Prevalence and clinical characteristics of elevated 1-alpha,25-dihydroxyvitamin D in pediatric nephrolithiasis and related disorders

INTRODUCTION: The incidence of pediatric nephrolithiasis (kidney stones) has been increasing over the past several years. While environmental factors, such as poor fluid intake, high-salt diet, and obesity, can play a role, underlying metabolic factors account for at least one-third of cases of nephrolithiasis. Nephrolithiasis and related disorders, such as nephrocalcinosis and hypercalciuria, can lead to long-term kidney problems, including renal scarring, acute and chronic kidney disease, decreased renal function, or end-stage renal disease. The best treatment is prevention and is best guided by knowing the underlying cause. The majority of kidney stones are primarily comprised of calcium, and abnormal calcium metabolism and regulation can lead to nephrolithiasis, nephrocalcinosis, and hypercalciuria. Vitamin D is an important factor in calcium regulation in the body. The physiologically active form of vitamin D is 1α,25-dihydroxyvitamin D (1,25(OH)2D), which increases serum calcium by stimulating intestinal absorption of calcium, increasing renal calcium reabsorption, and mobilizing calcium from bone. Excess 1,25(OH)2D has been shown to be associated with hyperabsorption of calcium in the intestine, nephrolithiasis, hypercalcemia, and hypercalciuria. Production of 1,25(OH)2D requires hydroxylation of 25-hydroxyvitamin D by the kidney enzyme 1α-hydroxylase, which is regulated in turn by serum calcium, parathyroid hormone (PTH), and by 1,25(OH)2D itself. Tight control of 1,25(OH)2D levels is maintained in part by the breakdown of 1,25(OH)2D by the enzyme 24-hydroxylase, which is encoded by the gene CYP24A1. In the past few years, CYP24A1 mutations leading to decreased activity of 24-hydroxylase have been implicated in some cases of idiopathic infantile hypercalcemia as well as nephrolithiasis, nephrocalcinosis, and hypercalciuria. The prevalence of 24-hydroxylase deficiency is not known, and the spectrum of its clinical manifestations is not yet fully understood. Our study aims to describe the clinical characteristics of patients with laboratory findings suggestive of 24-hydroxylase deficiency, specifically high-normal or elevated serum 1,25(OH)2D. We aimed to determine the prevalence of elevated 1,25(OH)2D among pediatric patients with nephrolithiasis, and to compare clinical outcomes and biochemical findings in patients with normal versus elevated 1,25(OH)2D. PATIENTS AND METHODS: This study was a retrospective chart review. To determine the prevalence of high-normal (56-75 pg/mL) and high (>75 pg/mL) serum 1,25(OH)2D, we reviewed electronic medical records of patients seen in the Boston Children's Hospital Stone Clinic. We identified 346 patients who were evaluated for nephrolithiasis, were under 18 years of age at the time of presentation, and had at least one measurement of 1,25(OH)2D. Patients were classified based on their highest measured level of 1,25(OH)2D. To determine the clinical characteristics of patients with elevated 1,25(OH)2D, we reviewed clinical records and laboratory data of patients at Boston Children's Hospital with a diagnosis of nephrolithiasis, nephrocalcinosis, or hypercalciuria. We identified 83 patients who met our inclusion criteria: age of onset 55 pg/mL). RESULTS: Of 346 children with nephrolithiasis in whom 1,25(OH)2D was measured, 100 (28.9%) had high 1,25(OH)2D, and an additional 120 (34.7%) had high-normal 1,25(OH)2D. To determine the clinical characteristics of elevated 1,25(OH)2D, we analyzed the data of 40 patients with normal 1,25(OH)2D and 43 patients with elevated 1,25(OH)2D who had a history of nephrolithiasis, nephrocalcinosis, or hypercalciuria. Seventy-five children had nephrolithiasis, and 25/37 (67.6%) of children with elevated 1,25(OH)2D had a recurrence of nephrolithiasis, compared to only 9/38 (23.7%) of children with normal 1,25(OH)2D (p < .001). Urine calcium/creatinine ratio did not differ between the two groups. However, linear regression analysis showed an association between 1,25(OH)2D levels and urine calcium/creatinine ratio. Important secondary findings included a younger age of onset, higher serum 25-hydroxyvitamin D, and lower parathyroid hormone levels in patients with elevated 1,25(OH)2D. CONCLUSIONS: Important clinical findings of this study were the increased rate of recurrence and the younger age of onset in patients with elevated 1,25(OH)2D. While we recognize that mutations in CYP24A1 do not account for the majority of cases of elevated 1,25(OH)2D, we do advocate for special consideration for these patients. In the absence of a commercially-available assay for 24-hydroxylase activity, children with nephrolithiasis, nephrocalcinosis, or hypercalciuria and elevated 1,25(OH)2D should be closely monitored for recurrence or worsening of symptoms. Furthermore, we advise caution in the use of vitamin D repletion in at-risk patients

Qualitätsbegriffe und -konzepte im Bereich der institutionellen Kleinkindbetreuung

In der vorliegenden Diplomarbeit wird der Frage nachgegangen, wie sich der Qualitätsbegriff im Bereich der institutionellen Kleinkindbetreuung im Zeitraum von 1990 bis 2010 entwickelt hat. Dabei wird erläutert, in welchen Bereichen der Qualitätsbegriff seinen Ursprung fand und welche Qualitätszugänge bislang existieren. Verschiedene Qualitätsansätze, die sich im genannten Zeitraum im deutschsprachigen Raum (Deutschland und Österreich) etablieren konnten, und die Einfluss auf die Qualität im Kontext institutioneller Kleinkindbetreuung genommen haben, werden dargestellt. Außerdem werden die Qualitätsansätze von Wolfang Tietze und Wassilios E. Fthenakis eingehender erläutert und deren Gemeinsamkeiten bzw. Differenzen miteinander verglichen, um ein Stück weit herauszuarbeiten, wie Qualität im Bereich der institutionellen Kleinkindbetreuung in der jüngeren Vergangenheit definiert bzw. überprüft wird. Abschließend werden die Ergebnisse unter Bezugnahme auf die „Wiener Kinderkrippenstudie“ diskutiert, welche die so genannte Eingewöhnung in eine Kinderkrippe untersucht.This thesis concerns the development of quality within the last two decades in early child day care centres. Therefore, concepts of quality that have been established in Germany and Austria between 1990 and 2010 will be explained. In this context the publishers of the concepts should be compared of how they define quality, which aspects they seem to be important to optimize quality and how quality can be valued. The main point of this thesis concerns the concepts of quality of Wolfgang Tietze and Wassilios E. Fthenakis because their concepts of quality have been published recently and are discussed in German literature quite often. They should be compared in the context of which aspects they agree and in which aspects of quality they are different. This thesis also shows the results in the context of the so-called “Wiener Kinderkrippenstudie” in which should be explored how toddlers might feel when attending a child day care centre for the fist time and which aspects could help them to feel better. Finally, there should be a summary and thoughts about which aspects of quality could be explored in the future

Using Mediation To Defuse Potential Title VII Situations

This paper will provide an introduction to the use of mediation techniques used to defuse possible Title VII situations. The authors feel that many Title VII situations can be effectively handled through the use of properly conducted mediation. As a learning tool, students in the classroom have been given the chance to assume the role of plaintiff, defendant, lawyer and mediator. This gives the student an important insight to the situations they may be required to deal with during their careers. This paper will address several scenarios in which mediation has been undertaken, and the authors will analyze the correct methods that could have been used, as well as areas that were effectively managed.&nbsp; As a reference, video clips of actual mediation cases will be used to set up scenario discussions. These video clips are taken from several classroom situations that students have performed as course requirements

Grey wolf genomic history reveals a dual ancestry of dogs

The grey wolf (Canis lupus) was the first species to give rise to a domestic population, and they remained widespread throughout the last Ice Age when many other large mammal species went extinct. Little is known, however, about the history and possible extinction of past wolf populations or when and where the wolf progenitors of the present-day dog lineage (Canisfamiliaris) lived(1-8). Here we analysed 72 ancient wolf genomes spanning the last 100,000 years from Europe, Siberia and North America. We found that wolf populations were highly connected throughout the Late Pleistocene, with levels of differentiation an order of magnitude lower than they are today. This population connectivity allowed us to detect natural selection across the time series, including rapid fixation of mutations in the gene IFT8840,000-30,000 years ago. We show that dogs are overall more closely related to ancient wolves from eastern Eurasia than to those from western Eurasia, suggesting a domestication process in the east. However, we also found that dogs in the Near East and Africa derive up to half of their ancestry from a distinct population related to modern southwest Eurasian wolves, reflecting either an independent domestication process or admixture from local wolves. None of the analysed ancient wolf genomes is a direct match for either of these dog ancestries, meaning that the exact progenitor populations remain to be located.Peer reviewe

Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. For example, a key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process versus those that measure fl ux through the autophagy pathway (i.e., the complete process including the amount and rate of cargo sequestered and degraded). In particular, a block in macroautophagy that results in autophagosome accumulation must be differentiated from stimuli that increase autophagic activity, defi ned as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (inmost higher eukaryotes and some protists such as Dictyostelium ) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the fi eld understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. It is worth emphasizing here that lysosomal digestion is a stage of autophagy and evaluating its competence is a crucial part of the evaluation of autophagic flux, or complete autophagy. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. Along these lines, because of the potential for pleiotropic effects due to blocking autophagy through genetic manipulation it is imperative to delete or knock down more than one autophagy-related gene. In addition, some individual Atg proteins, or groups of proteins, are involved in other cellular pathways so not all Atg proteins can be used as a specific marker for an autophagic process. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field