Myxoma viral serpin, Serp-1, a unique interceptor of coagulation and innate immune pathways

Serpins maintain haemostasis through regulation of serine proteinases in the thrombotic and thrombolytic pathways. Viruses encode serpins that can alter thrombotic and thrombolytic responses producing, in some cases, disseminated intravascular coagulation (DIC). However, it has not been precisely defined how viral serpins induce these profound responses. The rabbit myxoma viral serpin, Serp-1 inhibits urokinase- and tissue-type plasminogen activators (uPA and tPA), plasmin and factor Xa in vitro and exhibits remarkable anti-inflammatory activity in various animal models. The effects of Serp-1 on activation of human platelets, endothelial cells, monocytes and T cells that mediate thrombosis and innate immune responses were therefore examined. We found that Serp-1 attenuated platelet and mononuclear cell adhesion to fibronectin and collagen. Serp-1 similarly inhibited monocyte migration into the peritoneum. Serp-1 inhibition of monocyte migration was lost in uPA receptor (uPAR) deficient mice. Serp-1 bound to the plasma membrane surface and altered uPA activation of endothelial cells (p=0.001), thrombin activation of platelets (p=0.021) and phorbol ester activation of endothelial (p=0.047), monocyte (p=0.011) and Jurkat T cells (p=0.012) as measured by intracellular calcium. Modulation of cellular activation was confirmed by membrane fluidity analysis. Microarray analysis of Serp-1 treated endothelial cells revealed alterations in Inositol 1,4,5-triphosphate receptor type II (ITPR2) a calcium-regulating gene. This study demonstrates the unique capacity of a viral serpin, Serp-1 to modify adhesion, activation, gene expression and calcium homeostasis in a wide range of cells that regulate coagulation and inflammation. Endothelial cells potentially represent a pivotal regulatory point for Serp-1 anti-inflammatory activity.     

N-terminal-pro-brain natriuretic peptide: a guide for early targeted indomethacin therapy for patent ductus arteriosus in preterm Infants

Aim: To determine whether N‐terminal‐pro‐brain natriuretic peptide (NT‐proBNP) level could be an effective guide for early targeted indomethacin therapy for patent ductus arteriosus (PDA) in preterm infants. Methods: An interventional study involved preterm infants, born at <33 weeks of gestation, who had plasma NT‐proBNP levels obtained at day 2 of life. Indomethacin therapy was given if plasma NT‐proBNP level was ≥10 180 pg/mL, the cut‐off for predicting hemodynamic significant PDA (hsPDA). Echocardiograms were performed within 6 h at the time of plasma NT‐proBNP collection and again at day 7, or whenever clinical hsPDA was suspected. Primary outcomes were the incidence of later hsPDA and unnecessary exposure rate to indomethacin. Results: Fifty infants were enrolled. On day 2, 19 (38%) infants had plasma NT‐proBNP above the cut‐off and received indomethacin therapy; none of them developed later hsPDA, while 1 of 31 infants with NT‐proBNP below the cut‐off level developed clinical hsPDA. Unnecessary exposure to indomethacin occurred in two infants (11%). Overall, no enrolled infants had either reopening of ductus or PDA ligation. Conclusion: Using NT‐proBNP level on day 2 as a guide for early targeted indomethacin therapy reduced later onset of hsPDA and the number of unnecessary exposures to indomethacin.     

Efficacy of oral erythromycin for treatment of feeding intolerance in preterm infants

OBJECTIVE: To determine the efficacy and safety of oral erythromycin (EM) for feeding intolerance in preterm infants < 35 weeks gestation. STUDY DESIGN: In this randomized, double-blinded, placebo-controlled trial, preterm infants with feeding intolerance were randomly allocated to a treatment group given EM ethyl succinate 10 mg/kg every 6 hours for 2 days, followed by 4 mg/kg every 6 hours for another 5 days, or to a control group given placebo. The primary outcome was time to full feeding (150 mL/kg/day) after the start of treatment. RESULTS: Each group comprised 23 preterm infants, almost all of whom were < 32 weeks gestation. Baseline characteristics were similar between the 2 groups. Times to full feeding were significantly shorter and the number of withheld feeds were significantly less in the EM group than the control group; the respective medians (interquartile ranges) were 7 days (6 to 9 days) versus 13 days (9 to 15 days) (P < .001) and 1 episode (0 to 2 episodes) versus 9 episodes (2 to 13 episodes) (P < .001). No significant differences in episodes of sepsis, necrotizing enterocolitis, and cholestasis were observed. CONCLUSIONS: Oral EM was effective and safe for treatment of feeding intolerance in preterm infants.     

Genetic polymorphisms in Thai neonates with hyperbilirubinemia

Aim:  Polymorphisms of the UGT1A1 gene, SLCO1B1 gene and GST gene have been associated with significant hyperbilirubinemia. We would like to determine whether the variation of UGT1A1 gene, SLCO1B1 gene and GST gene may play a significant role in neonatal hyperbilirubinemia in Thai infants.
Methods:  Ninety-one study subjects (hyperbilirubinemic group) and 86 control subjects were studied.
Results:  The cause of neonatal hyperbilirubinemia could not be identified in 64 infants (70.3%), ABO blood group incompatibility in 14.3% and Glucose-6-phosphate dehydrogenase (G-6-PD) deficiency in 8.8%. In the hyperbilirubinemic group, 23 of 91 (25.3%) infants demonstrated variant of UGT1A1 at nucleotides (nt) 211 as compared to 6 of 86 (7%) in the control group (p = 0.001). There were no significant differences between groups in the variants UGT1A1 at nt 686, SLCO1B1 gene at nt 388, 463 and the GST gene. Male infants with G-6-PD deficiency were associated with hyperbilirubinemia (21.2% vs. 4.8% in the control group) with an odds ratio (OR) of 5.37 (p =0.02). The relationship between G-6-PD and variant in UGT1A1 gene at nt 211 could not be determined.
Conclusion:  Thai infants with variant in the UGT1A1 at nt 211 or with G-6-PD deficiency are at higher risk for developing neonatal hyperbilirubinemia.     

Simple method of <100% oxygen resuscitation for preterm infants

Background: The aim of this study was to determine the feasibility of 50–60% oxygen resuscitation by a simple method using a self‐inflation bag without oxygen reservoir for positive pressure ventilation (PPV) or using a constant distance and flow rate for blow‐by oxygen. Methods: Newborn infants ≤35 weeks gestational age were eligible. Infants requiring PPV were initiated with bag‐mask PPV without oxygen reservoir. Nearly 100% oxygen was given by attaching oxygen reservoir if heart rate < 100 beats/min after PPV for 90 s or SpO₂ < 75% at 3 min. For those requiring blow‐by oxygen, oxygen flow 5 L/min via facemask was given 5 cm from the nose. Almost 100% oxygen was given by close‐fitting facemask to nose if SpO₂ < 80% at 5 min. Results: Ninety‐one infants were eligible; 67 of them required resuscitation. Thirty‐five infants required PPV; 27 (77.1%) responded to bag‐mask PPV without oxygen reservoir. For 32 infants requiring blow‐by oxygen, 28 (87.5%) reached the targeted SpO₂. No significant differences in clinical outcomes were observed between responders and non‐responders. Conclusions: The technique of <100% oxygen supplementation was effective for preterm newborn resuscitation with a high success rate. This technique may be useful for a limited‐resource setting.