Sven C. Weber

Thrombocytopenia in the First 24 Hours After Birth and Incidence of Patent Ductus Arteriosus

BACKGROUND: Experimental studies suggest that platelet-triggered ductal sealing is critically involved in definite ductus arteriosus closure. Whether thrombocytopenia contributes to persistently patent ductus arteriosus (PDA) in humans is controversial. This was a retrospective study of 1350 very low birth weight (VLBW; <1500 g) infants, including 592 extremely low birth weight (ELBW; <1000 g) infants. METHODS: All infants who had a platelet count in the first 24 hours after birth and an echocardiogram performed on day of life 4 to 5 were included. The incidence of thrombocytopenia was analyzed in infants with and without PDA, and in those who did or did not undergo PDA intervention. The impact of thrombocytopenia, gestational age, birth weight, gender, and sepsis on PDA was determined by receiver operating characteristic curve, odds ratio, and regression analyses. RESULTS: Platelet numbers within the first 24 hours after birth did not differ between VLBW/ELBW infants with and without spontaneous ductal closure. Platelet numbers were not associated with subsequent PDA treatment. Low platelet counts were not related to failure of pharma-cologic PDA treatment and the need for subsequent surgical ligation. Lower gestational age or birth weight, male gender, and sepsis were linked to the presence of PDA in VLBW infants on day of life 4 to 5. CONCLUSIONS: Thrombocytopenia in the first 24 hours after birth was not associated with PDA in this largest VLBW/ELBW infant cohort studied to date. Impaired platelet function, due to immaturity and critical illness, rather than platelet number, might play a role in ductus arteriosus patency.

Changing Expression of Cyclooxygenases and Prostaglandin Receptor EP4 During Development of the Human Ductus Arteriosus

Programmed proliferative degeneration of the human fetal ductus arteriosus (DA) in preparation for its definite postnatal closure has a large developmental variability and is controlled by several signaling pathways, most prominently by prostaglandin (PG) metabolism. Numerous studies in various mammalian species have shown interspecies and developmental differences in ductal protein expression of cyclooxygenase (COX) isoforms and PG E receptor subtypes (EP1-4). We examined COX1, COX2, and EP4 receptor protein expression immunohistochemically in 57 human fetal autopsy DA specimens of 11–38 wk of gestation. According to their histologic maturity, specimens were classified into four stages using a newly designed maturity score that showed that histologic maturity of the DA was not closely related to gestational age. COX1 expression was found in all DA regions and rose steadily during development. COX2 staining remained weak throughout gestation. EP4 receptor staining increased moderately during gestation and was limited to the intima and media. In conclusion, histologic maturity classification helps to address developmentally regulated processes in the fetal DA. Concerning prostaglandin metabolism our findings are in line with animal studies, which assigned COX1 the predominant role in the DA throughout gestation. EP4 receptor presumably plays a key role for active patency of the human DA in the third trimester.

Natural History of Patent Ductus Arteriosus in Very Low Birth Weight Infants after Discharge

Data on the natural history of infants discharged with patent ductus arteriosus is sparse. We report on the 36-months follow-up after hospitalization in 68 infants discharged with an open ductus arteriosus. Notwithstanding a high spontaneous closure rate, catheter intervention in 5 infants illustrates a critical need for cardiologic follow-up.

Polyoma virus‐associated progressive multifocal leukoencephalopathy after renal transplantation: Regression following withdrawal of mycophenolate mofetil

Weber SC, Uhlenberg B, Raile K, Querfeld U, Müller D. Polyoma virus‐associated progressive multifocal leukoencephalopathy after renal transplantation: Regression following withdrawal of mycophenolate mofetil. Pediatr Transplantation 2011: 15:E19–E24.

Isolation and Culture of Fibroblasts, Vascular Smooth Muscle, and Endothelial Cells From the Fetal Rat Ductus Arteriosus

The ductus arteriosus (DA), a fetal arterial shunt vessel between the proximal descending aorta and the pulmonary artery, closes shortly after birth. Initial functional closure as a result of the DAs smooth muscle contraction is followed by definite anatomical closure. The latter involves several complex mechanisms like endothelial cushion formation and smooth muscle cell migration resulting in fibrosis and sealing of the vessel. These complex steps indicate highly specialized functions of the DA vascular smooth muscle cells (VSMCs), endothelial cells, and fibroblasts. Herein, we describe a new reproducible method for isolating VSMCs, endothelial cells, and fibroblasts of high viability from fetal rat DA using immunomagnetic cell sorting. Purity of the different cell cultures was assessed by immunohistochemistry and flow cytometry and ranged between 85 and 94%. The capability of the VSMCs to react to hypoxic stimuli was assessed by intracellular calcium and ATP measurements and by VEGF mRNA expression analysis. VSMCs respond to hypoxia with decreases in intracellular calcium concentrations and ATP levels, whereas VEGF mRNA expression increased 3.2-fold. The purified vessel-specific different cell types are suitable for subsequent gene expression profiling and functional studies and provide important tools for improving our understanding of the complex processes involved in the closure of the DA.

Ductal closure in neonates: a developmental perspective on platelet-endothelial interactions.

Platelet–vasculature interactions are well known to play an important role in normal hemostasis and atherosclerosis in adults [1]. However, the impact of platelet–endothelial interactions on human development and neonatal disease is less well understood. Recently, Echtler et al. [2] published their investigations on the role of platelets in the closure of the ductus arteriosus. In utero, the ductus arteriosus serves to divert blood flow away from the lungs and toward the placenta by connecting the pulmonary artery to the aorta. A patent ductus arteriosus (PDA) in the first 3 days of life is a physiologic shunt in healthy term and preterm infants. However, a persistently patent ductus arteriosus in preterm infants, which occurs in approximately 60% of all infants born after less than 28 weeks of gestation [3], can lead to clinical complications depending on the degree of left-to-right shunting. The increase in pulmonary blood flow, especially in very immature infants (<1000 g), can cause left ventricular volume overload, pulmonary edema, loss of lung compliance, and subsequent cardiopulmonary deterioration, ultimately leading to chronic lung disease (CLD) [4]. Therefore, the understanding of the mechanisms underlying ductus arteriosus closure is of pivotal clinical importance especially for preterm infants.

The Expression of VEGF and its Receptors in the Human Ductus Arteriosus

Programmed proliferative degeneration of the human fetal ductus arteriosus (DA) preceding definite postnatal closure has a large developmental variability and is controlled by several signaling pathways. Among these vascular endothelial growth factor (VEGF) and its receptors (VEGF-Rs) play an important role. Until now, gestational age dependent expression of VEGF and its receptors has not been investigated in a large number of human DA tissue specimens. We examined protein expression of VEGF and the three VEGF-Rs immunohistochemically in 63 human fetal autopsy DA specimens of 11–38 wk gestation. Specimens were classified into different maturity stages according to their histologic appearance. VEGF and VEGF-Rs-staining was detected in all maturity stages. VEGF-staining was localized perinuclearly in all vascular layers and did not change during development. VEGF-R1 and VEGF-R3 expression was marked in the endothelium in early maturity stages and decreased during development. In contrast, -R2 predominated in the media in later developmental stages. Our results emphasize the importance of VEGF as a mediator during programmed proliferative degeneration of fetal DA and support the hypothesis that VEGF-R1 and VEGF-R3 are required for normal blood vessel development during embryogenesis. In contrast, VEGF-R2 is the predominant receptor in later angiogenic signaling.

Differentiation of Human SH-SY5Y Neuroblastoma Cells by All-Trans Retinoic Acid Activates the Interleukin-18 System

The clinical prognosis of children with high-stage neuroblastoma is still poor. Therapeutic approaches include surgery and cellular differentiation by retinoic acid, but also experimental interleukin-based immune modulation. However, the molecular mechanisms of all-trans retinoic acid (ATRA)-induced differentiation of neuroblastoma cells are incompletely understood. Herein, we examined the effect of ATRA on the activity of the interleukin-18 (IL-18) system in human SH-SY5Y neuroblastoma cells. It is shown that SH-SY5Y cells express IL-18 receptor (IL-18R) and the secreted antagonist IL-18-binding protein (IL-18BP), but no IL-18. SH-SY5Y cells are highly sensitive to ATRA treatment and react by cellular differentiation from a neuroblastic toward a more neuronal phenotype. This was associated with induction of IL-18 and reduction of IL-18BP expression, while IL-18R expression remained stable. Thereby, we identified the IL-18 system as a novel target of ATRA in neuroblastoma cells that might contribute to the therapeutic properties of retinoids in treatment of neuroblastoma.

Infant Botulism: Is There an Association With Thiamine Deficiency?

Infant botulism is an acute life-threatening condition and diagnosis is frequently delayed. Therefore, the best time window to administer specific antibodies, at present the only etiology-based therapy, is often missed, entailing long periods of hospitalization in the PICU. Here we present a 3-month-old boy with infant botulism and respiratory failure, who quickly and favorably responded to thiamine supplementation. From the feces we isolated Clostridium botulinum serotype A2. In addition to producing botulinum neurotoxin A, this strain carried the thiaminase I gene and produced thiaminase I. Accordingly, the child’s feces were positive for thiaminase I activity. Because C botulinum group I strains are capable of producing thiaminase I, we speculate that thiamine degradation might further aggravate the paralytic symptoms caused by botulinum neurotoxins in infant botulism. Thus, supportive supplementation with thiamine could be beneficial to speed up recovery and to shorten hospitalization in some patients with infant botulism.

Severe transient cardiac failure caused by placental chorangiosis.

Background: Chorangiomas are villous capillary tumors of the placenta with high impact on neonatal morbidity and mortality. Cardiac complications have occasionally been reported. Objective: To elucidate clinical features, diagnosis and treatment of cardiac failure caused by chorangiomas. Method:We report a case of a newborn, in whom massive chorangiomas were associated with severe cardiac failure, anemia, and thrombocytopenia. Results: Chorangiosis was not diagnosed prenatally. The pre-existing cardiac failure of the infant deteriorated soon after birth. Despite the severe stage, cardiac failure was reversible with intensive medical treatment including phosphodiesterase inhibitor. Complete recovery with no signs of cardiomyopathy was confirmed at the age of 5 months. Conclusions: Severe cardiac failure in the neonate can be caused by chorangiosis. The time of diagnosis and treatment seems to be critical for the outcome of the infant. Prenatal treatment interventions should be considered.