Christoph Bührer

Hypoxia upregulates the histone demethylase JMJD1A via HIF-1

The histone demethylase Jumonji domain containing 1A (JMJD1A) demethylates H3K9 residues and thereby transactivates distinct target genes. Investigating the effect of hypoxia on JMJD1A expression, we found increased JMJD1A mRNA in different organs of rats exposed to normobaric hypoxia (8% O(2)). Compared to adult samples, JMJD1A was increased in most tissues of human fetuses in whom oxygen supply is low compared to postnatal levels. Upregulation of JMJD1A mRNA and protein in cultured human cells exposed to hypoxia or iron scavengers in vitro was abrogated when hypoxia-inducible factor-1 (HIF-1) signaling was blocked by siRNAs. A single pivotal hypoxia responsive element (HRE) in the promoter of the human JMJD1A gene was identified that mediates JMJD1A upregulation by hypoxia, iron scavengers, and HIF-1. These findings demonstrate that JMJD1A can be stimulated by hypoxia both in vitro and in vivo involving binding of HIF-1 to a specific HRE in the JMJD1A promoter.

Maturation‐dependent oligodendrocyte apoptosis caused by hyperoxia

In the immature human brain, periventricular leukomalacia (PVL) is the predominant white matter injury underlying the development of cerebral palsy. PVL has its peak incidence during a well‐defined period in human brain development (23–32 weeks postconceptional age) characterized by extensive oligodendrocyte migration and maturation. We hypothesized that the dramatic rise of oxygen tissue tension associated with mammalian birth and additional oxygen exposure of the preterm infant during intensive care may be harmful to immature oligodendrocytes (OLs). We therefore investigated the effects of hyperoxia on rat oligodendroglia cells in vitro and in vivo. Immature OLs (OLN‐93), their progenitors [preoligodendrocytes (pre‐OL)], and mature OLs were subjected to 80% hyperoxia (24–96 hr). Flow cytometry was used to assess cell death. Cell viability was measured by metabolism of 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyl tetrazolium (MTT). In addition, 6‐day‐old rat pups were subjected to 80% oxygen (24 hr) and then sacrificed, and their brains were processed for immunfluorescence staining. Apoptosis was detected at various stages (annexin‐V, activated caspase‐3) after 24–48 hr of incubation in 80% oxygen in pre‐ and immature OLs. Mature OLs were resistant to oxygen exposure. These results were confirmed by MTT assay. This cell death was blocked by administration of the pan‐caspase inhibitor zVAD‐fmk. Degeneration of OLs was confirmed in 7‐day‐old rat brains by positive staining for activated caspase‐3. Hyperoxia triggers maturation‐dependent apoptosis in immature and pre‐OLs and involves caspase activation. This mechanism may be relevant to the white matter injury observed in infants born preterm.

Variability in pain response to a non-pharmacological intervention across repeated routine pain exposure in preterm infants: a feasibility study.

Aim: To explore the variability in pain response in preterm infants across time who received sucrose during routine heel stick.

A critical role for Fas/CD‐95 dependent signaling pathways in the pathogenesis of hyperoxia‐induced brain injury

Prematurely born infants are at risk for development of neurocognitive impairment in later life. Oxygen treatment has been recently identified as a trigger of neuronal and oligodendrocyte apoptosis in the developing rodent brain. We investigated the role of the Fas death receptor pathway in oxygen‐triggered developmental brain injury.

Ultrastructural and molecular analysis in fatal neonatal interstitial pneumonia caused by a novel ABCA3 mutation

Pulmonary surfactant is essential to maintain alveolar patency, and invariably fatal neonatal lung disease has been recognized to involve mutations in the genes encoding surfactant protein-B or ATP-binding cassette transporter family member ABCA3. The lipid transporter ABCA3 targets surfactant phospholipids to lamellar bodies that are lysosomal-derived organelles of alveolar type II cells. ABCA3−/− mice have grossly reduced surfactant phosphatidyl glycerol levels and die of respiratory failure soon after birth. We studied lung biopsy samples of two siblings with a novel homozygous ABCA3 mutation at nucleotide position 578 (c.578C>G), leading to a Pro193Arg amino-acid exchange, who died at 55 and 105 days of age. Light microscopy revealed thickened alveolar septa with abundant myxoid interstitial matrix, marked hyperplasia of type II pneumocytes, desquamation of alveolar macrophages and focal alveolar proteinosis. Surfactant protein-B was detected by immunohistochemistry after antigen retrieval. Transmission electron microscopy showed rare cytoplasmic inclusions with concentric membranes and eccentrically placed electron-dense aggregates. These ‘fried-egg’-appearing lamellar bodies differed both from normal lamellar bodies and the larger, poorly formed composite bodies with multiple vesicular inclusions observed in surfactant protein-B deficiency. In conclusion, our findings underscore that the implications of interstitial lung disease in infant lungs differ from those in adults. In infants with a desquamative interstitial pneumonitis pattern, surfactant or ABCA3 mutations should be evaluated. Importantly, these findings support the notion that electron microscopy is useful in distinguishing between surfactant protein-B and ABCA3 deficiency, and has an important role in evaluating biopsies or autopsies of term infants with unexplained severe respiratory failure and interstitial lung disease.

Coumarin embryopathy in an extremely low birth weight infant associated with neonatal hepatitis and ocular malformations

Coumarin embryopathy (CE) is a well-documented sequelae of prenatal exposure to vitaminxa0K antagonists. We report on a female premature infant (25xa0weeks gestation) born to a mother who had received phenprocoumon during pregnancy following mechanical heart valve replacement. The infant presented with impaired coagulation, intraventricular and minor parenchymal cerebral haemorrhages and midface hypoplasia typical of CE. In addition, there was hepatopathy with conjugated hyperbilirubinemia, elevated liver enzymes and repeated episodes of hypoglycemia upon attempts to discontinue glucose supplementation, all lasting for 4xa0months. There was corneal opacity with anterior segment dygenesis in the left eye, and persistent pupillary membrane, cataract and persistent hyperplastic primary vitreous in the right eye. While liver disease is an uncommon but serious side effect of vitaminxa0K antagonists, this is the first report describing neonatal hepatopathy as part of CE. In anticoagulation of pregnant women with mechanical heart valves, vitaminxa0K antagonists should be used with utmost restraint.

Rectal Paracetamol in Newborn Infants after Assisted Vaginal Delivery May Increase Pain Response

OBJECTIVEnTo assess the efficacy of paracetamol (acetaminophen) for neonatal pain relief.nnnSTUDY DESIGNnRandomized, double-blind placebo-controlled trial in 3 Swiss university hospitals. Term and near-term infants (n = 123) delivered by forceps or vacuum were randomized to receive 2 suppositories with paracetamol (60/80/100 mg in infants <3000 g/3000-4000 g/>4000 g birth weight) or placebo at 2 and 8 hours of life. Pain and discomfort during the first 24 hours was assessed by the échelle de douleur et dinconfort du nouveau né [neonatal pain and discomfort scale] score. The response to the subsequent heel prick for metabolic screening at days 2-3 of life was investigated by the Bernese Pain Scale for Neonates (BPSN).nnnRESULTSnThe échelle de douleur et dinconfort du nouveau né [neonatal pain and discomfort scale] pain scale ratings after assisted vaginal delivery were low and declined within 4 hours of life (P < .01) irrespective of paracetamol administration. At 2-3 days of life, BPSN scores after heel prick were significantly higher in infants who had received paracetamol, compared with controls, both when BPSN were scored by nurses at the bedside (median [IQR] 4 [2-7] vs 2 [0-5], P = .017) or off-site from videos (4 [2-8] vs 2 [1-7], P = .04). Thirty-five of 62 (57%) infants treated with paracetamol cried after heel prick, compared with 25 of 61 (41%) controls (P = .086).nnnCONCLUSIONSnInfants born by assisted vaginal delivery have low pain scores in the immediate period after birth. Paracetamol given to newborns soon after birth may aggravate a subsequent stress response.

CRIB, CRIB‐II, birth weight or gestational age to assess mortality risk in very low birth weight infants?

Aim: The mortality risk of very low birth weight (VLBW) (<1500 g) infants has been estimated by the Clinical Risk Index for Babies (CRIB). Superior discriminatory power has been claimed for the revised CRIB‐II score based on birth weight, gestational age, sex, temperature and base excess (BE) at admission. This analysis compared the power of CRIB, CRIB‐II, birth weight and gestational age to predict death prior to discharge.

Erythropoietin and ischemic conditioning – why two good things may be bad

The production of red blood cells is under the tight control of erythropoietin (Epo), and administration of recombinant human Epo (rhEpo) and its derivatives has become a well-established way to treat and prevent anaemia in various patients, including preterm newborn infants (1). Beyond treating anaemia, significant interest in Epo, as a novel cytoprotective agent in both neuronal and vascular systems, has been fuelled by the discovery that Epo and its receptor play a significant biological role in tissues outside the haematopoietic system. Epo has been identified as a neuroprotective agent in a wide variety of experimental models, from neuronal cell culture to in vivo brain injury. These studies suggest that Epo may protect cells against damage caused by such diverse pathological conditions as stroke, cortical trauma, inflammation, demyelinating conditions, radiation, cytostatic agents, toxin-induced epileptic seizures and retinal ischemia. Despite the widespread use of rhEpo for treatment and prevention of anaemia (rhEpo actually constitutes the fourth top-selling therapeutic category behind statins, protonpump inhibitors and antipsychotics (2)) and the wealth of experimental data demonstrating the potent neuroprotective properties of Epo, astonishingly few clinical observations demonstrate any direct effect of Epo in human neurological diseases. In very low birth weight preterm infants, administration of rhEpo in a variety of dosages up to 2100 U/kg/week intravenously has been tested in several randomized controlled trials aimed at the prevention of anaemia. As expected, rhEpo significantly reduced the total volume of blood transfused and the number of transfusions per infant, but had no effect on neurodevelopmental outcome and increased the rate of severe retinopathy of prematurity (1). In adults, to date only one randomized controlled clinical trial has shown some neuroprotective effects of rhEpo in adults suffering from stroke (3). De-

Failed detection of complex congenital heart disease (including double outlet right ventricle and total anomalous pulmonary venous return) by neonatal pulse oximetry screening

We report on a newborn infant with complex congenital heart disease (CHD) featuring double outlet right ventricle and hypoplastic left ventricle who had postductal oxygen saturation well above 95% and thus eluded pulse oximetry screening for CHD.