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Background: Perinatal brain injury in preterm infants is a major cause of neurological handicap. The role of the neurotrophin receptor p75 (p75NTR) in the pathogenesis and repair of neonatal excitotoxic brain injury is unknown. Depending on a complex interplay of neurotrophin signalling, p75NTR can, in addition to its trophic function, also induce apoptosis. Hypothesis: We hypothesised that excitotoxicity increases p75NTR expression and p75NTR knockout (KO) mice have a significantly smaller lesion size upon excitotoxicity as compared to wild-type (WT) mice. Methods: We used an established animal model of neonatal excitotoxic brain injury mimicking several key aspects of human preterm brain damage. We subjected five-day-old WT and KO mice to excitotoxic injury by means of a single intracranial ibotenate injection (N-methyl-D-aspartate receptor agonist, NMDAR) into one brain hemisphere. Lesion size, number of activated caspase-3- and apoptosis-inducing factor (AIF)-positive cells were determined as outcome parameters. Gender analyses were taken into account retrospectively. Results: NMDAR-mediated excitotoxicity induced an upregulation of p75NTR expression in the peri-lesion area. Lesion size was significantly increased in female KO as compared to male KO animals. Knockout of p75NTR reduced the number of activated caspase-3 but not AIF-positive cells after NMDAR-mediated excitotoxic injury independently of gender. Conclusion: Since NMDAR-mediated excitotoxic brain injury induced p75NTR expression and caspase-3-activated apoptosis in p75NTR KO animals was decreased, we conclude that activation of p75NTR contributes to NMDAR-mediated apoptosis in the neonatal brain. An increase in lesion size in female animals after excitotoxic brain injury suggests that in females p75NTR seems to play a dual role.

Background and aim: Preterm birth is the major cause of infant mortality and morbidity in both developed and developing countries. In Europe, the prevalence rate of premature birth ranges from 5.5 to 11.4% - an average of 7.1% of all live births. In this report, we aim to compare the current health and social policies, as well as practices in 13 EU member states. Materials and methods: Using desk research, relevant information was gathered from each of the 13 European countries with regard to the prevalence of preterm birth, the cost of preterm birth to healthcare budgets, and the relevant policies, guidelines and practices in place at the national and, in some cases, regional level. The information comes from a range of sources, including government and parent association websites, published scientific literature and media reports. Results: Despite the growing prevalence and increasing costs, neonatal and preterm infant health rank low on the policy agendas of EU member states. Conclusion: Based on the findings, there are a number of recommendations that should be considered. The European Union should (i) recognize the growing challenge of prematurity in Europe and its significant impact on infant morbidity and mortality, (ii) improve neonatal health through the development and implementation of coordinated EU health and social policies, (iii) address the lack of comparable European data on prematurity, including prevalence, mortality, acute morbidity and long-term impairment, (iv) also increase the standard of neonatal care across Europe by supporting the development and implementation of European medical guidelines and quality standards, (v) support the development of European postgraduate training programmes in Peri- and Neonatology in order to increase the quality and availability of trained healthcare professionals.

Background Inflammation and reactive oxygen species (ROS) are important in the development of perinatal brain injury. The ROS-generating enzyme NADPH oxidase (Nox2) is present in inflammatory cells and contributes to brain injury in adult animal models. Hypothesis NADPH oxidase contributes to ROS formation and development of injury in the immature brain and inhibition of NADPH oxidase attenuates perinatal brain injury. Methods We used animal models of term hypoxia–ischemia (HI) (P9 mice) as well as ibotenate-induced excitotoxic injury (P5 mice) mimicking features of periventricular leukomalacia in preterm infants. In vitro microglia cell cultures were used to investigate NADPH oxidase-dependent ROS formation. In vivo we determined the impact 1) of HI on NADPH oxidase gene expression 2) of genetic (gp91-phox/Nox2 knock-out) and 3) of pharmacological NADPH oxidase inhibition on HI-induced injury and NMDA receptor-mediated excitotoxic injury, respectively. Endpoints were ROS formation, oxidative stress, apoptosis, inflammation and extent of injury. Results Hypoxia–ischemia increased NADPH oxidase subunits mRNA expression in total brain tissue in vivo. In vitro ibotenate increased NADPH oxidase-dependent formation of reactive oxygen species in microglia. In vivo the inhibition of NADPH oxidase did not reduce the extent of brain injury in any of the animal models. In contrast, the injury was increased by inhibition of NADPH oxidase and genetic inhibition was associated with an increased level of galectin-3 and IL-1β. Conclusion NADPH oxidase is upregulated after hypoxia–ischemia and activated microglia cells are a possible source of Nox2-derived ROS. In contrast to findings in adult brain, NADPH oxidase does not significantly contribute to the pathogenesis of perinatal brain injury. Results obtained in adult animals cannot be transferred to newborns and inhibition of NADPH oxidase should not be used in attempts to attenuate injury.

Continuous wave (cw) and pulsed wave (pw) Doppler velocimetry are both used to measure blood flow velocity in cerebral arteries. We examined whether data obtained with the two methods are interchangeable and equally useful for clinical application. We studied 20 infants at an age between 1 day and 2 1/2 months and a body weight between 1.2 and 3.4 kg. Cw Doppler measurements were performed using an Angiomatic (Medimatic) and pw measurements using a Mark 600 Duplex Scanner (ATL). We applied both methods within an interval as short as possible. For the data analysis the pulsatility index (PI) was used, a parameter fairly independent of the emission angle. PI was 0.66 +/- 0.06 (mean +/- SD) using the cw and 0.8 +/- 0.08 using the pw method. The linear correlation between the pulsatility indices obtained with the cw and the pw method respectively was statistically significant (r = 0.53, n = 20, p less than 0.0025), the variation around the regression line rather large. The slope of the regression line differed significantly from that of the identity line (y = 0.391x + 0.54). Therefore the PI values obtained with the two methods are not interchangable and require to be judged according to normal values. Both methods, however, yield PI values which correlate and can thus be equally used. The choice of the method rather depends on the goal to be achieved. The pw method seems to be more suitable for precise momentaneous descriptions and the cw method for continuous monitoring of cerebral blood flow.

Durch Hypothermie ist es moglich, den Gehirnschaden eines asphyktischen Neugeborenen zu verringern. Die historische Betrachtung zeigt, dass das Paradigma Kuhlung fur asphyktische Neugeborene erst ein halbes Jahrhundert nach Erstanwendung erneut Interesse findet. Die Evidenz fur ihre neuroprotektive Wirkung wird bisher nur aus tierexperimentellen Untersuchungen abgeleitet. Die wenigen Publikationen uber Hypothermie bei Neugeborenen beschreiben relativ geringe Nebenwirkungen. Randomisierte kontrollierte Studien sind im Gange, welche eine milde Hypothermie mit einer Kerntemperatur um 33,5 oder 34,5°C fur 3 Tage entweder durch eine Kuhlung vom Kopf her bei gleichzeitiger Warmung des restlichen Korpers oder durch eine Kuhlmatte erzielen. Die Diagnostik und Prognostik der Asphyxie und ihrer Folgen bzw. der damit verbundene Einsatz der Hypothermie wird am besten durch das amplitudenintegrierte EEG bewerkstelligt. Die Messung der Gehirntemperatur und die Steuerung der Hypothermie sind bisher ungeloste Probleme. Die Unsicherheit in der Prognose und die Schwierigkeit der folgenschweren Entscheidungen stellen Eltern, Arzte und Pflegepersonal vor schwerwiegende ethische Entscheidungen.

Background In mechanically ventilated preterm infants with respiratory distress syndrome (RDS), exogenous surfactant application has been demonstrated both to decrease DNA-synthesis but also and paradoxically to increase epithelial cell proliferation. However, the effect of exogenous surfactant has not been studied directly on alveolar type II cells (ATII cells), a key cell type responsible for alveolar function and repair. Objective The aim of this study was to investigate the effects of two commercially available surfactant preparations on ATII cell viability and DNA synthesis. Methods Curosurf® and Alveofact® were applied to two ATII cell lines (human A549 and mouse iMATII cells) and to primary rat ATII cells for periods of up to 24 h. Cell viability was measured using the redox indicator resazurin and DNA synthesis was measured using BrdU incorporation. Results Curosurf® resulted in slightly decreased cell viability in all cell culture models. However, DNA synthesis was increased in A549 and rat ATII cells but decreased in iMATII cells. Alveofact® exhibited the opposite effects on A549 cells and had very mild effects on the other two cell models. Conclusion This study showed that commercially available exogenous surfactants used to treat preterm infants with RDS can have profound effects on cell viability and DNA synthesis.

Serum lactate provides important information about tissue perfusion in critically ill patients. Aim of this study is to evaluate anion gap as a screening method to detect hyperlactatemia at a pediatric intensive care unit. In infants and children of different ages and diagnosis we determined blood gases, electrolytes and lactate. Sensitivity of anion gap was increasing with increasing hyperlactatemia. For the total population the test exhibited a sensitivity of 64% and a specificity of 76%, respectively. The power of anion gap as a screening method to detect hyperlactatemia was similarly fair for all age groups. Therefore hyperlactatemia has also to be included in the differential diagnosis of non-anion gap metabolic acidosis.

Objective Hypoxic ischemic injury plays an important role in the pathogenesis of preterm brain damage. We have shown that granulocyte colony stimulating factor (GCSF) and stem cell factor (SCF) increase excitotoxic brain injury in newborn mice, when administered in the acute phase of the insult. Administration after the acute phase significantly reduces the injury. The aim of this study was to evaluate the effect of haematopoietic growth factors (GCSF/SCF and Fms like tyrosine kinase 3 ligand (FL)) in a neonatal model of hypoxic/hyperoxic ischemic (HHI) brain injury. Methods Unilateral carotid artery ligation was performed in mice on postnatal day 5 (P5) followed by hypoxia (8% O2) for 15 min alternating with hyperoxia (100% O2) for 10 min, totally 65 min. 60 hours later i) GCSF/SCF, ii) FL or iii) vehicle was randomly injected intraperitoneally repetitively every 24 hours, 3 or 5 times. Endpoints were set at P10, P21 and P120, histological and neurobehavioral outcome was anlayzed. Results HHI resulted in a moderate to severe brain injury with white matter cysts and cortical atrophy. Although there were animals which seemed to benefit (in terms of lesion size and outcome) from these treatments, this did not reach statistical significance. Conclusion In the excitotoxic injury model the same treatment regimen reduced brain damage. Thus we speculate that the effect of these treatments strongly depends on the severity of brain injury. Thus in severe damage with great tissue loss, the “matrix” (e.g. cells secreting chemoattractants) required for neuroregeneration might be lost.

Although the efficacy of electronic foetal heart rate (FHR) monitoring and intermittent scalp blood sampling is well established, these methods still result in a considerable number of false positive and negative predictions. Consequently, methods, which improve the accuracy of prediction, are still under study. Heat flux measurements from the foetal scalp have been shown to relate to the metabolic condition of the foetus during delivery. In this study, we investigated the predictive power of measuring scalp heat flux and monitoring the FHR electronically, and the combination of both. In 136 foetuses the scalp heat flux was measured by means of a heat flux transducer, 2.5 cm in diameter, attached to the foetal scalp after the cervix had dilated to greater than 2.5 cm. Heat flux was regarded as abnormal, if the heat flux was less than 10 w/m2 or greater than 21 w/m2, or fell by more than 20% of its initial value during the last 30 min before delivery. FHR tracings were considered abnormal, if they resulted in therapeutic consequences like oxygen mask for the mother, scalp blood sampling or immediate operative delivery. Foetuses were considered acidotic, if their pH in the arterial cord blood was less than 7.20. Accuracy of prediction was described by appropriate parameters. The scalp heat flux method resulted in a higher specificity (80.4% vs. 72.5%), positive predictive value (59.2% vs. 51.7%), and overall accuracy (82% vs. 77%) than FHR monitoring. Sensitivity of FHR monitoring was slightly higher than the one of heat flux method (88.2% vs 85.3%). Combining both methods resulted in a sensitivity of 100% thus detecting all acidotic foetuses, but specificity fell to 62%.(ABSTRACT TRUNCATED AT 250 WORDS)

Background Periventricular leukomalacia (PVL) is a major cause of neurological handicap in pre-term infants. At present, there are no effective or causal therapies available. Thyroid hormones play an essential role in brain development and are reported to be decreased in pre-terms and following brain injury in adults. Hypothesis Excitotoxic brain damage of newborn mice decreases thyroid hormone concentrations. Exogenous T3 administration restores thyroid hormone levels and reduces perinatal brain damage in an animal model of PVL. Design and method To create white and gray matter (WM/GM) lesion mimicking several key aspects of PVL, we injected ibotenic acid (Ibo), a glutamate analog, into the right hemisphere (intracranially (i.c.)) of 5-day-old mice. T3 (10 μg/kg body weight (bw)) was injected intraperitoneally (i.p.) 1 h or repeatedly 1/24/48/72/96 h post-insult. We determined lesion size, number of apoptotic cells in WM/GM and serum T3/T4 concentration at 24 and 120 h after injury. Serum T3/T4 concentration was also determined before and 1 and 2 h after T3 administration. Results Excitotoxic brain damage did not alter serum T3/T4 concentrations within 120 h of injury. Serum T3 levels were distinctly elevated within 1 h of T3 injection; however, this elevation was relatively short-lived (half-life estimated to be less than 12 h). Neither single nor repetitive T3 treatment regimen reduced excitotoxic lesion size, but it did reduce apoptosis. Conclusions T3 replacement does not prevent excitotoxic cell death, but it does reduce developmental neuronal apoptosis, which could participate to the beneficial neuropsychological effects of hormone therapy. Further study is therefore warranted.

Granulocyte-colony stimulating factor (G-CSF) has been shown to reduce brain lesion size and mortality in adult mice after hypoxic-ischemic injury. Another hematopoietic growth factor, stem cell factor (SCF), has been shown to be up-regulated in the brains of adult rodents following brain damage, where it stimulates postlesional neurogenesis. Injection of the excitotoxic agent ibotenate into the brain of newborn mice produces a brain lesion characterized by neuronal death and white matter cysts, which is similar to periventricular leucomalacia. The aim of the present study was to investigate whether administration of SCF and G-CSF is neuroprotective against ibotenate lesions in neonatal mice. Contrary to our expectations, cortical and white matter brain lesions induced by ibotenate were enhanced following the administration of 50 microg/kg SCF or 200 microg/kg G-CSF. Dose-response studies indicated that G-CSF could increase grey matter lesions even at lower dosages (22 and 66 microg/kg). Administration of SCF and G-CSF in combination also increased cortical and white matter lesions, to 133 +/- 8% and 187 +/- 12%. In the undamaged brain, G-CSF or G-CSF+SCF treatment had no effect on apoptosis in the grey or white matter; however, these treatments significantly increased apoptosis in the damaged brain. Our data clearly demonstrate that G-CSF and SCF are not neuroprotective and result in deleterious enhancement of excitotoxic brain damage in newborn mice. We conclude that G-CSF and SCF should be used cautiously in newborn infants with brain lesions; if they are used, long term neurologic and neurodevelopmental follow-up is warranted.

Using an established mouse model of human periventricular leukomalacia, we investigated whether EPO could reduce excitotoxic damage. When administered 1 h following intracerebral injection of 10 μg ibotenic acid at day 5 of life, both a single injection of EPO (5000 IU/kg bw) and repetitive administrations of EPO reduced white and gray matter lesion size. The therapeutic window for protection was small as the protective effect of EPO was lost when EPO administration was delayed to 4 h post-insult. EPO-mediated upregulation of EPO-R, but not EPO, mRNA was observed within 4 h of the excitotoxic insult. The EPO effect was gender independent. Minor hematopoetic effects were observed following EPO treatment. We conclude that a single dose of EPO is sufficient to reduce excitotoxic brain injury and may therefore possess therapeutic relevance in the clinical setting.

Objective: Recent studies have suggested direct pulmonary effects of furosemide in asthmatics and infants with bronchopulmo- nary dysplasia. We tested the hypothesis that intratracheally administered furosemide also increases respiratory compliance in children after cardiac surgery, and investigated whether furosemide has a topical and/or systemic action. Study design: Prospective study with intra-individual control. In twelve infants and toddlers (age: 10 ± 8 months, weight: 6.9 ± 3 kg) mechanically ventilated for compromised lung mechanics after cardiac surgery, 0.5 mg/kg furosemide was intratracheally administered to the lungs. Lung mechanics were serially assessed using a computerised system (Sensormedics 2600) during a 2 h control and 2 h intervention period. Urine output was measured by an indwelling bladder catheter and levels of furosemide were determined in blood and tracheal aspirates. Results: Static compliance improved within 30 min in all patients, reached a maximum of 44 (20–85) % above baseline and remained improved throughout the study (p < 0.05). An immediate, short and significant diuretic effect of intratracheally applied furosemide was observed. Furosemide levels 1 h after intervention were 795 ng/ml in the blood and 431 μg/ml (i. e. 1000-fold higher) in the tracheal aspirate. Changes in compliance were correlated only to urine output values over the 2 h (r = 0.82, p = 0.044, n = 9) after furosemide administration. Conclusion: We conclude that intratracheally applied furosemide improves static compliance in infants and toddlers with compromised lung mechanics after cardiac surgery. We demonstrated that furosemide is absorbed from the lung and has a systemic effect within 15 min after its intratracheal instillation.

Brain temperature depends on the balance of cerebral heat production and heat loss via cerebral circulation and head surface. We investigated whether brain temperature and heat loss via the head surface differed in neonates with abnormal cerebral metabolism or circulation. We measured the core temperature of the head noninvasively by the zero-gradient method, skin temperature of the head, the heat flux from the head, and esophageal and operative environmental temperature in seven healthy neonates, seven neonates with cerebral damage, and two neonates with cerebral hypoperfusion caused by an incurable congenital heart disease. Cerebral blood flow velocity in the anterior cerebral artery and systemic blood pressure were also measured. Brain temperature profile was measured in two premature infants with external ventricular drainage. Core temperature of the head, considered to represent brain temperature, was up to 1.5 degree C higher in infants with cerebral hypoperfusion than in normal neonates. The core temperature of the head was higher than the esophageal temperature in all except two infants with the most severe cerebral damage. The difference between core temperature of the head and esophageal temperature was 0.72 +/- 0.12 degree C in normal neonates, 0.16 +/- 0.4 degree C in infants with cerebral damage, and ranged from 0.9 to 1.2 degree C in infants with cerebral hypoperfusion. The relationship of core of the head to esophageal temperature discriminated between all 16 newborn infants according to their brain pathologic condition, except one infant with a mild ischemic-hypoxic encephalopathy. In conclusion, brain temperature depends on cerebral perfusion and level of brain injury.(ABSTRACT TRUNCATED AT 250 WORDS)

A previously healthy 2 year old female child developed fever of unknown origin recurring in monthly cycles. The periodic fever attacks, family history and ethnologic criteria were in agreement with familial mediterranean fever, although further more major symptoms were missing. It was highly unusual to find repeatedly raised levels of angiotensin I converting enzyme, a finding previously not described in literature. Excluding any other differential diagnosis by intensive investigations, together with a positive metaraminol provocation test, the diagnosis of a rare, monosymptomatic variant of familial mediterranean fever was proposed. Amyloidosis was excluded by rectal biopsy. Monosymptomatic familial mediterranean fever is very seldom. We suggest to measure routinely angiotensin I converting enzyme for further evaluation of our findings.

Das Alter bzw. die Reife und das bisherige Wachstum spielen fur die Funktionstuchtigkeit der Organsysteme eine bedeutende Rolle. Die Klassifikation nach Reife und Wachstum des Kindes erlaubt daher, bestimmte spezifische Storungen vorherzusehen.

265 Too Little, Too Late: Policy Benchmarking Report on Neonatal Health and Social Policies in 13 European Countries

Serum lactate provides important information about tissue perfusion in critically ill patients. Aim of this study is to evaluate anion gap as a screening method to detect hyperlactatemia at a pediatric intensive care unit. In infants and children of different ages and diagnosis we determined blood gases, electrolytes and lactate. Sensitivity of anion gap was increasing with increasing hyperlactatemia. For the total population the test exhibited a sensitivity of 64% and a specificity of 76%, respectively. The power of anion gap as a screening method to detect hyperlactatemia was similarly fair for all age groups. Therefore hyperlactatemia has also to be included in the differential diagnosis of non-anion gap metabolic acidosis.

Postterm and growth-retarded fetuses share a common problem which can be characterized by a discrepancy between the supply of oxygen and nutrients to, and the demand of the fetus. But, this "insufficient" placental exchange function may also extend to and affect its thermal homeostasis; e.g. when the capacity of convective (placenta) pathways is shifted towards conductive (surface) pathways for heat loss. Therefore, fetal scalp heat flux measurements, where heat serves as an intrinsic tracer for metabolic activity and placental exchange function, promised a new kind of information. In 81 pregnant women during labor we measured fetal scalp heat flux by means of an heat flux transducer attached to the fetal head and after the cervix had dilated to 3 cm. In the healthy fetuses we found a positive linear relationship between scalp heat flux and different anthropometric variables such as body length (r = 0.432, n = 65, P less than 0.01), head circumference and gestational age. In comparison, postmature and growth-retarded fetuses showed higher heat flux values than appropriately grown fetuses of the same length head size and gestational age. Moreover, in those fetuses scalp heat flux decreased by approximately 4 watt/m2 during the second stage and differed in this regard from the control group who showed stable values during labor and delivery. We conclude that scalp heat flux measurements may indicate disturbances of placental exchange before acute hypoxia occurs.

Although the efficacy of electronic foetal heart rate (FHR) monitoring and intermittent scalp blood sampling is well established, these methods still result in a considerable number of false positive and negative predictions. Consequently, methods, which improve the accuracy of prediction, are still under study. Heat flux measurements from the foetal scalp have been shown to relate to the metabolic condition of the foetus during delivery. In this study, we investigated the predictive power of measuring scalp heat flux and monitoring the FHR electronically, and the combination of both. In 136 foetuses the scalp heat flux was measured by means of a heat flux transducer, 2.5 cm in diameter, attached to the foetal scalp after the cervix had dilated to greater than 2.5 cm. Heat flux was regarded as abnormal, if the heat flux was less than 10 w/m2 or greater than 21 w/m2, or fell by more than 20% of its initial value during the last 30 min before delivery. FHR tracings were considered abnormal, if they resulted in therapeutic consequences like oxygen mask for the mother, scalp blood sampling or immediate operative delivery. Foetuses were considered acidotic, if their pH in the arterial cord blood was less than 7.20. Accuracy of prediction was described by appropriate parameters. The scalp heat flux method resulted in a higher specificity (80.4% vs. 72.5%), positive predictive value (59.2% vs. 51.7%), and overall accuracy (82% vs. 77%) than FHR monitoring. Sensitivity of FHR monitoring was slightly higher than the one of heat flux method (88.2% vs 85.3%). Combining both methods resulted in a sensitivity of 100% thus detecting all acidotic foetuses, but specificity fell to 62%.(ABSTRACT TRUNCATED AT 250 WORDS)

In 163 Viennese pupils in standard 1 to 8, the weight of the schoolbag, the bodyweight and the ratio of these two parameters were examined in order to describe the amount of burden carried by those children. The results were: 1. The weight of the schoolbag war 4.0 kg (range 1 to 9 kg). 2. The pupils carried a schoolbag weighing on the average 10%, in standard 2 about 15% and in standard 8 about 6% of their bodyweight. 3. In every 6th pupil, the weight of the schoolbag constituted more than 15% of the bodyweight. 4. In analogy to pupils in standard 2, adults with a body weight of 70 kg would have to carry a weight of up to 17.5 kg to their working place. 5. While pupils have to carry a burden between 10 and 25% of their bodyweight, adults were carrying only between 1 and 10% of their bodyweight to work. We conclude that pupils are carrying daily a heavy burden in form of a schoolbag and adults apparently don't care about it.

Background: PVL is a major cause of neurodevelopmental delay and lifelong handicaps in preterm infants. Until now effective or causal therapy is not available. Thyroid hormons play essential role in brain maturation and are known to be decreased after brain injuries in adults. Substitution of T3, the metabolically most active thyroid hormone, thus might mitigate brain injuries.