Background: Necrotizing enterocolitis (NEC) and focal intestinal perforation (FIP) are major causes of morbidity in infants with extremely low birth weight (ELBW). Objective: To evaluate the surgical procedures applied, and the survival and long-term outcome of ELBW infants with NEC and FIP in a single-center study. Methods: Inborn and outborn ELBW infants (<1000 g) with NEC and FIP were analyzed retrospectively from 2002 to 2007. Data collected include surgical procedures, survival as well as complications, length of partial parenteral nutrition and hospital stay. The short-term and long-term outcomes after 2–7 years were assessed and compared with a matched control group. Results: Out of 280 ELBW infants, 28 underwent surgery, 19 because of FIP and 9 for NEC. Fourteen infants in the FIP group were treated with primary laparotomy and 5 with peritoneal drainage (PD). In the NEC group, only 1 infant was treated with PD. PD was used for unstable patients and was always followed by secondary laparotomy after stabilization. Five of 28 (18%) surgically treated ELBW infants and 4 (14%) matched controls died. The following complications occurred in the surgical group: complete (n = 1) or minor wound dehiscence (n = 4), stoma prolapse (n = 5), parastomal hernia (n = 2), stoma fistula (n = 1), and wound infection (n = 2). Dependency on parenteral nutrition was significantly shorter in infants with FIP, while there were no differences in time to stoma closure and length of hospital stay between those with FIP and those with NEC. Eleven of 23 (47.8%) surviving patients with FIP or NEC showed developmental delay, compared with 9 of 24 (37.5%) in the controls. Conclusions: The management of EBLW infants with NEC and FIP remains challenging. Our treatment approach was associated with low mortality. Developmental delay seems to be caused by extreme prematurity rather than NEC- or FIP-related bowel perforation.

Calcium is a key regulator of cardiac function and is modulated through the Ca2+-sensor protein S100A1. S100 proteins are considered to exert both intracellular and extracellular functions on their target cells. Here we report the impact of an increased intracellular S100A1 protein level on Ca2+-homeostasis in neonatal ventricular cardiomyocytes in vitro. Specifically, we compare the effects of exogenously added recombinant S100A1 to those resulting from the overexpression of a transduced S100A1 gene. Extracellularly added S100A1 enhanced the Ca2+-transient amplitude in neonatal ventricular cardiomyocytes (NVCMs) through a marked decrease in intracellular diastolic Ca2+-concentrations ([Ca2+]i). The decrease in [Ca2+]i was independent of sarcoplasmic reticulum Ca2+-ATPase (SERCA2a) activity and was probably the result of an increased sarcolemmal Ca2+-extrusion through the sodium-calcium exchanger (NCX). At the same time the Ca2+-content of the sarcoplasmic reticulum (SR) decreased. These effects were dependent on the uptake of extracellularly added S100A1 protein and its subsequent routing to the endosomal compartment. Phospholipase C and protein kinase C, which are tightly associated with this subcellular compartment, were found to be activated by endocytosed S100A1. By contrast, adenoviral-mediated intracellular S100A1 overexpression enhanced the Ca2+-transient amplitude in NVCMs mainly through an increase in systolic [Ca2+]i. The increased Ca2+-load in the SR was based on an enhanced SERCA2a activity while NCX function was unaltered. Overexpressed S100A1 colocalized with SERCA2a and other Ca2+-regulatory proteins at the SR, whereas recombinant S100A1 protein that had been endocytosed did not colocalize with SR proteins. This study provides the first evidence that intracellular S100A1, depending on its subcellular location, modulates cardiac Ca2+-turnover via different Ca2+-regulatory proteins.

S100A1 is a Ca2؉ -binding protein of the EF-hand type that belongs to the S100 protein family. It is specifically expressed in the myocardium at high levels and is considered to be an important regulator of cardiac contractility. Because the S100A1 protein is released into the extracellular space during ischemic myocardial injury, we examined the cardioprotective potential of the extracellular S100A1 protein on ventricular cardiomyocytes in vitro. In this report we show that extracellularly added S100A1 protein is endocytosed into the endosomal compartment of neonatal ventricular cardiomyocytes via a Ca 2؉ -dependent clathrin-mediated process. S100A1 uptake protects neonatal ventricular cardiomyocytes from 2-deoxyglucose and oxidative stressinduced apoptosis in vitro. S100A1-mediated antiapoptotic effects involve specific activation of the extracellular signal-regulated kinase 1/2 (ERK1/2) prosurvival pathway, including activation of phospholipase C, protein kinase C, mitogen-activated protein kinase kinase 1, and ERK1/2. In contrast, neither transsarcolemmal Ca 2؉ influx via the L-type channel nor protein kinase A activity seems to take part in the S100A1-mediated signaling pathway. In conclusion, this study provides evidence for the S100A1 protein serving as a novel cardioprotective factor in vitro. These findings warrant speculation that injury-dependent release of the S100A1 protein from cardiomyocytes may serve as an intrinsic mechanism to promote survival of the myocardium in vivo.

The observed anti-apoptotic phenotype in HB cell lines may contribute to resistance to cytotoxic drugs used in the standard treatment protocol of HB. These pre-clinical results suggest that apoptosis sensitizers with BH-3 mimicry, such as ABT-737, should be further evaluated in preclinical models of HB.

Treatment with sorafenib led to a potent inhibition of cell viability, tumour progression and angiogenesis. Sorafenib might therefore also be a promising treatment option for high risk or recurrent HB.