Aminoglycoside-induced nephrotoxicity in children

Aminoglycoside antibiotics, in particular gentamicin and tobramycin, are still commonly used in paediatric clinical practice. These drugs cause nephrotoxicity, which particularly affects the proximal tubule epithelial cells due to selective endocytosis and accumulation of aminoglycosides via the multi-ligand receptor megalin. Recent epidemiological studies, using more widely accepted definitions of acute kidney injury (AKI), have suggested that AKI may occur in between 20 and 33 % of children exposed to aminoglycosides. A consensus set of phenotypic criteria for aminoglycoside-induced nephrotoxicity have recently been published. These are specifically designed to provide robust phenotyping for pharmacogenomic studies, but they can pave the way for standardisation for all clinical studies. Novel renal biomarkers, in particular kidney injury molecule-1, identify aminoglycoside-induced proximal tubular injury earlier than traditional markers and have shown promise in observational studies. Further studies need to demonstrate a clear association with clinically relevant outcomes to inform translation into clinical practice. Extended interval dosing of aminoglycosides results in a reduction in nephrotoxicity, but its use needs to become more widespread. Inhibition of megalin-mediated endocytosis by statins represents a novel approach to the prevention of aminoglycoside-induced nephrotoxicity which is currently being evaluated in a clinical trial. Recommendations for future directions are provided

Urinary Biomarkers of Aminoglycoside-Induced Nephrotoxicity in Cystic Fibrosis: Kidney Injury Molecule-1 and Neutrophil Gelatinase-Associated Lipocalin

Aminoglycosides are commonly used for the treatment of pulmonary exacerbations in patients with cystic fibrosis (CF). However, they are potentially nephrotoxic. This prospective observational cohort study aimed to investigate the potential validity of two urinary renal biomarkers, Kidney Injury Molecule-1 (KIM-1) and Neutrophil Gelatinase-associated Lipocalin (NGAL), in identifying aminoglycoside-induced nephrotoxicity in children with CF. Children and young adults up to 20 years of age with a confirmed diagnosis of CF were recruited from ten United Kingdom hospitals. Participants provided urine samples for measurement of KIM-1 and NGAL concentrations, at baseline, at regular outpatient appointments, and before, during and after exposure to clinically-indicated treatment with the aminoglycoside tobramycin. 37/158 patients recruited (23.4%) received at least one course of IV tobramycin during the study. The median peak fold-change during tobramycin exposure for KIM-1 was 2.28 (IQR 2.69) and 4.02 (IQR 7.29) for NGAL, in the absence of serum creatinine changes. Baseline KIM-1 was positively associated with cumulative courses of IV aminoglycosides (R2 = 0.11; β = 0.03; p < 0.0001). KIM-1, in particular, may be a useful, non-invasive, biomarker of acute and chronic proximal tubular injury associated with exposure to aminoglycosides in patients with CF, but its clinical utility needs to be further evaluated in prospective studies

Reference intervals for urinary renal injury biomarkers KIM-1 and NGAL in healthy children

Aim: The aim of this study was to establish reference intervals in healthy children for two novel urinary biomarkers of acute kidney injury, kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL). Materials & Methods: Urinary biomarkers were determined in samples from children in the UK (n = 120) and the USA (n = 171) using both Meso Scale Discovery (MSD) and Luminex-based analytical approaches. Results: 95% reference intervals for each biomarker in each cohort are presented and stratified by sex or ethnicity where necessary, and age-related variability is explored using quantile regression. We identified consistently higher NGAL concentrations in females than males (p < 0.0001), and lower KIM-1 concentrations in African–Americans than Caucasians (p = 0.02). KIM-1 demonstrated diurnal variation, with higher concentrations in the morning (p < 0.001). Conclusion: This is the first report of reference intervals for KIM-1 and NGAL using two analytical methods in a healthy pediatric population in both UK and US-based populations

Spiny lobster development: where does successful metamorphosis to the puerulus occur?: a review

This review re-addresses the question: Where does metamorphosis to the puerulus mainly take place among the shallow-water palinurids? A decade ago we reviewed this ecological question in a paper that focused on phyllosomal development of the western rock lobster, Panulirus cygnus. The main region of occurrence of its metamorphosis was found to be in the slope region beyond the shelf break. Because the puerulus of P. cygnus is a non-feeding stage, it was hypothesised that metamorphosis will not occur until the final phyllosoma has reached some critical, and specific, level of stored energy reserves. For late larval development and successful metamorphosis of P. cygnus, the richest food resources seem to be located in the slope waters adjoining the shelf break off Western Australia. This, like most shelf break areas, is a region of higher zooplankton and micronekton biomass than is usually found further offshore, and is dominated (in winter-spring months) by the warm south-flowing Leeuwin Current. In this new review, distribution and abundance data of final phyllosomas and pueruli are examined from, Panulirusargus, Panulirus cygnus, Panulirus japonicus, Panulirus ornatus and Jasus edwardsii, and where possible, related to features of the satellite imagery of the areas in which they occur. We hypothesise that metamorphosis will occur where the final stages have partaken of sufficient, appropriate nutrition to provide them with a reserve of bioenergetic resources, and this can occur where oceanographic fronts effect greater planktonic productivity and concentrations of food organisms. This may be near the shelf-break, or out to large distances offshore, because of large-scale oceanographic events such as the prevailing current system, its off-shoots, mesoscale eddy fronts, counter-currents, etc. However, we contend that, in terms of population recruitment, metamorphosis in most shallow-water palinurid species occurs mainly in the slope waters adjoining the shelf break of the region to which the species is endemic. Although some final phyllosomas may metamorphose much further offshore, it is unlikely that these pueruli will reach the shore, let alone settle and successfully moult to the juvenile stage. All of the data indicate that successful metamorphosis from the final-stage phyllosoma to the puerulus stage in all species occurs offshore but close to the continental shelf

Persistence and Availability of Web Services in Computational Biology

We have conducted a study on the long-term availability of bioinformatics Web services: an observation of 927 Web services published in the annual Nucleic Acids Research Web Server Issues between 2003 and 2009

Hypernovae and Other Black-Hole-Forming Supernovae

During the last few years, a number of exceptional core-collapse supernovae (SNe) have been discovered. Their kinetic energy of the explosions are larger by more than an order of magnitude than the typical values for this type of SNe, so that these SNe have been called `Hypernovae'. We first describe how the basic properties of hypernovae can be derived from observations and modeling. These hypernovae seem to come from rather massive stars, thus forming black holes. On the other hand, there are some examples of massive SNe with only a small kinetic energy. We suggest that stars with non-rotating black holes are likely to collapse "quietly" ejecting a small amount of heavy elements (Faint supernovae). In contrast, stars with rotating black holes are likely to give rise to very energetic supernovae (Hypernovae). We present distinct nucleosynthesis features of these two types of "black-hole-forming" supernovae. Hypernova nucleosynthesis is characterized by larger abundance ratios (Zn,Co,V,Ti)/Fe and smaller (Mn,Cr)/Fe. Nucleosynthesis in Faint supernovae is characterized by a large amount of fall-back. We show that the abundance pattern of the most Fe deficient star, HE0107-5240, and other extremely metal-poor carbon-rich stars are in good accord with those of black-hole-forming supernovae, but not pair-instability supernovae. This suggests that black-hole-forming supernovae made important contributions to the early Galactic (and cosmic) chemical evolution.Comment: 49 pages, to be published in "Stellar Collapse" (Astrophysics and Space Science; Kluwer) ed. C. L. Fryer (2003

Useful pharmacodynamic endpoints in children: selection, measurement, and next steps.

Pharmacodynamic (PD) endpoints are essential for establishing the benefit-to-risk ratio for therapeutic interventions in children and neonates. This article discusses the selection of an appropriate measure of response, the PD endpoint, which is a critical methodological step in designing pediatric efficacy and safety studies. We provide an overview of existing guidance on the choice of PD endpoints in pediatric clinical research. We identified several considerations relevant to the selection and measurement of PD endpoints in pediatric clinical trials, including the use of biomarkers, modeling, compliance, scoring systems, and validated measurement tools. To be useful, PD endpoints in children need to be clinically relevant, responsive to both treatment and/or disease progression, reproducible, and reliable. In most pediatric disease areas, this requires significant validation efforts. We propose a minimal set of criteria for useful PD endpoint selection and measurement. We conclude that, given the current heterogeneity of pediatric PD endpoint definitions and measurements, both across and within defined disease areas, there is an acute need for internationally agreed, validated, and condition-specific pediatric PD endpoints that consider the needs of all stakeholders, including healthcare providers, policy makers, patients, and families.Pediatric Research advance online publication, 11 April 2018; doi:10.1038/pr.2018.38

Planetary nebulae: abundances and abundance gradients

In this work, a review is given of some recent results and problems involved in the determination of chemical abundances of galactic planetary nebulae, particularly regarding disk and bulge objects

Allergen Uptake, Activation, and IL-23 Production by Pulmonary Myeloid DCs Drives Airway Hyperresponsiveness in Asthma-Susceptible Mice

Maladaptive, Th2-polarized inflammatory responses are integral to the pathogenesis of allergic asthma. As regulators of T cell activation, dendritic cells (DCs) are important mediators of allergic asthma, yet the precise signals which render endogenous DCs “pro-asthmatic”, and the extent to which these signals are regulated by the pulmonary environment and host genetics, remains unclear. Comparative phenotypic and functional analysis of pulmonary DC populations in mice susceptible (A/J), or resistant (C3H) to experimental asthma, revealed that susceptibility to airway hyperresponsiveness is associated with preferential myeloid DC (mDC) allergen uptake, and production of Th17-skewing cytokines (IL-6, IL-23), whereas resistance is associated with increased allergen uptake by plasmacytoid DCs. Surprisingly, adoptive transfer of syngeneic HDM-pulsed bone marrow derived mDCs (BMDCs) to the lungs of C3H mice markedly enhanced lung IL-17A production, and rendered them susceptible to allergen-driven airway hyperresponsiveness. Characterization of these BMDCs revealed levels of antigen uptake, and Th17 promoting cytokine production similar to that observed in pulmonary mDCs from susceptible A/J mice. Collectively these data demonstrate that the lung environment present in asthma-resistant mice promotes robust pDC allergen uptake, activation, and limits Th17-skewing cytokine production responsible for driving pathologic T cell responses central to the development of allergen-induced airway hyperresponsiveness