Lack of effect of dietary nucleotide supplementation on erythrocyte 2,3-diphosphoglycerate concentration. A study on preterm neonates.

BACKGROUND: Recently we demonstrated an increased 2,3-diphosphoglycerate (2,3-DPG) erythrocyte concentration in rat pups subjected to nucleotide-enriched artificial feeding. DESIGN: The present study was carried out to test the hypothesis that a possible increase in 2,3-DPG concentration can also be obtained in human neonates who are fed nucleotide-enriched formula. Preterm neonates born or referred to the neonatal intensive care unit of the G. Gaslini Hospital, Genoa University, with a gestational age >30 weeks and <37 weeks were enrolled in our randomized trial. Recruitment took place within 48-72 hours from birth. Only newborns of mothers deciding not to breast-feed were eligible to be randomized for the supplemented group (FN) or non-supplemented group (RF). Breast-fed newborns were considered the control group (C). The study window (for supplementation and blood samples) was restricted to the first two weeks following birth (from the 2nd (t1) to the 16th (t2) day of life). At the end of our study, only 21 neonates were eligible for statistical analysis. RESULTS: The stimulating action of dietary nucleotides on 2,3-DPG concentration failed to be demonstrated; increases in 2,3-DPG concentration that were observed in newborns fed with nucleotide supplemented formula (FN) were comparable to those observed in newborns fed with regular formula (RF) and breast-fed newborns. CONCLUSIONS: The EC recommendation for the amount of nucleotides allowed in formula milk does not seem to be high enough to have positive effects on 2,3-DPG synthesis. Whether this possible 'pharmacological' effect can be achieved by a higher intake of ingested nucleotides and/or a change in the proportions of single nucleotides contained in milk formulas remain interesting end points to be elucidated.     

Orbitofrontal cortex and impulsivity in borderline personality disorder: an MRI study of baseline brain perfusion

Behavioral and neuroimaging studies in patients with borderline personality disorder (BPD) have associated orbitofrontal cortex (OFC) dysfunction with distinct symptom clusters such as impulsivity. It is unclear, however, whether abnormal patterns of OFC activity are also present during resting-state conditions and whether OFC dysfunction is specifically associated with impulsivity in BPD. This study tested the hypothesis that BPD patients would exhibit changes of OFC baseline perfusion and explored the relationship between regional cerebral blood flow and distinct BPD symptom clusters, such as impulsivity, dissociation tension and depressive symptoms. Using continuous arterial spin labeling magnetic resonance imaging at 3 Tesla, we investigated 16 women with BPD according to DSM-IV criteria and 16 healthy female control participants during resting-state conditions. Between-group comparisons were conducted using an analysis of variance (p?<?0.05 cluster corrected). Compared to controls, BPD patients exhibited decreased blood flow in the medial OFC, whereas increased blood flow was found in the left and right lateral OFC. Correlation analyses revealed a positive relationship between medial and lateral orbitofrontal blood flow and impulsivity scores, whereas measures of dissociation tension and depression did not exhibit a significant correlation with OFC perfusion. These data suggest that dysfunction of medial and lateral regions of the OFC could specifically mediate symptoms of impulsivity in BPD.     

Staphylococcal Esx Proteins Modulate Apoptosis and Release of Intracellular Staphylococcus aureus during Infection in Epithelial Cells

The opportunistic pathogen Staphylococcus aureus is one of the major causes of health care-associated infections. S. aureus is primarily an extracellular pathogen, but it was recently reported to invade and replicate in several host cell types. The ability of S. aureus to persist within cells has been implicated in resistance to antimicrobials and recurrent infections. However, few staphylococcal proteins that mediate intracellular survival have been identified. Here we examine if EsxA and EsxB, substrates of the ESAT-6-like secretion system (Ess), are important during intracellular S. aureus infection. The Esx proteins are required for staphylococcal virulence, but their functions during infection are unclear. While isogenic S. aureus esxA and esxB mutants were not defective for epithelial cell invasion in vitro, a significant increase in early/late apoptosis was observed in esxA mutant-infected cells compared to wild-type-infected cells. Impeding secretion of EsxA by deleting C-terminal residues of the protein also resulted in a significant increase of epithelial cell apoptosis. Furthermore, cells transfected with esxA showed an increased protection from apoptotic cell death. A double mutant lacking both EsxA and EsxB also induced increased apoptosis but, remarkably, was unable to escape from cells as efficiently as the single mutants or the wild type. Thus, using in vitro models of intracellular staphylococcal infection, we demonstrate that EsxA interferes with host cell apoptotic pathways and, together with EsxB, mediates the release of S. aureus from the host cell.     

A pharmacokinetic comparison of anrukinzumab,an anti- IL-13 monoclonal antibody,among healthy volunteers,asthma and ulcerative colitis patients

AimsAnrukinzumab is an anti-IL13 monoclonal antibody. The goals of this study are to characterize the pharmacokinetics of anrukinzumab in healthy volunteers and different disease states and to identify covariates.MethodsA population pharmacokinetic (PK) model was developed in NONMEM, using data from five clinical studies including healthy volunteers, asthma and ulcerative colitis (UC) patients. Different dosing regimens including different routes of administration were also included in the data.ResultsThe PK of anrukinzumab were described by a two compartment model with first order absorption and elimination. The population estimates (relative standard error) of the volumes of distribution in the central (V_c) and peripheral (V_p) compartments were 3.8 (4.6%) and 2.2 l (8.7%), respectively. In non-UC patients, the population estimate of the systemic clearance (CL) and inter-compartmental CL was 0.00732 l h^–1 (4.9%) and 0.0224 l h^–1 (15.4%). For subcutaneous administration, the absorption rate constant was 0.012 h^–1 (6.6%) and bioavailability was nearly 100% in healthy and mild to moderate asthma patients. Both V and CL increased with body weight. CL (but not V) decreased with increasing baseline albumin concentrations. UC patients had an increased CL of 72.3% (10.5%), after correction for differences in body weight and albumin. Moderate to severe asthma patients had decreased bioavailability compared with other populations.ConclusionsAnrukinzumab''s PK behave like a typical antibody. UC patients were identified to have a faster CL of anrukinzumab than healthy volunteers and asthma patients. This finding suggests a higher dose level may be required for this population.