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Search Results: 1 - 10 of 130491 matches for " Ihor V. Yosypiv "
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Congenital Anomalies of the Kidney and Urinary Tract: A Genetic Disorder?
Ihor V. Yosypiv
International Journal of Nephrology , 2012, DOI: 10.1155/2012/909083
Abstract: Congenital anomalies of the kidney and urinary tract (CAKUTs) occur in 3–6 per 1000 live births, account for the most cases of pediatric end-stage kidney disease (ESKD), and predispose an individual to hypertension and cardiovascular disease throughout life. Although CAKUTs are a part of many known syndromes, only few single-candidate causative genes have been implicated so far in nonsyndromic cases of human CAKUT. Evidence from mouse models supports the hypothesis that non-syndromic human CAKUT may be caused by single-gene defects. Because increasing numbers of children with CAKUT are surviving to adulthood, better understanding of the molecular pathogenesis of CAKUT, development of new strategies aiming at prevention of CAKUT, preservation of renal function, and avoidance of associated cardiovascular morbidity are needed. In this paper, we will focus on the knowledge derived from the study of syndromic and non-syndromic forms of CAKUT in humans and mouse mutants to discuss the role of genetic, epigenetic, and in utero environmental factors in the pathogenesis of non-syndromic forms of CAKUT in children with particular emphasis on the genetic contributions to CAKUT. 1. Introduction Congenital anomalies of the kidney and urinary tract (CAKUTs) occur in 3–6 per 1000 live births and are responsible for 34–59% of chronic kidney disease (CKD) and for 31% of all cases of end-stage kidney disease (ESKD) in children in the United States (Table 1) [1–8]. All children with ESKD require renal replacement therapy and up to 70% of them develop hypertension [9]. Given that the survival rate of children with ESKD is about 30 times lower than that of healthy children [10], new strategies are needed to prevent CAKUT, preserve renal function, and reduce associated cardiovascular morbidity. Table 1: Prevalence of CAKUT. CAKUTs comprise a wide range of renal system structural and functional malformations that occur at the level of the kidney (e.g., hypoplasia and dysplasia), collecting system (e.g., hydronephrosis and megaureter), bladder (e.g., ureterocele and vesicoureteral reflux), or urethra (e.g., posterior urethral valves) [16]. With improved prenatal screening, many cases of CAKUT are diagnosed by antenatal ultrasonography performed on 18–20 weeks of gestation. Most common antenatal manifestations of CAKUT include oligohydramnios or variations in gross morphology of the kidney, ureter, or bladder. Postnatal manifestations of CAKUT may include presence of palpable abdominal mass or single umbilical artery, feeding difficulties, decreased urine output, deficient
Developmental Programming of Hypertension and Kidney Disease
Euming Chong,Ihor V. Yosypiv
International Journal of Nephrology , 2012, DOI: 10.1155/2012/760580
Abstract: A growing body of evidence supports the concept that changes in the intrauterine milieu during “sensitive” periods of embryonic development or in infant diet after birth affect the developing individual, resulting in general health alterations later in life. This phenomenon is referred to as “developmental programming” or “developmental origins of health and disease.” The risk of developing late-onset diseases such as hypertension, chronic kidney disease (CKD), obesity or type 2 diabetes is increased in infants born prematurely at <37 weeks of gestation or in low birth weight (LBW) infants weighing <2,500?g at birth. Both genetic and environmental events contribute to the programming of subsequent risks of CKD and hypertension in premature or LBW individuals. A number of observations suggest that susceptibility to subsequent CKD and hypertension in premature or LBW infants is mediated, at least in part, by reduced nephron endowment. The major factors influencing in utero environment that are associated with a low final nephron number include uteroplacental insufficiency, maternal low-protein diet, hyperglycemia, vitamin A deficiency, exposure to or interruption of endogenous glucocorticoids, and ethanol exposure. This paper discusses the effect of premature birth, LBW, intrauterine milieu, and infant feeding on the development of hypertension and renal disease in later life as well as examines the role of the kidney in developmental programming of hypertension and CKD. 1. Introduction Despite the availability of a number of treatment options for hypertension, cardiovascular, and renal disease, the prevalence, morbidity, and mortality of these diseases in children and adults remain very high [1]. Therefore, elucidation of the causality and pathogenesis of these diseases is critical. Studies by Widdowson and McCance in the 1960s demonstrated that acceleration or retardation of the rate of growth induced by malnutrition during early postnatal life in rats led to distinct and different effects on anatomical, physiological, and chemical development [2]. In the 1980s, studies by Barker demonstrated that systolic blood pressure in older children is inversely related to their birth weight [3]. Around the same time, Brenner hypothesized that early loss of nephron mass results in hyperfiltration of remaining nephrons leading to subsequent hypertension, proteinuria, and progressive kidney injury [4]. These and subsequent studies have provided initial evidence that a suboptimal in utero environment may predispose or “program” an individual to an increased risk of
(Pro)renin Receptor in Kidney Development and Disease
Renfang Song,Ihor V. Yosypiv
International Journal of Nephrology , 2011, DOI: 10.4061/2011/247048
Abstract: The renin-angiotensin system (RAS), a key regulator of the blood pressure and fluid/electrolyte homeostasis, also plays a critical role in kidney development. All the components of the RAS are expressed in the developing metanephros. Moreover, mutations in the genes encoding components of the RAS in mice or humans are associated with a broad spectrum of congenital anomalies of the kidney and urinary tract (CAKUT). These forms of CAKUT include renal papillary hypoplasia, hydronephrosis, duplicated collecting system, renal tubular dysgenesis, renal vascular abnormalities, and aberrant glomerulogenesis. Emerging evidence indicates that (pro)renin receptor (PRR), a novel component of the RAS, is essential for proper kidney development and that aberrant PRR signaling is causally linked to cardiovascular and renal disease. This paper describes the role of the RAS in kidney development and highlights emerging insights into the cellular and molecular mechanisms by which the PRR may regulate this critical morphogenetic process. 1. Introduction 1.1. Brief Overview of Kidney Development During embryogenesis, the nephric duct (ND) is formed from the intermediate mesoderm on embryonic (E) day E22 in humans and E8 in mice [1]. The ND extends caudally and induces adjacent intermediate mesoderm to form two transient kidney types, pronephros and mesonephros. The pronephros degenerates in mammals, whereas the mesonephros involutes in females, but gives rise to male reproductive organs [1]. On 5th week of gestation in humans (E10.5 in mice), the caudal portion of the ND forms an epithelial outgrowth called the ureteric bud (UB). The metanephric kidney arises from two embryonic tissues: the UB and the metanephric mesenchyme (MM) [2, 3] (Figures 1(a)–1(d)). UB grows out from the ND, elongates, invades the MM, and then branches repeatedly within the mesenchyme to form the renal collecting system (the ureter, pelvis, calyces, and collecting ducts) [3–5]. Linear arrays of inner (medullary) collecting ducts converge centrally to form the papilla. Distal ureter subsequently translocates from the ND to fuse with the bladder which originates from the urogenital sinus (Figures 1(e)–1(g)) [6, 7]. Terminal UB tips induce surrounding MM-derived nephron progenitors to condense and then differentiate into nephrons (from the glomerulus to the distal tubule), thus forming the metanephric kidney (Figures 1(a)–1(d)) [3, 4]. Figure 1: Schematic representation of normal development of the kidney and urinary tract. (a): Invasion of the metanephric mesenchyme (MM) by the ureteric bud (UB) on
The Role of Renal Regulatory Mechanisms in the Evolution and Treatment of Pediatric Diabetic Ketoacidosis  [PDF]
Olugbenga A. Akingbola, Dinesh Singh, Ihor V. Yosypiv, Edwin M. Frieberg, Mary A. Younger, Samir S. El-Dahr
Open Journal of Endocrine and Metabolic Diseases (OJEMD) , 2013, DOI: 10.4236/ojemd.2013.31013
Abstract:

Diabetic ketoacidosis (DKA) is a life threatening complication of diabetes mellitus in pediatric patients with new onset insulin dependent diabetes. Despite advances in therapy mortality from DKA, especially in children less than two years, remains high. This review highlights the role of obligatory renal defense mechanisms in the evolution of DKA and its implication for therapy: to accomplish this goal the review starts with a cursory description of the pathogenesis and pathophysiology of metabolic derangements in DKA as a basis for understanding the renal compensatory mechanisms geared towards restoration of acid-base balance; then, the next section of the review describes how alterations in fluid and electrolyte balance at the onset of DKA and the extent of renal regulatory defense mechanisms geared towards its restoration can predispose to cerebral edema at the beginning of therapy. We conclude by suggesting that restoration of fluid and electrolyte balance should be based on the severity of metabolic acidosis as determined by the extent of renal impairment at the onset and during the course of DKA rather than strictly by protocols.

Receptor Tyrosine Kinases in Kidney Development
Renfang Song,Samir S. El-Dahr,Ihor V. Yosypiv
Journal of Signal Transduction , 2011, DOI: 10.1155/2011/869281
Abstract: The kidney plays a fundamental role in the regulation of arterial blood pressure and fluid/electrolyte homeostasis. As congenital anomalies of the kidney and urinary tract (CAKUT) constitute one of the most common human birth defects, improved understanding of the cellular and molecular mechanisms that lead to CAKUT is critical. Accumulating evidence indicates that aberrant signaling via receptor tyrosine kinases (RTKs) is causally linked to CAKUT. Upon activation by their ligands, RTKs dimerize, undergo autophosphorylation on specific tyrosine residues, and interact with adaptor proteins to activate intracellular signal transduction pathways that regulate diverse cell behaviours such as cell proliferation, survival, and movement. Here, we review the current understanding of role of RTKs and their downstream signaling pathways in the pathogenesis of CAKUT. 1. Introduction 1.1. Brief Overview of Kidney Development Development of the kidney and urinary tract begins when the nephric duct (ND) is formed from the intermediate mesoderm on embryonic (E) day E22 in humans and E8 in mice [6]. The ND extends caudally and forms an epithelial outgrowth called the ureteric bud (UB) (E28 in humans; E10.5 in mice), which invades the adjacent metanephric mesenchyme (MM) [6] (Figure 1). The permanent or metanephric kidney is formed via reciprocal inductive interactions between the UB and the MM [7, 8]. UB outgrowth from the ND is followed by its repetitive branching, a process called branching morphogenesis [9, 10]. Initial generations of UB branches will form the ureter, renal pelvis, and calyces, whereas subsequent generations of UB branches will give rise to collecting ducts. Distal ureter will translocate from the ND to eventually fuse with the bladder [11, 12]. Each UB tip is capable of inducing the adjacent metanephric mesenchyme to form nephrons (from the glomerulus through the distal tubule) [9]. UB signals to MM by secreting wingless 9b (Wnt9b), a soluble growth factor, which acts via canonical β catenin to induce expression of fibroblast growth factor 8 (FGF8), LIM homeobox 1 (Lhx1) and Wnt4 in the MM [7, 8, 13–15]. In turn, Wnt4 induces MM cells to undergo mesenchymal-to-epithelial transformation (MET) and differentiate into nephron epithelia [13]. Six2, a homeodomain transcription factor expressed in the MM, maintains MM cells in undifferentiated state, thereby allowing continued UB branching and nephron formation to proceed [16]. Aberrant UB branching or nephron endowment is causally linked to congenital anomalies of the kidney and urinary tract (CAKUT),
Deletion of the Prorenin Receptor from the Ureteric Bud Causes Renal Hypodysplasia
Renfang Song, Graeme Preston, Atsuhiro Ichihara, Ihor V. Yosypiv
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0063835
Abstract: The role of the prorenin receptor (PRR) in the regulation of ureteric bud (UB) branching morphogenesis is unknown. Here, we investigated whether PRR acts specifically in the UB to regulate UB branching, kidney development and function. We demonstrate that embryonic (E) day E13.5 mouse metanephroi, isolated intact E11.5 UBs and cultured UB cells express PRR mRNA. To study its role in UB development, we conditionally ablated PRR in the developing UB (PRRUB?/?) using Hoxb7Cre mice. On E12.5, PRRUB?/? mice had decreased UB branching and increased UB cell apoptosis. These defects were associated with decreased expression of Ret, Wnt11, Etv4/Etv5, and reduced phosphorylation of Erk1/2 in the UB. On E18.5, mutants had marked kidney hypoplasia, widespread apoptosis of medullary collecting duct cells and decreased expression of Foxi1, AE1 and H+-ATPase α4 mRNA. Ultimately, they developed occasional small cysts in medullary collecting ducts and had decreased nephron number. To test the functional consequences of these alterations, we determined the ability of PRRUB?/? mice to acidify and concentrate the urine on postnatal (P) day P30. PRRUB?/? mice were polyuric, had lower urine osmolality and a higher urine pH following 48 hours of acidic loading with NH4Cl. Taken together, these data show that PRR present in the UB epithelia performs essential functions during UB branching morphogenesis and collecting duct development via control of Ret/Wnt11 pathway gene expression, UB cell survival, activation of Erk1/2, terminal differentiation and function of collecting duct cells needed for maintaining adequate water and acid-base homeostasis. We propose that mutations in PRR could possibly cause renal hypodysplasia and renal tubular acidosis in humans.
Emergency Management of Hypertension in Children
Dinesh Singh,Olugbenga Akingbola,Ihor Yosypiv,Samir El-Dahr
International Journal of Nephrology , 2012, DOI: 10.1155/2012/420247
Abstract: Systemic arterial hypertension in children has traditionally been thought to be secondary in origin. Increased incidence of risk factors like obesity, sedentary life-styles, and faulty dietary habits has led to increased prevalence of the primary arterial hypertension (PAH), particularly in adolescent age children. PAH has become a global epidemic worldwide imposing huge economic constraint on health care. Sudden acute increase in systolic and diastolic blood pressure can lead to hypertensive crisis. While it generally pertains to secondary hypertension, occurrence of hypertensive crisis in PAH is however rare in children. Hypertensive crisis has been further subclassified depending on presence or absence of end-organ damage into hypertensive emergency or urgency. Both hypertensive emergencies and urgencies are known to cause significant morbidity and mortality. Increasing awareness among the physicians, targeted at investigation of the pathophysiology of hypertension and its complications, better screening methods, generation, and implementation of novel treatment modalities will impact overall outcomes. In this paper, we discuss the etiology, pathogenesis, and management of hypertensive crisis in children. An extensive database search using keywords was done to obtain the information. 1. Definitions and Epidemiology Primary arterial hypertension is a global epidemic affecting predominantly adult population [1]. Although secondary etiologies of hypertension predominate in children, the prevalence of primary arterial hypertension has been increasing at an alarming rate particularly in adolescents and older children [2]. Recent survey conducted by the National Health and Nutrition Examination Survey (NHANES) in 8–17-year-old children showed a prevalence of prehypertension and hypertension of about 10% and 4%, respectively, with a higher incidence in African American and Mexican Americans [3]. Increase in the prevalence of hypertension has paralleled the increased prevalence of childhood obesity [4]. Childhood obesity has increased by more than three times in the past three decades [5]. The Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in Children and Adolescents classified pediatric hypertension into various stages [6] (Table 1). In one study the incidence of stage 1 and 2 hypertension was reported to be 2.6% and 0.6%, respectively, in adolescent students [7]. The Joint National Committee on Detection, Evaluation, and Treatment of Hypertension, JNC7, has labeled acute severe elevation of blood pressure above
Integrability of geodesic flows for metrics on suborbits of the adjoint orbits of compact groups
Ihor V. Mykytyuk
Mathematics , 2014,
Abstract: Let $G/K$ be an orbit of the adjoint representation of a compact connected Lie group $G$, $\sigma$ be an involutive automorphism of $G$ and $\tilde G$ be the Lie group of fixed points of $\sigma$. We find a sufficient condition for the complete integrability of the geodesic flow of the Riemannian metric on $\tilde G/(\tilde G\cap K)$, which is induced by the bi-invariant Riemannian metric on $\tilde G$. The integrals constructed here are real analytic functions, polynomial in momenta. It is checked that this sufficient condition holds when $G$ is the unitary group $U(n)$ and $\sigma$ is its automorphism defined by the complex conjugation.
Mott transition in the asymmetric Hubbard model at half-filling within dynamical mean-field theory
Ihor V. Stasyuk,Orest B. Hera
Physics , 2005, DOI: 10.1140/epjb/e2005-00406-x
Abstract: We apply the approximate analytic methods to the investigation of the band structure of the asymmetric Hubbard model where the chemical potentials and electron transfer parameters depend on the electron spin (type of quasiparticles). The Hubbard-I and alloy-analogy approximations are the simplest approximations which are used. Within the alloy-analogy approximation, the energy band of particles does not depend on the transfer parameter of particles of another sort. It means that the gap in the spectrum opens at the critical value $U_{c}$ that is the same in two different limiting cases: the Falicov-Kimball model and the standard Hubbard model. The approximate analytic scheme of the dynamical mean-field theory is developed to include into the theory the scattering of particles responsible for the additional mechanism (due to the transfer of particles of another sort) of the band formation. We use the so-called GH3 approach that is a generalization of the Hubbard-III approximation. The approach describes the continuous Mott transition with the $U_{c}$ value dependent on a ratio of transfer parameters of different particles.
Densities of states of the Falicov-Kimball model off half filling in infinite dimensions
Ihor V. Stasyuk,Orest B. Hera
Physics , 2005, DOI: 10.1103/PhysRevB.72.045134
Abstract: An approximate analytical scheme of the dynamical mean field theory (DMFT) is developed for the description of the electron (ion) lattice systems with Hubbard correlations within the asymmetric Hubbard model where the chemical potentials and electron transfer parameters depend on an electron spin (a sort of ions). Considering a complexity of the problem we test the approximation in the limiting case of the infinite-$U$ spinless Falicov-Kimball model. Despite the fact that the Falicov-Kimball model can be solved exactly within DMFT, the densities of states of localized particles have not been completely investigated off half filling. We use the approximation to obtain the spectra of localized particles for various particle concentrations (chemical potentials) and temperatures. The effect of a phase separation phenomenon on the spectral function is considered.
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