels of serum 1,25-(OH)2D, and hyperphosphatemia. However, in the late stage of this disease, usually after many years of dialysis treatment, a subset of patients develop refractory SHPT in which excessive PTH secretion no longer responds to physiological influences or standard medical therapy. Therefore, medically refractory SHPT is quite different from the readily managed SHPT, which is characterized by an abnormal PTH-calcium secretory relationship [28,29], is “autonomous,” and is typically treated by surgical parathyroidectomy. VDR [30] and CaR [31] expression was reduced in the parathyroid tumors of these patients.
The majority of surgically removed uremic parathyroid glands were confirmed to be monoclonal neoplasms by X-chromosome inactivation analysis [32]. This monoclonality implies that somatic mutation of certain genes controlling cell proliferation occurred in a single parathyroid cell, conferring a selective growth advantage upon it and its progeny (Figure 4). Distinct chromosomal abnormalities in sporadic parathyroid adenomas [33] and uremia-associated parathyroid tumors [34] revealed that the molecular pathogenesis of tumorigenesis in these 2 categories of parathyroid tumors was different. However, the major genes involved in the pathogenesis of SHPT remain unknown.
The sigmoidal curve of the PTH-calcium relationship [56]. The analyses of PTH secretions inhibited by extracellular calcium in vitro revealed a sigmoidal PTH-calcium relationship [6]. The setpoint, the calcium concentration causing half-maximal inhibition of PTH secretion, is an indicator of sensitivity of parathyroid cells to extracellular calcium by the calcium receptor (CaR). (A) This relationship in healthy subjects was fitted to a symmetrical sigmoidal curve. (B) The normal sigmoidal curve will shift upward when secretory cell number is increased without changing its setpoint. (C) An altered sigmoidal curve is observed in human parathyroid adenomas, refractory secondary hyperparathyroidism of uremia, with the setpoint shifting to the right. In the case of severe setpoint shift, PTH secretion is persistent even at high calcium concentrations, due to so-called “autonomous” PTH secretion. An altered PTH-calcium relationship was also observed in PHPT model mice [4,52]. (D) Administration of calcimimetics or the presence of an activating mutation of CaR in autosomal dominant hypocalcemia (ADH) patients [57] increased the sensitivity of CaR to serum calcium concentration in parathyroid cells. Activations of CaR result in a shift of the PTH-calcium relationship curve to the left.
Reduced expression of Klotho and FGFR1 was noted in the hyperplastic parathyroid glands of SHPT patients [35], suggesting that reduced FGF-23 signaling in parathyroid cells plays a role in the development of SHPT. However, some studies of Klotho expression in uremic animals reported conflicting results [36-38]. Further studies are necessary to clarify the role of FGFR-Klotho signaling in uremic parathyroid glands.
The National Kidney Foundation Kidney Disease Outcomes Quality Initiative (K/DOQI, USA) published the “K/DOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease” in 2003 as evidence-based clinical practice guidelines [39]. In 2005, according to “Definition and classification of chronic kidney disease: a position statement from Kidney Disease: Improving Global Outcomes (KDIGO),” the term CKD-MBD was proposed, stating that the importance of bone and mineral metabolism in CKD should be conceptualized in terms of prognosis [20]; this means that bone and mineral metabolism in CKD can be considered a systemic disease. In 2009, KDIGO proposed the current clinical practice guidelines [40], which have been adopted in clinical settings.
The risk of all-cause mortality and CV events in patients with CKD-MBD on maintenance hemodialysis is well established. A greater mortality risk associated with phosphate, followed by calcium and PTH levels, was reported [41]. These 3 parameters are not only the best surrogate markers but also the best targets for CKD-MBD treatment.
All-cause mortality increased regardless of whether serum phosphate levels were higher or lower than the reference value, exhibiting a U-shaped distribution [42]. However, maintenance dialysis patients in stable condition are likely to develop hyperphosphatemia, indicating that hyperphosphatemia treatment should be a primary target. Diet therapy is the first-line therapy that can sufficiently control serum phosphate levels. If it is insufficient, phosphate binders are administered orally. Calcium-containing phosphate binder (e.g., calcium carbonate) have been used for a long time. However, concomitant use of active vitamin D products can lead to the development of hypercalcemia and increase serum calcium × phosphate product levels. Therefore, non-calcium-containing phosphate binder such as sevelamer hydrochloride and lanthanum carbonate are widely used.
Although hyperphosphatemia is a risk factor for mortality in dialysis patients, the effects of restricting phosphorus intake in these patients are unclear. When oral phosphorus intake is controlled, serum phosphate levels decrease, but poor nutritional status occurs as well. Thus, it is difficult to judge the true effect of the restriction of phosphorus intake, although studies using phosphate binders have been performed.
The Accelerated Mortality on Renal Replacement (ArMORR) study is a 1-year observational cohort study of 10,044 hemodialysis patients in 1,056 medical institutions in the US. According to this study, the 1-year survival rate of 3,555 patients prescribed phosphate binders before or within 90 days of initiating dialysis was higher than that of 5,055 patients who were not treated with these agents during the same period [43]. That study also compared survival in a subcohort of patients treated and not treated with phosphate binders matched by their baseline serum phosphate levels (i.e., a propensity score matched cohort study) and concluded that the survival rate was greater in the treated group, demonstrating the positive effect of these agents on the survival rate (Figure 5).
Survival of treated and untreated patients of the overall propensity score-matched cohort in the Accelerated Mortality on Renal Replacement (ArMORR) study [43]. A 1-year observational cohort study involving 10,044 dialysis patients in 1,056 medical institutions in the US studied the relationship between the effect of phosphate binders before and within 90 days of initiating dialysis and 1-year survival rate. The survival rate was greater in the group treated with phosphate binders. The subcohort study of patients treated and untreated with phosphate binders, matched by their baseline serum phosphate levels (i.e., the propensity score matched cohort), also demonstrated that the treated group had a better survival rate, demonstrating the positive effect of these agents on survival.
Many studies on maintenance dialysis patients have been performed. What about studies on patients who have just started dialysis? The Choices for Healthy Outcomes in Caring for End-Stage Renal Disease (CHOICE) study is a prospective cohort study of patients who just started hemodialysis or peritoneal dialysis [44]. That study included 1,007 subjects, 98% of whom were enrolled in the study within 4 months. The study was started at a median of 45 days after the patients started dialysis. The results obtained 2.5 years later indicated that higher serum phosphate levels were an independent predictor of all-cause mortality. In addition, the relative risk of all-cause mortality was also high in subjects whose serum phosphate levels were high at the start of dialysis but decreased 6 months later. The abovementioned results suggest that the serum phosphate level at the start of dialysis is an important prognostic factor.
Active vitamin D products inhibit PTH gene transcription and secretion as well as parathyroid cell proliferation in the parathyroid glands. Daily oral administration of 1α-(OH)D3 (alfacalcidol), 1,25-(OH)2D3 (calcitriol), and/or 26,27-hexafluoro-1,25-(OH)2D3 (falecalcitriol) is performed to prevent the progression of SHPT. However, the effect of this treatment is insufficient, because the expression of vitamin D receptor (VDR) decreases in uremia-associated parathyroid tumor.
A rapid increase in serum 1,25-(OH)2D levels due to intravenous administration of calcitriol can partly inhibit the synthesis and secretion of PTH in parathyroid cells, which express less VDR. Furthermore, 1,25-dihydroxy-22-oxavitamin D3 (maxacalcitol, OCT), an analog in which the carbon of calcitriol at position 22 is replaced with an oxygen atom, is characterized by a weaker intestinal calcium absorption capacity than that with the inhibition of PTH secretion. Therefore, it is unlikely to cause hypercalcemia.
Among the subjects in the ArMORR study who were not treated with active vitamin D analogs, 25OHD level, which exhibits individual nutritional vitamin D status, was elevated, while both all-cause mortality and CV mortality decreased (Figure 6). Furthermore, all-cause mortality and CV mortality decreased significantly in the subjects administered VDRA, regardless of 25OHD level, indicating that the prognosis of VDRA improved in the maintenance dialysis patients [45].
Multivariate-adjusted ORs of 90-day all-cause and cardiovascular (CV) mortality in the ArMORR study [45]. The ArMORR study involved 825 maintenance dialysis patients who were not treated with active vitamin D before or within 90 days of initiating dialysis to evaluate the effect of active vitamin D products on prognosis. 25OHD, which indicates the individual nutritional vitamin D status, was high in the subjects who were not treated with active vitamin D, while all-cause mortality and CV mortality decreased. Furthermore, all-cause mortality and CV mortality decreased significantly in the subjects administered with VDRA regardless of 25OHD levels.
Information on extracellular Ca2+ levels is transferred to parathyroid cells via CaR in the parathyroid glands, which control PTH secretion. Multivalent cations including Ca2+, Mg2+, and Gd3+ act on CaR as agonists. However, calcimimetics do not act as agonists but allosterically increase the sensitivity of CaR to multivalent cations [46].
Calcimimetic cinacalcet suppressed PTH secretion in cultured human pathological parathyroid cells obtained from primary hyperparathyroidism (PHPT) and SHPT patients, which exhibit reduced expression of CaR, the target molecule of cinacalcet [47]. These data support the clinical application of cinacalcet for PHPT and SHPT treatment.
Calcimimetic cinacalcet suppressed not only PTH secretion but also parathyroid cell proliferation, which prevented parathyroid hyperplasia in vivo in 5/6-nephrectomized rats, the animal model of SHPT [48]. Calcimimetic tecalcet also reversed the development of osteitis fibrosa in the SHPT rats [49]. In a relative hypocalcemic to normocalcemic environment, calcimimetics effectively suppress PTH secretion and parathyroid cell proliferation. Interestingly, cinacalcet suppressed aortic calcification in SHPT rats by decreasing serum PTH, calcium, and phosphate concentrations [50], suggesting that cinacalcet may be beneficial for the prevention of ectopic calcification as well as the improvement of morbidity and mortality in patients with CKD.
Cinacalcet also suppressed PTH secretion in PTH-cyclin D1 transgenic mice [51]. PTH-cyclin D1 transgenic mice are an animal model of PHPT that overexpress the cyclin D1 oncogene in the parathyroid glands, which was accomplished by using a transgene that mimics the human PTH-cyclin D1 gene rearrangement [52]. Tissue-specific overexpression of the cyclin D1 oncogene not only resulted in abnormal parathyroid cell proliferation but, notably, also led to the development of biochemical hyperparathyroidism with characteristic bone abnormalities.
Hypercalcemia may stimulate considerable CaR activity, as the expression of CaR was suppressed in the parathyroid glands of these mice [52]. These conditions are compatible with the status observed in refractory SHPT patients undergoing maintenance hemodialysis. Although older transgenic mice exhibited advanced hyperparathyroidism caused by severely decreased CaR expression, cinacalcet suppressed both serum calcium and PTH concentrations [51] and parathyroid growth [53]. CaR is a potentially useful target for a therapeutic agent such as cinacalcet to suppress PTH secretion, despite the reduction in CaR expression observed in the parathyroid glands of patients with advanced PHPT and SHPT.
A meta-analysis of 8 randomized, double-blind, placebo-controlled trials (total number of subjects, 1,429) revealed that calcimimetics significantly decrease serum PTH, serum calcium, and serum phosphate levels, in turn significantly decreasing the serum calcium × phosphate product [54] (Figure 7). The improvements in the abovementioned serum parameters due to calcimimetics were clarified in the analysis. However, no improvement in all-cause mortality or decreased parathyroidectomy was observed, and the incidence of bone fracture was not studied.
An observational study was performed using the United States Renal Data System to determine all-cause and CV mortality. Time-dependent Cox proportional hazards modeling found that all-cause and CV mortality rates were significantly reduced in cinacalcet-treated patients relative to those that did not receive cinacalcet treatment. Although this study revealed a significant survival benefit associated with cinacalcet, randomized clinical trials are needed to confirm a survival advantage associated with calcimimetics [55].
Percutaneous ethanol injection therapy (PEIT) is performed by directly injecting ethanol into a parathyroid tumor under ultrasound guidance to necrotize parathyroid tumor cells. Its merits include minimal invasiveness and multiple sessions. However, the technique sometimes induces recurrent laryngeal nerve paralysis, making it inapplicable in the presence of recurrent laryngeal nerve paralysis in the contralateral parathyroid gland.
Positive effect of cinacalcet on serum parameters in the meta-analysis of 8 randomized, double-blind, placebo-controlled trials (total number of subjects, 1,429) [54] Cinacalcet significantly decreased serum PTH, calcium, and phosphate levels, thereby significantly decreasing the serum calcium × phosphate product; WMD: weighted mean difference, SD: standard deviation, CI: confidence interval
PTX is recommended for the treatment of SHPT that is resistant to medical management. Isolation of the parathyroid glands always decreases serum PTH levels. However, there are often 5 or more parathyroid glands, and mediastinal or intrathyroid ectopic parathyroid tumors sometimes develop. Therefore, pre- and intraoperative detection of parathyroid glands is essential. The techniques for detecting them include subtotal extirpation, total extirpation, and total expiration followed by autotransplantation.
Clinical evidence regarding CKD-MBD is reported in the literature, and guidelines have been developed accordingly. Well-controlled serum phosphate, calcium and PTH levels improve the prognosis of dialysis patients. Many pharmaceuticals aiming to achieve this goal have been developed and launched. As the pathology of CKD-MBD is elucidated, the prognosis of dialysis patients and their quality of life will improve.
Derivative nonlinear Schrödinger (DNLS for brevity) equation is one of the several rare kinds of integrable nonlinear models. Research of DNLS equation has not only mathematic interest and significance, but also important physical application background. It was first found that the Alfven waves in space plasma [1, 2, 3] can be modeled with DNLS equation. The modified nonlinear Schrödinger (MNLS for brevity) equation, which is used to describe the sub-picosecond pulses in single mode optical fibers [4, 5, 6], is actually a transformed version of DNLS equation. The weak nonlinear electromagnetic waves in ferromagnetic, anti-ferromagnetic, or dielectric systems [5, 6, 7, 8, 9] under external magnetic fields can also be modeled by DNLS equation.
Although DNLS equation is similar to NLS equation in form, it does not belong to the famous AKNS hierarchy at all. As is well known, a nonlinear integrable equation can be transformed to a pair of Lax equation satisfied by its Jost functions, the original nonlinear equation is only the compatibility condition of the Lax pair, that is, the so-called zero-curvature condition. Another fact had been found by some scholars that those nonlinear integrable equations which have the same first operator of the Lax pair belong to the same hierarchy and can deal with the same inverse scattering transform (IST for brevity). As a matter of fact, the DNLS equation has a squared spectral parameter of
In this chapter, we will solve the DNLS equation under two kinds of boundary condition, that is, the vanishing boundary condition (VBC for brevity) and the non-vanishing boundary condition (NVBC for brevity), by means of three different methods – the revised IST method, the Marchenko formalism, and the Hirota’s bilinear derivative method. Meanwhile, we will search for different types of special soliton solution to the DNLS equation, such as the light/dark solitons, the pure solitons, the breather-type solitons, and the rogue wave solution, in one- or multi-soliton form.
For the VBC case of DNLS equation, which is just the concerned theme of the section, some attempts and progress have been made to solve the DNLS equation. Since Kaup and Newell proposed an IST with a revision in their pioneer works [10, 11], one-soliton solution was firstly attained and several versions of raw or explicit multi-soliton solutions were also obtained by means of different approaches [12, 13, 14, 15, 16, 17, 18, 19, 20]. Huang and Chen have got a
DNLS equation for the one-dimension wave function
with VBC, where the subscripts stand for partial derivative. Eq. (1) is also called Kaup-Newell (KN for brevity) equation. Its Lax pair is given by
and
where
In the limit of
The free Jost solution is a
The Jost solutions of (4) are defined by their asymptotic behaviors as
where
Since the first Lax equation of DNLS is similar to that of NLS, there are some similar properties of the Jost solutions. The monodromy matrix
where
It is easy to find from (2) and (9) that
and
Then we can get the following reduction relation and symmetry properties
and
The asymptotic behaviors of the Jost solutions in the limit of
Then we have
In the limit
In the limit
and
Eq. (21) leads to
which expresses the conjugate of solution
On the other hand, the zeros of
where
in order to maintain that
Due to
The 2 × 1 column function
An alternative form of IST equation is proposed as
Because in the limit of
The integral path for IST of the DNLS.
where
where a factor
Taking the symmetry and reduction relation (18) and (28) into consideration, from (31) and (33), we can obtain the revised Zakharov-Shabat equation for DNLS equation with VBC, that is,
Substituting Eqs. (34) and (35) into formula (26), we thus attain the
where
Let
where
where superscript “T” represents transposition of a matrix. Then Eqs. (39) and (40) can be rewritten as
where m = 1, 2,…, N. They can be rewritten in a more compact matrix form.
Then
where
Substituting Eqs. (48), (49) into (50) and (51) and then substituting (50) and (51) into formula (36), we thus attain
where
In the subsequent chapter, we will prove that
It is obvious that formula (52) has the usual standard form of soliton solution. Here in formula (52), some algebra techniques have been used and can be found in Appendix A.1 in Part 2.
We only need to prove that Eq. (55) holds. Firstly, we define N × N matrices P1, P2, Q1, Q2, respectively, as
Then
where
where
Similarly,
where
It is easy to find a kind of permutation symmetry existed between expressions (59) and (61), that is,
Comparing (58) with (62) and making use of (63), we thus complete verification of Eq. (55). The soliton solution is surely of a typical form as that in NLS equation and can be expressed as formula (52).
The time evolution factor of the scattering data can be introduced by standard procedure [21]. Due to the fact that the second Lax operator
Then the typical soliton arguments
where
Substituting expression (64) and (65) into formula (59) and then into (58), we have
with
About the calculation of the most complicate determinant
with
The above summation obviously can be decomposed into two parts: one is extended to m1 = 0, the other is extended to
with
Here
An interesting conclusion is found that, besides a permitted well-known constant global phase factor, there is also an undetermined constant complex parameter bn0 before each of the typical soliton factor
We give two concrete examples – the one- and two-soliton solutions as illustrations of the general explicit soliton solution.
In the case of one-soliton solution, N = 1,
It is different slightly from the definition in (66) for that here
and
The complex conjugate of one-soliton solution
where
and
And we get
where
and
where
Substituting (81) and (84) into formula (52), we thus get the two-soliton solution to the DNLS equation with VBC
Once again we find that, up to a permitted global constant phase factor, the above two-soliton solution is equivalent to that gotten in Ref. [23, 24], verifying the validity of our formula of
The complex conjugate of expression (52) gives the explicit expression of N-soliton solution as
Without the loss of generality, for
As
and in the vicinity of
Here the complex constant
Introducing a typical factor
and
In the vicinity of
Here
then
Each
So as
then as
That is to say, the
Finally, we indicate that the exact
is also integrable [23] and called modified nonlinear Schrödinger (MNLS for brevity) equation. It is well known that MNLS equation well describes transmission of femtosecond pulses in optical fibers [4, 5, 6] and is related to DNLS equation by a gauge-like transformation [23] formulated as
with
with
The
The newly revised IST technique for DNLS equation with VBC supplies substantial foundation for its direct perturbation theory.
Gel’fand-Levitan-Marchenko (GLM for brevity) equations can be viewed as an integral-transformed version of IST for those integrable nonlinear equations [21, 24, 28].
In this section, a simple method is used to derive and solve Marchenko equation (or GLM equation) for DNLS E with VBC [28]. Firstly, starting from the first Lax equation, we derive two conditions to be satisfied by the kernel matrix
DNLS equation is usual expressed as
with vanishing boundary,
The first Lax equation is
In the case of
where
As usual, we introduce the integral representation,
where the superscripts d and o mean the diagonal and off-diagonal elements, respectively. According to the conventional operation in IST, the time variable is suppressed temporarily. Here
Due to the symmetry of the first Lax operator
Substitute Eq. (115) into the first Lax Eq. (111). By simply partial integration, we have the following terms:
and
Use is made of that
According to equation
Or
and the equations in the integral
Therefore, Eq. (125) gives two conditions to be satisfied by the kernel matrix
Since (122) is an identity, Eq. (123) or (124) gives the solution
In Eq. (115), the
where
We now show the kernel
Making partial derivation in (128) with respect to x and y, respectively, we obtain
By partial integrating, Eq. (131) becomes
Use is made of the fact that
We find
Since
If we choose
then
Thus, Eq. (134) becomes
Now substituting (135) into (129), we find
Making partial derivation with respect to x and y, respectively, on the l.h.s. of Eq. (138), we have
or
Now we make a weighing summation as
Hence, we have
Noticing
We find that, as long as we choose a suitable form for
Considering the dependence of the Jost solutions on the squared spectral parameter
where
As is well known, Lax equations are linear equation so that a constant factor can be introduced in its solution, that is,
When there are N simple poles
where
Here and hereafter the superscript T represents transposing of a matrix. On the other hand, we assume that
Then
Substituting (146)–(149) into the Marchenko equation (128) and (129), we have
or
here
Both of them are N × N matrices and their matrix element are, respectively, expressed as
From (151) and (152), we immediately get
from (148), (156), and (157), we have
then
and
Substituting (160) and (161) into Eq. (124), we thus attain the N-soliton solution as follows in a pure Marchenko formalism.
where
and we will prove that in (136)
By means of some linear algebraic techniques, especially the Binet-Cauchy formula for some special matrices (see the Appendices 2–3 in Part2), the determinant D and C can be expanded explicitly as a summation of all possible principal minors. Firstly, we can prove identity (164) by means of Binet-Cauchy formula.
where
The complex constant factor
here
where
where
If we define matrices
and
where
Using above identity, comparing (169), (172), (173), and (174), we find that identity (164) holds and complete the computation of D.
Secondly, we compute the most complicate determinant
with n, m = 1, 2,…, N. We thus have
The above summation obviously can be decomposed into two parts: one is extended to m1 = 0 and the other extended to m1 ≥ 1. Subtracted from (176), the part that is extended to m1 ≥ 1, the remaining parts of (176) is just C in Eq. (163) (with
which leads to
here
In the case of one simple pole and one-soliton solution as
From (167) and (168), we have (suppose
Then from (181) and (182), we attain the one-soliton solution
By further redefinition of its soliton center and initial phase, the single soliton solution can be further rewritten as usual standard form. It is easy to find, up to a permitted well-known constant global phase factor, the one-soliton solution to DNLS equation gotten in the pure Marchenko formalism is in perfectly agreement with that gotten from other approaches [23, 24, 26, 27].
As
Up to a permitted constant global phase factor, the two-soliton solution gotten above is actually equivalent to that gotten from both IST and Hirota’s method [23, 24, 26, 27], verifying the validity of the algebraic techniques that is used and our formula of the generalized multi-soliton solution. Because Marchenko equations (128), (129), (144), and (145) had been strictly proved, the multi-soliton solution is certainly right as long as we correctly use the algebraic techniques, especially Binet-Cauchy formula for the principal minor expansion of some special matrices.
Bilinear derivative operator D had been found and defined in the early 1970s by Hirota R., a Japanese mathematical scientist [30, 31, 32, 33]. Hirota’s bilinear-derivative transform (HBDT for brevity) can be used to deal with some partial differential equation and to find some special solutions, such as soliton solutions and rogue wave solutions [26, 27, 32]. In this section, we use HBDT to solve DNLS equation with VBC and search for its soliton solution. The DNLS equation with VBC, that is,
is one of the typical integrable nonlinear models, which is of a different form from the following equation:
which had been solved in Ref. [14] by using HBDT. We have paid special attention to the following solution form in it [14]:
where
here and henceforth a bar over a letter represents complex conjugation.
In view of the existing experiences of dealing with the DNLS equation, in the present section, we attempt to use the solution form (192) and HBDT to solve the DNLS equation. We demonstrate our solving approach step by step, and naturally extend our conclusion to the n-soliton case in the end.
For two differentiable functions
which is different from the usual derivative, for example,
where
for example,
➂ Suppose
Especially, we have
After a suitable solution form, for example, (192) has been selected, under the Hirota’s bilinear derivative transform, a partial differential equation like (189) can be generally changed into [20, 26, 27].
where
Substituting the above expressions (199)–(202) into Eq. (189), the latter can be reduced to [26, 27].
We can extract the needed bilinear derivative equations from Eq. (203) as follows:
Functions
Substituting (207) and (208) into (204)–(206) and equating the sum of the terms with the same orders of
The above equations, (209)–(223), contain the whole information needed to search for a soliton solution of the DNLS equation with VBC.
For the one-soliton case, due to (209)–(211) and considering the transform property ③, we can select
From (212), one can select
where the vanishing boundary condition,
Substituting (226) and (227) into Eq. (213), we can attain
From (226) and (228), we can get an expression of
Due to (224) and (229), we can also easily verify that
which immediately leads to
in Eq. (215). Then from (215), we can select
where
which is characterized with two complex parameters
Then
It is easy to find, up to a permitted constant global phase factor
On the other hand, just like in Ref. [13], we can rewrite
Here
which makes us easily extend the solution form to the case of
For the two-soliton case, again from (209), we can select
The similar procedures to that used in the one-soliton case can be used to deduce
Substituting (242) and (243) into (215), one can attain
Substituting the expressions of
Due to (243) and (244), we can also easily verify that
Then from (244), (245), (246), and (221), we can select
It can also be rewritten in a standard form as follows:
where
which is characterized with four complex parameters
we can easily transform it to a two-soliton form given in Ref. [23], up to a permitted constant global phase factor.
Generally for the case of N-soliton solution, if we select
then using an induction method, we can write the
where
therein
Here, we have some discussion in order. Because what concerns us only is the soliton solutions, our soliton solution of DNLS equation with VBC is only a subset of the whole solution set. Actually in the whole process of deriving the bilinear-form equations and searching for the one and two-soliton solutions, some of the latter results are only the sufficient but not the necessary conditions of the former equations. Thereby some possible modes might have been missing. For example, the solutions of Eqs. (209)–(211) are not as unique as in (224) and (225), some other possibilities thus get lost here. This is also why we use a term “select” to determine a solution of an equation. In another word, we have selected a soliton solution. Meanwhile, we have demonstrated in Figures 2 and 3, the three-dimensional evolution of the one- and two-soliton amplitude with time and space, respectively. The elastic collision of two solitons in the two-soliton case has been demonstrated in Figure 4(a–d) too. It can be found that each soliton keeps the same form and characteristic after the collision as that before the collision. In this section, by means of introducing HBDT and employing an appropriate solution form (192), we successfully solve the derivative nonlinear Schrödinger equation with VBC. The one- and two-soliton solutions are derived and their equivalence to the existing results is manifested. The N-soliton solution has been given by an induction method. On the other hand, by using simple parameter transformations (e.g., (235) and (252)), the soliton solutions attained here can be changed into or equivalent to that gotten based on IST, up to a permitted global constant phase factor. This section impresses us so greatly for a fact that, ranked with the extensively used IST [23] and other methods, the HBDT is another effective and important tool to deal with a partial differential equation. It is especially suitable for some integrable nonlinear models.
The evolution of one-soliton solution with time and space under parameter Λ1=−1+0.2i,η10=1 in (234).
The evolution of two-soliton solution with time and space under parameter Λ1=1+0.3i,Λ2=1−0.3i,η10=η20=1 in (251).
The elastic collision between two solitons at 4 typical moments: (a) t = −10(normalized time); (b) t = −1; \t(c) t = 1; (d) t = 10, from −10 before collision to 10 after collision.
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\n'}]},successStories:{items:[]},authorsAndEditors:{filterParams:{sort:"featured,name"},profiles:[{id:"105746",title:"Dr.",name:"A.W.M.M.",middleName:null,surname:"Koopman-van Gemert",slug:"a.w.m.m.-koopman-van-gemert",fullName:"A.W.M.M. Koopman-van Gemert",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/105746/images/5803_n.jpg",biography:"Dr. Anna Wilhelmina Margaretha Maria Koopman-van Gemert MD, PhD, became anaesthesiologist-intensivist from the Radboud University Nijmegen (the Netherlands) in 1987. She worked for a couple of years also as a blood bank director in Nijmegen and introduced in the Netherlands the Cell Saver and blood transfusion alternatives. She performed research in perioperative autotransfusion and obtained the degree of PhD in 1993 publishing Peri-operative autotransfusion by means of a blood cell separator.\nBlood transfusion had her special interest being the president of the Haemovigilance Chamber TRIP and performing several tasks in local and national blood bank and anticoagulant-blood transfusion guidelines committees. Currently, she is working as an associate professor and up till recently was the dean at the Albert Schweitzer Hospital Dordrecht. She performed (inter)national tasks as vice-president of the Concilium Anaesthesia and related committees. \nShe performed research in several fields, with over 100 publications in (inter)national journals and numerous papers on scientific conferences. \nShe received several awards and is a member of Honour of the Dutch Society of Anaesthesia.",institutionString:null,institution:{name:"Albert Schweitzer Hospital",country:{name:"Gabon"}}},{id:"83089",title:"Prof.",name:"Aaron",middleName:null,surname:"Ojule",slug:"aaron-ojule",fullName:"Aaron Ojule",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Port Harcourt",country:{name:"Nigeria"}}},{id:"295748",title:"Mr.",name:"Abayomi",middleName:null,surname:"Modupe",slug:"abayomi-modupe",fullName:"Abayomi Modupe",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/no_image.jpg",biography:null,institutionString:null,institution:{name:"Landmark University",country:{name:"Nigeria"}}},{id:"94191",title:"Prof.",name:"Abbas",middleName:null,surname:"Moustafa",slug:"abbas-moustafa",fullName:"Abbas Moustafa",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/94191/images/96_n.jpg",biography:"Prof. Moustafa got his doctoral degree in earthquake engineering and structural safety from Indian Institute of Science in 2002. He is currently an associate professor at Department of Civil Engineering, Minia University, Egypt and the chairman of Department of Civil Engineering, High Institute of Engineering and Technology, Giza, Egypt. He is also a consultant engineer and head of structural group at Hamza Associates, Giza, Egypt. Dr. Moustafa was a senior research associate at Vanderbilt University and a JSPS fellow at Kyoto and Nagasaki Universities. He has more than 40 research papers published in international journals and conferences. He acts as an editorial board member and a reviewer for several regional and international journals. His research interest includes earthquake engineering, seismic design, nonlinear dynamics, random vibration, structural reliability, structural health monitoring and uncertainty modeling.",institutionString:null,institution:{name:"Minia University",country:{name:"Egypt"}}},{id:"84562",title:"Dr.",name:"Abbyssinia",middleName:null,surname:"Mushunje",slug:"abbyssinia-mushunje",fullName:"Abbyssinia Mushunje",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Fort Hare",country:{name:"South Africa"}}},{id:"202206",title:"Associate Prof.",name:"Abd Elmoniem",middleName:"Ahmed",surname:"Elzain",slug:"abd-elmoniem-elzain",fullName:"Abd Elmoniem Elzain",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Kassala University",country:{name:"Sudan"}}},{id:"98127",title:"Dr.",name:"Abdallah",middleName:null,surname:"Handoura",slug:"abdallah-handoura",fullName:"Abdallah Handoura",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"École Supérieure des Télécommunications",country:{name:"Morocco"}}},{id:"91404",title:"Prof.",name:"Abdecharif",middleName:null,surname:"Boumaza",slug:"abdecharif-boumaza",fullName:"Abdecharif Boumaza",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Abbès Laghrour University of Khenchela",country:{name:"Algeria"}}},{id:"105795",title:"Prof.",name:"Abdel Ghani",middleName:null,surname:"Aissaoui",slug:"abdel-ghani-aissaoui",fullName:"Abdel Ghani Aissaoui",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/105795/images/system/105795.jpeg",biography:"Abdel Ghani AISSAOUI is a Full Professor of electrical engineering at University of Bechar (ALGERIA). He was born in 1969 in Naama, Algeria. He received his BS degree in 1993, the MS degree in 1997, the PhD degree in 2007 from the Electrical Engineering Institute of Djilali Liabes University of Sidi Bel Abbes (ALGERIA). He is an active member of IRECOM (Interaction Réseaux Electriques - COnvertisseurs Machines) Laboratory and IEEE senior member. He is an editor member for many international journals (IJET, RSE, MER, IJECE, etc.), he serves as a reviewer in international journals (IJAC, ECPS, COMPEL, etc.). He serves as member in technical committee (TPC) and reviewer in international conferences (CHUSER 2011, SHUSER 2012, PECON 2012, SAI 2013, SCSE2013, SDM2014, SEB2014, PEMC2014, PEAM2014, SEB (2014, 2015), ICRERA (2015, 2016, 2017, 2018,-2019), etc.). His current research interest includes power electronics, control of electrical machines, artificial intelligence and Renewable energies.",institutionString:"University of Béchar",institution:{name:"University of Béchar",country:{name:"Algeria"}}},{id:"99749",title:"Dr.",name:"Abdel Hafid",middleName:null,surname:"Essadki",slug:"abdel-hafid-essadki",fullName:"Abdel Hafid Essadki",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"École Nationale Supérieure de Technologie",country:{name:"Algeria"}}},{id:"101208",title:"Prof.",name:"Abdel Karim",middleName:"Mohamad",surname:"El Hemaly",slug:"abdel-karim-el-hemaly",fullName:"Abdel Karim El Hemaly",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/101208/images/733_n.jpg",biography:"OBGYN.net Editorial Advisor Urogynecology.\nAbdel Karim M. A. El-Hemaly, MRCOG, FRCS � Egypt.\n \nAbdel Karim M. A. El-Hemaly\nProfessor OB/GYN & Urogynecology\nFaculty of medicine, Al-Azhar University \nPersonal Information: \nMarried with two children\nWife: Professor Laila A. Moussa MD.\nSons: Mohamad A. M. El-Hemaly Jr. MD. Died March 25-2007\nMostafa A. M. El-Hemaly, Computer Scientist working at Microsoft Seatle, USA. \nQualifications: \n1.\tM.B.-Bch Cairo Univ. June 1963. \n2.\tDiploma Ob./Gyn. Cairo Univ. April 1966. \n3.\tDiploma Surgery Cairo Univ. Oct. 1966. \n4.\tMRCOG London Feb. 1975. \n5.\tF.R.C.S. Glasgow June 1976. \n6.\tPopulation Study Johns Hopkins 1981. \n7.\tGyn. Oncology Johns Hopkins 1983. \n8.\tAdvanced Laparoscopic Surgery, with Prof. Paulson, Alexandria, Virginia USA 1993. \nSocieties & Associations: \n1.\t Member of the Royal College of Ob./Gyn. London. \n2.\tFellow of the Royal College of Surgeons Glasgow UK. \n3.\tMember of the advisory board on urogyn. FIGO. \n4.\tMember of the New York Academy of Sciences. \n5.\tMember of the American Association for the Advancement of Science. \n6.\tFeatured in �Who is Who in the World� from the 16th edition to the 20th edition. \n7.\tFeatured in �Who is Who in Science and Engineering� in the 7th edition. \n8.\tMember of the Egyptian Fertility & Sterility Society. \n9.\tMember of the Egyptian Society of Ob./Gyn. \n10.\tMember of the Egyptian Society of Urogyn. \n\nScientific Publications & Communications:\n1- Abdel Karim M. El Hemaly*, Ibrahim M. Kandil, Asim Kurjak, Ahmad G. Serour, Laila A. S. Mousa, Amr M. Zaied, Khalid Z. El Sheikha. \nImaging the Internal Urethral Sphincter and the Vagina in Normal Women and Women Suffering from Stress Urinary Incontinence and Vaginal Prolapse. Gynaecologia Et Perinatologia, Vol18, No 4; 169-286 October-December 2009.\n2- Abdel Karim M. El Hemaly*, Laila A. S. Mousa Ibrahim M. Kandil, Fatma S. El Sokkary, Ahmad G. Serour, Hossam Hussein.\nFecal Incontinence, A Novel Concept: The Role of the internal Anal sphincter (IAS) in defecation and fecal incontinence. Gynaecologia Et Perinatologia, Vol19, No 2; 79-85 April -June 2010.\n3- Abdel Karim M. El Hemaly*, Laila A. S. Mousa Ibrahim M. Kandil, Fatma S. El Sokkary, Ahmad G. Serour, Hossam Hussein.\nSurgical Treatment of Stress Urinary Incontinence, Fecal Incontinence and Vaginal Prolapse By A Novel Operation \n"Urethro-Ano-Vaginoplasty"\n Gynaecologia Et Perinatologia, Vol19, No 3; 129-188 July-September 2010.\n4- Abdel Karim M. El Hemaly*, Ibrahim M. Kandil, Laila A. S. Mousa and Mohamad A.K.M.El Hemaly.\nUrethro-vaginoplasty, an innovated operation for the treatment of: Stress Urinary Incontinence (SUI), Detursor Overactivity (DO), Mixed Urinary Incontinence and Anterior Vaginal Wall Descent. \nhttp://www.obgyn.net/urogyn/urogyn.asp?page=/urogyn/articles/ urethro-vaginoplasty_01\n\n5- Abdel Karim M. El Hemaly, Ibrahim M Kandil, Mohamed M. Radwan.\n Urethro-raphy a new technique for surgical management of Stress Urinary Incontinence.\nhttp://www.obgyn.net/urogyn/urogyn.asp?page=/urogyn/articles/\nnew-tech-urethro\n\n6- Abdel Karim M. El Hemaly, Ibrahim M Kandil, Mohamad A. Rizk, Nabil Abdel Maksoud H., Mohamad M. Radwan, Khalid Z. El Shieka, Mohamad A. K. M. El Hemaly, and Ahmad T. El Saban.\nUrethro-raphy The New Operation for the treatment of stress urinary incontinence, SUI, detrusor instability, DI, and mixed-type of urinary incontinence; short and long term results. \nhttp://www.obgyn.net/urogyn/urogyn.asp?page=urogyn/articles/\nurethroraphy-09280\n\n7-Abdel Karim M. El Hemaly, Ibrahim M Kandil, and Bahaa E. El Mohamady. Menopause, and Voiding troubles. \nhttp://www.obgyn.net/displayppt.asp?page=/English/pubs/features/presentations/El-Hemaly03/el-hemaly03-ss\n\n8-El Hemaly AKMA, Mousa L.A. Micturition and Urinary\tContinence. Int J Gynecol Obstet 1996; 42: 291-2. \n\n9-Abdel Karim M. El Hemaly.\n Urinary incontinence in gynecology, a review article.\nhttp://www.obgyn.net/urogyn/urogyn.asp?page=/urogyn/articles/abs-urinary_incotinence_gyn_ehemaly \n\n10-El Hemaly AKMA. Nocturnal Enuresis: Pathogenesis and Treatment. \nInt Urogynecol J Pelvic Floor Dysfunct 1998;9: 129-31.\n \n11-El Hemaly AKMA, Mousa L.A.E. Stress Urinary Incontinence, a New Concept. Eur J Obstet Gynecol Reprod Biol 1996; 68: 129-35. \n\n12- El Hemaly AKMA, Kandil I. M. Stress Urinary Incontinence SUI facts and fiction. Is SUI a puzzle?! http://www.obgyn.net/displayppt.asp?page=/English/pubs/features/presentations/El-Hemaly/el-hemaly-ss\n\n13-Abdel Karim El Hemaly, Nabil Abdel Maksoud, Laila A. Mousa, Ibrahim M. Kandil, Asem Anwar, M.A.K El Hemaly and Bahaa E. El Mohamady. \nEvidence based Facts on the Pathogenesis and Management of SUI. http://www.obgyn.net/displayppt.asp?page=/English/pubs/features/presentations/El-Hemaly02/el-hemaly02-ss\n\n14- Abdel Karim M. El Hemaly*, Ibrahim M. Kandil, Mohamad A. Rizk and Mohamad A.K.M.El Hemaly.\n Urethro-plasty, a Novel Operation based on a New Concept, for the Treatment of Stress Urinary Incontinence, S.U.I., Detrusor Instability, D.I., and Mixed-type of Urinary Incontinence.\nhttp://www.obgyn.net/urogyn/urogyn.asp?page=/urogyn/articles/urethro-plasty_01\n\n15-Ibrahim M. Kandil, Abdel Karim M. El Hemaly, Mohamad M. Radwan: Ultrasonic Assessment of the Internal Urethral Sphincter in Stress Urinary Incontinence. The Internet Journal of Gynecology and Obstetrics. 2003. Volume 2 Number 1. \n\n\n16-Abdel Karim M. El Hemaly. Nocturnal Enureses: A Novel Concept on its pathogenesis and Treatment.\nhttp://www.obgyn.net/urogynecolgy/?page=articles/nocturnal_enuresis\n\n17- Abdel Karim M. El Hemaly. Nocturnal Enureses: An Update on the pathogenesis and Treatment.\nhttp://www.obgyn.net/urogynecology/?page=/ENHLIDH/PUBD/FEATURES/\nPresentations/ Nocturnal_Enuresis/nocturnal_enuresis\n\n18-Maternal Mortality in Egypt, a cry for help and attention. The Second International Conference of the African Society of Organization & Gestosis, 1998, 3rd Annual International Conference of Ob/Gyn Department � Sohag Faculty of Medicine University. Feb. 11-13. Luxor, Egypt. \n19-Postmenopausal Osteprosis. The 2nd annual conference of Health Insurance Organization on Family Planning and its role in primary health care. Zagaziz, Egypt, February 26-27, 1997, Center of Complementary Services for Maternity and childhood care. \n20-Laparoscopic Assisted vaginal hysterectomy. 10th International Annual Congress Modern Trends in Reproductive Techniques 23-24 March 1995. Alexandria, Egypt. \n21-Immunological Studies in Pre-eclamptic Toxaemia. Proceedings of 10th Annual Ain Shams Medical Congress. Cairo, Egypt, March 6-10, 1987. \n22-Socio-demographic factorse affecting acceptability of the long-acting contraceptive injections in a rural Egyptian community. Journal of Biosocial Science 29:305, 1987. \n23-Plasma fibronectin levels hypertension during pregnancy. The Journal of the Egypt. Soc. of Ob./Gyn. 13:1, 17-21, Jan. 1987. \n24-Effect of smoking on pregnancy. Journal of Egypt. Soc. of Ob./Gyn. 12:3, 111-121, Sept 1986. \n25-Socio-demographic aspects of nausea and vomiting in early pregnancy. Journal of the Egypt. Soc. of Ob./Gyn. 12:3, 35-42, Sept. 1986. \n26-Effect of intrapartum oxygen inhalation on maternofetal blood gases and pH. Journal of the Egypt. Soc. of Ob./Gyn. 12:3, 57-64, Sept. 1986. \n27-The effect of severe pre-eclampsia on serum transaminases. The Egypt. J. Med. Sci. 7(2): 479-485, 1986. \n28-A study of placental immunoreceptors in pre-eclampsia. The Egypt. J. Med. Sci. 7(2): 211-216, 1986. \n29-Serum human placental lactogen (hpl) in normal, toxaemic and diabetic pregnant women, during pregnancy and its relation to the outcome of pregnancy. Journal of the Egypt. Soc. of Ob./Gyn. 12:2, 11-23, May 1986. \n30-Pregnancy specific B1 Glycoprotein and free estriol in the serum of normal, toxaemic and diabetic pregnant women during pregnancy and after delivery. Journal of the Egypt. Soc. of Ob./Gyn. 12:1, 63-70, Jan. 1986. Also was accepted and presented at Xith World Congress of Gynecology and Obstetrics, Berlin (West), September 15-20, 1985. \n31-Pregnancy and labor in women over the age of forty years. Accepted and presented at Al-Azhar International Medical Conference, Cairo 28-31 Dec. 1985. \n32-Effect of Copper T intra-uterine device on cervico