Characteristics and outcomes in children with congenital central hypoventilation syndrome on long-term mechanical ventilation in the Netherlands.

Congenital central hypoventilation syndrome (CCHS) is a rare condition characterized by central hypoventilation, leading to the majority of patients being dependent on ventilatory support during sleep. This condition is often accompanied by various associated symptoms, due to a PHOX2B gene variant involved in neuronal crest cell migration. This study is the first to review the characteristics and outcomes in children with CCHS on long-term mechanical ventilation in the Netherlands. We performed a retrospective study of all CCHS patients treated in the 4 Centers of Home Mechanical Ventilation of the University Medical Centers in the Netherlands from 2000 till 2022 by collecting information from the electronic medical records, documented during follow-up. We included 31 patients, out of which 27 exhibited a known genetic profile associated with CCHS, while no PHOX2B variant was identified in the remaining patients. Among the 27 patients with known genetic profiles, 10 patients had a non-polyalanine repeat expansion mutation (NPARM), followed by 20/27, 20/25, and 20/26 polyalanine repeat expansion mutations (PARMs) in descending order. The most common presentation involved respiratory failure or apneas during the neonatal period with an inability to wean off ventilation. The majority of patients required ventilatory support during sleep, with four patients experiencing life-threatening events related to this dependency. Daily use of ventilatory support varied among different genetic profiles. All genotypes reported comorbidities, with Hirschsprung's disease and cardiac arrhythmias being the most reported comorbidities. Notably, Hirschprung's disease was exclusively observed in patients with a 20/27 PHOX2B variant. CONCLUSION: Our study results suggest that in our cohort, the genotype is not easily associated to the phenotype in CCHS. Consistent with these findings and international literature, we recommend a thorough annual evaluation for all patients with CCHS to ensure optimal management and follow-up. WHAT IS KNOWN: • The majority of CCHS patients are dependent on ventilatory support. • Variants in the PHOX2B gene are responsible for the characteristics of CCHS. WHAT IS NEW: • This study provides insight into the clinical course and long-term outcomes of CCHS patients in the Netherlands. • In CCHS, the genotype is not easily associated with the phenotype, requiring a thorough life-long follow-up for all patients.

Walking with continuous positive airway pressure.

A ventilator-dependent child had been in the paediatric intensive care unit (PICU) ever since birth. As a result, she had fallen behind considerably in her development. After 18 months, continuous positive airway pressure was successfully administered via a tracheostomy tube with a novel lightweight device. This enabled her to walk in the PICU. With this device, the child was discharged home where she could walk with an action range of 10 m. Subsequently, her psychomotor development improved remarkably. To the authors' knowledge, this is the first case report of a patient, adult or paediatric, who could actually walk with a sufficient radius of action while receiving long-term respiratory support.

[Active management of children after ingestion of a button battery]. / Actiefbeleid bij een kind dat een knoopbatterij heeft ingeslikt.

Four children, three girls in the age range up to 14 months and a boy aged 10 years, were admitted because of button battery ingestion. In two patients, the course was uncomplicated, with spontaneous passage of the batteries. Two other patients, a girl aged 11 months and a girl aged 6 weeks, developed severe complications: stenosis of the oesophagus in one patient and a dramatic clinical course with a tracheo-oesophageal fistula and oesophageal damage in the other. Ingestion of foreign bodies in children is a common problem. With the increased use of miniature electronic devices, the incidence of button battery ingestion is rising. Ingestion of a battery is an indication for urgent referral and radiological examination. Electrochemical tissue damage and impaction may lead to serious complications within hours. If the battery is located in the oesophagus, endoscopic removal should be attempted as soon as possible. A conservative approach can be followed when the battery is located in the stomach or beyond, and complaints are absent.

Dexamethasone for treatment of patients mechanically ventilated for lower respiratory tract infection caused by respiratory syncytial virus.

BACKGROUND: A study was undertaken to evaluate the efficacy of dexamethasone in patients mechanically ventilated for lower respiratory infection caused by respiratory syncytial virus (RSV-LRTI). METHODS: In a multicentre randomised controlled trial patients were randomised to receive either intravenous dexamethasone (0.15 mg/kg 6 hourly for 48 hours) or placebo. End points were the duration of mechanical ventilation, length of stay (LOS) in the pediatric intensive care unit (PICU) and in hospital, and the duration of supplemental oxygen administration. RESULTS: Thirty seven patients received dexamethasone and 45 received placebo. There was no significant difference in any of the end points between the two groups. In a post hoc analysis patients were stratified into those with mild gas exchange anomalies (PaO(2)/FiO(2) >200 mm Hg and/or mean airway pressure 10 cm H(2)O, pneumonia group). In the 39 patients with bronchiolitis the duration of mechanical ventilation was 4.3 days shorter in the dexamethasone group than in the placebo group (4.9 v 9.2 days, 95% CI -7.8 to -0.8, p=0.02) and the duration of supplemental oxygen was 3.6 days shorter (7.7 v 11.3 days, 95% CI -8.0 to -0.1, p=0.048). No differences in end points were found in the pneumonia group. CONCLUSIONS: Dexamethasone had no beneficial effect in patients mechanically ventilated for RSV-LRTI but was found to have a beneficial effect in patients with bronchiolitis.

Agonist-promoted trafficking of human bradykinin receptors: arrestin- and dynamin-independent sequestration of the B2 receptor and bradykinin in HEK293 cells.

In this study, we analysed the agonist-promoted trafficking of human B(2) (B(2)R) and B(1) (B(1)R) bradykinin (BK) receptors using wild-type and green fluorescent protein (GFP)-tagged receptors in HEK293 cells. B(2)R was sequestered to a major extent upon exposure to BK, as determined by the loss of cell-surface B(2)R using radioligand binding and by imaging of B(2)R-GFP using laser-scanning confocal fluorescence microscopy. Concurrent BK sequestration was revealed by the appearance of acid-resistant specific BK receptor binding. The same techniques showed that B(1)R was sequestered to a considerably lesser extent upon binding of des-Arg(10)-kallidin. B(2)R sequestration was rapid (half-life approximately 5 min) and reached a steady-state level that was significantly lower than that of BK sequestration. B(2)R sequestration was minimally inhibited by K44A dynamin (22.4+/-3.7%), and was insensitive to arrestin-(319-418), which are dominant-negative mutants of dynamin I and beta-arrestin respectively. Furthermore, the B(2)R-mediated sequestration of BK was completely insensitive to both mutants, as was the association of BK with a caveolae-enriched fraction of the cells. On the other hand, agonist-promoted sequestration of the beta(2)-adrenergic receptor was dramatically inhibited by K44A dynamin (81.2+/-16.3%) and by arrestin-(319-418) (36.9+/-4.4%). Our results show that B(2)R is sequestered to a significantly greater extent than is B(1)R upon agonist treatment in HEK293 cells. Furthermore, B(2)R appears to be recycled in the process of sequestering BK, and this process occurs in a dynamin- and beta-arrestin-independent manner and, at least in part, involves caveolae.

[Clinical thinking and decision-making in practice. A child with dyspnea and excess pleural fluid]. / Klinisch denken en beslissen in de praktijk. Een kind met dyspneu en overmatig pleuravocht.

Pleural fluid was diagnosed on an X-ray in a 9-month-old boy with acute dyspnoea without fever. Thoracentesis showed exudate and the patient was diagnosed as having empyema and was treated with continuous chest tube drainage and antibiotics. The culture of the pleural fluid was negative. A month after discharge the boy developed recurrent pleural effusion with dyspnoea. A mass in the right hemithorax was found upon additional diagnostic evaluation. Microscopic evaluation of tumour biopsy specimen showed a malignancy. Infantile fibromatosis was diagnosed in a surgical specimen. The patient died after having developed a recurrent tumour. Infectious causes are not likely in a child with pleural fluid without fever. Pleural fluid has to be analysed in transudate or exudate. Exudate requires a complete diagnostic evaluation.

T cell subset analysis in peripheral blood of children with RSV bronchiolitis.

Respiratory syncytial virus (RSV) bronchiolitis is partially an immune-mediated disease in which RSV-specific T cells play a predominant role. The peripheral blood T cell response was studied in patients with RSV bronchiolitis in order to detect evidence for T cell redistribution during natural RSV infection and if so, which subsets are involved. 18 patients with RSV bronchiolitis and 13 control patients were studied. The white blood cell count, the number of T cells and T cell subsets in blood on admission and after 1 week were measured. The absolute count of natural killer cells and gamma delta + T cells on admission were significantly lower in RSV patients in comparison with the control group. During the course of RSV bronchiolitis CD8+ T cells and IL-2 receptor-positive T cells increased significantly. In the ventilated patients the total lymphocytes and the number of T cells and several T cell subsets with surface molecules compatible with an activation state of the cell were decreased in comparison with the non-ventilated RSV patients on admission. During RSV bronchiolitis, consistent shifts in T cell subsets can be demonstrated in the peripheral blood compatible with redistribution from the circulation probably towards the lungs. These findings are more pronounced in patients with severe disease.

Bradykinin sequesters B2 bradykinin receptors and the receptor-coupled Galpha subunits Galphaq and Galphai in caveolae in DDT1 MF-2 smooth muscle cells.

In this report, we show that the vasoactive peptide agonist bradykinin (BK) when bound to B2 BK receptors on DDT1 MF-2 smooth muscle cells promotes the recruitment and sequestration of the occupied receptors and the receptor-coupled G-protein alpha subunits Galphaq and Galphai in caveolae. Association of ligand receptor complexes and Galpha subunits with caveolae was indicated by their co-enrichment on density gradients with caveolin, a marker protein for caveolae. Caveolin and Galpha subunits were monitored by immunoblotting, whereas receptors were monitored as ligand receptor complexes formed by labeling receptors with the agonist BK or the antagonist NPC17731 prior to cell disruption and caveolae enrichment. These complexes were detected with radioligand and by immunoblotting with BK antibodies. A direct interaction of Galpha subunits with caveolin was also indicated by their co-immunoprecipitation. Immunoelectron microscopy revealed that the enriched caveolin, Galpha subunits, and BK receptor complexes were present in structures of 0.1-0.2 microm. At 4 degrees C, BK and NPC17731 receptor complexes were detected in caveolae, and both complexes were sensitive to acid washing prior to cell disruption and caveolae enrichment. Elevation of the temperature to 37 degrees C increased the amount of BK receptor complexes in caveolae with a maximal response at 10 min (continuous labeling) or 20 min (single-round labeling), and the complexes became acid-resistant. These conditions also increased the amount of Galphaq and Galphai in caveolae with a maximal response at 5-10 min. In contrast, the NPC17731 receptor complexes remained acid-sensitive and dissociated at this temperature, and antagonists did not increase the amount of Galpha subunits in caveolae. These results show that some agonists that act through G-protein-coupled receptors promote the association of their receptors and receptor-coupled Galpha subunits with caveolae.

Spinal osteomyelitis caused by Proteus mirabilis in a child.

Osteomyelitis due to Proteus mirabilis is rare. Spinal osteomyelitis caused by this organism has only been described in adults. This is the first paediatric case of P. mirabilis vertebral osteomyelitis.

[Bilirubin encephalopathy in an icteric bile-vomiting infant with high intestinal obstruction]. / Bilirubine-encefalopathie bij een icterische, 'gallig' spugende zuigeling met hogedarmobstructie.

In a 5-day-old full-term, dehydrated boy with bilious vomiting and a cephalhaematoma, bilirubin encephalopathy was diagnosed at a serum bilirubin level of 395 mumol/l. The patient was rehydrated intravenously and treated with phototherapy and an exchange transfusion, after which the serum bilirubin level decreased. The neurological condition normalised during his stay in the hospital. Hyperbilirubinaemia was caused by an increased enterohepatic circulation due to a high intestinal obstruction and resorption of the cephalhaematoma. Toxicity was caused by dehydration and fasting. Even with new bilirubin guidelines it remains important to distinguish a healthy neonate from an ill jaundiced neonate, because at lower serum bilirubin levels symptoms may occur that fit the clinical picture of a bilirubin encephalopathy.

Ether lipid synthesis: purification and identification of alkyl dihydroxyacetone phosphate synthase from guinea-pig liver.

Alkyl-dihydroxyacetone phosphate synthase, the second enzyme involved in ether phospholipid biosynthesis from dihydroxyacetone phosphate and responsible for glycero-ether bond formation, has been purified from guinea-pig liver. Alkyl-dihydroxyacetone phosphate synthase was solubilized from a membrane fraction prepared from an enriched peroxisome fraction with Triton X-100 and potassium chloride. The solubilized enzyme was further purified by chromatography on QAE-Sephadex, Matrex Red, Phosphocellulose and Concanavalin A. Upon sodium dodecyl sulfate-polyacrylamide gel electrophoresis alkyl-dihydroxyacetone phosphate synthase appears as a 65 kDa band. Chromatofocusing revealed an isoelectric point of pH 5.9 for the enzyme. The pH optimum of alkyl-dihydroxyacetone phosphate synthase was found to be between pH 7 and 8 in a 50 mM potassium phosphate buffer. The specific activity of the enzyme was estimated to be at least 350 nmol.min-1.mg-1, corresponding to a purification of at least 13,000-fold.