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Background The Fontan operation is a palliative procedure and a substantial number of patients eventually experiences late Fontan circulation failure. Previous concepts of Fontan failure implicate increasing pulmonary vascular resistance (PVR) as a key contributor to late circulatory failure. However, data to support this assumption are sparse. We sought to characterize longitudinal hemodynamic and echocardiographic findings in adult failing Fontan patients. Methods We performed a retrospective cohort study in adult Fontan patients, identifying patients with Fontan failure. Hemodynamic, echocardiographic and clinical data were recorded. Results Of 173 adult patients (median follow-up after Fontan 20.2 years [IQR 15.7-24.3]), 48 (28%) showed signs of clinical Fontan failure. Thirty-seven patients (77.1%) exhibited ventricular dysfunction (systolic dysfunction defined by ejection fraction ≤45%, n = 22, or diastolic dysfunction defined by systemic ventricular end-diastolic pressure (SVEDP) ≥12 mmHg, n = 15). Elevated indexed PVR (≥2.5 WU*m2) was only observed in 9 (18.8%) patients. Ejection fraction declined from 60% [IQR 55-65] to 47% [IQR 35-55] during follow-up (p Conclusions Systolic and diastolic ventricular dysfunction are frequent features in late Fontan failure in adults, while increases in PVR were rarely observed. The intricate interplay between hemodynamic compromises in Fontan failure deserves further research to optimize treatment strategies and outcome.

Reverse Potts shunt is a palliative procedure aimed at decompressing the pressure-overloaded right ventricle in severe pulmonary hypertension (PH). We, herein, report the first case of an interventional creation of an “endogenous” reverse Potts shunt by stenting a pre-existing small but patent ductus arteriosus (PDA) in a 2 months old female infant with severe, supra-systemic PH, associated with a novel combination of a compound heterozygous ABCA3 mutation and additional heterozygous genetic variants of surfactant protein B (SFTPB) and C (SFTPC). The aforementioned combination of human genetic mutations has not been described before in viable infants, children or adults. The catheter intervention was performed via percutaneous femoral arterial access and was well-tolerated. Subsequently, the infant improved by means of clinical status, echocardiographic systolic right ventricular (RV) function, and serum NT-proBNP levels as biomarker of right atrial and RV pressure load. In conclusion, this single case report suggests that interventional stenting of a pre-existing PDA to create an “endogenous” reverse Potts shunt is feasible and efficacious in infants less than 3 months old with severe PH and impending RV failure associated with developmental lung disease.

Fieber und Zeichen einer entzundlichen Erkrankung zahlen zu den haufigsten Symptomenkomplexen, die zur akuten kinderarztlichen Vorstellung fuhren. Die allgemein verbreiteten Vorstellungen uber die Ursachen und Auspragungen von Fieber, uber physiologische und pathologische immunologische Prozesse bei Entzundungsreaktionen sowie die daraus abzuleitenden therapeutischen Masnahmen unterliegen einem stetigen Wandel. Sowohl Patienten als auch Behandelnde werden von konzeptionellen Uberlegungen beeinflusst, die sich, historisch betrachtet, kontinuierlich weiterentwickeln. In dieser Ubersichtarbeit werden die Erkenntnisse zu immunologischen Vorgangen, die Fieberreaktionen und Entzundungen zugrunde liegen, veranschaulicht. Anhand von medizinhistorisch relevanten Meilensteinen mit vorrangig phanomenologischen Beschreibungen sowie einigen herausragenden Schritten hin zum modernen Verstandnis der immunologischen Mechanismen werden die Vorstellungen zur Infektionsabwehr, aber auch die modernen Konzepte von Autoimmunitat und -inflammation zusammengefasst. In der Gegenwart werden bedeutsame Anstrengungen unternommen, um das Wissen uber molekulare Zusammenhange in klinisch anwendbare Therapieprinzipien zu uberfuhren. Die immer komplexer werdenden Erklarungsmodelle werden in der Zukunft mit potenziell zielgerichteten Therapien, personalisierter „Prazisionsmedizin“ und technologischen Neuerungen zur Weiterentwicklung der Entzundungsmedizin beitragen.

Challenges and special aspects related to the management and prognosis of pulmonary hypertension (PH) in middle- to low-income regions (MLIRs) range from late presentation to comorbidities, lack of resources and expertise, cost, and rare options of lung transplantation. Expert consensus recommendations addressing the specific challenges for prevention and therapy of PH in MLIRs with limited resources have been lacking. To date, 6 MLIR-PH registries containing mostly adult patients with PH exist. Importantly, the global prevalence of PH is much higher in MLIRs compared with high-income regions: group 2 PH (left heart disease), pulmonary arterial hypertension associated with unrepaired congenital heart disease, human immunodeficiency virus, or schistosomiasis are highly prevalent. This consensus statement provides selective, tailored modifications to the current PH guidelines to address the specific challenges faced in MLIRs, resulting in the first pragmatic and cost-effective consensus recommendations for PH care providers, patients, and their families.

Background:Thrombocytopenia is a risk factor for patent ductus arteriosus. Immature and mature platelets exhibit distinct haemostatic properties; however, whether platelet maturity plays a role in postnatal, ductus arteriosus closure is unknown.Methods:In this observational study, counts of immature and mature platelets (=total platelet count − immature platelet count) were assessed on days 1, 3, and 7 of life in very low birth weight infants (Results:Counts of mature platelets did not differ on day 1 in infants with (n = 24) and without (n = 45) haemodynamically significant patent ductus arteriosus, while infants with significant patent ductus arteriosus exhibited lower counts of mature platelet on postnatal days 3 and 7. Relative counts of immature platelets (fraction, in %) were higher in infants with patent ductus arteriosus on day 7 but not on days 1 and 3. Receiver operating characteristic curve analysis unraveled associations between both lower mature platelet counts and higher immature platelet fraction (percentage) values on days 3 and 7, with haemodynamically significant ductus arteriosus. Logistic regression analysis revealed that mature platelet counts, but not immature platelet fraction values, were independent predictors of haemodynamically significant patent ductus arteriosus.Conclusion:During the first week of postnatal life, lower counts of mature platelets and higher immature platelet fraction values are associated with haemodynamically significant patent ductus arteriosus. Lower counts of mature platelet were found to be independent predictors of haemodynamically significant patent ductus arteriosus.

Objectives Exchange transfusion (ET) and intravenous immunoglobulin are potentially life-saving treatment options in newborns with gestational alloimmune liver disease (GALD). Since 2008, early ET has been the standard of care for symptomatic neonates with suspected GALD in our unit. The present study's aim was to investigate the outcomes of this approach. Methods From 2008 to 2018, all neonates who received ET for suspected GALD were identified, and their clinical course and outcomes were analyzed in a descriptive cohort study. In survivors, liver function parameters before ET and maximum values after ET and at discharge were compared. Results During the 11-year period, 12 infants received ET for suspected GALD at a median (range) chronological age of 11 (1-23) days and gestational age of 38 (32-40) weeks. Signs of impaired liver function, most frequently postnatal hypoglycemia, hyperferritinemia, direct hyperbilirubinemia, and coagulopathy, were present in all infants. Survival without a liver transplant in the overall cohort was 10 of 12 (83.3%) and 7 of 9 (78%) in those fulfilling the criteria of acute liver failure. Two patients died, one of them after liver transplantation. Direct bilirubin typically increased after ET, even in survivors. All survivors recovered and were discharged from the pediatric hepatology outpatient clinic after 8 (3-11) months of follow-up. Conclusions In newborns with suspected GALD, a limited diagnostic work-up followed by early ET may lead to favorable outcomes. More data are required to develop an evidence-based clinical approach to GALD.

While invasive assessment of hemodynamics and testing of acute vasoreactivity in the catheterization laboratory is the gold standard for diagnosing pulmonary hypertension (PH) and pulmonary vascular disease (PVD) in children, transthoracic echocardiography (TTE) serves as the initial diagnostic tool. International guidelines suggest several key echocardiographic variables and indices for the screening studies when PH is suspected. However, due to the complex anatomy and special physiological considerations, these may not apply to patients with congenital heart disease (CHD). Misinterpretation of TTE variables can lead to delayed diagnosis and therapy, with fatal consequences, or–on the other hand-unnecessary invasive diagnostic procedures that have relevant risks, especially in the pediatric age group. We herein provide an overview of the echocardiographic workup of children and adolescents with PH with a special focus on children with CHD, such as ventricular/atrial septal defects, tetralogy of Fallot or univentricular physiology. In addition, we address the use of echocardiography as a tool to assess eligibility for exercise and sports, a major determinant of quality of life and outcome in patients with PH associated with CHD.

Zusammenfassung Eine pathologische Druckerhöhung im pulmonalen Gefäßsystem (pulmonale Hypertonie, PH) wurde bisher definiert durch einen invasiv gemessenen mittleren pulmonalarteriellen Druck (mPAP) ≥25 mm Hg in Ruhe. Auf dem 6th World Symposium on Pulmonary Hypertension (WSPH) in Nizza 2018 wurde eine neue Definition der PH vorgeschlagen, die die Senkung der Obergrenze des normalen mPAP von 24 auf 20 mm Hg beinhaltet. Obwohl keine Evidenz aus pädiatrischen Studien hierfür vorliegt, wurde diese neue PH-Definition (mPAP >20 mm Hg) aus Gründen der Einheitlichkeit auch von der pädiatrischen „Task Force“ des WSPH 2018 übernommen. Die vorliegende Stellungnahme der Arbeitsgemeinschaft Pulmonale Hypertonie (AGPH) der Deutschen Gesellschaft für Pädiatrische Kardiologie und angeborene Herzfehler e. V. (DGPK) erläutert die zugrunde liegende Rationale und mögliche Konsequenzen dieser Definitionsänderung. Insbesondere stellt sie klar, dass diese Änderung der Definition aktuell keinen Einfluss auf die Verschreibung von Medikamenten zur gezielten spezifischen Therapie der pulmonalarteriellen Hypertonie hat.

Background:Vascular endothelial growth factor is critically involved in ductus arteriosus closure. Polymorphisms in the vascular endothelial growth factor gene have been associated with several diseases in neonates and adults.Aim:Herein, we investigated if vascular endothelial growth factor polymorphism rs2010963 status is associated with patent ductus arteriosus incidence and/or pharmacological treatment success.Methods:We assessed rs2010963 status in 814 preterm infants (Results:We could not find any statistically significant difference in the incidence of patent ductus arteriosus depending on vascular endothelial growth factor rs2010963 polymorphism status. Furthermore, no statistically significant associations between vascular endothelial growth factor polymorphism rs2010963 status and cyclooxygenase inhibitor treatment success were observed.Conclusion:Our results indicate that there is no association between vascular endothelial growth factor polymorphism rs2010963 status and the occurrence of patent ductus arteriosus or the response to cyclooxygenase inhibitor treatment in a large cohort of preterm infants. Additional studies are needed to determine the role of genetic factors on patent ductus arteriosus incidence and treatment response.

Pulmonary hypertension (PH), and especially pulmonary arterial hypertension (PAH), are chronic, progressive, and fatal conditions for which - apart from bilateral lung transplantation - there is currently no cure. However, recently developed, so-called "targeted" ("advanced") PAH medications, are now approved for adult PAH, and have improved quality of life and survival of affected children and adults. In 2020, two prospective pediatric observational studies on add-on macitentan and selexipag, respectively, have been published. Due the lack of approved pediatric PAH-medications, the well-founded rationale for combination therapy in childhood, and the absence of serious adverse effects, advanced pharmacotherapy should not be withheld from young PH patients. Such an "off-label use" of PAH-targeted medications in children with PH, and its financial reimbursement by health insurances, are urgently needed. The decision on the specific, vasoactive pharmacotherapy should be made by a PH expert with sufficient experience in the diagnosis and treatment of children with PH - followed by close out-patient monitoring. Combination pharmacotherapy should include the option of combining drugs of all substance classes (phosphodiesterase inhibitors, soluble guanylate cyclase stimulators, endothelin receptor antagonists, drugs targeting prostacyclin pathways, and calcium channel blockers in select cases) - including "off-label, pediatric drug formulations". Neither the lack of approval for modern PAH drugs directed against PAH nor the limited evidence-based study data available for children, should preclude PH expert centers to offer these therapies early and in combination to young patients with progressive PH, in order to improve exercise capacity, quality of life, and survival.

BACKGROUND: Macitentan, a dual endothelin receptor antagonist (ERA), was approved in 2014 for the treatment of adults with idiopathic pulmonary arterial hypertension (PAH). Once-per-day dosing and low potential hepatic toxicity make macitentan an appealing therapeutic option for children with PAH, but reports on its use in pediatric patients are still lacking. METHODS: Prospective observational study of 18 children [10 male; median age: 8.5, minimum (min.): 0.6, maximum (max.): 16.8 years] with pulmonary hypertension (PH). Four of these 18 patients were treatment-naïve and started on a de novo macitentan therapy. The remaining 14/18 children were already on a PH-targeted pharmacotherapy (sildenafil or bosentan as monotherapy or in combination). Nine children who were on bosentan were switched to macitentan. We analyzed the 6-minute walking distance (6MWD), NYHA functional class (FC)/modified ROSS score, invasive hemodynamics, echocardiographic variables and the biomarker N-terminal pro-brain natriuretic peptide (NT-proBNP). RESULTS: The median follow up was 6 months (min.: 0.5, max.: 30). Macitentan treatment was associated with improvement of invasive hemodynamics, e.g., the ratio of mean pulmonary arterial pressure/mean systemic arterial pressure decreased from a median of 62% (min.: 30%, max.: 87%) to 49% (min.: 30%, max.: 69%), P

Objective The right ventricular outflow tract (RVOT) is pivotal for adequate RV function and known to be adversely affected by elevated pulmonary arterial pressure (PAP) in adults with pulmonary hypertension (PH). Aim of this study was to determine the effects of increased RV pressure afterload in children with PH on RVOT size, function, and flow parameters. Methods We conducted a transthoracic echocardiographic study in 51 children with PH (median age: 5.3 years; range 1.5 months to 18 years) and determined the following RVOT variables: RVOT diameter, RVOT velocity time integral (VTI), ratio of tricuspid regurgitation velocity (TRV)/RVOT VTI, and RVOT systolic excursion (SE). Results In our pediatric PH cohort, the age-specific RVOT diameter z-score was higher compared to normal values. Deviation from normal RVOT diameter values increased with age, disease severity, and New York Heart Association functional class. Significant correlations were found between RVOT diameter and the RV end-diastolic area and right atrial area. The age-specific RVOT VTIz-score values were significantly lower in children with PH vs healthy controls. The TRV/RVOT VTI ratio increased with rising systolic RV pressure, while the RVOT SE was similar between PH children and control subjects. Conclusions In pediatric PH cohort, the RVOT VTI is decreased, and the TRV/RVOT VTI ratio and the RVOT diameter increased compared to healthy subjects. Assessment of RVOT variables, together with established RV parameters, allows for a comprehensive assessment of global right heart size and performance in children with PH.

BackgroundCyclooxygenase inhibitors are widely applied to facilitate ductal closure in preterm infants. The mechanisms that lead to patent ductus arteriosus closure are incompletely understood. Vascular endothelial growth factor plays pivotal roles during ductal closure and remodelling.AimThe aim of this study was to investigate the effects of ibuprofen and indomethacin on the expression of vascular endothelial growth factor and its receptors in a primary rat ductus arteriosus endothelial cell culture.MethodsProtein expression of vascular endothelial growth factor and vascular endothelial growth factor receptor 1 and 2 was confirmed in rat ductus arteriosus and aorta by immunofluorescence staining. Fetal rat endothelial cells were isolated from ductus arteriosus and aorta using immunomagnetic cell sorting and treated with ibuprofen or indomethacin. mRNA expression levels were assessed by quantitative polymerase chain reaction analysis.ResultsIn ductal endothelial cells, ibuprofen significantly induced vascular endothelial growth factor and its receptor 2, but not receptor 1, whereas indomethacin did not alter the expression levels of the vascular endothelial growth factor system. In contrast, ibuprofen significantly induced vascular endothelial growth factor and its receptors 1 and 2 in aortic endothelial cells, whereas indomethacin only induced vascular endothelial growth factor receptor 2.ConclusionOur results indicate differential effects of ibuprofen and indomethacin on the expression levels of the vascular endothelial growth factor system in ductus arteriosus endothelial cells. In addition, vessel-specific differences between ductal and aortic endothelial cells were found. Further in vivo studies are needed to elucidate the biological significance of these findings.

Pulmonary hypertension is a complex and progressive condition that is either idiopathic or heritable, or associated with one or multiple health conditions, with or without congenital or acquired cardiovascular disease. Recent developments have tremendously increased the armamentarium of diagnostic and therapeutic approaches in children and young adults with pulmonary hypertension that is still associated with a high morbidity and mortality. These modalities include non-invasive imaging, pharmacotherapy, interventional and surgical procedures, and supportive measures. The optimal, tailored diagnostic and therapeutic strategies for pulmonary hypertension in the young are rapidly evolving but still face enormous challenges: Healthcare providers need to take the patient’s age, development, disease state, and family concerns into account when initiating advanced diagnostics and treatment. Therefore, there is a need for guidance on core and advanced medical training in paediatric pulmonary hypertension. The Association for European Paediatric and Congenital Cardiology working group “pulmonary hypertension, heart failure and transplantation” has produced this document as an expert consensus statement; however, all recommendations must be considered and applied in the context of the local and national infrastructure and legal regulations.

The European Pediatric Pulmonary Vascular Disease Network is a registered, non-profit organization that strives to define and develop effective, innovative diagnostic methods and treatment options in all forms of pediatric pulmonary hypertensive vascular disease, including pulmonary hypertension (PH) associated with bronchopulmonary dysplasia, PH associated with congenital heart disease (CHD), persistent PH of the newborn, and related cardiac dysfunction. The executive writing group members conducted searches of the PubMed/MEDLINE bibliographic database (1990-2018) and held face-to-face and web-based meetings. Ten section task forces voted on the updated recommendations, based on the 2016 executive summary. Clinical trials, meta-analyses, guidelines, and other articles that include pediatric data were searched using the term "pulmonary hypertension" and other keywords. Class of recommendation (COR) and level of evidence (LOE) were assigned based on European Society of Cardiology/American Heart Association definitions and on pediatric data only, or on adult studies that included >10% children or studies that enrolled adults with CHD. New definitions by the World Symposium on Pulmonary Hypertension 2018 were included. We generated 10 tables with graded recommendations (COR/LOE). The topics include diagnosis/monitoring, genetics/biomarkers, cardiac catheterization, echocardiography, cardiac magnetic resonance/chest computed tomography, associated forms of PH, intensive care unit/lung transplantation, and treatment of pediatric PH. For the first time, a set of specific recommendations on the management of PH in middle- and low-income regions was developed. Taken together, these executive, up-to-date guidelines provide a specific, comprehensive, detailed but practical framework for the optimal clinical care of children and young adults with PH.

AIM To investigate interinstitutional differences in preterm infant stabilisation between two European tertiary neonatal centres with particular focus on intubation timing, surfactant administration, caffeine therapy and neonatal morbidity and mortality. METHODS Retrospective (2012-2014) study of very low birth weight (VLBW) preterm infants admitted to John Radcliffe Hospital (UK centre) and Charite Medical Centre (German centre). Timing of intubation, surfactant and caffeine administration and respiratory outcomes were examined. RESULTS Gestational age, birth weight and five-minute Apgar scores of VLBW infants from the UK centre (n = 86) were comparable to those from the German centre (n = 96). Significant differences in antenatal steroid therapy, intubation timing and surfactant therapy were noted. Timing of caffeine initiation differed significantly between centres (median 0 [0-2.5] UK vs. 2 [1.5-4] days German centre); however, caffeine was discontinued at a similar corrected gestational age of 34.7 weeks. Mechanical ventilation was significantly longer at the UK centre, but there was no difference in bronchopulmonary dysplasia (BPD) (44% UK vs. 36% German centre) or mortality (15% UK vs. 13% German centre). CONCLUSION Timing of primary intubation and caffeine therapy differed significantly between centres. However, earlier intubation and caffeine administration in the UK centre were not associated with a changed incidence of BPD.

Determination of biventricular dimensions, function, and ventricular–ventricular interactions (VVI) is an essential part of the echocardiographic examination in adults with pulmonary hypertension (PH); however, data from according pediatric studies are sparse. We hypothesized that left and right heart dimensions/function and VVI variables indicate disease severity and progression in children with PH. Left heart, right heart, and VVI variables (e.g. end-systolic LV eccentricity index [LVEI], right ventricular [RV]/left ventricular [LV] dimension ratio) were echocardiographically determined in 57 children with PH, and correlated with New York Heart Association (NYHA) functional class (FC), N-terminal-pro brain natriuretic peptide (NT-proBNP), and invasive hemodynamic variables (e.g. pulmonary vascular resistance index [PVRi]). Clinically sicker patients (higher NYHA FC) had lower LV ejection fraction (LVEF) and higher LVEI – a surrogate of LV compression. In PH children, the ratio of systolic pulmonary arterial pressure divided by systolic systemic arterial pressure (sPAP/sSAP) and the PVRi correlated well with the LVEI ( P

We, herein, report the first use of a Magmaris® magnesium-based vascular scaffold for native aortic coarctation in a 1,980 g infant with multiple malformations. Due to the low body weight, complex illness, and clinical instability, it was decided to delay surgical correction. After insufficient results had been obtained by balloon angioplasty, Magmaris® implantation was chosen to bridge the patient to surgery by stabilizing left ventricular function and to allow for sufficient growth. Due to significant early stent restenosis and complete loss of radial force, the patient required balloon reangioplasty only 21 days after Magmaris® implantation and early surgical correction. In addition, high systemic sirolimus levels were detected 48 hr after the intervention (5 ng/mL). Although the bioresorbable scaffold was successfully used as a short-term bridge-to-surgery in our case, due to significant early stent failure (loss of radial force), this approach does not seem promising for long-term bridging of infants with aortic coarctation. In addition, the consequences of sirolimus-induced systemic immunosuppression may further limit the applicability of Magmaris® scaffolds in infants with congenital heart disease.

Clinical, laboratory, and placental manifestations of perinatal listeriosis are highly variable. Herein, we retrospectively analyzed all patients treated for neonatal listeriosis at the Charité University Medical Center in Berlin, Germany, 1999-2013. A total of 16 cases were identified. In 14 patients listeriosis was confirmed in neonatal specimens, while in two only the placenta tested positive. Elevated C-reactive protein and/or interleukin-6 levels were only inconsistently found, while a marked white blood cell left shift was present in all infants, if available. All but one infant manifested symptoms on the first day of life. Most patients required respiratory support, while none developed meningoencephalitis as evidenced by clinical or cerebrospinal fluid findings. Two patients died, all other patients survived without sequelae. In conclusion, perinatal listeriosis is still associated with significant morbidity and mortality. Clinical and laboratory findings are highly heterogeneous, but extreme leukocyte left shift seems to be a common feature.

Summary Neonatal thrombocytopenia is widespread in preterm and term neonates admitted to neonatal intensive care units, with up to one-third of infants demonstrating platelet counts 9 /L. Thrombocytopenia may arise from maternal, placental or fetal/neonatal origins featuring decreased platelet production, increased consumption, or both mechanisms. Over the past years, innovations in managing neonatal thrombocytopenia were achieved from prospectively obtained clinical data on thrombocytopenia and bleeding events, animal studies on platelet life span and production rate and clinical use of fully automated measurement of reticulated platelets (immature platelet fraction). This review summarizes the pathophysiology of neonatal thrombocytopenia, current management including platelet transfusion thresholds and recent developments in megakaryopoietic agents. Furthermore, we propose a novel index score for bleeding risk in thrombocytopenic neonates to facilitate clinician's decision-making when to transfuse platelets.

Primary human hepatocytes are widely used for basic research, pharmaceutical testing, and therapeutic concepts in regenerative medicine. Human hepatocytes can be isolated from resected liver tissue. Preoperative portal vein embolization (PVE) is increasingly used to decrease the risk of delayed postoperative liver regeneration by induction of selective hypertrophy of the future remnant liver tissue. The aim of this study was to investigate the effect of PVE on the outcome of hepatocyte isolation. Primary human hepatocytes were isolated from liver tissue obtained from partial hepatectomies (n = 190) using the two-step collagenase perfusion technique followed by Percoll purification. Of these hepatectomies, 27 isolations (14.2%) were performed using liver tissue obtained from patients undergoing PVE before surgery. All isolations were characterized using parameters that had been described in the literature as relevant for the outcome of hepatocyte isolation. The isolation outcomes of the PVE and the non-PVE groups were then compared before and after Percoll purification. Metabolic parameters (transaminases, urea, albumin, and vascular endothelial growth factor secretion) were measured in the supernatant of cultured hepatocytes for more than 6 days (PVE: n = 4 and non-PVE: n = 3). The PVE and non-PVE groups were similar in regard to donor parameters (sex, age, and indication for surgery), isolation parameters (liver weight and cold ischemia time), and the quality of the liver tissue. The mean initial viable cell yield did not differ between the PVE and non-PVE groups (10.16 ± 2.03 × 10(6) cells/g vs. 9.70 ± 0.73 × 10(6) cells/g, p = 0.499). The initial viability was slightly better in the PVE group (77.8% ± 2.03% vs. 74.4% ± 1.06%). The mean viable cell yield (p = 0.819) and the mean viability (p = 0.141) after Percoll purification did not differ between the groups. PVE had no effect on enzyme leakage and metabolic activity of cultured hepatocytes. Although PVE leads to drastic metabolic alterations and changes in hepatic blood flow, embolized liver tissue is a suitable source for the isolation of primary human hepatocytes and is equivalent to untreated liver tissue in regard to cell yield and viability.

BACKGROUND: Echocardiographic determination of RV end‐systolic base/apex (RVES b/a) ratio was proposed to be of clinical value for assessment of pulmonary arterial hypertension (PAH) in adults. HYPOTHESIS: We hypothesized that the RVES b/a ratio will be affected in children with PAH and aimed to correlate RVES b/a ratio with conventionally used echocardiographic and hemodynamic variables, and with New York Heart Association (NYHA) functional class. METHODS: First we determined normal pediatric values for RVES b/a ratio in 157 healthy children (68 males; age range, 0.5–17.7 years). We then conducted an echocardiographic study in 51 children with PAH (29 males; age range, 0.3–17.8 years). RESULTS: RVES b/a ratio was lower compared with age‐ and sex‐matched healthy controls (P < 0.001). In children with PAH, RVES b/a ratio decreased with worsening NYHA class. RVES b/a ratio inversely correlated with RV/LV end‐systolic diameter ratio (ρ = −0.450, P = 0.001) but did not correlate with RV systolic function parameters (eg, tricuspid annular plane systolic excursion) and correlated with cardiac catheterization–determined pulmonary vascular resistance index (ρ = −0.571, P < 0.001). ROC analysis unraveled excellent performance of RVES b/a ratio to detect PAH in children (AUC: 0.95, 95% CI: 0.89–1.00, P < 0.001). CONCLUSIONS: The RVES b/a ratio decreased in children with PAH compared with age‐ and sex‐matched healthy subjects. The RVES b/a ratio inversely correlated with both echocardiographic and hemodynamic indicators of increased RV pressure afterload and with NYHA class, suggesting that RVES b/a ratio reflects disease severity in PAH children.

Data on the natural history of infants discharged with patent ductus arteriosus is sparse. We report on the 36-months follow-up after hospitalization in 68 infants discharged with an open ductus arteriosus. Notwithstanding a high spontaneous closure rate, catheter intervention in 5 infants illustrates a critical need for cardiologic follow-up.

Objective: The indications and strategies for treatment of patent ductus arteriosus (PDA) are controversial, and the safety and long-term benefits of surgical PDA closure remain uncertain. The aim of this study was to compare the lung function of very low birth weight (VLBW) infants after PDA treatment with a cyclooxygenase inhibitor or surgical ligation. Study design: A total of 114 VLBW infants (birth weight FRC ) by the rapid thoracoabdominal compression technique, exhaled NO (FeNO), and arterialized capillary blood gas analysis. Results: On the day of the LFT, the 2 groups had similar postconceptional age and body weight. However, the PDA ligation group was more immature at birth ( p p FRC ( p = 0.006), increased airway resistance (R aw ) ( p p aw and reduced respiratory compliance. Conclusions: PDA ligation is associated with impaired lung function in infants with a postmenstrual age of 48 weeks.

Several studies have identified circulating biomarkers to be associated with the presence and severity of pulmonary arterial hypertension (PAH). Recent evidence supports a role for galectin-3 (Gal-3) and the mineralcorticoid aldosterone in left ventricular failure. However, studies on aldosterone together with Gal-3 in PAH are lacking.We investigated a novel Aldosterone-galectin-3 (Gal-3) tandem and several other potential PAH biomarkers and their association with the disease severity.A total of 57 patients, 41 with idiopathic PAH. (IPAH) and 16 with PAH associated with connective tissue disease (CTD), and 8 age-matched, non-relative controls were studied. Gal-3, aldosterone and other potential protein plasma concentrations were measured by single ELISA and multi-array MSD (Meso Scale Discovery) technology.Gal-3 values were increased in both patients with IPAH (12.2±0.6 ng/mL; p0.05) and with PAH-CTD (14.1±1.6 ng/mL; p0.05) versus control (8.5±0.9 ng/mL), while aldosterone was significantly elevated in IPAH only (248.5±38.8 pg/mL vs control 71.9±18.2 pg/mL; p0.05). In addition, aldosterone, Gal-3, and N-terminal pro-brain natriuretic peptide (NT-proBNP) values were all higher in patients in WHO functional class II-III versus PAH functional class I or controls. The vascular injury marker intercellular adhesion molecule 1 (ICAM-1) was increased in IPAH and PAH-CTD versus controls (559.5±18.2 pg/mL and 734.1±59.4 pg/mL vs controls 394.8±39.3 pg/mL, p0.05, p0.0001, respectively), whereas vascular cell adhesion molecule 1 (VCAM-1) and proinflammatory, anti-angiogenic interleukin-12 (IL-12) were elevated in PAH-CTD only (879.5±110.0 pg/mL and 391.2±70.3 pg/mL vs controls 489.8±44.6 pg/mL, p0.01, and 102.1±15.2 pg/mL, p0.01, respectively).Heightened Gal-3 and aldosterone plasma concentrations in PAH patients indicate a role for Gal-3 signalling in the pathobiology of IPAH and PAH-CTD, and may serve as biomarkers for functional status and progression of disease.

A patent ductus arteriosus (PDA) is associated with several adverse clinical conditions. Several strategies for PDA treatment exist, although data regarding the benefits of PDA treatment on outcomes are sparse. Moreover, the optimal treatment strategy for preterm neonates with PDA remains subject to debate. It is still unknown whether and when PDA treatment should be initiated and which approach (conservative, pharmacologic, or surgical) is best for individual patients (tailored therapies). This article reviews the current strategies for PDA treatment with a special focus on recent developments such as oral ibuprofen, high-dose regimens, and the use of paracetamol (oral, intravenous).

BACKGROUND:Experimental studies suggest that platelet-triggered ductal sealing is critically involved in definite ductus arteriosus closure. Whether thrombocytopenia contributes to persistently patent ductus arteriosus (PDA) in humans is controversial. This was a retrospective study of 1350 very low birth weight (VLBW; METHODS:All infants who had a platelet count in the first 24 hours after birth and an echocardiogram performed on day of life 4 to 5 were included. The incidence of thrombocytopenia was analyzed in infants with and without PDA, and in those who did or did not undergo PDA intervention. The impact of thrombocytopenia, gestational age, birth weight, gender, and sepsis on PDA was determined by receiver operating characteristic curve, odds ratio, and regression analyses.RESULTS:Platelet numbers within the first 24 hours after birth did not differ between VLBW/ELBW infants with and without spontaneous ductal closure. Platelet numbers were not associated with subsequent PDA treatment. Low platelet counts were not related to failure of pharma-cologic PDA treatment and the need for subsequent surgical ligation. Lower gestational age or birth weight, male gender, and sepsis were linked to the presence of PDA in VLBW infants on day of life 4 to 5.CONCLUSIONS:Thrombocytopenia in the first 24 hours after birth was not associated with PDA in this largest VLBW/ELBW infant cohort studied to date. Impaired platelet function, due to immaturity and critical illness, rather than platelet number, might play a role in ductus arteriosus patency.

Background Bronchopulmonary sequestration (BPS) and congenital cystic adenomatoid malformation (CCAM) represent rare hamartomatous abnormalities of the lung. Dysregulation of cytokines that influence pulmonary vasculogenesis and epithelial growth, both known to be altered in BPS and CCAM, may play a role in their pathogenesis. Objective We hypothesized that expression of vascular endothelial growth factor (VEGF) or its receptors might be altered in CCAM and BPS, possibly distinguishing CCAM from BPS, or from controls. Methods Lung biopsy specimens obtained from infants who had undergone surgery for BPS ( n = 4) or CCAM ( n = 5) within the first month of life and normal lung autopsy samples ( n = 4) serving as controls were investigated immunohistochemically for the protein expression levels of VEGF and its corresponding receptors. Results VEGF, vascular endothelial growth factor receptor 1 (VEGFR1), vascular endothelial growth factor receptor 2 (VEGFR2), and vascular endothelial growth factor receptor 3 (VEGFR3) staining was detected in CCAM and BPS specimens, as well as in control samples. VEGFR2 expression increased from controls to CCAM and from CCAM to BPS, the difference between controls and BPS being significant. The expression of VEGF, VEGFR1, and VEGFR3 was similar among the three groups. Consistent with a possible involvement of VEGFR2 in altered vasculogenesis-bronchiogenesis interaction, its expression was predominantly found in bronchial but not alveolar regions. Conclusions The data suggest a possible role of VEGF-VEGFR2 interaction in the pathogenesis of congenital bronchopulmonary cystic malformations. However, VEGFR2 does not represent a suitable histochemical marker to distinguish between BPS and CCAM.

The number of circulating endothelial progenitor cells (EPCs) inversely correlates with cardiovascular risk and clinical outcome, and thus has been proposed as a valuable biomarker for risk assessment, disease progression, and response to therapy. However, current strategies for isolation of these rare cells are limited to complex, laborious approaches. The goal of this study was the design and validation of a disposable microfluidic platform capable of selectively capturing and enumerating EPCs directly from human whole blood in healthy and diseased subjects, eliminating sample preprocessing. We then applied the "EPC capture chip" clinically and determined EPC numbers in blood from patients with pulmonary arterial hypertension (PAH). Blood was collected in tubes and injected into polymeric microfluidic chips containing microcolumns pre-coated with anti-CD34 antibody. Captured cells were immunofluorescently stained for the expression of stem and endothelial antigens, identified and counted. The EPC capture chip was validated with conventional flow cytometry counts (r = 0.83). The inter- and intra-day reliability of the microfluidic devices was confirmed at different time points in triplicates over 1-5 months. In a cohort of 43 patients with three forms of PAH (idiopathic/heritable, drug-induced, and connective tissue disease), EPC numbers are ≈50% lower in PAH subjects vs. matched controls and inversely related to two potential disease modifiers: body mass index and postmenopausal status. The EPC capture chip (5 × 30 × 0.05 mm(3)) requires only 200 μL of human blood and has the strong potential to serve as a rapid bedside test for the screening and monitoring of patients with PAH and other proliferative cardiovascular, pulmonary, malignant, and neurodegenerative diseases.

Background: Sick neonates frequently develop severe thrombocytopenia. Objective and Methods: In order to test the ability of fetal mice to increase their megakaryocyte size and ploidy in response to thrombocytopenia, we injected an antiplatelet antibody (MWReg30) into pregnant mice daily for 7 days, and into nonpregnant adult mice to serve as controls. After that time, platelet counts were obtained and megakaryocytes in the bone marrow, liver, and spleen were stained with anti-von Willebrand factor antibody, individually measured, and quantified. Results: Our study demonstrated that megakaryocytopoiesis in newborn mice shares many features of human fetal/neonatal megakaryocytopoiesis, including the small size of megakaryocytes. In response to thrombocytopenia, adult mice increased megakaryocyte volume and concentration, primarily in the spleen. Newborn mice, in contrast, increased the megakaryocyte concentration in the spleen, but exhibited no increase in megakaryocyte volume in any of the organs studied. In fact, the megakaryocyte mass was significantly lower in the bone marrow of thrombocytopenic neonates than in age-matched controls. Conclusions: We concluded that fetuses have a limited ability to increase their megakaryocyte mass in response to consumptive thrombocytopenia, compared to adult mice. These observations provide further evidence for the existence of biological differences between fetal/neonatal and adult megakaryocytopoiesis.

Anemia and thrombocytopenia are the most common hematological problems in neonates. Red blood cell (RBC) and platelet transfusions are the mainstays of therapy, but data to guide neonatal transfusion practices have been sparse. Recombinant hematopoietic growth factors represent another therapeutic alternative, but their use in this population requires a solid understanding of the developmental differences between fetal and adult hematopoiesis.Recently, follow-up studies from children randomized as neonates to either liberal or restrictive RBC transfusion approaches were published. Results of these studies have so far been contradictory and have generated more questions than answers. New developmental stage-specific problems associated with RBC transfusions were also uncovered, such as the transfusion-associated necrotizing enterocolitis. Finally, two thrombopoietin (Tpo) mimetics were approved by the FDA for the treatment of adults with chronic immune thrombocytopenia, thus offering a novel potential therapeutic alternative for thrombocytopenic neonates.In this review, we will discuss the currently available data regarding neonatal RBC and platelet transfusion thresholds, as well as the potential limitations, and concerns associated with the use of erythropoietin and Tpo mimetics in this patient population. Finally, we will point out specific areas wherein additional research is critically needed.

The Food and Drug Administration recently approved two novel thrombopoiesis-stimulating agents, Romiplostim (AMG-531, Nplate) and Eltrombopag (Promacta), for the treatment of adults with immune thrombocytopenic purpura. For physicians taking care of critically ill neonates, this offers the opportunity of decreasing platelet transfusions and potentially improving the outcomes of neonates with severe and prolonged thrombocytopenia. However, several developmental factors need to be taken into consideration. First, the population of thrombocytopenic neonates likely to benefit from these agents needs to be carefully selected. Second, the mechanisms underlying neonatal and adult thrombocytopenia differ from each other and are incompletely understood, and pre-clinical evidence suggests that the response of neonates to thrombopoietic factors might be different from that of adults. Finally, the potential non-hematopoietic effects of thrombopoietin have not been well established. Here, we will discuss these issues in detail, and will highlight the critical developmental differences between neonates and adults that need to be considered as we think about introducing these agents into neonatal care.