Juha Puntila

Cutting edge: human CD4-CD8- thymocytes express FOXP3 in the absence of a TCR.

The best candidate for regulatory T (Treg) cell lineage-determining factor is currently the Forkhead box transcription factor FOXP3. FOXP3 up-regulation has been linked to TCR-mediated signals, and in mice the abrogation of TCR expression or signals also prevents FoxP3 expression. In contrast, the TCR dependence of human FOXP3 is assumed but not established. In this study we show on a single cell level that 1.4% (range 0.1–3.8%) of CD4−CD8− thymocytes in healthy humans express FOXP3, two thirds of them without any detectable αβ TCR. These TCR−FOXP3+ cells were mostly CD25− and did not express γδ TCR or B cell, NK cell, or monocyte-associated markers. Like mature Treg cells, they were mostly CD2+CD127low and expressed cytoplasmic CTLA-4. Our results suggest that in immature human thymocytes the expression of FOXP3 precedes surface TCR, in which case TCR-mediated signals cannot be responsible for the thymic up-regulation of FOXP3.

Prevention of postoperative pericardial adhesions in children with hypoplastic left heart syndrome

Reoperations for congenital cardiac defects are associated with an increased surgical risk due to adhesions. We compared the capability of a polytetrafluoroethylene (PTFE) membrane, synthetic polyethyleneglycol hydrogel (PEG), and a combination of them to prevent postoperative pericardial adhesions in patients with hypoplastic left heart syndrome (HLHS). Eighteen consecutive patients with HLHS were included. At the end of the Norwood I operation the cranial and the caudal half of the heart of each patient was randomized to receive a PTFE membrane, a synthetic PEG, a combination of them, or no treatment (control). Tenacity and density of adhesions, epicardial visibility, and adhesions between the heart and the sternum were analyzed semiquantitatively at a subsequent bidirectional Glenn operation. The PTFE membrane significantly decreased adhesion formation between the heart and the sternum (P<0.001). However, the PTFE membrane, with or without synthetic PEG, impaired epicardial visibility (P<0.05) when compared to synthetic PEG or controls. Synthetic PEG alone did not significantly reduce the formation of pericardial adhesions. Tenacity and density of adhesions were not affected by any of the treatment modalities. The PTFE membrane significantly decreases postoperative adhesions between the heart and the sternum, but impairs epicardial visibility. Synthetic PEG does not prevent formation of pericardial adhesions.

The effect of continuous wound infusion of ropivacaine on postoperative pain after median sternotomy and mediastinal drain in children

Postoperative pain after median sternotomy is usually treated with i.v. opioids. We hypothesized that continuous wound infusion of ropivacaine decreases postoperative morphine consumption and improves analgesia in children who undergo cardiac surgery.

Heart-Type Fatty Acid Binding Protein and High-Dose Methylprednisolone in Pediatric Cardiac Surgery

OBJECTIVES Corticosteroids possess cardioprotection in experimental cardiac ischemia/reperfusion. The authors hypothesized that if cardioprotection of corticosteroids occured during pediatric cardiac surgery, then methylprednisolone used in cardiopulmonary bypass prime would reduce postoperative concentrations of heart-type fatty-acid-binding protein, a cardiac biomarker. DESIGN A double-blind, placebo-controlled, randomized clinical trial. SETTING Operating room and pediatric intensive care unit of a university hospital. PARTICIPANTS Forty-five infants and young children undergoing ventricular or atrioventricular septal defect correction. INTERVENTIONS The patients received one of the following: 30 mg/kg of methylprednisolone intravenously after anesthesia induction (n = 15), 30 mg/kg of methylprednisolone in cardiopulmonary bypass prime solution (n = 15), or placebo (n = 15). MEASUREMENTS AND MAIN RESULTS Plasma heart-type fatty-acid-binding protein (hFABP) was measured. Preoperatively, hFABP did not differ among the study groups. Methylprednisolone administered preoperatively and in the cardiopulmonary bypass prime solution reduced hFABP by 44% (p = 0.010) and 38% (p = 0.033) 6 hours postoperatively. hFABP significantly correlated with concomitant troponin T after protamine administration (R = 0.811, p < 0.001) and 6 hours postoperatively (R = 0.806, p < 0.001). CONCLUSIONS Methylprednisolone in cardiopulmonary bypass prime solution administered only a few minutes before cardiac ischemia confered cardioprotection of the same magnitude as preoperative methylprednisolone as indicated by hFABP concentrations. Rapid cardioprotective actions of corticosteroids in pediatric heart surgery observed previously experimentally may have occurred.

Interleukin-7 promotes human regulatory T cell development at the CD4+CD8+ double-positive thymocyte stage

Although mature human FOXP3+ regulatory T cells are CD127 (IL‐7Rα) negative, CD4+CD8+ FOXP3+ thymocytes express relatively high levels of CD127 and are responsive to IL‐7. However, the role of IL‐7 in human regulatory T cell development is poorly known. We show that at the CD4+CD8+ stage, FOXP3+ thymocytes are highly susceptible to apoptosis, and IL‐7 selectively rescues them from death, leading to an increased frequency of FOXP3+ cells. IL‐7 also promotes the development of regulatory T cell phenotype by inducing up‐regulation of FOXP3+ and CTLA‐4 expression. In contrast, IL‐7 does not enhance proliferation of FOXP3+thymocytes or induce demethylation of FOXP3+ regulatory T cell‐specific demethylated region. After the CD4+CD8+ stage, the FOXP3+ thymocytes down‐regulate CD127 expression but despite very low levels of CD127, remain responsive to IL‐7. These results suggest that IL‐7 affects human regulatory T cell development in the thymus by at least 2 distinct mechanisms: suppression of apoptosis and up‐regulation of FOXP3+ expression.

Left superior vena cava draining to left atrium with partially anomalous pulmonary venous connection and left-to-right shunt – multimodality imaging and percutaneous treatment

Corresponding author: Linda Litwin, Department of Congenital Heart Defects and Pediatric Cardiology, SMDZ, Silesian University Medical, 9 M. Curie-Sklodowskiej St, 41-800 Zabrze, Poland, phone: +48 784 053 435, e-mail: linda.litwin@med.sum.edu.pl Received: 16.02.2018, accepted: 11.04.2018. Left superior vena cava draining to left atrium with partially anomalous pulmonary venous connection and left-to-right shunt – multimodality imaging and percutaneous treatment

Resection of the stenotic segment with individually tailored anastomosis for symptomatic congenital tracheal stenosis in infants

OBJECTIVES To analyse retrospectively population-based results of congenital tracheal stenosis (CTS) repair in infants in Finland. METHODS Data on infants who were operated on for CTS in Helsinki Childrens Hospital between August 1988 and May 2013 were analysed retrospectively. Fibreoptic bronchoscopy was performed perioperatively and in follow-up of all the surviving patients. The median follow-up time was 7 (range 1-20) years. RESULTS Thirteen infants were operated on for CTS. Resection of the stenotic segment with individually tailored anastomosis was used in 12 patients and slide tracheoplasty in 1 patient. The median age at the operation was 2.9 (range 0.2-19) months. Eight (62%) patients had associated cardiovascular defects, which were corrected during the same operation. The median length of stenosis was 35% (range 25-60%) of the total length of the trachea. The median length of time of postoperative mechanical ventilation was 10 (range 5-19) days. The median length of time of intensive care treatment was 15 (range 7-40) days. One patient died from hypoplastic lung tissue and fibrosis, and multiorgan failure. One patient required reoperation, and 3 other patients received balloon bronchodilatations postoperatively. There was no late mortality. All of the 12 survivors had a good outcome. CONCLUSION Resection with individually tailored anastomosis with up to 55% of the stenotic segment of the trachea presented a good long-term outcome.

Response to Comment on “Cutting Edge: Human CD4−CD8− Thymocytes Express FOXP3 in the Absence of a TCR”

The best candidate for regulatory T (Treg) cell lineage-determining factor is currently the Forkhead box transcription factor FOXP3. FOXP3 up-regulation has been linked to TCR-mediated signals, and in mice the abrogation of TCR expression or signals also prevents FoxP3 expression. In contrast, the TCR dependence of human FOXP3 is assumed but not established. In this study we show on a single cell level that 1.4% (range 0.1-3.8%) of CD4(-)CD8(-) thymocytes in healthy humans express FOXP3, two thirds of them without any detectable alphabeta TCR. These TCR(-)FOXP3(+) cells were mostly CD25(-) and did not express gammadelta TCR or B cell, NK cell, or monocyte-associated markers. Like mature Treg cells, they were mostly CD2(+)CD127(low) and expressed cytoplasmic CTLA-4. Our results suggest that in immature human thymocytes the expression of FOXP3 precedes surface TCR, in which case TCR-mediated signals cannot be responsible for the thymic up-regulation of FOXP3.