Vascular and pulmonary effects of ibuprofen on neonatal lung development.

BACKGROUND: Ibuprofen is a nonsteroidal anti-inflammatory drug that is commonly used to stimulate closure of a patent ductus arteriosus (PDA) in very premature infants and may lead to aberrant neonatal lung development and bronchopulmonary dysplasia (BPD). METHODS: We investigated the effect of ibuprofen on angiogenesis in human umbilical cord vein endothelial cells (HUVECs) and the therapeutic potential of daily treatment with 50 mg/kg of ibuprofen injected subcutaneously in neonatal Wistar rat pups with severe hyperoxia-induced experimental BPD. Parameters investigated included growth, survival, lung histopathology and mRNA expression. RESULTS: Ibuprofen inhibited angiogenesis in HUVECs, as shown by reduced tube formation, migration and cell proliferation via inhibition of the cell cycle S-phase and promotion of apoptosis. Treatment of newborn rat pups with ibuprofen reduced pulmonary vessel density in the developing lung, but also attenuated experimental BPD by reducing lung inflammation, alveolar enlargement, alveolar septum thickness and small arteriolar wall thickening. CONCLUSIONS: In conclusion, ibuprofen has dual effects on lung development: adverse effects on angiogenesis and beneficial effects on alveolarization and inflammation. Therefore, extrapolation of the beneficial effects of ibuprofen to premature infants with BPD should be done with extreme caution.

Combination of pioglitazone, a PPARγ agonist, and synthetic surfactant B-YL prevents hyperoxia-induced lung injury in adult mice lung explants.

INTRODUCTION: Hyperoxia-induced lung injury is characterized by acute alveolar injury, disrupted epithelial-mesenchymal signaling, oxidative stress, and surfactant dysfunction, yet currently, there is no effective treatment. Although a combination of aerosolized pioglitazone (PGZ) and a synthetic lung surfactant (B-YL peptide, a surfactant protein B mimic) prevents hyperoxia-induced neonatal rat lung injury, whether it is also effective in preventing hyperoxia-induced adult lung injury is unknown. METHOD: Using adult mice lung explants, we characterize the effects of 24 and 72-h (h) exposure to hyperoxia on 1) perturbations in Wingless/Int (Wnt) and Transforming Growth Factor (TGF)-ß signaling pathways, which are critical mediators of lung injury, 2) aberrations of lung homeostasis and injury repair pathways, and 3) whether these hyperoxia-induced aberrations can be blocked by concomitant treatment with PGZ and B-YL combination. RESULTS: Our study reveals that hyperoxia exposure to adult mouse lung explants causes activation of Wnt (upregulation of key Wnt signaling intermediates ß-catenin and LEF-1) and TGF-ß (upregulation of key TGF-ß signaling intermediates TGF-ß type I receptor (ALK5) and SMAD 3) signaling pathways accompanied by an upregulation of myogenic proteins (calponin and fibronectin) and inflammatory cytokines (IL-6, IL-1ß, and TNFα), and alterations in key endothelial (VEGF-A and its receptor FLT-1, and PECAM-1) markers. All of these changes were largely mitigated by the PGZ + B-YL combination. CONCLUSION: The effectiveness of the PGZ + B-YL combination in blocking hyperoxia-induced adult mice lung injury ex-vivo is promising to be an effective therapeutic approach for adult lung injury in vivo.

Lung Surfactant Protein B Peptide Mimics Interact with the Human ACE2 Receptor.

Lung surfactant is a complex mixture of phospholipids and surfactant proteins that is produced in alveolar type 2 cells. It prevents lung collapse by reducing surface tension and is involved in innate immunity. Exogenous animal-derived and, more recently, synthetic lung surfactant has shown clinical efficacy in surfactant-deficient premature infants and in critically ill patients with acute respiratory distress syndrome (ARDS), such as those with severe COVID-19 disease. COVID-19 pneumonia is initiated by the binding of the viral receptor-binding domain (RBD) of SARS-CoV-2 to the cellular receptor angiotensin-converting enzyme 2 (ACE2). Inflammation and tissue damage then lead to loss and dysfunction of surface activity that can be relieved by treatment with an exogenous lung surfactant. Surfactant protein B (SP-B) is pivotal for surfactant activity and has anti-inflammatory effects. Here, we study the binding of two synthetic SP-B peptide mimics, Super Mini-B (SMB) and B-YL, to a recombinant human ACE2 receptor protein construct using molecular docking and surface plasmon resonance (SPR) to evaluate their potential as antiviral drugs. The SPR measurements confirmed that both the SMB and B-YL peptides bind to the rhACE2 receptor with affinities like that of the viral RBD-ACE2 complex. These findings suggest that synthetic lung surfactant peptide mimics can act as competitive inhibitors of the binding of viral RBD to the ACE2 receptor.

Efficacy, dose-response, and aerosol delivery of dry powder synthetic lung surfactant treatment in surfactant-deficient rabbits and premature lambs.

BACKGROUND: Dry powder (DP) synthetic lung surfactant may be an effective means of noninvasive delivery of surfactant therapy to premature infants supported with nasal continuous positive airway pressure (nCPAP) in low-resource settings. METHODS: Four experimental DP surfactant formulations consisting of 70% of phospholipids (DPPC:POPG 7:3), 3% Super Mini-B (SMB) or its sulfur-free derivate B-YL as SP-B peptide mimic, 25% of lactose or trehalose as excipient, and 2% of NaCl were formulated using spray drying. In vitro surface activity was confirmed with captive bubble surfactometry. Surfactant particle size was determined with a cascade impactor and inhaled dose was quantified using a spontaneously breathing premature lamb lung model supported with CPAP. In vivo surfactant efficacy was demonstrated in three studies. First, oxygenation and lung compliance were monitored after intratracheal instillation of resuspended DP surfactant in intubated, ventilated, lavaged, surfactant-deficient juvenile rabbits. In dose-response studies, ventilated, lavaged, surfactant-deficient rabbits received 30, 60, 120 or 240 mg/kg of DP B-YL:Lactose or B-YL:Trehalose surfactant by aerosol delivery with a low flow aerosol chamber via their endotracheal tube. Noninvasive aerosolization of DP B-YL:Trehalose surfactant via nasal prongs was tested in spontaneous breathing premature lambs supported with nCPAP. Intratracheal administration of 200 mg/kg of Curosurf®, a liquid porcine surfactant, was used as a positive control. RESULTS: Mass median aerosol diameter was 3.6 µm with a geometric standard deviation of 1.8. All four experimental surfactants demonstrated high surface efficacy of intratracheal instillation of a bolus of ~ 100 mg/kg of surfactant with improvement of oxygenation and lung compliance. In the dose-response studies, rabbits received incremental doses of DP B-YL:Lactose or B-YL:Trehalose surfactant intratracheally and showed an optimal response in oxygenation and lung function at a dose of 120-240 mg/kg. Aerosol delivery via nasal prongs of 1 or 2 doses of ~ 100 mg/kg of B-YL:Trehalose surfactant to premature lambs supported with nCPAP resulted in stabilization of spontaneous breathing and oxygenation and lung volumes comparable to the positive control. CONCLUSION: These studies confirm the clinical potential of DP synthetic lung surfactant with B-YL peptide as a SP-B mimic to alleviate surfactant deficiency when delivered as a liquid bolus or as an aerosol.

Structural and functional stability of the sulfur-free surfactant protein B peptide mimic B-YL in synthetic surfactant lipids.

BACKGROUND: Optimal functionality of synthetic lung surfactant for treatment of respiratory distress syndrome in preterm infants largely depends on the quality and quantity of the surfactant protein B (SP-B) peptide mimic and the lipid mixture. B-YL peptide is a 41-residue sulfur-free SP-B mimic with its cysteine and methionine residues replaced by tyrosine and leucine, respectively, to enhance its oxidation resistance. AIM: Testing the structural and functional stability of the B-YL peptide in synthetic surfactant lipids after long-term storage. METHODS: The structural and functional properties of B-YL peptide in surfactant lipids were studied using three production runs of B-YL peptides in synthetic surfactant lipids. Each run was held at 5 °C ambient temperature for three years and analyzed with structural and computational techniques, i.e., MALDI-TOF mass spectrometry, ATR-Fourier Transform Infrared Spectroscopy (ATR-FTIR), secondary homology modeling of a preliminary B-YL structure, and tertiary Molecular Dynamic simulations of B-YL in surfactant lipids, and with functional methods, i.e., captive bubble surfactometry (CBS) and retesting in vivo surface activity in surfactant-deficient young adult rabbits. RESULTS: MALDI-TOF mass spectrometry showed no degradation of the B-YL peptide as a function of stored time. ATR-FTIR studies demonstrated that the B-YL peptide still assumed stable alpha-helical conformations in synthetic surfactant lipids. These structural findings correlated with excellent in vitro surface activity during both quasi-static and dynamic cycling on CBS after three years of cold storage and in vivo surface activity of the aged formulations with improvements in oxygenation and dynamic lung compliance approaching those of the positive control surfactant Curosurf®. CONCLUSIONS: The structure of the B-YL peptide and the in vitro and in vivo functions of the B-YL surfactant were each maintained after three years of refrigeration storage.

Neonatal hematological parameters and the risk of moderate-severe bronchopulmonary dysplasia in extremely premature infants.

OBJECTIVE: To evaluate the association between hematological parameters at birth and the risk of moderate-severe bronchopulmonary dysplasia (BPD) in a cohort of extremely preterm infants. METHODS: This is a retrospective study of all extremely premature infants admitted to the neonatal intensive care unit, Shenzhen Maternity and Child Healthcare Hospital from January 2016 to May 2018. Extremely prematurity was defined as a delivery at a gestational age ≤ 28 weeks or a birth weight ≤ 1000 g. BPD was diagnosed if oxygen exposure exceeded 28 days and the severity was decided at 36 weeks PMA or discharge. Multivariable analysis was performed to assess the independence of the association between hematological parameters at birth and risk of moderate or severe BPD. RESULTS: A total of 115 extremely premature infants were analyzed in this study. The median platelet count, neutrophil and monocyte count at birth were significantly higher in infants with moderate-severe BPD compared to infants without BPD (228 vs 194*109/l, P = 0.004; 5.0 vs 2.95*109/l, P = 0.023; 0.88 vs 0.63*109/l, P = 0.026, respectively) whereas the mean platelet volume was significantly lower in infants with moderate-severe BPD than those without BPD (9.1 vs 9.4 fl, P = 0.002). After adjusting for covariates, the risk of moderate-severe BPD was independently associated with platelet count≥207*109/l (odds ratio 3.794, 95% confidence interval: 1.742-8.266, P = 0.001). CONCLUSION: Our findings suggest that hematologic parameters at birth are different in extremely preterm infants who will develop moderate-severe BPD. A higher platelet count at birth may increase the risk of moderate-severe BPD after extremely premature birth.

Stability of an amphipathic helix-hairpin surfactant peptide in liposomes.

Surfactant protein B (SP-B; 79 residues) is a member of the saposin superfamily and plays a pivotal role in lung function. The N- and C-terminal regions of SP-B, cross-linked by two disulfides, were theoretically predicted to fold as charged amphipathic helices, suggesting participation in surfactant activities. Previous studies with oxidized Super Mini-B (SMB), a construct based on the N- and C-regions of SP-B (i.e., residues 1-25 and 63-78) joined with a designer turn (-PKGG-) and two disulfides, indicated that freshly prepared SMB in lipids folded as a surface active, α-helix-hairpin. Because other peptides modeled on α-helical SP domains lost helicity and surfactant activity on storage, experiments were here performed on oxidized SMB in surfactant liposomes stored at ~2-8°C for ≤5.5years. Captive bubble surfactometry confirmed low minimum surface tensions for fresh and stored SMB preparations. FTIR spectroscopy of fresh and stored SMB formulations showed secondary structures compatible with the peptide folding as α-helix-hairpin. A homology (I-TASSER) model of oxidized SMB demonstrated a globular protein, exhibiting a core of hydrophobic residues and a surface of polar residues. Since mass spectroscopy indicated that the disulfides were maintained on storage, the stability of SMB may be partly due to the disulfides bringing the N- and C-α-helices closer. Mass spectroscopy of stored SMB preparations showed some methionine oxidation, and also partial deacylation of surfactant phospholipids to form lyso-derivatives. However, the stable conformation and activity of stored SMB surfactant suggest that the active helix-hairpin resists these chemical changes which otherwise may lead to surfactant inhibition.

Cerebral imaging and neurodevelopmental outcome after entero- and human parechovirus sepsis in young infants.

Enterovirus (EV) and human parechovirus (HPeV) are major causes of sepsis-like illness in infants under 90 days of age and have been identified as neurotropic. Studies about acute and long-term neurodevelopment in infants with sepsis-like illness without the need for intensive care are few. This study investigates cerebral imaging and neurodevelopmental outcome following EV and HPeV infection in these infants. We studied infants under 90 days of age who were admitted to a medium care unit with proven EV- or HPeV-induced sepsis-like illness. In addition to standard care, we did a cerebral ultrasound and cerebral magnetic resonance imaging (MRI), as well as neurodevelopmental follow-up at 6 weeks and 6 months and Bayley Scale of Infant and Toddler Development 3rd edition (BSID-III) investigation at 1 year of age. Twenty-six infants, 22 with EV and 4 with HPeV, were analysed. No abnormalities were detected at cerebral imaging. At 1 year of age, two infants had a moderate delay on both the motor and cognitive scale, one on the cognitive scale only and three others on the gross motor scale only. CONCLUSION: Although our study population, especially the number of HPeV positive infants is small, our study shows that these infants do not seem to develop severe neurodevelopmental delay and neurologic sequelae more often than the normal Dutch population. Follow-up to school age allows for more reliable assessments of developmental outcome and is recommended for further studies to better assess outcome. What is known: • Enterovirus and Human Parechovirus infections are a major cause of sepsis-like illness in young infants. • After intensive care treatment for EV or HPeV infection, white matter abnormalities and neurodevelopmental delay have been described. What is new: • In our 'medium care' population, no abnormalities at cerebral imaging after EV- or HPeV-induced sepsis-like illness have been found. • At 1 year of age, infants who had EV- or HPeV-induced sepsis-like illness do not seem to develop severe neurodevelopmental delay and neurologic sequelae more often than the normal population.

The perfusion index of healthy term infants during transition at birth.

UNLABELLED: Perfusion index is a continuous parameter provided by pulse oximetry and might be useful for evaluating hemodynamic changes at birth and identifying transitional problems. The objective was to describe perfusion index values in term infants immediately after birth. Perfusion index of 71 healthy term born infants were recorded during the first 10 min after birth, using a pulse oximetry sensor placed preductally. A Wilcoxon signed-rank test was used to compare between time points. No significant trend in perfusion index could be observed in term-delivered infants. There was a significant difference between 2 and 3 min (2.4 (1.6-5.0) vs. 2.3 (1.6-3.7), p = 0.05) and between 3 and 4 min after birth (2.3 (1.6-3.7) vs. 2.1 (1.4-3.2), p < 0.001). There was no significant change in median PI values in the following 8 min. CONCLUSION: Perfusion index does not change significantly during transition at birth in healthy term infants born by normal vaginal delivery or cesarean section. Large variation in perfusion index causes monitoring this parameter to have limited value. WHAT IS KNOWN: • Perfusion index is a non-invasive indicator for peripheral perfusion. • Perfusion index values <1.24 are seen as an accurate predictor for severity of illness for infants admitted to the neonatal intensive care unit. What is new: • Although significant physiological changes occur during birth, perfusion index remains stable. • Large variation in perfusion index causes monitoring of this value to have limited value as an additional parameter for evaluating transition at birth.

Metformin attenuates hyperoxia-induced lung injury in neonatal rats by reducing the inflammatory response.

Because therapeutic options are lacking for bronchopulmonary dysplasia (BPD), there is an urgent medical need to discover novel targets/drugs to treat this neonatal chronic lung disease. Metformin, a drug commonly used to lower blood glucose in type 2 diabetes patients, may be a novel therapeutic option for BPD by reducing pulmonary inflammation and fibrosis and improving vascularization. We investigated the therapeutic potential of daily treatment with 25 and 100 mg/kg metformin, injected subcutaneously in neonatal Wistar rats with severe experimental BPD, induced by continuous exposure to 100% oxygen for 10 days. Parameters investigated included survival, lung and heart histopathology, pulmonary fibrin and collagen deposition, vascular leakage, right ventricular hypertrophy, and differential mRNA expression in the lungs of key genes involved in BPD pathogenesis, including inflammation, coagulation, and alveolar development. After daily metformin treatment rat pups with experimental BPD had reduced mortality, alveolar septum thickness, lung inflammation, and fibrosis, demonstrated by a reduced influx of macrophages and neutrophils and hyperoxia-induced collagen III and fibrin deposition (25 mg/kg), as well as improved vascularization (100 mg/kg) compared with control treatment. However, metformin did not ameliorate alveolar enlargement, small arteriole wall thickening, vascular alveolar leakage, and right ventricular hypertrophy. In conclusion metformin prolongs survival and attenuates pulmonary injury by reducing pulmonary inflammation, coagulation, and fibrosis but does not affect alveolar development or prevent pulmonary arterial hypertension and right ventricular hypertrophy in neonatal rats with severe hyperoxia-induced experimental BPD.

Mask versus Nasal Tube for Stabilization of Preterm Infants at Birth: Respiratory Function Measurements.

OBJECTIVE: To compare the nasal tube with face mask as interfaces for stabilization of very preterm infants at birth by using physiological measurements of leak, obstruction, and expired tidal volumes during positive pressure ventilation (PPV). STUDY DESIGN: In the delivery room, 43 infants <30 weeks gestation were allocated to receive respiratory support by nasal tube or face mask. Respiratory function, heart rate, and oxygen saturation were measured. Occurrence of obstruction, amount of leak, and tidal volumes were compared using a Mann-Whitney U test or a Fisher exact test. RESULTS: The first 5 minutes after initiation of PPV were analyzed (1566 inflations in the nasal tube group and 1896 inflations in the face mask group). Spontaneous breathing coincided with PPV in 32% of nasal tube and 34% of face mask inflations. During inflations, higher leak was observed using nasal tube compared with face mask (98% [33%-100%] vs 14 [0%-39%]; P < .0001). Obstruction occurred more often (8.2% vs 1.1%; P < .0001). Expired tidal volumes were significantly lower during inflations when using nasal tube compared with face mask (0.0 [0.0-3.1] vs 9.9 [5.5-12.8] mL/kg; P < .0001) and when spontaneous breathing coincided with PPV (4.4 [2.1-8.4] vs 9.6 [5.4-15.2] mL/kg; P < .0001) but were similar during breathing on continuous positive airway pressure (4.7 [2.8-6.9] vs 4.8 [2.7-7.9] mL/kg; P > 0.05). Heart rate was not significantly different between groups, but oxygen saturation was significantly lower in the nasal tube group the first 2 minutes after start of respiratory support. CONCLUSIONS: The use of a nasal tube led to large leak, more obstruction, and inadequate tidal volumes compared with face mask. TRIAL REGISTRATION: Trial registration Registered with the Dutch Trial Registry (NTR 2061) and the Australia and New Zealand Clinical Trials Register (ACTRN 12610000230055).

Synthetic lung surfactant reduces alveolar-capillary protein leakage in surfactant-deficient rabbits.

PURPOSE OF THE STUDY: Alveolar-capillary leakage of proteinaceous fluid impairs alveolar ventilation and surfactant function and decreases lung compliance in acute lung injury. We investigated the correlation between lung function and total protein levels in bronchoalveolar lavage fluid (BALF) of ventilated, lavaged surfactant-deficient rabbits treated with various clinical and synthetic lung surfactant preparations. MATERIALS AND METHODS: 109 ventilated, young adult New Zealand White rabbits underwent lung lavage to induce surfactant-deficiency (PaO2 <100 torr in 100% O2), were treated with a clinical surfactant or a synthetic surfactant preparation with surfactant protein B (SP-B) and/or surfactant protein C (SP-C) analogs, and mechanically ventilated for 120 min. Total protein levels in postmortem BALF were correlated with arterial PO2 (PaO2) and dynamic lung compliance values at 120 min post-surfactant treatment. RESULTS: Repeated lung lavages decreased mean PaO2 values from 540 to 58 torr and lung compliance from 0.64 to 0.33 mL/kg/cm H2O. Two hours after surfactant therapy and mechanical ventilation, mean PaO2 values had increased to 346 torr and lung compliance to 0.44 mL/kg/cm H2O. Eighty-six rabbits (79%) responded to surfactant therapy with an increase in PaO2 to values >200 torr. Fourteen non-responders received inactive surfactant preparations. BALF protein levels were inversely correlated with PaO2 and lung compliance (P < .001). Surfactant preparations containing both SP-B and SP-C proteins or peptide analogs outperformed single protein/peptide preparations. CONCLUSIONS: Clinical and synthetic surfactant therapy reduces alveolar-capillary protein leakage in surfactant-deficient rabbits. Surfactant preparations with both SP-B and SP-C (analogs) were more efficient than preparations with SP-B or SP-C alone.

Angiotensin II type 2 receptor ligand PD123319 attenuates hyperoxia-induced lung and heart injury at a low dose in newborn rats.

Intervening in angiotensin (Ang)-II type 2 receptor (AT2) signaling may have therapeutic potential for bronchopulmonary dysplasia (BPD) by attenuating lung inflammation and preventing arterial hypertension (PAH)-induced right ventricular hypertrophy (RVH). We first investigated the role of AT2 inhibition with PD123319 (0.5 and 2 mg·kg(-1)·day(-1)) on the beneficial effect of AT2 agonist LP2-3 (5 µg/kg twice a day) on RVH in newborn rats with hyperoxia-induced BPD. Next we determined the cardiopulmonary effects of PD123319 (0.1 mg·kg(-1)·day(-1)) in two models: early treatment during continuous exposure to hyperoxia for 10 days and late treatment starting on day 6 in rat pups exposed postnatally to hyperoxia for 9 days, followed by a 9-day recovery period in room air. Parameters investigated included lung and heart histopathology, fibrin deposition, vascular leakage, and differential mRNA expression. Ten days of coadministration of LP2-3 and PD123319 abolished the beneficial effects of LP2-3 on RVH in experimental BPD. In the early treatment model PD123319 attenuated cardiopulmonary injury by reducing alveolar septal thickness, pulmonary influx of inflammatory cells, including macrophages and neutrophils, medial wall thickness of small arterioles, and extravascular collagen III deposition, and by preventing RVH. In the late treatment model PD123319 diminished PAH and RVH, demonstrating that PAH is reversible in the neonatal period. At high concentrations PD123319 blocks the beneficial effects of the AT2-agonist LP2-3 on RVH. At low concentrations PD123319 attenuates cardiopulmonary injury by reducing pulmonary inflammation and fibrosis and preventing PAH-induced RVH but does not affect alveolar and vascular development in newborn rats with experimental BPD.

Improvement in neurodevelopmental outcome in survivors of twin-twin transfusion syndrome treated with laser surgery.

OBJECTIVE: To compare the incidence of neurodevelopmental impairment in surviving children from pregnancies with twin-twin transfusion syndrome (TTTS) treated with laser surgery between 2 time periods. STUDY DESIGN: We compared the neurodevelopmental outcome between the first consecutive cohort of TTTS pregnancies treated with laser surgery from 2000 to 2005, with a cohort treated between 2008 and 2010. Neurologic, cognitive, and motor development was evaluated using Bayley scales at 2 years of age corrected for prematurity. RESULTS: A total of 229 twin pregnancies were treated with laser surgery, 113 in the first cohort and 106 in the recent cohort. Overall survival increased from 70% (158/226) to 80% (170/212) (P = .014). The incidence of neurodevelopmental impairment decreased from 18% (28/152) to 6% (10/155) (P < .01). In multivariate analysis, severe cerebral injury at birth was independently associated with neurodevelopmental impairment (odds ratio, 34.86; 95% confidence interval, 11.83-102.75; P < .01). CONCLUSION: Overall survival in TTTS has improved over time, with a concomitant reduction in the incidence of neurodevelopmental impairment. Research focused on prevention of cerebral injury is needed to further improve outcomes of these complicated twin pregnancies.

Noninvasive measurements of hemodynamic transition directly after birth.

BACKGROUND: Cardiac output depends on stroke volume and heart rate (HR). Only HR is used to monitor hemodynamic transition. METHODS: In 24 term newborns born via cesarean section, HR and preductal blood pressure (BP) were measured. Also, using echocardiography, left ventricular dimensions and (Doppler derived) left ventricular output (LVO) were examined at 2, 5, and 10 min after birth. RESULTS: Mean (SD) HR and BP did not change with time (mean HR: 157 (21) bpm at 2 min, 154 (17) bpm at 5 min, and 155 (14) bpm at 10 min; mean BP: 51.2 (15.4) mm Hg at 2 min, 50.5 (11.7) mm Hg at 5 min, and 49.6 (9.5) mm Hg at 10 min). Left ventricular end-diastolic diameter increased from 2 to 5 min (14.3 (1.3) vs. 16.3 (1.7) mm; P < 0.001) and stabilized at 10 min (16.7 (1.4) mm). LVO increased between 2 and 5 min (151 (47) vs. 203 (55) ml/kg/min; P < 0.001) and stabilized at 10 min (201 (45) ml/kg/min). LVO increase was associated with rise in left ventricular stroke volume (r = 0.94; P < 0.001), not with rise in HR (r = 0.37; P value not significant). CONCLUSION: Left ventricular dimensions and LVO significantly increased the first 5 min after birth and stabilized at 10 min, whereas BP remained stable. LVO and left ventricular dimension increase are presumably due to increasing left ventricular preload resulting from pulmonary blood flow and ductal shunting increase.

The effect of early catch-up growth on health and well-being in young adults.

AIM: To study the effect of catch-up growth in the 1st year on cognition, health-related quality of life (HRQoL), problem behavior and growth in young adults. METHODS: We included individuals without severe complications and born small for gestational age (SGA; n = 228 for weight, n = 203 for length) or with a low head circumference (HC, n = 178) or a low weight adjusted for length (n = 64) in the Collaborative Project on Preterm and SGA Infants. Neonatal growth was standardized (standard deviation scores for gestational age, SDSGA) according to GA-specific reference charts. Catch-up growth was defined as SDSGA at 1 year of age adjusted for SDSGA at birth. Cognition was defined by the Multicultural Capacity Test-Intermediate Level, HRQoL by the London Handicap Scale (LHS) and the Health Utility Index Mark 3 categorized into 4 levels (Multi-Attribute Utility, MAU), and problem behavior by the Young Adult Self-Report. We adjusted for potential confounders. RESULTS: Most adults were born preterm (93.7%). A higher catch-up growth in the 1st year was associated with better cognition (B = 2.57, 95% CI 0.08-5.05 for weight), less disabilities according to the LHS (B = 2.06, 95% CI 0.35-3.78 for HC) and the MAU (OR = 0.67, 95% CI 0.48-0.95 for HC) and higher final height (B = 0.33, 95% CI 0.18-0.47 for weight; B = 0.41, 95% 0.28-0.55 for length, and B = 0.18, 95% CI 0.04-0.33 for HC) in young adulthood. CONCLUSION: There are long-term benefits of catch-up growth.

Acute peripartum twin-twin transfusion syndrome: incidence, risk factors, placental characteristics and neonatal outcome.

AIM: The aim of this study was to examine the incidence, placental characteristics and outcome in acute peripartum twin-twin transfusion syndrome (TTTS). MATERIAL AND METHODS: All consecutive cases of monochorionic (MC) twins admitted to our center were included in the study. We excluded cases with chronic TTTS or twin anemia polycythemia sequence. Acute peripartum TTTS was defined when the inter-twin hemoglobin difference at birth was >8 g/dL. RESULTS: A total of 241 MC twin pregnancies were included in the study. Acute peripartum TTTS was detected in six cases (2.5%, 6/241). Vaginal delivery occurred more often in the acute peripartum TTTS group compared to the control group of uncomplicated MC pregnancies, 100% (6/6) versus 57% (135/235) (P = 0.002), respectively. Acute anemia was detected only in firstborn twins. Placental angioarchitecture in acute peripartum TTTS was similar to the placentas in the control group. CONCLUSIONS: The incidence of acute peripartum TTTS is low (2.5%). Birth order and mode of delivery appear to be associated with increased risk of acute peripartum TTTS.

Structure and Function of Canine SP-C Mimic Proteins in Synthetic Surfactant Lipid Dispersions.

Lung surfactant is a mixture of lipids and proteins and is essential for air breathing in mammals. The hydrophobic surfactant proteins B and C (SP-B and SP-C) assist in reducing surface tension in the lung alveoli by organizing the surfactant lipids. SP-B deficiency is life-threatening, and a lack of SP-C can lead to progressive interstitial lung disease. B-YL (41 amino acids) is a highly surface-active, sulfur-free peptide mimic of SP-B (79 amino acids) in which the four cysteine residues are replaced by tyrosine. Mammalian SP-C (35 amino acids) contains two cysteine-linked palmitoyl groups at positions 5 and 6 in the N-terminal region that override the ß-sheet propensities of the native sequence. Canine SP-C (34 amino acids) is exceptional because it has only one palmitoylated cysteine residue at position 4 and a phenylalanine at position 5. We developed canine SP-C constructs in which the palmitoylated cysteine residue at position 4 is replaced by phenylalanine (SP-Cff) or serine (SP-Csf) and a glutamic acid-lysine ion-lock was placed at sequence positions 20-24 of the hydrophobic helical domain to enhance its alpha helical propensity. AI modeling, molecular dynamics, circular dichroism spectroscopy, Fourier Transform InfraRed spectroscopy, and electron spin resonance studies showed that the secondary structure of canine SP-Cff ion-lock peptide was like that of native SP-C, suggesting that substitution of phenylalanine for cysteine has no apparent effect on the secondary structure of the peptide. Captive bubble surfactometry demonstrated higher surface activity for canine SP-Cff ion-lock peptide in combination with B-YL in surfactant lipids than with canine SP-Csf ion-lock peptide. These studies demonstrate the potential of canine SP-Cff ion-lock peptide to enhance the functionality of the SP-B peptide mimic B-YL in synthetic surfactant lipids.

Ambrisentan reduces pulmonary arterial hypertension but does not stimulate alveolar and vascular development in neonatal rats with hyperoxic lung injury.

Ambrisentan, an endothelin receptor type A antagonist, may be a novel therapeutic agent in neonatal chronic lung disease (CLD) by blocking the adverse effects of the vasoconstrictor endothelin-1, especially pulmonary arterial hypertension (PAH)-induced right ventricular hypertrophy (RVH). We determined the cardiopulmonary effects of ambrisentan treatment (1-20 mg·kg(-1)·day(-1)) in neonatal rats with CLD in 2 models: early treatment during continuous exposure to hyperoxia for 10 days and late treatment starting on day 6 in rat pups exposed postnatally to hyperoxia for 9 days, followed by a 9-day recovery period in room air. Parameters investigated included survival, lung and heart histopathology, right ventricular function, fibrin deposition, and differential mRNA expression in the lungs. In the early treatment model, we investigated the role of nitric oxide synthase (NOS) inhibition with N(ω)-nitro-L-arginine methyl ester (L-NAME; 25 mg·kg(-1)·day(-1)) during ambrisentan treatment. In the early treatment model, ambrisentan improved survival with reduced lung fibrin and collagen III deposition, arterial medial wall thickness, and RVH. These changes were not affected by L-NAME administration. Ambrisentan did not reduce the influx of macrophages and neutrophils or prevent reduced irregular elastin expression. In the late treatment model, ambrisentan diminished PAH, RVH, and right ventricular peak pressure, demonstrating that RVH is reversible in the neonatal period. Alveolarization and vascularization were not affected by ambrisentan. In conclusion, ambrisentan prolongs survival and reduces lung injury, PAH, and RVH via a NOS-independent mechanism but does not affect inflammation and alveolar and vascular development in neonatal rats with CLD.

Agonists of MAS oncogene and angiotensin II type 2 receptors attenuate cardiopulmonary disease in rats with neonatal hyperoxia-induced lung injury.

Stimulation of MAS oncogene receptor (MAS) or angiotensin (Ang) receptor type 2 (AT2) may be novel therapeutic options for neonatal chronic lung disease (CLD) by counterbalancing the adverse effects of the potent vasoconstrictor angiotensin II, consisting of arterial hypertension (PAH)-induced right ventricular hypertrophy (RVH) and pulmonary inflammation. We determined the cardiopulmonary effects in neonatal rats with CLD of daily treatment during continuous exposure to 100% oxygen for 10 days with specific ligands for MAS [cyclic Ang-(1-7); 10-50 µg·kg(-1)·day(-1)] and AT2 [dKcAng-(1-7); 5-20 µg·kg(-1)·day(-1)]. Parameters investigated included lung and heart histopathology, fibrin deposition, vascular leakage, and differential mRNA expression in the lungs of key genes involved in the renin-angiotensin system, inflammation, coagulation, and alveolar development. We investigated the role of nitric oxide synthase inhibition with N(ω)-nitro-l-arginine methyl ester (25 mg·kg(-1)·day(-1)) during AT2 agonist treatment. Prophylactic treatment with agonists for MAS or AT2 for 10 days diminished cardiopulmonary injury by reducing alveolar septum thickness and medial wall thickness of small arterioles and preventing RVH. Both agonists attenuated the pulmonary influx of inflammatory cells, including macrophages (via AT2) and neutrophils (via MAS) but did not reduce alveolar enlargement and vascular alveolar leakage. The AT2 agonist attenuated hyperoxia-induced fibrin deposition. In conclusion, stimulation of MAS or AT2 attenuates cardiopulmonary injury by reducing pulmonary inflammation and preventing PAH-induced RVH but does not affect alveolar and vascular development in neonatal rats with experimental CLD. The beneficial effects of AT2 activation on experimental CLD were mediated via a NOS-independent mechanism.