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PubMed | Pediatric Research Institute Citta della Speranza, University of Udine, Marche Polytechnic University, Azienda Ospedaliero Universitaria Ospedali Riuniti and University of Padua
Type: Journal Article | Journal: Lipids | Year: 2016

Several studies reported the association between total plasma phytosterol concentrations and the parenteral nutrition-associated cholestasis (PNAC). To date, no data are available on phytosterol esterification in animals and in humans during parenteral nutrition (PN). We measured free and esterified sterols (cholesterol, campesterol, stigmasterol, and sitosterol) plasma concentrations during PN in 16 preterm infants (500-1249g of birth weight; Preterm-PN), in 11 term infants (Term-PN) and in 12 adults (Adult-PN). Gas chromatography-mass spectrometry was used for measurements. Plasma concentrations of free cholesterol (Free-CHO), free phytosterols (Free-PHY) and esterified phytosterols (Ester-PHY) were not different among the three PN groups. Esterified cholesterol (Ester-CHO) was statistically lower in Preterm-PN than Adult-PN. Preterm-PN had significantly higher Free-CHO/Ester-CHO and Free-PHY/Ester-PHY ratios than Adult-PN (Free-CHO/Ester-CHO: 1.10.7 vs. 0.60.2; Free-PHY/Ester-PHY: 4.12.6 vs. 1.30.8; *P<0.05). Free-CHO/Ester-CHO and Free-PHY/Ester-PHY ratios of Term-PN (Free-CHO/Ester-CHO: 1.10.4; Free-PHY/Ester-PHY: 2.91.7) were not different from either Preterm-PN or from Adult-PN. Plasma Free-CHO/Ester-CHO and Free-PHY/Ester-PHY were unchanged after 24h on fat-free PN both in Preterm-PN and in Adult-PN. Free-PHY/Ester-PHY did not correlate with phytosterol intake in Preterm-PN. Free-PHY/Ester-PHY of Preterm-PN was positively correlated with the Free-CHO/Ester-CHO and negatively correlated with gestational age and birth weight. In conclusion, PHY were esterified to a lesser extent than CHO in all study groups; the esterification was markedly decreased in Preterm-PN compared to Adult-PN. The clinical consequences of these findings warrant further investigations.

Aveic S.,Pediatric Research Institute Citta della Speranza | Tonini G.P.,Pediatric Research Institute Citta della Speranza
Cancer Cell International | Year: 2016

A growing field of evidence suggests the involvement of oncogenic receptor tyrosine kinases (RTKs) in the transformation of malignant cells. Constitutive and abnormal activation of RTKs may occur in tumors either through hyperactivation of mutated RTKs or via functional upregulation by RTK-coding gene amplification. In several types of cancer prognosis and therapeutic responses were found to be associated with deregulated activation of one or more RTKs. Therefore, targeting various RTKs remains a significant challenge in the treatment of patients with diverse malignancies. However, a frequent issue with the use of RTK inhibitors is drug resistance. Autophagy activation during treatment with RTK inhibitors has been commonly observed as an obstacle to more efficacious therapy and has been associated with the limited efficacy of RTK inhibitors. In the present review, we discuss autophagy activation after the administration of RTK inhibitors and summarize the achievements of combination RTK/autophagy inhibitor therapy in overcoming the reported resistance to RTK inhibitors in a growing number of cancers. © 2016 The Author(s).

Carnielli V.P.,Marche Polytechnic University | Giorgetti C.,Marche Polytechnic University | Simonato M.,Pediatric Research Institute Citta della Speranza | Vedovelli L.,Pediatric Research Institute Citta della Speranza | Cogo P.,University of Udine
Neonatology | Year: 2016

Respiratory distress syndrome is a common problem in preterm infants and the etiology is multifactorial. Lung underdevelopment, lung hypoplasia, abnormal lung water metabolism, inflammation, and pulmonary surfactant deficiency or disfunction play a variable role in the pathogenesis of respiratory distress syndrome. High-quality exogenous surfactant replacement studies and studies on surfactant metabolism are available; however, the contribution of surfactant deficiency, alteration or dysfunction in selected neonatal lung conditions is not fully understood. In this article, we describe a series of studies made by applying stable isotope tracers to the study of surfactant metabolism and lung water. In a first set of studies, which we call 'endogenous studies', using stable isotope-labelled intravenous surfactant precursors, we showed the feasibility of measuring surfactant synthesis and kinetics in infants using several metabolic precursors including plasma glucose, plasma fatty acids and body water. In a second set of studies, named 'exogenous studies', using stable isotope-labelled phosphatidylcholine tracer given endotracheally, we could estimate surfactant disaturated phosphatidylcholine pool size and half-life. Very recent studies are focusing on lung water and on the endogenous biosynthesis of the surfactant-specific proteins. Information obtained from these studies in infants will help to better tailor exogenous surfactant treatment in neonatal lung diseases. © 2016 S. Karger AG, Basel.

PubMed | Pediatric Research Institute Citta della Speranza, Marche Polytechnic University and Bambino Gesu Childrens Hospital
Type: Journal Article | Journal: Clinical nutrition (Edinburgh, Scotland) | Year: 2016

Provision of long chain polyunsaturated fatty acids (LCP) both of the omega-3 and omega-6 families is recommended for preterm infants (PI). Fish oil (FO) contains omega-3 and omega-6 LCP and it is incorporated in the fat blend of the new generation lipid emulsions (LE). Omega-3 LCP have been shown to reduce the expression of genes involved in lipogenesis, which could be important for several organs development. The aim of this study was to ascertain if the use of intravenous FO has an effect on lipogenesis in PI.Forty PI were randomized to receive two LE: MSF (50:40:10 Medium Chain Triglycerides (MCT): Soybean oil (SO): FO) or MS (50:50 MCT:SO). We measured plasma lipids on day 7 and the fractional and absolute synthesis rates (FSR and ASR) of cholesterol and of selected fatty acids (FA) after (2)H2O body water labeling.Plasma phospholipids (PL), free cholesterol (FC), and cholesterol esters (CE) concentrations were all lower in MSF than in MS. In spite of lower plasma FC and CE concentrations, cholesterol biosynthesis was similar between the two study groups (FC: FSR 16.01.4 vs 14.11.1%/d, p=0.74; ASR 6.80.6 vs 7.10.6mgkg(-1)d(-1), p=0.93; CE: FSR 3.60.5 vs 4.20.4%/d, p=0.38; ASR: 3.30.4 vs 4.40.5mgkg(-1)d(-1), p=0.13, in MSF and MS respectively). FSR and ASR of selected FA were, or tended to be, lower in MSF than in MS. ASR of PL palmitate (4.00.3 vs 4.80.4mgkg(-1)d(-1), p=0.045), PL oleate (0.20.04 vs 0.40.05mgkg(-1)d(-1), p=0.02) and CE oleate (0.50.1 vs 0.90.1mgkg(-1)d(-1), p=0.03) were significantly lower in MSF than in MS. There were no differences in plasma TG FA biosynthesis.Cholesterol biosynthesis was not affected by 10% FO during neonatal parenteral nutrition. Ten percent FO caused a statistically significant reduction in the lipogenesis of selected FA and an overall tendency towards a reduced lipogenesis. The magnitude seems to be limited and the biological significance is unknown. Our data warrant follow-up studies in PI who receive intravenous FO, especially in those infants who receive larger doses than in the present study. Since this trial started in 2007, trial registration was not required.

PubMed | University of Padua, University of Udine, Pediatric Research Institute Citta della Speranza and Marche Polytechnic University
Type: | Journal: Interactive cardiovascular and thoracic surgery | Year: 2017

Improved congenital heart defect (CHD) operations have reduced operative mortality to 3%. The major concern is now long-term neurological outcomes. We measured plasma glial fibrillary acidic protein (GFAP), an early marker of brain injury, during different phases of cardiopulmonary bypass (CPB), to correlate the increase of GFAP to clinical parameters or specific operative phases.We performed a prospective, single-centre, observational study in children undergoing cardiac operations. We studied 69 children with CHD and biventricular heart physiology: 26 had tetralogy of Fallot; 17 transposition of the great arteries; and 26 ventricular/atrial septal defects with or without associated arch defects. GFAP levels were measured by ELISA at different stages of CPB. We recorded clinical and surgical parameters and applied multivariable and logistic regressions to assess which parameters were independent predictors of variations in plasma GFAP.GFAP increased during CPB and peaked at the end of rewarming. Multivariable regression showed degree of hypothermia as the only significant independent predictor of GFAP increase, adjusted for age, prematurity, type of CHD, cyanosis, aortic cross-clamp time, haemodilution, neurological risk time interval and rewarming rate. Temperature nadir and neurological risk time interval were significant independent predictors of a GFAP value > 0.46ng/ml.Hypothermia degree during CPB is correlated with GFAP plasma increase in children with biventricular heart defects undergoing surgical repair. Rewarming is the most critical CPB phase for GFAP increase. The implication of high plasma GFAP is still under evaluation. Follow-up studies are ongoing to assess the reliability of GFAP as a marker of brain injury and/or as a predictor of neurodevelopmental abnormalities.

PubMed | Pediatric Research Institute Citta della Speranza, University of Udine, Marche Polytechnic University, Urbino University and University of Padua
Type: | Journal: Clinical nutrition (Edinburgh, Scotland) | Year: 2017

Phytosterols in vegetable oil (VO)-based lipid emulsions (LE) likely contribute to parenteral nutrition-associated cholestasis (PNAC) in preterm infants. No characterization of plasma phytosterol half-lives has been done in very low birth weight (VLBW) preterm infants receiving parenteral nutrition (PN) with LE.In a prospective cohort study, 45 VLBW preterm infants who received PN underwent serial blood sample measurements of sitosterol (SITO), campesterol (CAMP), and stigmasterol (STIGM). Plasma phytosterol half-lives were calculated from the phytosterol concentrations-decay curves by using a single-compartment model.After the stop of the intravenous LE, study infants had significantly lower plasma total CAMP, STIGM and SITO concentrations. The decay of plasma phytosterol concentrations was monoexponential. Half-life of plasma total CAMP, STIGM and SITO was 13.56.9, 10.34.5 and 10.34.0 days, respectively. Plasma phytosterol half-lives did not correlate with gestational age, birth weight, cumulative phytosterol intakes and plasma conjugated bilirubin.VLBW preterm infants on PN with LE had rather long plasma phytosterol half-lives similar to hypercholesterolemic adults and phytosterolemic homozygotes patients. We speculate that the accumulation of phytosterols could contribute to their vulnerability to PNAC.The Ethics Committee of Marche-Italy (DG/469); www.clinicaltrials.gov (identification number NCT02758834).

PubMed | University of Padua, Pediatric Research Institute Citta della Speranza, Marche Polytechnic University and Bambino Gesu Childrens Hospital
Type: Journal Article | Journal: Pediatric research | Year: 2015

Term newborns with pneumonia show a reduced pulmonary compliance due to multiple and ill-defined factors. Surfactant proteins (SPs) changes could have a role in the reduced compliance but the matter is still unsettled. The aim of this study was to clarify the meaning of SPs changes during pneumonia in term newborns.In 28 term ventilated newborns, 13 with pneumonia and 15 with no lung disease, we measured SP-B, SP-A, disaturated-phosphatidylcholine (DSPC), and total phospholipids (PL) concentrations in tracheal aspirates at intubation and close to extubation. We also measured DSPC kinetics using (U-(13)C-PA)dipalmitoyl-phosphatidylcholine.At baseline, SP-B, expressed as % of PL, was significantly different between the groups, being 3.5-fold higher in pneumonia than controls. Conversely, SP-A did not vary between the groups. At extubation, SP-B and SP-A concentrations had decreased significantly in newborns with pneumonia, while there was no significant change in controls. DSPC t1/2 was significantly shorter in the pneumonia group (11.8 (5.5-19.8) h vs. 26.6 (19.3-63.6) h, P = 0.011).In term newborns with pneumonia, SP-B increases with respect to PL, and DSPC is turned over at a faster rate. Diseases resolution is associated with the restoration of the normal ratio between SP-B and PL.

PubMed | University of Padua, Pediatric Research Institute Citta della Speranza, Marche Polytechnic University and Bambino Gesu Childrens Hospital
Type: Journal Article | Journal: The Canadian journal of cardiology | Year: 2016

Univentricular congenital heart defects require open-heart surgery soon after birth, and are associated with risk of brain injury and poor neurologic outcome.This is a prospective, observational study on children undergoing cardiac surgery. Plasma glial fibrillary acidic protein (GFAP), as an early marker of brain injury, was measured by ELISA at the end of anaesthesia induction, initiation of cardiopulmonary bypass (CPB), the end of cooling, the end of rewarming, the end of CPB, and after protamine administration. We recorded clinical and surgical parameters to assess which CPB phase and clinical parameters were associated with a GFAP increase.We studied 13 children less than 50 months of age: 8 underwent Norwood or Damus-Kaye-Stansel palliation (group 1) and 5 underwent Fontan procedure (group 2). A GFAP increase was only observed in group 1, with the highest median value at the end of rewarming. No quantifiable levels of GFAP were measured at pre-bypass and the start of CPB stages in all patients. End of cooling and CPB-end GFAP, GFAP maximum value, and GFAP area under the curve all correlated with the CPB time spent at a cerebral regional saturation < 45% (P = 0.021, 0.028, 0.007, 0.021, respectively).Children with univentricular heart defects exhibit a CPB plasma-GFAP increase only after stage 1 palliation. The maximum GFAP increase occurred at the end of rewarming. Further studies are needed to identify which clinical or surgical parameter(s) could reflect a GFAP increase during surgery for congenital heart defects, and whether GFAP levels correlate with the neurologic outcome.

PubMed | Pediatric Research Institute Citta della Speranza, University of Udine, Marche Polytechnic University and University of Paris Descartes
Type: Journal Article | Journal: Lipids | Year: 2016

Finger or heel-pricked blood sampling for fatty acid analysis is suitable especially in newborn infants where blood sampling is difficult and phlebotomy for research can be unethical. The aim of this study was to evaluate dried blood long chain polyunsaturated fatty acids (LC-PUFA) stability during storage at -28 C. We collected 12 blood cord samples that were analyzed immediately after blood drawing, with and without drying the blood on filter paper. Dried samples were then analyzed 7 days and 1, 3, and 6 months after collection. Butylated hydroxytoluene was added to all samples. Fatty acid composition and (13)C enrichment were measured by gas chromatography and by gas chromatography-isotope ratio mass spectrometry, respectively. The fatty acid composition, expressed in mol%, of the major LC-PUFA at day 7 was not statistically different from time 0, however lower values were found by the first month of storage. The (13)C enrichment of 20:4n-6 and 22:6n-3 did not differ during the whole study period. LC-PUFA analysis from dried umbilical cord blood in neonates should be performed within a week, major losses of LC-PUFA occur afterwards. However, fatty acids obtained from dried blood maintain their (13)C enrichment value for up to 6 months and thus these samples are suitable for natural abundance isotopic studies.

PubMed | University of Padua, University of Udine, Marche Polytechnic University and Pediatric Research Institute Citta della speranza
Type: Journal Article | Journal: PloS one | Year: 2016

It is unknown whether Whole-Body Hypothermia (WBH) affects pulmonary function. In vitro studies, at relatively low temperatures, suggest that hypothermia may induce significant changes to the surfactant composition. The effect of WBH on surfactant kinetics in newborn infants is unknown. We studied in vivo kinetics of disaturated-phosphatidylcholine (DSPC) in asphyxiated newborns during WBH and in normothermic controls (NTC) with no or mild asphyxia. Both groups presented no clinically apparent lung disease.Twenty-seven term or near term newborns requiring mechanical ventilation were studied (GA 38.62.2 wks). Fifteen during WBH and twelve NTC. All infants received an intra-tracheal dose of 13C labelled DSPC and tracheal aspirate were performed. DSPC amount, DSPC half-life (HL) and pool size (PS) were calculated.DSPC amount in tracheal aspirates was 0.42 [0.22-0.54] and 0.36 [0.10-0.58] mg/ml in WBH and NTC respectively (p = 0.578). DSPC HL was 24.9 [15.7-52.5] and 25.3 [15.8-59.3] h (p = 0.733) and DSPC PS was 53.2 [29.4-91.6] and 40.2 [29.8-64.6] mg/kg (p = 0.598) in WBH and NTC respectively.WBH does not alter DSPC HL and PS in newborn infants with no clinical apparent lung disease.

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