The Protective Effects of Calcineurin on Pancreatitis in Mice Depend on the Cellular Source.

Background & Aims: Calcineurin is a ubiquitously expressed central Ca-responsive signaling molecule that mediates acute pancreatitis, but little is known about its effects. We compared the effects of calcineurin expression by hematopoietic cells vs pancreas in mouse models of pancreatitis and pancreatitis-associated lung inflammation.

Methods: We performed studies with mice with hematopoietic-specific or pancreas-specific deletion of protein phosphatase 3, regulatory subunit B, alpha isoform (PPP3R1, also called CNB1), in mice with deletion of CNB1 (Cnb1) and in the corresponding controls for each deletion of CNB1.

Pharmacokinetics of glycerol phenylbutyrate in pediatric patients 2 months to 2 years of age with urea cycle disorders.

Introduction: Glycerol phenylbutyrate (GPB) is approved in the US and EU for the chronic management of patients ≥2 months of age with urea cycle disorders (UCDs) who cannot be managed by dietary protein restriction and/or amino acid supplementation alone. GPB is a pre-prodrug, hydrolyzed by lipases to phenylbutyric acid (PBA) that upon absorption is beta-oxidized to the active nitrogen scavenger phenylacetic acid (PAA), which is conjugated to glutamine (PAGN) and excreted as urinary PAGN (UPAGN). Pharmacokinetics (PK) of GPB were examined to see if hydrolysis is impaired in very young patients who may lack lipase activity.

Transient High Pressure in Pancreatic Ducts Promotes Inflammation and Alters Tight Junctions via Calcineurin Signaling in Mice.

Background & Aims: Pancreatitis after endoscopic retrograde cholangiopancreatography (PEP) is thought to be provoked by pancreatic ductal hypertension, via unknown mechanisms. We investigated the effects of hydrostatic pressures on the development of pancreatitis in mice.

Methods: We performed studies with Swiss Webster mice, B6129 mice (controls), and B6129 mice with disruption of the protein phosphatase 3, catalytic subunit, βisoform gene (Cnab mice).

Contribution of Breastfeeding to False-Positive Saliva Polymerase Chain Reaction for Newborn Congenital Cytomegalovirus Screening.

Real-time polymerase chain reaction (PCR) of saliva is highly sensitive for newborn congenital cytomegalovirus (CMV) screening. This study uses nationally published CMV seroprevalence and breastfeeding rates to estimate the contribution of CMV DNA in breast milk to false-positive saliva PCR results. The false-positive rates adjusted for breastfeeding ranged from 0.

Paediatric traumatic brain injury: prognostic insights and outlooks.

Purpose Of Review: Traumatic brain injury (TBI) is a leading cause of death and disability in children. Prognostication of outcome following TBI is challenging in this population and likely requires complex, multimodal models to achieve clinically relevant accuracy. This review highlights injury characteristics, physiological indicators, biomarkers and neuromonitoring modalities predictive of outcome that may be integrated for future development of sensitive and specific prognostic models.

Brain-Specific Serum Biomarkers Predict Neurological Morbidity in Diagnostically Diverse Pediatric Intensive Care Unit Patients.

Background: Unexpected neurological morbidity in Pediatric Intensive Care Units (PICUs) remains high and is difficult to detect proactively. Brain-specific biomarkers represent a novel approach for early detection of neurological injury. We sought to determine whether serum concentrations of neuron-specific enolase (NSE), myelin basic protein (MBP), and S100B, specific for neurons, oligodendrocytes, and glia, respectively, were predictive of neurological morbidity in critically ill children.

Newborn Dried Blood Spot Polymerase Chain Reaction to Identify Infants with Congenital Cytomegalovirus-Associated Sensorineural Hearing Loss.

Objective: To determine the utility of dried blood spot (DBS) polymerase chain reaction (PCR) in identifying infants with cytomegalovirus (CMV) infection-associated sensorineural hearing loss (SNHL).

Study Design: Newborns at 7 US hospitals between March 2007 and March 2012 were screened for CMV by saliva rapid culture and/or PCR. Infected infants were monitored for SNHL during the first 4 years of life to determine sensitivity, specificity, and positive and negative likelihood ratios of DBS PCR for identifying CMV-associated SNHL.

Autophagy Biomarkers Beclin 1 and p62 are Increased in Cerebrospinal Fluid after Traumatic Brain Injury.

Background: Autophagy is a process that recycles damaged proteins and organelles. Beclin 1 is involved in the nucleation phase, while p62 is consumed during the elongation phase. We hypothesized that these autophagy biomarkers are increased in cerebrospinal fluid (CSF) after traumatic brain injury (TBI) in children and associated with unfavorable outcome.

Probenecid and N-Acetylcysteine Prevent Loss of Intracellular Glutathione and Inhibit Neuronal Death after Mechanical Stretch Injury In Vitro.

Probenecid and N-acetylcysteine (NAC) can preserve intracellular levels of the vital antioxidant glutathione (GSH) via two distinct biochemical pathways. Probenecid inhibits transporter-mediated GSH efflux and NAC serves as a cysteine donor for GSH synthesis. We hypothesized that probenecid and NAC alone would maintain intracellular GSH concentrations and inhibit neuronal death after traumatic stretch injury, and that the drugs in combination would produce additive effects.

Preterm infant body composition cannot be accurately determined by weight and length.

Background: Body composition is a key metric for assessing nutrition in preterm infants. In many neonatal intensive care units body composition is estimated using anthropometric indices which mathematically combine body weight and length. However, the accuracy of these indices is unknown in preterm infants.

Determinants of Pediatric Echocardiography Laboratory Productivity: Analysis from the Second Survey of the American Society of Echocardiography Committee on Echocardiography Laboratory Productivity.

Background: The American Society of Echocardiography Committee on Pediatric Echocardiography Laboratory Productivity aimed to study factors that could influence the clinical productivity of physicians and sonographers and assess longitudinal trends for the same. The first survey results indicated that productivity correlated with the total volume of echocardiograms.

Methods: Survey questions were designed to assess productivity for (1) physician full-time equivalent (FTE) allocated to echocardiography reading (echocardiograms per physician FTE per day), (2) sonographer FTE (echocardiograms per sonographer FTE per year), and (3) machine utilization (echocardiograms per machine per year).

SERPINB12 Is a Slow-Binding Inhibitor of Granzyme A and Hepsin.

The clade B/intracellular serpins protect cells from peptidase-mediated injury by forming covalent complexes with their targets. SERPINB12 is expressed in most tissues, especially at cellular interfaces with the external environment. This wide tissue distribution pattern is similar to that of granzyme A (GZMA).

Expression of ATP-Binding Cassette Transporters B1 and C1 after Severe Traumatic Brain Injury in Humans.

Adenosine triphosphate-binding cassette (ABC) transport proteins ABCC1 and ABCB1 (also known as multidrug resistance-associated protein 1 and p-glycoprotein, respectively), are key membrane efflux transporters of drugs and endogenous substrates, including in the brain. The impact of traumatic brain injury (TBI) on ABCC1 and ABCB1 expression in humans is unknown. We hypothesized that ABCC1 and ABCB1 expression would be altered in brain tissue from patients acutely after severe TBI.

Comparison of saliva PCR assay versus rapid culture for detection of congenital cytomegalovirus infection.

As part of the CMV and Hearing Multicenter Screening (CHIMES) study, 72,239 newborns were screened for cytomegalovirus by rapid culture and real-time PCR of saliva samples. Of the 266 infants with congenital cytomegalovirus infection, discordance between rapid culture and PCR was observed in 14 children, and 13 were identified only by PCR, demonstrating the superiority of the PCR assay.

High surgical burden for infants with severe chronic lung disease (sCLD).

Background/purpose: Infants with severe chronic lung disease (sCLD) may require surgical procedures to manage their medical problems; however, the scope of these interventions is undefined. The purpose of this study was to characterize the frequency, type, and timing of operative interventions performed in hospitalized infants with sCLD.

Methods: The Children's Hospital Neonatal Database was used to identify infants with sCLD from 24 children's hospital's NICUs hospitalized over a recent 16-month period.

Identification, mechanism of action, and antitumor activity of a small molecule inhibitor of hippo, TGF-β, and Wnt signaling pathways.

Embryonic signaling pathways, in particular those mediated by Wnt and TGF-β, are known to play key roles in tumor progression through the induction of epithelial-mesenchymal transition (EMT). Their simultaneous targeting could therefore represent a desirable anticancer strategy. On the basis of recent findings that both Wnt and TGF-β-associated pathways are regulated by Hippo signaling in mammalian cells, we reasoned that targeting the latter would be more effective in inhibiting EMT.

Histone acetylation-mediated regulation of the Hippo pathway.

The Hippo pathway is a signaling cascade recently found to play a key role in tumorigenesis therefore understanding the mechanisms that regulate it should open new opportunities for cancer treatment. Available data indicate that this pathway is controlled by signals from cell-cell junctions however the potential role of nuclear regulation has not yet been described. Here we set out to verify this possibility and define putative mechanism(s) by which it might occur.

Hyperoxia and hypoxia in children resuscitated from cardiac arrest.

Background: Ischemia depletes antioxidant reserves and impairs mitochondrial electron transport. Oxygen within blood reperfusing ischemic tissue can form free radicals, worsen oxidative stress, and exacerbate tissue injury (reperfusion injury). One strategy for limiting reperfusion injury is to limit delivery of "luxuriant" oxygen during or after reperfusion.

Role of the beta catenin destruction complex in mediating chemotherapy-induced senescence-associated secretory phenotype.

Cellular senescence is considered as a tumor suppressive mechanism. Recent evidence indicates however that senescent cells secrete various growth factors and cytokines, some of which may paradoxically promote cancer progression. This phenomenon termed senescence-associated secretory phenotype (SASP) must be inhibited in order for anti-proliferative agents to be effective.

Cerebrospinal fluid levels of high-mobility group box 1 and cytochrome C predict outcome after pediatric traumatic brain injury.

High-mobility group box 1 (HMGB1) is a ubiquitous nuclear protein that is passively released from damaged and necrotic cells, and actively released from immune cells. In contrast, cytochrome c is released from mitochondria in apoptotic cells, and is considered a reliable biomarker of apoptosis. Thus, HMGB1 and cytochrome c may in part reflect the degree of necrosis and apoptosis present after traumatic brain injury (TBI), where both are felt to contribute to cell death and neurological morbidity.

A tertiary care center's experience with therapeutic hypothermia after pediatric cardiac arrest.

Objective: To describe the use and feasibility of therapeutic hypothermia after pediatric cardiac arrest.

Design: Retrospective cohort study.

Setting: Pediatric tertiary care university hospital.

Nystagmus in infancy and childhood.

Involuntary occular oscillations in infancy and childhood can be understood, diagnosed, classified and treated as a result of modern electrophysiology and neuroanatomical knowledge.

Nuclear and mitochondrial interaction involving mt-Nd2 leads to increased mitochondrial reactive oxygen species production.

NADH dehydrogenase subunit 2, encoded by the mtDNA, has been associated with resistance to autoimmune type I diabetes (T1D) in a case control study. Recently, we confirmed a role for the mouse ortholog of the protective allele (mt-Nd2(a)) in resistance to T1D using genetic analysis of outcrosses between T1D-resistant ALR and T1D-susceptible NOD mice. We sought to determine the mechanism of disease protection by elucidating whether mt-Nd2(a) affects basal mitochondrial function or mitochondrial function in the presence of oxidative stress.

O6-methylguanine-DNA methyltransferase expression strongly correlates with outcome in childhood malignant gliomas: results from the CCG-945 Cohort.

Purpose: O6-methylguanine-DNA methyltransferase (MGMT) functions to counteract the cytotoxic effects of alkylating agents, such as nitrosoureas, which play a central role in the treatment of childhood malignant gliomas. Epigenetic silencing of MGMT has been associated with prolonged survival in adults with malignant gliomas, although the association between MGMT expression status and outcome in pediatric malignant gliomas has not been defined.

Methods: We examined the association between MGMT expression and survival duration using tumor samples from the Children's Cancer Group 945 study, the largest randomized trial for childhood malignant gliomas completed to date.