Fenoldapam for Acute Kidney Injury in Children

We report two cases of children with severe cardiomyopathy requiring treatment with ventricular assist devices who developed acute kidney injury and were treated with fenoldopam. Therapy with fenoldopam appeared successful in one case in that renal replacement therapy was avoided with improvement in urine output and renal function. These are the first reported cases of fenoldopam use in children with acute kidney injury receiving mechanical circulatory support

Nonsteroidal Anti-Inflammatory Drugs Are an Important Cause of Acute Kidney Injury in Children

Objective To characterize nonsteroidal anti-inflammatory drug (NSAID)-associated acute kidney injury (AKI) in children. Study design We conducted a retrospective chart review of children diagnosed with AKI through the use of International Classification of Diseases, Ninth Revision diagnosis code 584.5 or 584.9 from January 1999 to June 2010. Medical records were reviewed to confirm the diagnosis of AKI and to quantify NSAID administration. Pediatric RIFLE criteria were used to codify AKI. Patients were not classified as having NSAID-associated AKI if they had a diagnosis explaining AKI or comorbid clinical conditions predisposing to AKI development. Results Patients (N = 1015) were identified through International Classification of Diseases, Ninth Revision screening. Twenty-one children had clinical, laboratory, and radiographic studies suggesting NSAID-associated acute tubular necrosis and 6 had findings suggesting NSAID-associated acute interstitial nephritis, representing 2.7% (27 of 1015) of the total cohort with AKI and 6.6% when excluding complex patients with multifactorial AKI. Children with NSAID-associated AKI had a median (range) age of 14.7 years (0.5-17.7 years); 4 patients (15%) were (75%) for whom dosing data were available received NSAIDs within recommended dosing limits. Patients (100% vs 0%, P \u3c .001), intensive care unit admission (75% vs 9%, P = .013), and a longer length of stay (median 10 vs 7 days, P = .037). Conclusions NSAID-associated AKI accounted for 2.7% of AKI in this pediatric population. AKI typically occurred after the administration of correctly dosed NSAIDs. Young children with NSAID-associated AKI may have increased disease severity

Gaining the PROMIS perspective from children with nephrotic syndrome: a Midwest pediatric nephrology consortium study

Background and objectives Nephrotic syndrome (NS) represents a common disease in pediatric nephrology typified by a relapsing and remitting course and characterized by the presence of edema that can significantly affect the health-related quality of life in children and adolescents. The PROMIS pediatric measures were constructed to be publically available, efficient, precise, and valid across a variety of diseases to assess patient reports of symptoms and quality of life. This study was designed to evaluate the ability of children and adolescents with NS to complete the PROMIS assessment via computer and to initiate validity assessments of the short forms and full item banks in pediatric NS. Successful measurement of patient reported outcomes will contribute to our understanding of the impact of NS on children and adolescents. Design This cross-sectional study included 151 children and adolescents 8-17 years old with NS from 16 participating institutions in North America. The children completed the PROMIS pediatric depression, anxiety, social-peer relationships, pain interference, fatigue, mobility and upper extremity functioning measures using a web-based interface. Responses were compared between patients experiencing active NS (n = 53) defined by the presence of edema and patients with inactive NS (n = 96) defined by the absence of edema. Results All 151 children and adolescents were successfully able to complete the PROMIS assessment via computer. As hypothesized, the children and adolescents with active NS were significantly different on 4 self-reported measures (anxiety, pain interference, fatigue, and mobility). Depression, peer relationships, and upper extremity functioning were not different between children with active vs. inactive NS. Multivariate analysis showed that the PROMIS instruments remained sensitive to NS disease activity after adjusting for demographic characteristics. Conclusions Children and adolescents with NS were able to successfully complete the PROMIS instrument using a web-based interface. The computer based pediatric PROMIS measurement effectively discriminated between children and adolescents with active and inactive NS. The domain scores found in this study are consistent with previous reports investigating the health-related quality of life in children and adolescents with NS. This study establishes known-group validity and feasibility for PROMIS pediatric measures in children and adolescents with NS

Gaining the Patient Reported Outcomes Measurement Information System (PROMIS) perspective in chronic kidney disease: a Midwest Pediatric Nephrology Consortium study

Chronic kidney disease is a persistent chronic health condition commonly seen in pediatric nephrology programs. Our study aims to evaluate the sensitivity of the Patient Reported Outcomes Measurement Information System (PROMIS) pediatric instrument to indicators of disease severity and activity in pediatric chronic kidney disease

Investigation of Yersinia pestis Laboratory Adaptation through a Combined Genomics and Proteomics Approach

The bacterial pathogen Yersinia pestis, the cause of plague in humans and animals, normally has a sylvatic lifestyle, cycling between fleas and mammals. In contrast, laboratory-grown Y. pestis experiences a more constant environment and conditions that it would not normally encounter. The transition from the natural environment to the laboratory results in a vastly different set of selective pressures, and represents what could be considered domestication. Understanding the kinds of adaptations Y. pestis undergoes as it becomes domesticated will contribute to understanding the basic biology of this important pathogen. In this study, we performed a parallel serial passage experiment (PSPE) to explore the mechanisms by which Y. pestis adapts to laboratory conditions, hypothesizing that cells would undergo significant changes in virulence and nutrient acquisition systems. Two wild strains were serially passaged in 12 independent populations each for ~750 generations, after which each population was analyzed using whole-genome sequencing, LC-MS/MS proteomic analysis, and GC/MS metabolomics. We observed considerable parallel evolution in the endpoint populations, detecting multiple independent mutations in ail, pepA, and zwf, suggesting that specific selective pressures are shaping evolutionary responses. Complementary LC-MS/MS proteomic data provide physiological context to the observed mutations, and reveal regulatory changes not necessarily associated with specific mutations, including changes in amino acid metabolism and cell envelope biogenesis. Proteomic data support hypotheses generated by genomic data in addition to suggesting future mechanistic studies, indicating that future whole-genome sequencing studies be designed to leverage proteomics as a critical complement

A Quantitative Systems Pharmacology Model of Gaucher Disease Type 1 Provides Mechanistic Insight Into the Response to Substrate Reduction Therapy With Eliglustat

Gaucher's disease type 1 (GD1) leads to significant morbidity and mortality through clinical manifestations, such as splenomegaly, hematological complications, and bone disease. Two types of therapies are currently approved for GD1: enzyme replacement therapy (ERT), and substrate reduction therapy (SRT). In this study, we have developed a quantitative systems pharmacology (QSP) model, which recapitulates the effects of eliglustat, the only first-line SRT approved for GD1, on treatment-na\uefve or patients with ERT-stabilized adult GD1. This multiscale model represents the mechanism of action of eliglustat that leads toward reduction of spleen volume. Model capabilities were illustrated through the application of the model to predict ERT and eliglustat responses in virtual populations of adult patients with GD1, representing patients across a spectrum of disease severity as defined by genotype-phenotype relationships. In summary, the QSP model provides a mechanistic computational platform for predicting treatment response via different modalities within the heterogeneous GD1 patient population

Gaining the PROMIS perspective from children with nephrotic syndrome: a Midwest pediatric nephrology consortium study

Background and objectives Nephrotic syndrome (NS) represents a common disease in pediatric nephrology typified by a relapsing and remitting course and characterized by the presence of edema that can significantly affect the health-related quality of life in children and adolescents. The PROMIS pediatric measures were constructed to be publically available, efficient, precise, and valid across a variety of diseases to assess patient reports of symptoms and quality of life. This study was designed to evaluate the ability of children and adolescents with NS to complete the PROMIS assessment via computer and to initiate validity assessments of the short forms and full item banks in pediatric NS. Successful measurement of patient reported outcomes will contribute to our understanding of the impact of NS on children and adolescents. Design This cross-sectional study included 151 children and adolescents 8-17 years old with NS from 16 participating institutions in North America. The children completed the PROMIS pediatric depression, anxiety, social-peer relationships, pain interference, fatigue, mobility and upper extremity functioning measures using a web-based interface. Responses were compared between patients experiencing active NS (n?=?53) defined by the presence of edema and patients with inactive NS (n?=?96) defined by the absence of edema. Results All 151 children and adolescents were successfully able to complete the PROMIS assessment via computer. As hypothesized, the children and adolescents with active NS were significantly different on 4 self-reported measures (anxiety, pain interference, fatigue, and mobility). Depression, peer relationships, and upper extremity functioning were not different between children with active vs. inactive NS. Multivariate analysis showed that the PROMIS instruments remained sensitive to NS disease activity after adjusting for demographic characteristics. Conclusions Children and adolescents with NS were able to successfully complete the PROMIS instrument using a web-based interface. The computer based pediatric PROMIS measurement effectively discriminated between children and adolescents with active and inactive NS. The domain scores found in this study are consistent with previous reports investigating the health-related quality of life in children and adolescents with NS. This study establishes known-group validity and feasibility for PROMIS pediatric measures in children and adolescents with NS

Effects of mutant PepA protein on CarAB protein levels.

<p>Evolved populations expressing mutant PepA protein have increased CarA (dark grey bars) and CarB (light grey bars) relative to ancestral cells, consistent with derepression of the <i>carAB</i> operon. Each population was measured in triplicate. Specific <i>pepA</i> alleles are given in parentheses. Error bars reflect standard deviation of the mean. A, Yp1945-derived populations. B, Yp2126-derived populations.</p