Surface LAMP-2 Is an Endocytic Receptor That Diverts Antigen Internalized by Human Dendritic Cells into Highly Immunogenic Exosomes.

The lysosome-associated membrane protein (LAMP) family includes the dendritic cell endocytic receptors DC-LAMP and CD68, as well as LAMP-1 and LAMP-2. In this study we identify LAMP-1 (CD107a) and LAMP-2 (CD107b) on the surface of human monocyte-derived dendritic cells (MoDC) and show only LAMP-2 is internalized after ligation by specific Abs, including H4B4, and traffics rapidly but transiently to the MHC class II loading compartment, as does Ag conjugated to H4B4. However, pulsing MoDC with conjugates of primary (keyhole limpet hemocyanin; KLH) and recall (Bet v 1) Ags (H4B4*KLH and H4B4*Bet v 1) induced significantly less CD4 cell proliferation than pulsing with native Ag or Ag conjugated to control mAb (ISO*KLH and ISO*Bet v 1). In H4B4*KLH-pulsed MoDC, the duration of KLH residence in MHC class II loading compartments was significantly reduced, as were surface HLA-DR and DR-bound KLH-derived peptides. Paradoxically, MoDC pulsed with H4B4*KLH, but not the other KLH preparations, induced robust proliferation of CD4 cells separated from them by a transwell membrane, indicating factors in the supernatant were responsible. Furthermore, extracellular vesicles from supernatants of H4B4*KLH-pulsed MoDC contained significantly more HLA-DR and KLH than those purified from control MoDC, and KLH was concentrated specifically in exosomes that were a uniquely effective source of Ag in standard T cell proliferation assays. In summary, we identify LAMP-2 as an endocytic receptor on human MoDC that routes cargo into unusual Ag processing pathways, which reduces surface expression of Ag-derived peptides while selectively enriching Ag within immunogenic exosomes. This novel pathway has implications for the initiation of immune responses both locally and at distant sites.

Left ventricular pumping during the transition-adaptation sequence in preterm infants: impact of the patent ductus arteriosus.

BackgroundPostnatally, the immature left ventricle (LV) is subjected to high systemic afterload. Hypothesizing that LV pumping would change during transition-adaptation, we analyzed the LV in preterm infants (GA≤32+6), clinically stable or with a hemodynamically significant patent ductus arteriosus (hPDA) by applying a pump model.MethodsPumping was characterized by EA (effective arterial elastance, reflecting afterload), EES (end-systolic LV elastance, reflecting contractility), EA/EES coupling ratios, descriptive EA:EES relations, and EA/EES graphs. Data calculated from echocardiography and blood pressure were analyzed by diagnosis (S group: clinically stable, no hPDA, n=122; hPDA group, n=53) and by periods (early transition: days of life 1-3; late transition: 4-7; and adaptation: 8-30).ResultsS group: LV pumping was characterized by an increased EA/EES coupling ratio of 0.65 secondary to low EES in early transition, a tandem rise of both EA and EES in late transition, and an EA/EES coupling ratio of 0.45 secondary to high EES in adaptation; hPDA group: time-trend analyses showed significantly lower EA (P<0.0001) and EES (P=0.006). Therefore, LV pumping was characterized by a lower EA/EES coupling ratio (P=0.088) throughout transition-adaptation.ConclusionsIn stable infants, facing high afterload, the immature LV, enhanced by the physiological PDA, increases its contractility. In hPDA, facing low afterload, the overloaded immature LV exhibits a consistently lower contractility.

Fetal MRI detects early alterations of brain development in Tetralogy of Fallot.

OBJECTIVE: Prenatal imaging has identified alterations of brain growth in fetuses with congenital heart disease. However, little is known about the timing of altered brain development and its occurrence in specific congenital heart disease subgroups. This magnetic resonance imaging study aimed to identify early (median, 25 gestational weeks [GW]) changes in fetal total brain (TBV), gray matter (GMV), and subcortical brain (SBV) volumes in Tetralogy of Fallot (TOF) cases in utero. STUDY DESIGN: Fetal magnetic resonance imaging (1.5 Tesla) was performed in 24 fetuses who were diagnosed with TOF and 24 normal age-matched control fetuses (20-34 GW). TBV, GMV, SBV, intracranial cavity, cerebellar, ventricular, and external cerebrospinal fluid volumes were quantified by manual segmentation based on coronal T2-weighted sequences. Mixed model analyses of variance and t-tests were conducted to compare cases and control fetuses. RESULTS: TBV was significantly lower (P < .001) in early (<25 GW) and late TOF cases. Both GMV (P = .003) and SBV (P = .001) were affected. The GMV-to-SBV ratio declined in fetuses with TOF (P = .026). Compared with normal fetuses, ventricular volume was increased (P = .0048). External cerebrospinal fluid was enlarged in relation to head size (P < .001). Intracranial cavity volume (P = .314) and cerebellar volume (P = .074) were not significantly reduced in fetuses with TOF. CONCLUSION: TOF is associated with smaller volumes of gray and white matter and enlarged cerebrospinal fluid spaces. These changes are present at ≤25 GW and indicate altered fetal brain growth in this pathophysiologic entity during early stages of human brain development.

Preterm infants who later require duct ligation show different vital signs and pH in early postnatal life.

AIM: The study investigated early postnatal vital signs in very low birthweight (VLBW) infants who later developed patent ductus arteriosus (PDA). We hypothesised that the early postnatal course of vital signs and blood gas variables might differ between infants whose PDA closed spontaneously, those who responded to ibuprofen and those who later required PDA ligation. METHODS: We analysed computerised records of VLBW infants born <28 weeks of gestational age, including vital signs, arterial pH values and echocardiographic data from the first postnatal days. RESULTS: In total, 104 infants were included in the study. In the group of infants born <26 weeks of gestational age and requiring ibuprofen for PDA (n = 34), 12 infants ultimately required surgical ligation. Infants requiring ligation showed significantly lower oxygen saturation (p = 0.019), mean blood pressure (p = 0.034) and higher heart rate fluctuation ranges (p = 0.040) in the first five postnatal days than those who responded to ibuprofen. In multivariable logistic regression analysis, lower pH values in the first 48 h predicted the subsequent requirement for ligation independent of gestational age (p = 0.004). CONCLUSION: Patients <26 weeks of gestational age requiring PDA ligation showed significant differences in the course of vital signs and pH during the first days of life.

The Effects of Hemodynamic Alterations on Lung Volumes in Fetuses with Tetralogy of Fallot: An MRI Study.

This study assessed whether the presence of tetralogy of Fallot (TOF) affects fetal lung development and whether these fetuses are at risk of pulmonary hypoplasia (PH). Furthermore, we investigated whether the degree of the concomitant pulmonary valve (PV) stenosis or a stenosis in the branch pulmonary arteries correlates with the fetal lung volume. Lung volumetry was performed in 16 fetuses with TOF who underwent MRI between gestational weeks 21 and 35 and in 22 controls. Fetal biometric data and the diameters of the PVs were evaluated by ultrasound. PV and branch pulmonary artery diameters were standardized (z-scores), and fetal lung volume/fetal body weight (FLV/FBW) ratios (ml/g) were calculated. The mean FLV/FBW ratio (0.031 ± 0.009 ml/g) in the TOF group was statistically significantly lower than in the control group (0.041 ± 0.009 ml/g; P = 0.003). None of the fetuses with TOF met the criterion for PH. FLV did not correlate with the degree of PV stenosis, but rather with the presence of a significant stenosis in at least one branch pulmonary artery. The presence of TOF moderately affects fetal lung growth, which is apparently not dependent on the degree of the PV stenosis. However, only an additional stenosis in at least one branch pulmonary artery was associated with a small FLV, but not with PH. Thus, reduced pulmonary blood flow may be offset by additional factors, such as the ability to establish a sufficient collateral system and to alter structural vascular size and, thus, pulmonary vascular resistance.

Fetal cardiac disease and fetal lung volume: an in utero MRI investigation.

OBJECTIVES: Magnetic resonance imaging (MRI) is a powerful, noninvasive tool to study fetal lung volumes after 18 weeks of gestation in vivo. In neonates with congenital heart disease (CHD), proper lung function is essential for postnatal survival. Antenatal detection of abnormal pulmonary development may help to optimize prenatal and perinatal management of at-risk fetuses. We aimed to investigate lung volumes in fetuses with prenatally diagnosed heart disease. METHODS: A cross-sectional, retrospective study of 105 consecutive singleton pregnancies with CHD and a control, non-CHD group (n = 115), that underwent fetal MRI was performed. The heart defects detected were divided into four groups. Lung volumes of fetuses with heart disease were compared with control, non-CHD fetuses. In addition, z-scores of lung volumes were calculated for the CHD group (normal range z-scores from -2-+2). RESULTS: As a group, fetuses with CHD have significantly smaller lung volumes compared with control fetuses when corrected by gestational age (GA) (p = 0.049). Of the 105 CHD fetuses studied, 18 had lung volumes with a z-score < -2. Fetuses with different types of CHD showed similar lung volumes. CONCLUSION: Our data indicate that postpartum pulmonary symptoms and outcome in neonates with congenital heart disease may be attributed to the cardiac disease itself and in part to smaller lung volumes.

Tachycardia-induced cardiomyopathy after functional closure of the foramen ovale in a fetus.

Although fetal tachyarrhythmias are relatively rare, they are an important causes of fetal morbidity and mortality. We report a 30-week pregnant woman with fetal tachycardia, fetal hydrops and ascites. Fetal heart rate was 230 bpm. Fetal heart rate was 230 bpm. M-mode echocardiography revealed a tachycardia with a 1:1 relationship between atrial and ventricular conduction and a short time interval between ventricular and atrial contraction. These findings suggested a diagnosis of atrioventricular re-entrant tachycardia. On the third day digoxin treatment, the fetal heart rate was still 225 bpm with a 1:1 relationship between atrial and ventricular conduction. At this time, no flow across the foramen ovale was detected. Functional closure of the foramen ovale was suspected.

Ventricular interaction in children after repair of tetralogy of Fallot: a longitudinal echocardiographic study.

AIMS: Progressive right ventricular (RV) dilation due to pulmonary regurgitation (PR) after repair of tetralogy of Fallot (TOF) may impair left ventricular (LV) filling. Our aim was to analyse long-term time courses of M-mode LV and RV measurements and to relate these to the degree of PR. METHODS AND RESULTS: Retrospective longitudinal cohort of children (n = 88) after repair of TOF followed by serial echocardiography over 9 years. LV and RV diameters were expressed by z-scores based on normal paediatric reference values. Time courses of LV and RV diameter z-scores, degree of PR, and influence of co-variables were analysed using mixed regression models. LV diameter z-scores were significantly lowered before repair, increased after surgery, but fell again over time; thus, mean LV diameters were significantly lower than normal population means at all times. LV diameter z-scores correlated negatively with RV dilation and degree of PR. Notably, they were significantly higher in patients with previous shunts. After pulmonary valve replacement, LV diameter z-scores recovered to normal, whereas RV diameter z-scores remained abnormal. CONCLUSION: Our results confirm progressive adverse RV-LV interaction in the long-term post-operative follow-up of TOF. The use of z-scores facilitated the analysis of time courses of LV and RV diameters.

Special schooling in children with congenital heart disease: a risk factor for being disadvantaged in the world of employment.

The objective of this study was to evaluate type of schooling in children with congenital heart disease (CHD) who were inpatients at a tertiary pediatric cardiology center. This retrospective cohort study included 227 consecutive children with CHD (male, 125; female, 102) who had been inpatients from 1996 to 2005. Data on type of schooling had been documented by the in-hospital teacher at the time of admission. Medical data were obtained by reviewing medical charts. The primary endpoint was the percentage of children requiring special schooling, which was related to the respective percentage in the Austrian pediatric background population. Furthermore, the influence of clinical and demographic covariables was assessed. Fifteen percent (vs. 3.6% in the background population) of the study cohort required special schooling; 86% of them had a history of cardiac surgery. Cardiopulmonary bypass surgery in the first year of life showed a trend for an association with an increased frequency of special schooling. There were no significant associations with the Aristotle Basic Score (a measure for procedure complexity in CHD), gender, or first language. In conclusion, the need for special schooling is increased in children with CHD.

Effects of Feedback on Chest Compression Quality: A Randomized Simulation Study.

OBJECTIVES: Our aim for this study was to test whether visual and verbal feedback compared with instructor-led feedback improve the quality of pediatric cardiopulmonary resuscitation (CPR). METHODS: There were 653 third-year medical students randomly assigned to practice pediatric CPR on 1 of 2 manikins (infant and adolescent; n = 344 and n = 309, respectively). They were further randomly assigned to 1 of 3 feedback groups: The instructor feedback (IF) group (n = 225) received traditional, instructor-led feedback without any additional feedback device. The device feedback (DF) group (n = 223) received real-time visual feedback from a feedback device. The instructor and device feedback (IDF) group (n = 205) received verbal feedback from an instructor who continuously reviewed the trainees' performance using the feedback device. After the training, participants' CPR performance was assessed on the same manikin while no feedback was being provided. RESULTS: For the primary outcome of total compression score, participants in the DF and IDF groups performed similarly, with both groups showing scores significantly (P < .001) better than those of the IF group. The same findings held for correct hand position and the proportion of complete release. For compression rate, the DF group was at the higher end of the guideline for 100 to 120 chest compressions per minute compared with the IF and IDF groups (both P < .001). No effect of feedback on compression depth was found. CONCLUSIONS: Chest compression performance significantly improved with both visual and verbal feedback compared with instructor-led feedback. Feedback devices should be implemented during pediatric resuscitation training to improve resuscitation performance.

Discrepancy between invasive and non-invasive blood pressure readings in extremely preterm infants in the first four weeks of life.

BACKGROUND: The agreement between invasive and non-invasive blood pressure (BP) readings in the first days of life of preterm infants is contentiously debated. OBJECTIVE: To compare mean, systolic and diastolic invasive (IBP) and non-invasive BP (NBP) readings obtained during routine care in the first four weeks of life of extremely preterm infants. METHODS: We extracted pairs of IBP and NBP readings obtained from preterm infants born below 28 weeks of gestation from the local database. After exclusion of erroneous measurements, we investigated the repeated measures correlation and analyzed the agreement (bias) and precision adjusted for multiple measurements per individual. RESULTS: Among 335 pairs of IBP and NBP readings obtained from 128 patients, we found correlation coefficients >0.65 for mean, systolic and diastolic BP values. The bias for mean BP readings was -0.4 mmHg (SD 6.1), for systolic BP readings 6.2 mmHg (SD 8.1), and for diastolic BP readings -4.3 mmHg (SD 6.5). Overestimation of systolic IBP and underestimation of diastolic IBP by the non-invasive measurement were found both in the group with gestational age from 23 to 25.9 weeks and in the group with gestational age from 26 to 27.9 weeks. Systolic NBP readings tended to exceed invasive readings in the range <50 mmHg (bias 9.9 mmHg) whereas diastolic NBP readings were lower than invasive values particularly in the range >30 mmHg (bias -5.5 mmHg). CONCLUSION: The disagreement between invasive and non-invasive BP readings in infants extends to the first four weeks of life. Biases differ for mean, systolic and diastolic BP values. Our observation implies that they may depend on the range of the blood pressure. Awareness of these biases and preemptive concomitant use of IBP and NPB readings may contribute to reducing over- or under-treatment.

Lymphoma in Danon disease with chronic rhabdomyolysis treated with EPOCH-R: A case report.

Rare disorders often represent a challenge for clinicians and require close collaboration of an interdisciplinary team.We present the complex case of a 22-year-old male with Danon disease and late-onset of posttransplant lymphoproliferative disorder after heart transplantation. The critical aspects of his condition were: pre-existing rhabdomyolysis; infiltration of muscle and gut with lymphoma; advanced clinical stage with bulky disease; nonresponsiveness to the reduction of immunosuppression and rituximab monotherapy; expected cardiotoxicity of anthracyclines. Therefore, the patient was treated with the EPOCH-R protocol, which includes continuous administration of doxorubicin over 4 days, instead of R-CHOP, in which the anthracycline is given in a short single infusion. Complete remission was achieved after the third cycle; rhabdomyolysis did not increase and heart function was not affected. The patient received a total of 6 cycles and is still in metabolic complete remission.We conclude that patients with Danon disease can be treated with anthracycline-containing chemotherapy and that continuous infusion of EPOCH-R does not exacerbate pre-existing rhabdomyolysis.

Infantile sialic acid storage disease and protein-losing gastroenteropathy.

We report on a boy who presented at birth with gastroschisis and thereafter developed the characteristic clinical symptoms of infantile sialic acid storage disease within the first two months of life. Measurements of free sialic acid excretion (tenfold increase) in the urine and a 15-fold elevation of free sialic acid in cultured fibroblasts proved the diagnosis. The clinical course was complicated by hypertrophic cardiomyopathy, recurrent infections, hypothyroidism, and intestinal protein losses, which had never been described before in an infantile sialic acid storage disease patient. The child died at the age of 10 months. Clinical and laboratory findings are discussed and compared with other cases described in the literature.

Self-concept in male and female adolescents with congenital heart disease.

Cognitive achievement, behavioural problems, and various dimensions of personality were assessed in 48 male and female patients with congenital heart disease (CHD) aged from 12 to 16 years in comparison to a control group. The CHD group showed a lower speed of cognitive processing but seemed to have less state-anxiety and to possess a higher superego strength. Male adolescents with CHD presented with a reduced perceived capacity and self-esteem. This was not true for adolescent girls with CHD. The negative self-concept of boys with CHD may be partly explained by reduced physical ability interfering with peer relationships.

Ventriculo-arterial coupling in children with Still's murmur.

Still's murmur is the most common innocent heart murmur in children and considered flow related; however, so far the cause of the murmur has not yet been fully explained. Assessment of the hemodynamic ventriculo-arterial interaction and the proportional anatomical dimensions of the left ventricle and the aortic root were the objective for this study. This case-control study was conducted at the Division of Pediatric Cardiology, Vienna Medical University, including healthy children with and without Still's murmur. To assess ventriculo-arterial interaction, the model of ventriculo-arterial coupling (VAC) was applied. The model describes the interaction between the left ventricle (left ventricular contractility, ELV) and the arterial system (effective arterial elastance, EA) by the VAC ratio EA/ELV. The parameters EA and ELV can be derived from M-mode echocardiography thereby allowing a noninvasive pressure-volume analysis. Outcomes comprised VAC ratio and diameters of both the aortic root (AOD) and the left ventricle in end diastole (LVED) and end systole (LVES) as well as their relative proportions, ejection fraction (EF), stroke volume (SV), blood pressure (BP), and heart rate (HR). Forty-three healthy children with Still's murmur (mean age 5.2 years) and 42 healthy children without murmur (mean age 5.8 years) participated in this study. Children with Still's murmur had a significantly lower VAC ratio EA/ELV (0.5 ± 0.13 vs. 0.59 ± 0.15; P < 0.005), a significantly higher EF% (67.1 ± 5.8 vs. 63.3 ± 5.6; P < 0.005, P < 0.01), and a larger SV per kg bodyweight (1.84 ± 0.33 vs. 1.68 ± 0.38; P < 0.05) than controls. BP, HR, and diameters of AOD, LVED, and LVES as well as their relative anatomic proportions did not differ between children with Still's murmur and controls. Still's murmur seems to be generated by a subtle alteration in ventriculo-arterial coupling in healthy children. This result can be translated to parents, as they may be informed that their child's innocent murmur is caused by a more "lively interplay between the heart and the aorta."

Structural congenital brain disease in congenital heart disease: results from a fetal MRI program.

OBJECTIVE: To identify the type and incidence of fetal brain pathology in fetuses with a prenatal diagnosis of congenital heart disease (CHD). PATIENTS AND METHODS: 67 pregnant women underwent a fetal MR-examinations between 20 and 38 gestational weeks. MR was done on a 1.5 T superconducting system. The type of cardiac malformation was defined by fetal echocardiography. Fetuses with a chromosomal abnormality or an extracardiac anomaly were excluded. RESULTS: Fetal MRI scans in the final study cohort (53 fetuses) yielded normal results in 32 fetuses and a brain abnormality in 21 fetuses. Congenital brain disease (CBD) was found in 39% of the final study cohort of fetuses with CHD. MRI findings were classified into malformations, acquired lesions and widening of the ventricles and/or outer CSF spaces (malformations: 7 fetuses, acquired lesions: 5 fetuses, changes in CSF spaces: 9 fetuses). Asymmetry of the ventricles was the most common finding in the CSF group. CONCLUSIONS: Our data suggest that fetal MRI can be used to characterize structural CBD in CHD. Advanced MRI techniques such as diffusion tensor imaging and proton spectroscopy are tools that, in the future, will certainly shed light on the spectrum of structural and functional CBDs that are associated with CHD.