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Rotterdam, Netherlands

Buijs E.A.B.,Erasmus MC Sophia Childrens Hospital | Buijs E.A.B.,Erasmus Medical Center | Reiss I.K.M.,Erasmus MCSophia Childrens Hospital | Kraemer U.,Erasmus MC Sophia Childrens Hospital | And 4 more authors.
Pediatric Critical Care Medicine | Year: 2014

Objective: To study whether dopamine, norepinephrine, and epinephrine improve not only mean arterial blood pressure and heart rate but also microcirculatory perfusion in children with congenital diaphragmatic hernia. Design: Prospective observational cohort study from November 2009 to July 2012. Setting: ICU of a level III university children's hospital. Patients: Twenty-eight consecutive congenital diaphragmatic hernia newborns of whom seven did not receive any catecholaminergic support and 21 received dopamine as the drug of first choice. Fourteen of the latter also received either norepinephrine or epinephrine in addition to dopamine. Twenty-eight healthy neonates, matched for gestational age, postnatal age, and gender, served as controls. Interventions: None. Measurements and Main Results: Data were obtained before and after dopamine start and before and after norepinephrine or epinephrine start in case it was given. For the congenital diaphragmatic hernia without catecholaminergic support, data were obtained at admission days 1 and 2 and for the controls on day 1 of life. The buccal microcirculation was studied using Sidestream Dark Field imaging. Also macrocirculatory, respiratory, and biochemical variables were collected. Mean arterial blood pressure had improved after dopamine start, whereas the microcirculation had not. After the start of either norepinephrine or epinephrine, both blood pressure and heart rate had increased. However, the microcirculation failed to improve again. The microcirculation in the healthy controls was better than that in the congenital diaphragmatic hernia patients with catecholaminergic support. After cutoff values for abnormal microcirculation had been defined, abnormal microcirculation after dopamine start predicted the need for additional catecholaminergic support (area under the curve, 0.74-0.88; sensitivity, 77-77%; specificity, 69-77%). Likewise, microcirculatory impairment was associated with the need for extracorporeal membrane oxygenation. Conclusions: Catecholaminergic drug support with dopamine, norepinephrine, and/or epinephrine improved macrocirculatory function but did not improve the microcirculation in neonates with congenital diaphragmatic hernia. The microcirculation was not only impaired but it also predicted poor outcome. Copyright © 2014 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.

Duijkers F.A.M.,Erasmus MCSophia Childrens Hospital | De Menezes R.X.,Erasmus MCSophia Childrens Hospital | De Menezes R.X.,VU University Amsterdam | Goossens-Beumer I.J.,Erasmus MCSophia Childrens Hospital | And 5 more authors.
Cellular Oncology | Year: 2013

Background Epigenetic alterations are inherent to cancer cells, and epigenetic drugs are currently primarily used to treat hematological malignancies. Pediatric neuro-ectodermal tumors originate from neural crest cells and also exhibit epigenetic alterations involving e.g. apoptotic pathways, which suggests that these tumors may also be sensitive to epigenetic drugs. This notion prompted us to assess molecular and functional effects of low dosage epigenetic drugs in neuroectodermal tumor-derived cell lines of pediatric origin. Results In 17 neuroblastoma (NBL) and 5 peripheral primitive neuro-ectodermal tumor (PNET) cell lines a combination treatment of 5-aza-2'-deoxycytidine (DAC) and Trichostatin A (TSA) at nanomolar dosages was found to reduce proliferation and to induce wide-spread DNA demethylation, accompanied by major changes in gene expression profiles. Approximately half of the genes that were significantly up-regulated upon treatment exhibited a significant demethylation in their promoter regions. In the NBL cell lines, almost every cellular pathway (193/200) investigated showed expression alterations after treatment, especially a marked up-regulation of genes in the p53 pathway. The combination treatment also resulted in up-regulation of known epigenetically regulated genes such as X-chromosomal genes, tissue-specific genes and a limited number of imprinted genes, as well as known tumor suppressor genes and oncogenes. Conclusions Nanomolar dosages of epigenetic drugs have a dramatic impact on the genomes of neuro-ectodermal tumorderived cell lines, including alterations in DNA methylation and concomitant alterations in gene expression. © International Society for Cellular Oncology 2013.

Roofthooft D.W.E.,Erasmus MCSophia Childrens Hospital | van Beynum I.M.,Erasmus MCSophia Childrens Hospital | de Klerk J.C.A.,Erasmus MCSophia Childrens Hospital | van Dijk M.,Erasmus MCSophia Childrens Hospital | And 5 more authors.
European Journal of Pediatrics | Year: 2015

Finding the optimal pharmacological treatment of a patent ductus arteriosus (PDA) in preterm neonates remains challenging. There is a growing interest in paracetamol as a new drug for PDA closure. In this prospective observational cohort study, we evaluated the effectiveness of intravenous paracetamol in closing a PDA in very low birth weight infants with a hemodynamically significant PDA who either did not respond to ibuprofen or had a contraindication for ibuprofen. They received high-dose paracetamol therapy (15 mg/kg/6 h intravenous) for 3–7 days. Cardiac ultrasounds were performed before and 3 and 7 days after treatment. Thirty-three patients were included with a median gestational age of 251/7 weeks (IQR 1.66), a median birth weight of 750 g (IQR 327), and a median postnatal age of 14 days (IQR 12). Paracetamol was ineffective in 27/33 patients (82 %). Even more, after previous exposure to ibuprofen, this was even 100 %. Conclusion: In this study, paracetamol after ibuprofen treatment failure was not effective for PDA closure in VLBW infants. From the findings of this study, paracetamol treatment for PDA closure cannot be recommended for infants with a postnatal age >2 weeks. Earlier treatment with paracetamol for PDA might be more effective.What is known:• The ductus arteriosus fails to close after birth in 30 to 60 % of prematurely born neonates and is a significant cause of morbidity and mortality in these infants.• Paracetamol gained importance as an alternative drug in PDA closure.What is new:• Paracetamol for PDA closure after ibuprofen treatment failure was not effective in VLBW infants.• Effect of paracetamol on PDA closure was observed when given as primary treatment. © 2015, The Author(s).

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