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.

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).

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.

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.

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.

The influence of central review on outcome associations in childhood malignant gliomas: results from the CCG-945 experience.

To examine the influence of the pathology review mechanism on the results of analyses of therapeutic efficacy and biological prognostic correlates for pediatric high-grade gliomas, we evaluated the effects of using single-expert review or consensus review, as alternatives to institutional classification, in determining outcome results of a large randomized trial. The study group was the randomized cohort of Children's Cancer Group study 945, which compared efficacy of 2 chemotherapy regimens adjuvant to surgery and radiation. Trial eligibility required institutional histopathologic diagnosis of high-grade glioma.

Inhibition of Ras and related guanosine triphosphate-dependent proteins as a therapeutic strategy for blocking malignant glioma growth: II--preclinical studies in a nude mouse model.

Objective: Preliminary studies have demonstrated that the Ras family and related guanosine triphosphate-dependent proteins are overactivated in malignant gliomas and that inhibition of the activation of such proteins, by blockade of their post-translational processing, reduces tumor cell growth in vitro. The current study evaluates the utility of this therapeutic strategy in vivo, using preclinical glioma model systems.

Methods: We examined the efficacy against U-87 human malignant glioma cells, in both subcutaneous and intracranial nude mouse models, of selective peptidomimetic inhibitors of farnesyltransferase (FTI-276) and geranylgeranyltransferase (GGTI-297), which are involved in critical steps in the post-translational processing of Ras and related guanosine triphosphate-dependent proteins.

Pure endotoxin does not pass across the intestinal epithelium in vitro.

Numerous reports suggest that endotoxin (LPS) may play a central role in triggering the inflammatory cascade that leads to the systemic inflammatory response syndrome. Although conditions that promote bacterial translocation in vivo may also facilitate direct translocation of LPS, the exact mechanisms by which LPS crosses the intestinal barrier to reach the systemic circulation are unknown. This study was designed to determine whether pure endotoxin could pass across injured rat ileal mucosa in the Ussing chamber.

Inhibition of Ras and related G-proteins as a therapeutic strategy for blocking malignant glioma growth.

Objective: Preliminary studies have demonstrated that the Ras family and related guanosine 5'-triphosphate-dependent proteins (G-proteins) are overactivated in malignant gliomas and may function as indirect mediators of glial transformation initiated by deregulated upstream signaling elements. We postulated that inhibiting the activation of such proteins might represent a promising strategy for blocking the aberrant proliferation of these tumors.

Methods And Results: Accordingly, we examined the therapeutic efficacy against malignant glioma cells in vitro of a series of selective peptidomimetic inhibitors of farnesylation (FTI-277) and geranylgeranylation (GGTI-286 and GGTI-298), which are critical steps in the post-translational processing (prenylation) of these proteins.

Transmucosal passage of bacteria across rat intestinal epithelium in the Ussing chamber: effect of nutritional factors and bacterial virulence.

Transmucosal passage of bacteria across the intestine, the essential and prerequisite step for bacterial translocation, cannot be effectively studied using in vivo models of translocation. We have adapted the Ussing chamber into a fresh, sterile organ culture system that can facilitate the study of bacterial-epithelial interactions. Intestinal membranes were mounted in the Ussing chamber and perfused with a solution rich in putative mucosal micronutrients.