Comparative two time-point proteome analysis of the plasma from preterm infants with and without bronchopulmonary dysplasia

Background: In this study, we aimed to analyze differences in plasma protein abundances between infants with and without bronchopulmonary dysplasia (BPD), to add new insights into a better understanding of the pathogenesis of this disease. Methods: Cord and peripheral blood of neonates (≤ 30 weeks gestational age) was drawn at birth and at the 36th postmenstrual week (36 PMA), respectively. Blood samples were retrospectively subdivided into BPD(+) and BPD(−) groups, according to the development of BPD. Results: Children with BPD were characterized by decreased afamin, gelsolin and carboxypeptidase N subunit 2 levels in cord blood, and decreased galectin-3 binding protein and hemoglobin subunit gamma-1 levels, as well as an increased serotransferrin abundance in plasma at the 36 PMA. Conclusions: BPD development is associated with the plasma proteome changes in preterm infants, adding further evidence for the possible involvement of disturbances in vitamin E availability and impaired immunological processes in the progression of prematurity pulmonary complications. Moreover, it also points to the differences in proteins related to infection resistance and maintaining an adequate level of hematocrit in infants diagnosed with BPD

Comparison of whole genome expression profile between preterm and full-term newborns

Objectives: Evaluate the time dependent expression of genes in preterm neonates and verify the influence of ontogenic maturation and the environmental factors on the gene expression after birth. Material and methods: The study was carried out on 20 full-term newborns and 62 preterm newborns (mean birth weight = 1002 [g] (SD: 247), mean gestational age = 27.2 weeks (SD: 1.9)). Blood samples were drawn from all the study participants at birth and at the 36th week postmenstrual age from the preterm group to assess whole genome expression in umbilical cord blood and in peripheral blood leukocytes, respectively. (SurePrint G3 Human Gene Expression v3, 8x60K Microarrays (Agilent)). Results: A substantial number of genes was found to be expressed differentially at the time of birth and at 36 PMA in comparison to the term babies with more genes being down-regulated than up-regulated. However, the fold change in the majority of cases was < 2.0. Extremely preterm and very preterm infants were characterized by significantly down-regulated cytokine and chemokine related pathways. The number of down-regulated genes decreased and number of up-regulated genes increased at 36 PMA vs. cord blood. There were no specific gene expression pathway profiles found within the groups of different gestational ages. Conclusions: Preterm delivery is associated with a different gene expression profile in comparison to term delivery. The gene expression profile changes with the maturity of a newborn measured by the gestational age

Resuscitation of Newborn Piglets. Short-Term Influence of FiO2 on Matrix Metalloproteinases, Caspase-3 and BDNF

Perinatal hypoxia-ischemia is a major cause of mortality and cerebral morbidity, and using oxygen during newborn resuscitation may further harm the brain. The aim was to examine how supplementary oxygen used for newborn resuscitation would influence early brain tissue injury, cell death and repair processes and the regulation of genes related to apoptosis, neurodegeneration and neuroprotection.Anesthetized newborn piglets were subjected to global hypoxia and then randomly assigned to resuscitation with 21%, 40% or 100% O(2) for 30 min and followed for 9 h. An additional group received 100% O(2) for 30 min without preceding hypoxia. The left hemisphere was used for histopathology and immunohistochemistry and the right hemisphere was used for in situ zymography in the corpus striatum; gene expression and the activity of various relevant biofactors were measured in the frontal cortex. There was an increase in the net matrix metalloproteinase gelatinolytic activity in the corpus striatum from piglets resuscitated with 100% oxygen vs. 21%. Hematoxylin-eosin (HE) staining revealed no significant changes. Nine hours after oxygen-assisted resuscitation, caspase-3 expression and activity was increased by 30-40% in the 100% O(2) group (n = 9/10) vs. the 21% O(2) group (n = 10; p<0.04), whereas brain-derived neurotrophic factor (BDNF) activity was decreased by 65% p<0.03.The use of 100% oxygen for resuscitation resulted in increased potentially harmful proteolytic activities and attenuated BDNF activity when compared with 21%. Although there were no significant changes in short term cell loss, hyperoxia seems to cause an early imbalance between neuroprotective and neurotoxic mechanisms that might compromise the final pathological outcome

Antioxidant Protects against Increases in Low Molecular Weight Hyaluronan and Inflammation in Asphyxiated Newborn Pigs Resuscitated with 100% Oxygen

BACKGROUND: Newborn resuscitation with 100% oxygen is associated with oxidative-nitrative stresses and inflammation. The mechanisms are unclear. Hyaluronan (HA) is fragmented to low molecular weight (LMW) by oxidative-nitrative stresses and can promote inflammation. We examined the effects of 100% oxygen resuscitation and treatment with the antioxidant, N-acetylcysteine (NAC), on lung 3-nitrotyrosine (3-NT), LMW HA, inflammation, TNFα and IL1ß in a newborn pig model of resuscitation. METHODS & PRINCIPAL FINDINGS: Newborn pigs (n = 40) were subjected to severe asphyxia, followed by 30 min ventilation with either 21% or 100% oxygen, and were observed for the subsequent 150 minutes in 21% oxygen. One 100% oxygen group was treated with NAC. Serum, bronchoalveolar lavage (BAL), lung sections, and lung tissue were obtained. Asphyxia resulted in profound hypoxia, hypercarbia and metabolic acidosis. In controls, HA staining was in airway subepithelial matrix and no 3-NT staining was seen. At the end of asphyxia, lavage HA decreased, whereas serum HA increased. At 150 minutes after resuscitation, exposure to 100% oxygen was associated with significantly higher BAL HA, increased 3NT staining, and increased fragmentation of lung HA. Lung neutrophil and macrophage contents, and serum TNFα and IL1ß were higher in animals with LMW than those with HMW HA in the lung. Treatment of 100% oxygen animals with NAC blocked nitrative stress, preserved HMW HA, and decreased inflammation. In vitro, peroxynitrite was able to fragment HA, and macrophages stimulated with LMW HA increased TNFα and IL1ß expression. CONCLUSIONS & SIGNIFICANCE: Compared to 21%, resuscitation with 100% oxygen resulted in increased peroxynitrite, fragmentation of HA, inflammation, as well as TNFα and IL1ß expression. Antioxidant treatment prevented the expression of peroxynitrite, the degradation of HA, and also blocked increases in inflammation and inflammatory cytokines. These findings provide insight into potential mechanisms by which exposure to hyperoxia results in systemic inflammation

A survey of transcutaneous blood gas monitoring among European neonatal intensive care units

BACKGROUND: PCO(2 )and PO(2 )are important monitoring parameters in neonatal intensive care units (NICU). Compared to conventional blood gas measurements that cause significant blood loss in preterms, transcutaneous (tc) measurements allow continuous, non-invasive monitoring of blood gas levels. The aim of the study was to survey the usage and opinions among German speaking NICUs concerning tc blood gas monitoring. METHODS: A questionnaire was developed and sent to 56 head nurses of different NICUs in Germany, Switzerland and Austria. RESULTS: A completely answered questionnaire was obtained from 41 NICUs. In two of these units tc measurements are not performed. In most NICUs (77%), both P(tc)O(2 )and P(tc)CO(2 )are measured simultaneously. Most units change the sensors every 3 hours; however, the recommended temperature of 44°C is used in only 15% of units. In only 8% of units are arterial blood gases obtained to validate tc values. Large variations were found concerning the targeted level of oxygen saturation [median upper limit: 95% (range 80–100%); median lower limit: 86% (range 75–93%)] and PO(2 )[median upper limit: 70 mmHg (range 45–90 mmHg); median lower limit: 44 mmHg (range 30–60 mmHg)]. CONCLUSION: Our survey shows that the use of tc monitors remains widespread among German speaking NICUs, despite earlier data suggesting that their use had been abandoned in many NICUs worldwide. In addition, we suggest that the current method of monitoring oxygenation may not prevent hyperoxemia in preterm infants

Structural Analysis to Determine the Core of Hypoxia Response Network

The advent of sophisticated molecular biology techniques allows to deduce the structure of complex biological networks. However, networks tend to be huge and impose computational challenges on traditional mathematical analysis due to their high dimension and lack of reliable kinetic data. To overcome this problem, complex biological networks are decomposed into modules that are assumed to capture essential aspects of the full network's dynamics. The question that begs for an answer is how to identify the core that is representative of a network's dynamics, its function and robustness. One of the powerful methods to probe into the structure of a network is Petri net analysis. Petri nets support network visualization and execution. They are also equipped with sound mathematical and formal reasoning based on which a network can be decomposed into modules. The structural analysis provides insight into the robustness and facilitates the identification of fragile nodes. The application of these techniques to a previously proposed hypoxia control network reveals three functional modules responsible for degrading the hypoxia-inducible factor (HIF). Interestingly, the structural analysis identifies superfluous network parts and suggests that the reversibility of the reactions are not important for the essential functionality. The core network is determined to be the union of the three reduced individual modules. The structural analysis results are confirmed by numerical integration of the differential equations induced by the individual modules as well as their composition. The structural analysis leads also to a coarse network structure highlighting the structural principles inherent in the three functional modules. Importantly, our analysis identifies the fragile node in this robust network without which the switch-like behavior is shown to be completely absent

Parental and infant characteristics and childhood leukemia in Minnesota

<p>Abstract</p> <p>Background</p> <p>Leukemia is the most common childhood cancer. With the exception of Down syndrome, prenatal radiation exposure, and higher birth weight, particularly for acute lymphoid leukemia (ALL), few risk factors have been firmly established. Translocations present in neonatal blood spots and the young age peak of diagnosis suggest that early-life factors are involved in childhood leukemia etiology.</p> <p>Methods</p> <p>We investigated the association between birth characteristics and childhood leukemia through linkage of the Minnesota birth and cancer registries using a case-cohort study design. Cases included 560 children with ALL and 87 with acute myeloid leukemia (AML) diagnoses from 28 days to 14 years. The comparison group was comprised of 8,750 individuals selected through random sampling of the birth cohort from 1976–2004. Cox proportional hazards regression specific for case-cohort studies was used to compute hazard ratios (HR) and 95% confidence intervals (CIs).</p> <p>Results</p> <p>Male sex (HR = 1.41, 95% CI 1.16–1.70), white race (HR = 2.32, 95% CI 1.13–4.76), and maternal birth interval ≥ 3 years (HR = 1.31, 95% CI 1.01–1.70) increased ALL risk, while maternal age increased AML risk (HR = 1.21/5 year age increase, 95% CI 1.0–1.47). Higher birth weights (>3798 grams) (HRALL = 1.46, 1.08–1.98; HRAML = 1.97, 95% CI 1.07–3.65), and one minute Apgar scores ≤ 7 (HRALL = 1.30, 95% CI 1.05–1.61; HRAML = 1.62, 95% CI 1.01–2.60) increased risk for both types of leukemia. Sex was not a significant modifier of the association between ALL and other covariates, with the exception of maternal education.</p> <p>Conclusion</p> <p>We confirmed known risk factors for ALL: male sex, high birth weight, and white race. We have also provided data that supports an increased risk for AML following higher birth weights, and demonstrated an association with low Apgar scores.</p

Infusing Sodium Bicarbonate Suppresses Hydrogen Peroxide Accumulation and Superoxide Dismutase Activity in Hypoxic-Reoxygenated Newborn Piglets

The effectiveness of sodium bicarbonate (SB) has recently been questioned although it is often used to correct metabolic acidosis of neonates. The aim of the present study was to examine its effect on hemodynamic changes and hydrogen peroxide (H(2)O(2)) generation in the resuscitation of hypoxic newborn animals with severe acidosis.Newborn piglets were block-randomized into a sham-operated control group without hypoxia (n = 6) and two hypoxia-reoxygenation groups (2 h normocapnic alveolar hypoxia followed by 4 h room-air reoxygenation, n = 8/group). At 10 min after reoxygenation, piglets were given either i.v. SB (2 mEq/kg), or saline (hypoxia-reoxygenation controls) in a blinded, randomized fashion. Hemodynamic data and blood gas were collected at specific time points and cerebral cortical H(2)O(2) production was continuously monitored throughout experimental period. Plasma superoxide dismutase and catalase and brain tissue glutathione, superoxide dismutase, catalase, nitrotyrosine and lactate levels were assayed.Two hours of normocapnic alveolar hypoxia caused cardiogenic shock with metabolic acidosis (PH: 6.99 ± 0.07, HCO(3)(-): 8.5 ± 1.6 mmol/L). Upon resuscitation, systemic hemodynamics immediately recovered and then gradually deteriorated with normalization of acid-base imbalance over 4 h of reoxygenation. SB administration significantly enhanced the recovery of both pH and HCO(3-) recovery within the first hour of reoxygenation but did not cause any significant effect in the acid-base at 4 h of reoxygenation and the temporal hemodynamic changes. SB administration significantly suppressed the increase in H(2)O(2) accumulation in the brain with inhibition of superoxide dismutase, but not catalase, activity during hypoxia-reoxygenation as compared to those of saline-treated controls.Despite enhancing the normalization of acid-base imbalance, SB administration during resuscitation did not provide any beneficial effects on hemodynamic recovery in asphyxiated newborn piglets. SB treatment also reduced the H(2)O(2) accumulation in the cerebral cortex without significant effects on oxidative stress markers presumably by suppressing superoxide dismutase but not catalase activity