Accuracy of Pulse Oximetry Screening for Critical Congenital Heart Defects after Home Birth and Early Postnatal Discharge.

OBJECTIVE: To assess the accuracy of pulse oximetry screening for critical congenital heart defects (CCHDs) in a setting with home births and early discharge after hospital deliveries, by using an adapted protocol fitting the work patterns of community midwives. STUDY DESIGN: Pre- and postductal oxygen saturations (SpO2) were measured ≥1 hour after birth and on day 2 or 3. Screenings were positive if the SpO2 measurement was <90% or if 2 independent measures of pre- and postductal SpO2 were <95% and/or the pre-/postductal difference was >3%. Positive screenings were referred for pediatric assessment. Primary outcomes were sensitivity, specificity, and false-positive rate of pulse oximetry screening for CCHD. Secondary outcome was detection of noncardiac illnesses. RESULTS: The prenatal detection rate of CCHDs was 73%. After we excluded these cases and symptomatic CCHDs presenting immediately after birth, 23 959 newborns were screened. Pulse oximetry screening sensitivity in the remaining cohort was 50.0% (95% CI 23.7-76.3) and specificity was 99.1% (95% CI 99.0-99.2). Pulse oximetry screening was false positive for CCHDs in 221 infants, of whom 61% (134) had noncardiac illnesses, including infections (31) and respiratory pathology (88). Pulse oximetry screening did not detect left-heart obstructive CCHDs. Including cases with prenatally detected CCHDs increased the sensitivity to 70.2% (95% CI 56.0-81.4). CONCLUSION: Pulse oximetry screening adapted for perinatal care in home births and early postdelivery hospital discharge assisted the diagnosis of CCHDs before signs of cardiovascular collapse. High prenatal detection led to a moderate sensitivity of pulse oximetry screening. The screening also detected noncardiac illnesses in 0.6% of all infants, including infections and respiratory morbidity, which led to early recognition and referral for treatment.

Effect of oxidative stress on respiratory epithelium from children with Down syndrome.

Children with Down syndrome are at high risk for acute respiratory distress syndrome. In Down syndrome, both regulation of inflammation and apoptosis, important in acute respiratory distress syndrome pathophysiology, are abnormal. This has been linked to an imbalance in free radical scavengers. We investigated the expression of free radical scavengers and the effect of oxidative stress in terms of apoptosis and inflammation in respiratory epithelium from children with Down syndrome compared with control subjects. We cultured primary nasal epithelial cells from Down syndrome children (n=12) and controls (n=17) and exposed them to oxidative stress by supplementing superoxide. First we showed that the expression of the free radical scavengers CuZn-superoxide dismutase was 28% higher (p=0.06), catalase was 36% lower (p=0.04) and glutathione peroxidase was 73% lower (p=0.004) in Down syndrome children compared with controls. We found no significant difference in apoptosis, between Down syndrome and control subjects after exposure to oxidative stress. We also found no significant difference in levels of interleukin (IL)-1ß, IL-6, IL-8, vascular endothelial growth factor and granulocyte colony-stimulating factor in primary nasal epithelial cell supernatant after exposure to oxidative stress between Down syndrome and control subjects. We found an imbalance in free radical scavengers in respiratory epithelial cells from children with Down syndrome, but this did not result in increased levels of either apoptosis or inflammation upon exposure to oxidative stress.

Imbalance between pulmonary angiotensin-converting enzyme and angiotensin-converting enzyme 2 activity in acute respiratory distress syndrome.

OBJECTIVE: Angiotensin-converting enzyme and its effector peptide angiotensin II have been implicated in the pathogenesis of acute respiratory distress syndrome. Recently, angiotensin-converting enzyme 2 was identified as the counter-regulatory enzyme of angiotensin-converting enzyme that converts angiotensin II into angiotensin-(1-7). The aim of this study was to determine pulmonary angiotensin-converting enzyme and angiotensin-converting enzyme 2 activity in patients with acute respiratory distress syndrome. DESIGN: Prospective observational pilot study. SETTING: A PICU of a university hospital. PATIENTS: Fourteen patients admitted, requiring mechanical ventilation for respiratory syncytial virus lower respiratory tract infection. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Two groups of patients were distinguished at admission: a group fulfilling the criteria for acute respiratory distress syndrome and a non-acute respiratory distress syndrome group. Angiotensin-converting enzyme and angiotensin-converting enzyme 2 activity were measured in bronchoalveolar lavage fluid. Patients with acute respiratory distress syndrome had increased angiotensin-converting enzyme activity and decreased angiotensin-converting enzyme 2 activity (p < 0.001) compared with the control group. CONCLUSION: It is shown for the first time that in acute respiratory distress syndrome, enhanced angiotensin-converting enzyme activity is paralleled by a reduced angiotensin-converting enzyme 2 activity, similar to that found in an experimental rat model of acute respiratory distress syndrome. The reduced angiotensin-converting enzyme 2 activity may be counteracted by restoring angiotensin-(1-7) level, thereby offering a novel treatment modality for this syndrome.

Biallelic BUB1 mutations cause microcephaly, developmental delay, and variable effects on cohesion and chromosome segregation.

Budding uninhibited by benzimidazoles (BUB1) contributes to multiple mitotic processes. Here, we describe the first two patients with biallelic BUB1 germline mutations, who both display microcephaly, intellectual disability, and several patient-specific features. The identified mutations cause variable degrees of reduced total protein level and kinase activity, leading to distinct mitotic defects. Both patients' cells show prolonged mitosis duration, chromosome segregation errors, and an overall functional spindle assembly checkpoint. However, while BUB1 levels mostly affect BUBR1 kinetochore recruitment, impaired kinase activity prohibits centromeric recruitment of Aurora B, SGO1, and TOP2A, correlating with anaphase bridges, aneuploidy, and defective sister chromatid cohesion. We do not observe accelerated cohesion fatigue. We hypothesize that unresolved DNA catenanes increase cohesion strength, with concomitant increase in anaphase bridges. In conclusion, BUB1 mutations cause a neurodevelopmental disorder, with clinical and cellular phenotypes that partially resemble previously described syndromes, including autosomal recessive primary microcephaly, mosaic variegated aneuploidy, and cohesinopathies.

Potential role of soluble TRAIL in epithelial injury in children with severe RSV infection.

Lower respiratory tract infection by respiratory syncytial virus (RSV) is a frequent cause of acute lung injury in young children and infants. Studies in adults and animals suggest that tumor necrosis factor receptor (TNFR) ligands may mediate lung injury by causing apoptosis of epithelial cells. The main goal of the present study was to determine whether the TNF-related apoptosis-inducing ligand (Apo2L/TRAIL) pathway may be implicated in epithelial injury during severe RSV infection in children. We report elevated levels of soluble (s)TRAIL released by leukocytes in bronchoalveolar lavage fluid (BALF) of patients with RSV-associated respiratory failure (n = 22) as compared with mechanically ventilated patients without pulmonary illness (n = 7). Primary bronchial epithelial cells of children without pulmonary disease obtained by nonbronchoscopic cytobrushing expressed both death receptors TRAIL-R1 and -R2, and were found to be susceptible for cell death by human recombinant sTRAIL in vitro. Furthermore, BALF from a patient with RSV induced cell death in these cells, which was partly attenuated by inhibiting TRAIL signaling. These data suggest that the TRAIL pro-apoptotic pathway may contribute to lung epithelial injury in severe RSV infection in children.

[A teenager with painless swelling of the PIP-joints]. / Een tiener met pijnloze zwellingen aan de vingers.

A 13-year-old boy was seen with symmetric bilateral swelling around the proximal interphalangeal joints. He did not have pain or loss of function or other signs of arthritis. Inflammation parameters and rheumatologic markers were negative. X-ray and MRI revealed soft tissue swelling. This confirmed the diagnosis pachydermodactyly, a rare benign form of fibromatosis.

Pulmonary epithelial apoptosis in fetal down syndrome: not higher than normal.

Children with Down syndrome (DS) are at high risk for acute lung injury (ALI). Pulmonary epithelial apoptosis is an important factor in the pathophysiology of ALI. Whether the risk of ALI in DS is associated with a high level of pulmonary epithelial apoptosis is not known. We hypothesized that the percentage of apoptotic epithelial cells is higher in DS than in control lungs. Lung tissue sections from autopsies of 21 fetuses with DS and 12 controls were stained with antibodies against the epithelial marker pan-cytokeratin (CK) and apoptosis marker activated caspase-3 (aC3). Spectral imaging software was used to quantify the mean percentage of pixels that showed colocalization of CK and aC3. Mean (standard deviation [SD]) gestational age in weeks was 18.7 (1.4) in DS and 18.9 (2.0) in controls (P  =  0.67). The mean (SD) percentage of CK-positive pixels was 27.2% (4.7%) in DS compared to 27.1% (6.2%) in controls (P  =  0.97). The median (interquartile range [IQR]) percentage of CK-positive pixels that showed colocalization of aC3 was 0.16% (0.18%) in DS compared to 0.27% (0.24%) in controls (P  =  0.45). The mean (SD) number of CK-positive pixels increased from 22.5% (5.2%) to 30.4% (4.6%) with the appearance of saccular morphology in controls but not in DS (P  =  0.01). The percentage of apoptotic epithelial cells in DS fetal lungs does not differ from that in controls. However, we did find a difference in the development of epithelial structures between DS and controls that may be associated with anomalies in alveolar development found at birth in DS.