CXCR-4 expression by circulating endothelial progenitor cells and SDF-1 serum levels are elevated in septic patients

Background: Endothelial progenitor cell (EPC) numbers are increased in septic patients and correlate with survival. In this study, we investigated, whether surface expression of chemokine receptors and other receptors important for EPC homing is upregulated by EPC from septic patients and if this is associated with clinical outcome. Methods: Peripheral blood mononuclear cells from septic patients (n = 30), ICU control patients (n = 11) and healthy volunteers (n = 15) were isolated by Ficoll density gradient centrifugation. FACS-analysis was used to measure the expression of the CXC motif chemokine receptors (CXCR)-2 and − 4, the receptor for advanced glycation endproducts (RAGE) and the stem cell factor receptor c-Kit. Disease severity was assessed via the Simplified Acute Physiology Score (SAPS) II. The serum concentrations of vascular endothelial growth factor (VEGF), stromal cell-derived factor (SDF)-1α and angiopoietin (Ang)-2 were determined with Enzyme linked Immunosorbent Assays. Results: EPC from septic patients expressed significantly more CXCR-4, c-Kit and RAGE compared to controls and were associated with survival-probability. Significantly higher serum concentrations of VEGF, SDF-1α and Ang-2 were found in septic patients. SDF-1α showed a significant association with survival. Conclusions: Our data suggest that SDF-1α and CXCR-4 signaling could play a crucial role in EPC homing in the course of sepsis

CXCR-4 expression by circulating endothelial progenitor cells and SDF-1 serum levels are elevated in septic patients

Background: Endothelial progenitor cell (EPC) numbers are increased in septic patients and correlate with survival. In this study, we investigated, whether surface expression of chemokine receptors and other receptors important for EPC homing is upregulated by EPC from septic patients and if this is associated with clinical outcome. Methods: Peripheral blood mononuclear cells from septic patients (n = 30), ICU control patients (n = 11) and healthy volunteers (n = 15) were isolated by Ficoll density gradient centrifugation. FACS-analysis was used to measure the expression of the CXC motif chemokine receptors (CXCR)-2 and − 4, the receptor for advanced glycation endproducts (RAGE) and the stem cell factor receptor c-Kit. Disease severity was assessed via the Simplified Acute Physiology Score (SAPS) II. The serum concentrations of vascular endothelial growth factor (VEGF), stromal cell-derived factor (SDF)-1α and angiopoietin (Ang)-2 were determined with Enzyme linked Immunosorbent Assays. Results: EPC from septic patients expressed significantly more CXCR-4, c-Kit and RAGE compared to controls and were associated with survival-probability. Significantly higher serum concentrations of VEGF, SDF-1α and Ang-2 were found in septic patients. SDF-1α showed a significant association with survival. Conclusions: Our data suggest that SDF-1α and CXCR-4 signaling could play a crucial role in EPC homing in the course of sepsis

Physiological-based cord clamping versus immediate cord clamping for infants born with a congenital diaphragmatic hernia (PinC):study protocol for a multicentre, randomised controlled trial

Introduction Pulmonary hypertension is a majordeterminant of postnatal survival in infants with acongenital diaphragmatic hernia (CDH). The current careduring the perinatal stabilisation period in these infantsmight contribute to the development of pulmonaryhypertension after birth—in particular umbilical cordclamping before lung aeration. An ovine model ofdiaphragmatic hernia demonstrated that cord clampingafter lung aeration, called physiological-based cordclamping (PBCC), avoided the initial high pressures in thelung vasculature while maintaining adequate blood flow,thereby avoiding vascular remodelling and aggravationof pulmonary hypertension. We aim to investigate if theimplementation of PBCC in the perinatal stabilisation periodof infants born with a CDH could reduce the incidence ofpulmonary hypertension in the first 24 hours after birth.Methods and analysis We will perform a multicentre,randomised controlled trial in infants with an isolatedleft-sided CDH, born at ≥35.0 weeks. Before birth, infantswill be randomised to either PBCC or immediate cordclamping, stratified by treatment centre and severity ofpulmonary hypoplasia on antenatal ultrasound. PBCCwill be performed using a purpose- built resuscitationtrolley. Cord clamping will be performed when the infantis considered respiratory stable, defined as a heartrate >100 bpm, preductal oxygen saturation >85%,while using a fraction of inspired oxygen of <0.5. Theprimary outcome is pulmonary hypertension diagnosedin the first 24 hours after birth, based on clinical andechocardiographic parameters. Secondary outcomesinclude neonatal as well as maternal outcomes.Ethics and dissemination Central ethical approvalwas obtained from the Medical Ethical Committee ofthe Erasmus MC, Rotterdam, The Netherlands (METC2019-0414). Local ethical approval will be obtained bysubmitting the protocol to the regulatory bodies and localinstitutional review boards

Spontaneous breathing approach in mild congenital diaphragmatic hernia: A resuscitation algorithm

BackgroundInfants with a congenital diaphragmatic hernia (CDH) and expected mild pulmonary hypoplasia have an estimated survival rate of 90%. Current guidelines for delivery room management do not consider the individual patient's disease severity, but an individualized approach with spontaneous breathing instead of routine mechanical ventilation could be beneficial for the mildest cases. We developed a resuscitation algorithm for this individualized approach serving two purposes: improving the success rate by structuring the approach and providing a guideline for other centers.MethodsAn initial algorithm was discussed with all local stakeholders. Afterwards, the resulting algorithm was refined using input from international experts.ResultsEligible CDH infants: left-sided defect, observed to expected lung-to-head ratio ≥50%, gestational age at birth ≥37.0 weeks, and no major associated structural or genetic abnormalities. To facilitate fetal-to-neonatal transition, we propose to start stabilization with non-invasive respiratory support and to adjust this individually.ConclusionsInfants with mild CDH might benefit from an individualized approach for neonatal resuscitation. Herein, we present an algorithm that could serve as guidance for centers implementing this

The endothelium in sepsis: inflammatory response and progenitor cell involvement

Het endotheel is de bekleding van de binnenwand van alle bloedvaten, en speelt een belangrijke rol in het ziekteverloop bij sepsis. In dit proefschrift hebben wij deze ontstekingsreacties van het endotheel in verschillende septische condities bestudeerd alsmede het gedrag van uit beenmerg afkomstige endotheel-voorlopercellen. In eerste instantie hebben we ons gericht op het bestuderen van reacties van endotheelcellen van verschillende individuen op LPS of endotoxine. We vonden dat een lage gevoeligheid voor LPS samenviel met een lage gevoeligheid voor andere cytokines. Verder hebben we de effecten van een CO producerende molecuul (CORM-3) op de endotheliale expressie van inflammatoire adhesiemoleculen gemeten. CORM-3 remde de TNFα geinduceerde expressie van VCAM-1 en E-selectine. De modulatie van VCAM-1 berust gedeeltelijk op posttranscriptionele controle, en is onafhankelijk van HO-1. Via een genoombrede genexpressie profilering bleek dat CORM-3 proteasoom en porphyrine routes beïnvloedt. Ook werd de MAPKinase p42/p44 door CORM-3 geactiveerd, wat echter geen invloed had op de remming van VCAM-1. In het laatste onderdeel toonden we aan dat de bloedwaarden van EPCs in septische patiënten beduidend hoger zijn dan die in gezonde vrijwilligers en niet-septische patiënten. Sepsis non-survivors hadden beduidend lagere EPC waarden dan de overlevenden. Serum concentraties van VEGF, GM-CSF en EPO waren hoger in septische patiënten dan in gezonde vrijwilligers en niet-septische patiënten, en correleerden met de circulerende EPC aantallen. Samengevat tonen de resultaten dat sepsis de functie van endotheelcellen sterk kan beïnvloeden, waarmee het endotheel als een belangrijk doelwit voor therapeutische interventies kan worden gezien

Genetics of diaphragmatic hernia

Congenital diaphragmatic hernia (CDH) is a life-threatening malformation characterised by failure of diaphragmatic development with lung hypoplasia and persistent pulmonary hypertension of the newborn (PPHN). The incidence is 1:2000 corresponding to 8% of all major congenital malformations. Morbidity and mortality in affected newborns are very high and at present, there is no precise prenatal or early postnatal prognostication parameter to predict clinical outcome in CDH patients. Most cases occur sporadically, however, genetic causes have long been discussed to explain a proportion of cases. These range from aneuploidy to complex chromosomal aberrations and specific mutations often causing a complex phenotype exhibiting multiple malformations along with CDH. This review summarises the genetic variations which have been observed in syndromic and isolated cases of congenital diaphragmatic hernia