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S100B protein has been recently proposed as a consolidated marker of brain damage and death in adult, children and newborn patients. The present study evaluates whether the longitudinal measurement of S100B at different perioperative time-points may be a useful tool to identify the occurrence of perioperative early death in congenital heart disease (CHD) newborns. We conducted a case-control study in 88 CHD infants, without pre-existing neurological disorders or other co-morbidities, of whom 22 were complicated by perioperative death in the first week from surgery. Control group was composed by 66 uncomplicated CHD infants matched for age at surgical procedure. Blood samples were drawn at five predetermined time-points before during and after surgery. In all CHD children, S100B values showed a pattern characterized by a significant increase in protein's concentration from hospital admission up to 24-h after procedure reaching their maximum peak (P<0.01) during cardiopulmonary by-pass and at the end of the surgical procedure. Moreover, S100B concentrations in CHD death group were significantly higher (P<0.01) than controls at all monitoring time-points. The ROC curve analysis showed that S100B measured before surgical procedure was the best predictor of perioperative death, among a series of clinical and laboratory parameters, reaching at a cut-off of 0.1 μg/L a sensitivity of 100% and a specificity of 63.7%. The present data suggest that in CHD infants biochemical monitoring in the perioperative period is becoming possible and S100B can be include among a series of parameters for adverse outcome prediction.

Background: Perinatal asphyxia (PA) is a leading cause of mortality and morbidity in newborns: its prognosis depends both on the severity of the asphyxia and on the immediate resuscitation to restore oxygen supply and blood circulation. Therefore, we investigated whether measurement of S100B, a consolidated marker of brain injury, in salivary fluid of PA newborns may constitute a useful tool for the early detection of asphyxia-related brain injury., Methods: We conducted a cross-sectional study in 292 full-term newborns admitted to our NICUs, of whom 48 suffered PA and 244 healthy controls admitted at our NICUs. Saliva S100B levels measurement longitudinally after birth; routine laboratory variables, neurological patterns, cerebral ultrasound and, magnetic resonance imaging were performed. The primary end-point was the presence of neurological abnormalities at 12-months after birth., Results: S100B salivary levels were significantly (P<0.001) higher in newborns with PA than in normal infants. When asphyxiated infants were subdivided according to a good (Group A; n = 15) or poor (Group B; n = 33) neurological outcome at 12-months, S100B was significantly higher at all monitoring time-points in Group B than in Group A or controls (P<0.001, for all). A cut-off >3.25 MoM S100B achieved a sensitivity of 100% (CI5-95%: 89.3%-100%) and a specificity of 100% (CI5-95%: 98.6%-100%) as a single marker for predicting the occurrence of abnormal neurological outcome (area under the ROC curve: 1.000; CI5-95%: 0.987-1.0)., Conclusions: S100B protein measurement in saliva, soon after birth, is a useful tool to identify which asphyxiated infants are at risk of neurological sequelae.

Background: S100B protein, previously proposed as a consolidated marker of brain damage in congenital heart disease (CHD) newborns who underwent cardiac surgery and cardiopulmonary bypass (CPB), has been progressively abandoned due to S100B CNS extra-source such as adipose tissue. The present study investigated CHD newborns, if adipose tissue contributes significantly to S100B serum levels., Methods: We conducted a prospective study in 26 CHD infants, without preexisting neurological disorders, who underwent cardiac surgery and CPB in whom blood samples for S100B and adiponectin (ADN) measurement were drawn at five perioperative time-points., Results: S100B showed a significant increase from hospital admission up to 24 h after procedure reaching its maximum peak (P < 0.01) during CPB and at the end of the surgical procedure. Moreover, ADN showed a flat pattern and no significant differences (P > 0.05) have been found all along perioperative monitoring. ADN/S100B ratio pattern was identical to S100B alone with the higher peak at the end of CPB and remained higher up to 24 h from surgery., Conclusions: The present study provides evidence that, in CHD infants, S100B protein is not affected by an extra-source adipose tissue release as suggested by no changes in circulating ADN concentrations.

Perinatal asphyxia (PA) still constitutes a common complication involving a large number of infants with or without congenital heart diseases (CHD). PA affects 0.2-0.6% of full-term neonates, 20% of which suffer mortal hypoxic-ischemic encephalopathy, and among survivors 25% exhibit permanent consequences at neuropsychological level. Each year, about one third of 1000 live births underwent to surgical intervention in early infancy and/or are at risk for ominous outcome. Advances in brain monitoring, in anesthetic and cardiothoracic surgical techniques, including selective or total body cooling, cardiopulmonary bypass (CPB) and deep hypothermic circulatory arrest, have essentially reduced mortality expanding the possibility to address functional neurologic and cardiac outcomes in long-term survivors. However, open-heart surgery constitutes a time-frame of planned ischemia-reperfusion injury, which is a price to pay in the treatment or palliation of CHD. Infants who underwent heart surgery and non-CHD infants complicated by PA share similarities in their neurodevelopmental profile and a common form of brain damage due to hypoxic-ischemic injury. The purpose of the present review was to evaluate different mechanisms implicated in brain injury following CPB and PA and how it is possible to monitor such injury by means of available biomarkers (S100B protein, Activin A, Adrenomedullin).

S100B protein has been recently proposed as a consolidated marker of brain damage and death in adult, children and newborn patients. The present study evaluates whether the longitudinal measurement of S100B at different perioperative time-points may be a useful tool to identify the occurrence of perioperative early death in congenital heart disease (CHD) newborns. We conducted a case-control study in 88 CHD infants, without pre-existing neurological disorders or other co-morbidities, of whom 22 were complicated by perioperative death in the first week from surgery. Control group was composed by 66 uncomplicated CHD infants matched for age at surgical procedure. Blood samples were drawn at five predetermined timepoints before during and after surgery. In all CHD children, S100B levels showed a pattern characterized by a significant increase in protein's concentration from hospital admission up to 24-h after procedure reaching their maximum peak (P<0.01) during cardiopulmonary by-pass and at the end of the surgical procedure. Moreover, S100B concentrations in CHD death group were significantly higher (P<0.01) than controls at all monitoring time-points. The ROC curve analysis showed that S100B measured before surgical procedure was the best predictor of perioperative death, among a series of clinical and laboratory parameters, reaching at a cut-off of 0.1 µg/L a sensitivity of 100% and a specificity of 63.7%. The present data suggest that in CHD infants biochemical monitoring in the perioperative period is becoming possible and S100B can be included among a series of parameters for adverse outcome prediction.

Aim: Intraventricular haemorrhage (IVH) is the most common variety of cerebral haemorrhage and cause of neurological disabilities in preterm newborns. We evaluated the usefulness of urine Activin A concentrations for the early detection of perinatal IVH., Methods: We conducted a case-control study on 100 preterm newborns (20 with IVH and 80 without IVH) in whom urine Activin A was measured at five predetermined time-points in the first 72 h after birth. IVH diagnosis and the extension of the lesion were performed by ultrasound scanning within the first 72 h and at 1 week after birth, respectively., Results: Urine Activin A in infants who developed IVH was significantly higher than in controls at all monitoring time-points (p < 0.01 for all), increasing progressively from first urination to 24 h when it reached the highest peak (p < 0.001). At a cut-off 0.08 ng/L, at the first void, Activin A sensitivity and specificity were 68.7% (CI: 41.3-89%) and 84.5% (CI: 75-91.5%)., Conclusion: Activin A measurements in urine soon after birth can constitute a promising tool for identifying preterm infants at risk of IVH., (©2013 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

Background: Late preterm deliveries (LP, between 34 and 36wks), have considerably increased in the last decades. About 20-25% of LP infants who require intensive care and morbidity on public health are of great magnitude. Therefore, we aimed at offering a reference curve in LP period of a well-established neurotrophic and brain damage marker namely S100B protein., Methods: We collected, between December 2009 and March 2012, urine samples, at first void (within 6-hours from birth) for S100B assessment, in 277 healthy LP infants consecutively admitted to our units. Standard clinical and laboratory monitoring parameters were also recorded. S100B was measured by using a commercially available immunoluminometric assay., Results: S100B pattern in LP infants was characterized by a slight decrease in protein's concentration from 34 to 35wks. From 35wks onwards S100B started to increase reaching a significant difference (P=0.008) at 36wks. When corrected for gender, significantly higher (P<0.01, for all) S100B concentrations in female were observed from 34 to 36wks. Polynomial type-1 regression analysis showed a significant correlation (R=-0.05; P<0.001) between gestational age and S100B in LP infants considering either the whole study population or when corrected for gender., Conclusions: S100B in LP infants is gestational age and gender dependent. The present reference curve, for S100B in LP period, offers additional support to protein's neurotrophic role and suggests that gestational age and gender have to be taken into due account, whenever S100B is measured, in order to avoid bias factors., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Background: Hypoxic-ischemic encephalopathy (HIE) is one of the most important causes of brain injury in preterm infants. Preterm HIE is predominantly caused by global hypoxia-ischemia (HI). In contrast, focal ischemia is most common in the adult brain and known to result in cerebral inflammation and activation of the peripheral immune system. These inflammatory responses are considered to play an important role in the adverse outcomes following brain ischemia. In this study, we hypothesize that cerebral and peripheral immune activation is also involved in preterm brain injury after global HI., Methods: Preterm instrumented fetal sheep were exposed to 25 minutes of umbilical cord occlusion (UCO) (n = 8) at 0.7 gestation. Sham-treated animals (n = 8) were used as a control group. Brain sections were stained for ionized calcium binding adaptor molecule 1 (IBA-1) to investigate microglial proliferation and activation. The peripheral immune system was studied by assessment of circulating white blood cell counts, cellular changes of the spleen and influx of peripheral immune cells (MPO-positive neutrophils) into the brain. Pre-oligodendrocytes (preOLs) and myelin basic protein (MBP) were detected to determine white matter injury. Electro-encephalography (EEG) was recorded to assess functional impairment by interburst interval (IBI) length analysis., Results: Global HI resulted in profound activation and proliferation of microglia in the hippocampus, periventricular and subcortical white matter. In addition, non-preferential mobilization of white blood cells into the circulation was observed within 1 day after global HI and a significant influx of neutrophils into the brain was detected 7 days after the global HI insult. Furthermore, global HI resulted in marked involution of the spleen, which could not be explained by increased splenic apoptosis. In concordance with cerebral inflammation, global HI induced severe brain atrophy, region-specific preOL vulnerability, hypomyelination and persistent suppressed brain function., Conclusions: Our data provided evidence that global HI in preterm ovine fetuses resulted in profound cerebral inflammation and mobilization of the peripheral innate immune system. These inflammatory responses were paralleled by marked injury and functional loss of the preterm brain. Further understanding of the interplay between preterm brain inflammation and activation of the peripheral immune system following global HI will contribute to the development of future therapeutic interventions in preterm HIE.

Background: Low cardiac output syndrome (LCOS) remains a major perioperative complications in infants subjected to open-heart surgery with cardiopulmonary bypass (CPB). The present study investigated whether perioperative blood assessment of a potent vasoactive peptide namely adrenomedullin (AM) can predict the risk of LCOS., Methods: We measured AM levels in 48 patients (LCOS: n = 9; controls: n = 39) undergone to open-heart surgery with CPB at five predetermined time points before, during and after the surgery. Clinical, laboratory and perioperative data were analyzed by a multiple logistic regression model., Results: AM significantly decreased (p < 0.01) during and after the surgical procedure exhibiting a dip at the end of the CPB. Multivariable analysis demonstrated significant correlations among LCOS, AM measured at the end of CPB (p < 0.001), and cooling duration (p < 0.05). AM at 27 pg/L cutoff achieved a sensitivity of 100% and a specificity of 64.1%, while cooling at 11-min cutoff combined a sensitivity of 55.6% and a specificity of 92.3% for LCOS prediction., Conclusions: This study suggests that AM can constitute, alone or combined with standard parameters, a promising predictor of LCOS in infants subjected to open-heart surgery with CPB.

Objective: There is growing evidence on the usefulness of biomarkers in the early detection of preterm infants at risk for brain damage. However, among different tools Activin A, S100B protein and adrenomedullin assessment offer the possibility to investigate brain/multiorgan function and development. This could be especially useful in perinatal medicine that requires even more non-invasive techniques in order to fulfill the minimal handling in diagnostic and therapeutic strategy performance., Materials and Methods: The concept of Unconventional Biological Fluid (UBF: urine and saliva) is becoming even stronger and regards the assessment in non-invasive biological fluids of biochemical markers involved in the cascade of events leading to brain damage., Results: Activin A, S100B protein and adrenomedullin in UBF were increased in preterm newborns developing brain damage and/or ominous outcome., Conclusions: The present manuscript offers an update on the usefulness of Activin A, S100B protein an adrenomedullin in UBF as brain damage markers. The findings open a new cue on the use of these markers in daily neonatal intensive care unit (NICU) activities.

In the framework of long-term scientific collaboration among the founder members coming from Holland and Italy there was a growing consensus to activate a philosophical doctorate (PhD) program, involving young Italian researchers in the field of perinatal medicine, neonatology and pediatrics. The aims were to promote excellence in research, offering to young Italian physicians the opportunity to maturate an International research experience leading to PhD degree, and to promote human and technological improvement energies in perinatal, neonatal and pediatrics research. Thus, an official collaboration among the Dutch Universities from Maastricht and Utrecht and the Italian Children's Hospital from Alessandria, has been activated on March 1st 2010, finalized to the PhD program. The experimental phase included the selection of projects and relative candidates after an interview-selection focusing on their scientific attitudes and the availability on their research projects. Candidates' selection started on May 2010 and on September 29th ten projects and candidates have been approved by the scientific commission. Research topics included: perinatal asphyxia, aging and the origin of adulthood neurodegenerative disease, neuroprotective strategies, biochemical pulmonology, intrauterine growth retardation and perinatal teratology. To date, all projects have been approved by local Ethics Committee from the University/Hospital of origin of the candidates. Five manuscripts have been published and/or submitted to international Journals regarding pneumology, perinatal asphyxia and teratology, whilst about 60-70% of data regarding clinical studies have already been collected.

Background: Brain S100B assessment in maternal blood has been proposed as a useful tool for early perinatal brain damage detection. Among potential confounding factors the possibility of a protein gradient between maternal and fetal bloodstreams under pathophysiological conditions is consistent. The present study investigates in healthy and small gestational age fetuses (SGA) whether S100B concentrations differ among fetal and maternal bloodstreams., Methods: We conducted a case-control study in 160 pregnancies (SGA: n=80; healthy: n=80), in which standard monitoring parameters were recorded. S100B was assessed in arterial cord and in maternal blood samples at birth. Eighty non pregnant women (NP), matched for age at sampling, served as controls (1 SGA vs. 1 healthy vs. 1 NP)., Results: Fetal S100B in SGA and healthy groups was significantly higher (P<0.01) than that detected in the maternal district and in NP women groups, respectively. No differences in protein's gradient between fetal and maternal bloodstreams (P>0.05) were observed between groups. No differences (P>0.05) in fetal S100B have been found between the studied groups. Maternal S100B of SGA and healthy groups was significantly higher (P<0.01) than that detected in NP women. No differences in maternal S100B concentrations (P>0.05) were observed between SGA and control groups., Conclusion: The present study shows that S100B is pregnancy-dependent with the presence of a protein's gradient between fetal and maternal bloodstreams. The present data suggests that non-invasive fetal brain monitoring is becoming possible in opening a new cue on further investigations on S100B fetal/maternal gradient changes under pathological conditions., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Objective: To measure the effect of intensive therapy and the lasting effect of a standardized functional training programme with vs. without the addition of chemodernervation of the muscles of the forearm and hand., Patients and Methods: Twenty children with spastic hemiplegia, aged 4-16 years, were matched for baseline characteristics and randomized to standardized task-oriented therapy for 6 months with or without botulinum toxin injections. Dynamic kinematic outcome measures were: speed, accuracy, end-point spread and performance. Measurements of active and passive range of motion, stretch-restricted angle of the elbow and wrist, Ashworth scores and Melbourne Assessment of Unilateral Upper Limb Function were made. All measures were performed at baseline, 2 weeks after injection of botulinum toxin and after 6 months (at the end of therapy), and 3 months after end of the therapy., Results: Clinical measures showed improvement in both groups. However, no significant differences emerged between groups on functional measures. Directly after the botulinum toxin injection all kinematic outcome measures showed a decrease, but baseline values were re-established during the therapy period. After botulinum toxin injections a temporarily significant greater increase in speed and performance was found. These results illustrate the need for further quantitative research into the effects of botulinum toxin.

Object: It remains uncertain if closure of a myelomeningocele at midgestation changes the neurological condition at birth in an infant born with spina bifida. The authors conducted a study to provide a detailed analysis of the morphology of the spinal cord with the myelomeningocele at the time fetal surgery usually is performed., Methods: The myelomeningocele of a 20-week-gestation-age fetus was examined, and data were compared with those obtained in a neurologically intact specimen of the same age. In vitro high-field 9.4-tesla magnetic resonance (MR) microscopy was used to examine the fetal material. High-field MR spectroscopy provided images in the three orthogonal planes with a resolution comparable with low-power optical microscopy. The authors observed that the fetal cord of the myelomeningocele specimen was tapered and tethered at S3-4 while the conus medullaris in the normal fetus reaches L-4. No neurulation defects were noted. The axial MR images clearly revealed the nonfusion of the mesodermal structures. The absence of neurulation defects suggests that at least in some cases of spina bifida the spinal cord initially is well developed but is damaged later on chemically and mechanically. This might be an argument in favor of intrauterine myelomeningocele repair. By 20 weeks' gestation, however, the deformation of the cord inside the myelomeningocele is severe. An optimization of the preoperative assessment by means of MR imaging therefore might be considered a valuable contribution to intrauterine surgery. The in vitro high-field MR microscopic findings of this study could be used as references for clinical intrauterine MR imaging., Conclusions: The detailed in vitro high-field MR analysis of a 20-week-gestation-age fetus with spina bifida demonstrated that an improvement of the preoperative intrauterine imaging should be pursued to detect those cases without neurulation defects and with minimal deformation of the spinal cord.