S100B maternal blood levels are gestational age- and gender-dependent in healthy pregnancies.

BACKGROUND: S100B is a well-established biomarker of central nervous system (CNS) development and damage in the perinatal period. Because the fetal CNS induces an overproduction of S100B measurable in the maternal bloodstream we evaluated S100B protein in healthy pregnancies in order to provide a reference curve of the protein in the second and third trimesters and to provide information on CNS development when standard monitoring procedures could be silent or unavailable. METHODS: Between July 2012 and December 2014 we conducted a prospective study in 1213 healthy pregnancies delivering healthy newborns. Maternal blood samples were collected for standard monitoring procedures and S100B assessment. S100B correlations with selected outcomes (gestational age at sampling, gender of fetus, gestational age and weight at birth, delivery mode) were calculated using multiple forward stepwise regression analysis. RESULTS: S100B concentrations in the second and third trimesters of pregnancy were found to be gestational age-, gender- and delivery mode-dependent (p<0.05, for all). Multiple forward stepwise regression analysis with S100B as the dependent variable and gestational age at sampling, gender, delivery mode, gestational age and weight at birth as independent variables, showed a significant correlation between S100B and gestational age at sampling (R=0.13; p<0.001). CONCLUSIONS: The present findings offering a S100B protein reference curve in maternal blood suggest that non-invasive fetal CNS monitoring is becoming feasible and open the way to further research in neuro-biomarker assessment in the maternal bloodstream.

Urine S100 BB and A1B dimers are valuable predictors of adverse outcome in full-term asphyxiated infants.

AIM: To investigate whether S100A1B and BB dimers are predictors of early perinatal death in newborns with perinatal asphyxia (PA). METHODS: The study compared 38 full-term newborns with PA [neonatal death n = 11; hypoxic ischaemic encephalopathy (HIE): n = 27] with a control group of 38 healthy infants. Clinical and laboratory parameters were recorded at eight time points and urine collected for S100B assessment. Multivariate analysis was performed in order to analyse the influence of various clinical parameters on the occurrence of neonatal death. RESULTS: A1B and BB in PA nonsurvivor infants were significantly higher (p < 0.001) than in controls at all monitoring time points. BB at first void (cut-off>42 ng/L) was the best predictor of early neonatal death (p < 0.05) of all the clinical and laboratory parameters studied. CONCLUSION: These results suggest that S100s are valuable predictors of adverse outcome in PA infants. It is also suggested that these biomarkers be used in daily clinical practice, due to their low cost and stress, reproducibility and the possibility of longitudinal monitoring.

TNF-α gene polymorphisms and excessive daytime sleepiness in pediatric obstructive sleep apnea.

OBJECTIVE: To assess sleepiness, TNF-α plasma levels, and genomic variance in the TNF-α gene in children with obstructive sleep apnea (OSA). STUDY DESIGN: Children being evaluated for OSA (n = 60) and matched control children (n = 80) were assessed with a modified Epworth Sleepiness Scale questionnaire and underwent a blood draw the morning after nocturnal polysomnography. TNF-α plasma concentrations were assayed using ELISA, and genomic DNA was extracted. Genotyping and allelic frequencies were determined for 4 TNF-α single nucleotide polymorphisms using real-time polymerase chain reaction genotyping assays. RESULTS: Morning TNF-α levels and Epworth Sleepiness Scale scores were increased in the presence of OSA, but substantial variability was present. Although TNF-α plasma concentrations were globally increased in OSA, most of the variance was attributable to the presence or absence of TNF-α -308G gene polymorphism. CONCLUSIONS: TNF-α levels are increased in a subset of children with OSA, particularly among those harboring the TNF-α -308G single nucleotide polymorphism. Among the latter, significant increases in excessive daytime sleepiness symptoms are also present. The relatively high variability of excessive daytime sleepiness in pediatric OSA may be related to underlying TNF-α gene polymorphisms, particularly -308G.

Dietary and physical activity patterns in children with obstructive sleep apnea.

OBJECTIVE: To assess dietary and physical activity patterns and morning circulating blood levels of the orexigenic hormones ghrelin and visfatin in children with either obesity, obstructive sleep apnea (OSA), or both conditions. STUDY DESIGN: In this cross-sectional design, 5- to 9-year-old participants (n = 245) from the community were identified. After overnight polysomnography, caregivers filled out a food and physical activity questionnaire, and the child underwent a fasting blood draw for ghrelin and visfatin plasma levels. RESULTS: Compared with control subjects, obese children with OSA ate 2.2-times more fast food, ate less healthy food such as fruits and vegetables, and were 4.2-times less frequently involved in organized sports. OSA was positively correlated with plasma ghrelin levels (R(2), 0.73; P < .0001), but not visfatin levels, particularly when obesity was present. CONCLUSION: OSA and obesity in children may adversely impact dietary preferences and may be particularly detrimental to daily physical activity patterns. Furthermore, increased ghrelin levels support the presence of increased appetite and caloric intake in obese patients with OSA, which in turn may further promote the severity of the underlying conditions.

Sleep measures and morning plasma TNF-alpha levels in children with sleep-disordered breathing.

BACKGROUND: Sleep disordered breathing in children is associated with severity-dependent increases in excessive daytime sleepiness (EDS). TNF-alpha is an inflammatory cytokine that has been implicated in EDS. Since, at any given level of apnea-hypopnea index, there is significant variability in EDS, we hypothesized that morning tumor necrosis factor (TNF)-alpha plasma levels may provide a biologic correlate of EDS. METHODS: Children being evaluated for sleep disordered breathing underwent a blood draw after nocturnal polysomnography, and TNF-alpha plasma concentrations were assayed using ELISA. In a subset of 15 children with sleep disordered breathing and in 15 matched control subjects, whole blood cultures in the presence of lipopolysaccharide and Multiple Sleep Latency Test were conducted. Furthermore, 22 children with obstructive sleep apnea had TNF-alpha levels assayed and underwent nocturnal polysomnography and Multiple Sleep Latency Test before and after adenotonsillectomy. RESULTS: In 298 children, morning TNF-alpha levels were globally increased in the presence of obstructive sleep apnea, particularly in more severe cases, and correlated with obstructive apnea-hypopnea index and sleep pressure score, a measure of respiratory-induced sleep fragmentation, but not with nadir Sa02. A stepwise logistic regression analysis revealed that sleep pressure score and body mass index accounted for 36.2% of the adjusted variance in TNF-alpha levels (P < 0.0001). Furthermore, multiple sleep latencies were correlated with whole blood culture-derived TNF-alpha levels (n = 15), and morning TNF-alpha levels decreased after adenotonsillectomy in 22 children. CONCLUSIONS: TNF-alpha levels are increased in pediatric obstructive sleep apnea, are primarily driven by sleep fragmentation and body mass index, and are closely associated with the degree of sleepiness, as measured by Multiple Sleep Latency Test. Furthermore, surgical treatment of obstructive sleep apnea results in significant reductions in TNF-alpha levels with reciprocal prolongations in sleep latency.

Type I epithelial cells are the main target of whole-body hypoxic preconditioning in the lung.

Whole-body hypoxic preconditioning (WHPC) prolongs survival of mice exposed to severe hypoxia by attenuating pulmonary edema and preserving gas exchange. However, the cellular and molecular mechanism(s) of this protection remains unclear. The objective of this study was to identify the cellular target(s) of WHPC in the lung. Conscious mice were exposed to hypoxia (7% O(2)) for 6 hours with or without pretreatment of WHPC ([8% O(2)] x 10 min/[21% O(2)] x 10 min; 6 cycles). Hypoxia caused severe lung injury, as shown by the development of high-permeability-type pulmonary edema and the release of lactate dehydrogenase and creatine kinase into the airspace and the circulation. All these signs of hypoxic lung injury were significantly attenuated by WHPC. Hypoxia also caused a remarkable release of type I cell markers (caveolin-2 and receptor for advanced glycation end products) in lung lavage that was almost completely abolished by WHPC. Conversely, hypoxia-induced release of type II cell markers (surfactant-associated proteins A and D) was only marginal, and was unaffected by WHPC. Electron microscopic analysis demonstrated considerable hypoxic damage in alveolar type I cells and vascular endothelial cells. Notably, WHPC completely eliminated hypoxic damage in the former and alleviated it in the latter. Type II cells appeared normal. Furthermore, WHPC up-regulated protein expression of cytoprotective genes in the lung, such as heat shock proteins and manganese superoxide dismutase. Thus, WHPC attenuates hypoxic lung injury through protection of cells constituting the respiratory membrane, especially hypoxia-vulnerable type I epithelial cells. This beneficial effect may involve up-regulation of cytoprotective genes.

Genome-wide gene expression profiling in children with non-obese obstructive sleep apnea.

BACKGROUND: Obstructive sleep apnea (OSA) is a multi-factorial and highly prevalent disorder in which both genetic and environmental factors may be involved. If left untreated, OSA may lead to significant cardiovascular and neurocognitive and behavioral morbidities. We hypothesized that pediatric OSA would lead to altered gene expression in circulating leukocytes. METHODS AND RESULTS: Oligonucleotide-based microarray technology was used to identify mRNAs that may be differentially regulated in non-obese children with polysomnographically-established OSA compared to matched control children. Total morning blood RNA from 40 children (20 OSA and 20 controls) was extracted, labeled, and hybridized onto independent oligonucleotide-based microarrays. Of the 44,000 transcripts, 1217 transcripts were differentially expressed in OSA (p-value <0.05), with 68 transcripts (38 RefSeq accession numbers, 30 ESTs) fulfilling high stringency criteria. False Discovery rate (FDR) was used to determine the significance-difference of OSA vs. normal samples. Microarray data were further validated using quantitative RT-PCR techniques. Biological pathways pertinent to the differentially expressed genes were explored and revealed prominent involvement of inflammatory pathways. CONCLUSIONS: RNA derived from peripheral leukocytes confirms the presence of altered expression of functionally relevant gene clusters in pediatric OSA. Large-scale genomic approaches may provide further insights into adaptive and end-organ injury related mechanisms in the context of OSA in children.

Plasma IGF-1 levels and cognitive dysfunction in children with obstructive sleep apnea.

BACKGROUND: Pediatric OSA is associated with substantial morbidity in cognitive function. However, for any given OSA severity level, altered cognitive performance may or may not be present. Since IGF-1 is neuroprotective, we hypothesized that higher systemic IGF-1 levels may identify children at lower susceptibility for cognitive morbidity. METHODS: Consecutive habitually snoring and non-snoring children ages 5-7 years were recruited from the community, and underwent overnight polysomnography, and neurocognitive testing and a blood draw the next morning. Snoring children were divided into OSA or no OSA, and OSA children were further subdivided into those with >=2 abnormal cognitive subtests and into those with normal cognitive scores. Plasma levels of IGF-1 were also measured using ELISA. RESULTS: Among snoring children without OSA, circulating IGF-1 was 910 +/- 110 pg/mL compared with 1070 +/- 240 pg/mL in those with OSA (p<0.01). However, IGF-1 was 540 +/- 70 pg/mL in children with OSA and cognitive deficits, compared to 1370 +/- 170 microg/L in children with OSA and normal cognitive scores (p<0.001). CONCLUSIONS: IGF-1 levels are higher in children with OSA, particularly in those who do not manifest neurocognitive deficits, suggesting that the magnitude of the IGF-1 response elicited by OSA may play a significant protective role against the neurocognitive dysfunction associated with OSA.

Increased cellular proliferation and inflammatory cytokines in tonsils derived from children with obstructive sleep apnea.

Adenotonsillar hypertrophy is the major pathophysiological mechanism underlying obstructive sleep apnea (OSA) and recurrent tonsillitis (RI) in children. The increased expression of various mediators of the inflammatory response in tonsils of patients with OSA prompted our hypothesis that the enhanced local and systemic inflammation in children with OSA would promote tonsillar proliferation. Mixed cell cultures from tonsils recovered during adenotonsillectomy in children with OSA and RI were established, and proliferative rates were assessed. Cells were also cultured to determine the levels of proinflammatory cytokines and antioxidant protein levels and mRNA expression. Global cell proliferative rates from OSA tonsils were significantly higher than RI (p < 0.01), with CD3, CD4, and CD8 cell proliferation being higher in OSA (p < 0.05). Moreover, proinflammatory cytokines, such as TNF-alpha, IL-6, and IL-1alpha, were highly expressed in OSA-derived tonsils. Furthermore, thioredoxin (TRX), an antioxidant protein, was also highly expressed in OSA tonsils at the mRNA and protein levels (p < 0.01). Thus, T cells are in a highly proliferative state in the tonsils of children with OSA and are associated with increased production of proinflammatory cytokines and TRX, when compared with children with RI.

Obstructive sleep apnea and endothelial function in school-aged nonobese children: effect of adenotonsillectomy.

BACKGROUND: Obstructive sleep apnea (OSA) in children is associated with cardiovascular morbidity such as systemic and pulmonary hypertension. However, it remains unclear whether endothelial dysfunction occurs in pediatric OSA and whether it is reversible on effective treatment of OSA. METHODS AND RESULTS: Consecutive nonobese children (aged 6 to 11 years) who were diagnosed with OSA after overnight polysomnography and control children matched on the basis of age, gender, ethnicity, and body mass index underwent blood draw the next morning for soluble CD40 ligand, asymmetric dimethylarginine (ADMA), and nitrotyrosine levels, as well as 2 iterations of 60-second cuff-occlusion tests for assessment of endothelial function. These tests were repeated 4 to 6 months after adenotonsillectomy. OSA children showed blunted reperfusion kinetics after release of occlusion, which completely normalized in 20 of 26 patients after adenotonsillectomy. All 6 children in whom no improvements occurred had a strong family history of cardiovascular disease (versus 2 of the remaining 20 patients; P<0.04). Plasma nitrotyrosine and ADMA levels were similar in OSA and control children; however, soluble CD40 ligand levels were higher in OSA children and were reduced after treatment, particularly in those with normalized hyperemic responses. CONCLUSIONS: Postocclusive hyperemia is consistently blunted in children with OSA, and such altered endothelial function is reversible 4 to 6 months after treatment, particularly if a family history of cardiovascular disease is not present. Although no evidence for either nitric oxide-dependent oxidative/nitrosative stress or for the increased presence of the circulating nitric oxide synthase inhibitor ADMA was found in children with OSA, soluble CD40 ligand levels were increased in OSA and reflected the changes in endothelial function after treatment.

Systemic inflammation in non-obese children with obstructive sleep apnea.

BACKGROUND: Obstructive sleep apnea (OSA) has been associated with increased systemic inflammatory responses that may contribute to an increased risk for end-organ morbidity. The changes in levels of pro-inflammatory cytokine IL-6 , and the anti-inflammatory cytokine IL-10, both of which play a major role in atherogenesis, a major consequence of OSA, have not specifically been assessed in pediatric patients. METHODS: Consecutive non-obese children (aged 4-9years) who were polysomnographically diagnosed with OSA, and age-, gender-, ethnicity-, and BMI-matched control children underwent a blood draw the next morning after a sleep study and plasma samples were assayed for interleukins 6 (IL-6) and 10 (IL-10). These tests were repeated 4-6months after tonsillectomy and adenoidectomy (T&A) in children with OSA. RESULTS: IL-6 levels were higher and IL-10 plasma levels were lower in children with OSA and returned to control levels after T&A. CONCLUSIONS: Systemic inflammation is a constitutive component and consequence of OSA in many children, even in the absence of obesity, and is reversible upon treatment in most patients.

Plasma levels of adhesion molecules ICAM-1 and VCAM-1 in athletes with sickle cell trait with or without alpha-thalassemia during endurance exercise and recovery.

The aim of the study was to examine the effects of endurance exercise on circulating vascular cell adhesion molecule-1 (sVCAM-1) and intercellular adhesion molecule-1 (sICAM-1) in sickle cell trait (SCT) athletes with or without alpha-thalassemia. Five athletes with SCT, 7 athletes with both SCT and alpha-thalassemia (SCTAT) and 8 control athletes (CONT) performed an incremental test on cycloergometer followed 72 hours later by a 60-min endurance exercise with a workload set at 70% P(peak) (peak power). We assessed levels of sICAM-1, sVCAM-1 and TNF-alpha at rest, immediately after endurance exercise and 1, 2, and 24 hours of recovery. Although, CONT and SCTAT groups exhibited similar basal plasma levels of adhesion molecules and TNF-alpha, SCT group had higher sVCAM-1 basal concentrations. No significant variation in sVCAM-1, sICAM-1 and TNF-alpha was measured following endurance exercise. Consequently, sVCAM-1 remained elevated in the SCT group after exercise and during the recovery period. In conclusion, our findings support the concept that SCT athletes might be at risk for microcirculatory disturbances, but these adhesive processes were not further impaired in response to endurance exercise. In addition, alpha-thalassemia co existing trait may be protective both at rest and after endurance exercise in SCT subjects.

Adipokines in children with sleep disordered breathing.

STUDY OBJECTIVE: Associations between SDB, the metabolic syndrome, and circulating levels of adipokines have emerged in adults but have not been examined in snoring children, who, in contradistinction to adults, display insulin resistance and lipid abnormalities as a function of adiposity rather than SDB. Therefore, we aimed to examine associations between circulating adipokines levels, insulin resistance, and measures of SDB in children. DESIGN: Prospective study. SETTING: Polysomnographic evaluation and assessment of plasma levels of leptin, adiponectin, resistin, glucose, insulin, and CRP. PARTICIPANTS: 130 children (mean age 8.2 +/- 2.8 years; 39% obese) were studied. MEASUREMENTS AND RESULTS: Log adiponectin levels were lower in obese than nonobese children (3.8 +/- 0.31 vs 4.0 +/- 0.30 corresponding to 8,381.4 +/- 5,841.0 vs 12,853.2 +/- 7,780.2 ng/ml, P < 0.0001) and were inversely correlated with BMI Z scores (r = -0.47, P < 0.0001) but not with log AHI. Log leptin concentrations were higher in the obese group than the nonobese group (4.2 +/- 0.32 vs 3.4 +/- 0.57 corresponding to 19,542.6 +/- 13,643.6 vs 5,875.5 +/- 8,425.7 pg/ml, P < 0.0001), correlated with BMI Z scores (r = 0.64, P < 0.0001), and were significantly lower in children with AHI < or = 1/hr than children with AHI > 1/hr (P = 0.006) and in children with SpO2 nadir > or = 90% than children with SpO2 nadir < 90%, even after controlling for BMI Z score (P < 0.03). No significant differences were found in log resistin levels as a function of obesity or AHI. Significant correlations between log adiponectin levels and log Insulin/Glucose (I/G) ratios (-0.28, P = 0.006) and between log leptin levels and log I/G ratios (r = 0.66, P < 0.0001) emerged. CONCLUSIONS: In close agreement with the absence of a measurable effect of SDB on insulin resistance in children, circulating adipokines levels are primarily attributable to the ponderal index. However, SDB and associated hypoxemia may contribute to the elevation of leptin levels.

Effects of progressive and maximal exercise on plasma levels of adhesion molecules in athletes with sickle cell trait with or without alpha-thalassemia.

The aim of the study was to examine the effects of exercise on soluble vascular cell adhesion molecule-1 (sVCAM-1) and intercellular adhesion molecule-1 (sICAM-1) in sickle cell trait (SCT) athletes with or without alpha-thalassemia. Six athletes with SCT, seven athletes with both SCT and alpha-thalassemia (SCTAT), and seven control athletes (Cont) performed an incremental and maximal test on cycloergometer. Levels of sICAM-1 and sVCAM-1 were assessed at rest, immediately after the end of exercise, and 1, 2, and 24 h after exercise. Although Cont and SCTAT groups exhibited similar basal plasma levels of inflammatory and adhesion molecules, the SCT group had higher sVCAM-1 basal concentrations. Incremental exercise resulted in a significant increase of sVCAM-1 in all subjects, which remained elevated only in the SCT group during the recovery period. In conclusion, as sVCAM-1 increased with exercise and during the recovery period, our findings support the concept that SCT athletes might be at risk for microcirculatory disturbances and adhesive phenomena developing at rest and several hours after exercise. alpha-Thalassemia might be considered protective among exercising SCT subjects.

Plasma adhesion molecules in children with sleep-disordered breathing.

STUDY OBJECTIVES: To determine whether childhood sleep-disordered breathing (SDB) is associated with elevated levels of plasma adhesion molecules. DESIGN: Prospective, observational study. SETTING: Sleep Medicine Center of Kosair Children's Hospital. PARTICIPANTS: Thirty-nine children with SDB (apnea-hypopnea index [AHI] > 5/h), 47 children with mild SDB (AHI 1 to 5/h), and 42 healthy control subjects (AHI < 1/h). MEASUREMENTS AND RESULTS: One hundred twenty-eight children underwent a standard polysomnographic assessment with a blood draw the following morning. Plasma levels of CRP and the adhesion molecules intercellular adhesion molecule (ICAM)-1 and P-selectin were measured. No differences were observed in ICAM-1 levels among the groups; however, obese children had higher ICAM-1 levels than nonobese children (425.0 +/- 123.0 ng/mL vs 375.6 +/- 107.1 ng/mL, p = 0.04) [mean +/- SD]. P-selectin levels were significantly higher in the SDB group (84.0 +/- 52.2 ng/mL) and the mild SDB group (89.3 +/- 49.9 ng/mL) when compared to control subjects (49.5 +/- 22.3 ng/mL; p < 0.001 for both groups). Furthermore, P-selectin correlated with AHI (r = 0.32, p < 0.001), respiratory arousal index (r = 0.27, p = 0.002), and nadir of oxygen saturation as measured by pulse oximetry (r = - 0.19, p = 0.038). Plasma CRP levels were found to correlate with P-selectin even after controlling for BMI (r = 0.20, p = 0.05). No correlations were found between CRP and ICAM-1. CONCLUSIONS: Children with SDB have plasma elevations of P-selectin, a marker of platelet activation, lending support to the premise that inflammatory processes are elicited by SDB in children, and may contribute to accelerated risk for cardiovascular morbidity. In contrast, elevations in ICAM-1 are primarily associated with obesity rather than SDB.

Inflammatory mediators in exhaled breath condensate of children with obstructive sleep apnea syndrome.

BACKGROUND: Upper airway inflammation is now recognized in adults with obstructive sleep apnea (OSA) syndrome. However, the role played by eicosanoids such as leukotrienes and prostaglandins is unclear. OBJECTIVE: To investigate whether eicosanoids are measurable in exhaled breath condensate (EBC), and to determine whether differences in these inflammatory mediators emerge among children with and without sleep-disordered breathing (SDB). METHODS: EBC was collected from 50 consecutive snoring children undergoing overnight polysomnography for suspected SDB, and from 12 nonsnoring control subjects. Prostaglandin E2 (PGE2), leukotriene B4 (LTB4), and cysteinyl leukotrienes (cys-LTs: leukotriene C4 [LTC4]/leukotriene D4 [LTD4]/leukotriene E4 [LTE4]) EBC levels were analyzed using enzyme-linked immunosorbent assay. RESULTS: LTB4 levels were elevated in children with an apnea-hypopnea index (AHI) > 5/h (SDB; 97.6 +/- 6.3 pg/mL) compared to children with an AHI < 5/h (mild SDB; 66.4 +/- 19.1 pg/mL; p < 0.01) and control subjects (27.8 +/- 3.7 pg/mL; p < 0.01). Similarly, cys-LT (LTC4/LTD4/LTE4) concentrations were also increased in SDB (45.1 +/- 10.6 pg/mL in SDB vs 27.6 +/- 8.3 pg/mL in mild SDB, and 15.7 +/- 7.6 pg/mL in control subjects; p < 0.01). In contrast, PGE2 concentrations were similar among the three groups. CONCLUSIONS: Inflammatory mediators such as leukotrienes and prostaglandins can be readily quantified in EBC collected from the upper airway of children. Disease severity-dependent increases in leukotriene concentrations (LTB4 and LTC4/LTD4/LTE4) emerge among children and may serve as a noninvasive tool in the clinical assessment of these children.

The clinical and diagnostic utility of S100B in preterm newborns.

Preterm birth is still the most important cause of perinatal mortality and morbidity. Follow-up studies showed that the majority of neurological abnormalities during childhood are already present in the first week after birth. In this light, the knowledge of the timing of the insult and/or of the contributing factors is of utmost relevance in order to avoid adverse neurological outcome. Notwithstanding, the considerable advances in perinatal clinical care and monitoring, the early detection of cases at risk for brain damage is still a challenge because, when radiological pictures are still negative, brain damage may be already at a subclinical stage, with symptoms hidden by therapeutic strategies. Thus, it could be very relevant to measure quantitative parameters, such as neuroproteins, able to detect subclinical lesions at a stage when routine brain monitoring procedures are still silent. In the last decade, the assay of the brain-specific protein S100B in different biological fluids proved useful information on brain function and damage in the perinatal period. Therefore, the present study provides an overview of the most recent findings on S100B role as a reliable marker of brain development/damage in preterm high risk fetuses and newborns.

Antenatal glucocorticoids supplementation and central nervous system development.

Maternal antenatal therapy with glucocorticoids (GC) is routinely used to prevent lung immaturity. The potential harmful effects on other organs, including in particular the central nervous system (CNS), are still controversial. In the present review we aimed to investigate: i) the beneficial and detrimental effects of antenatal GC treatment in both human and animal models; ii) the potential usefulness of biochemical markers such as calcium binding proteins (S100B, synaptophysin) and cytoskeletal protein of neurons and dendrites (MAP2) in the perinatal period, and iii) whether the assessment of brain markers in different biological fluids could constitute a promising tool for the monitoring of CNS function and/or developmental in fetuses and newborns whose mothers assumed GC antenatally.

Fingolimod modulates peripheral effector and regulatory T cells in MS patients.

Multiple sclerosis (MS) is a complex neurological disease where, in genetically predisposed individuals, the unbalanced interplay between pathogenic and regulatory T cells will result in the progression of the autoimmune assault to neural antigens. Fingolimod (FTY720), an oral sphingosine 1-phosphate modulator recently approved for the treatment of MS, inhibits the egress of T cells from lymph nodes acting specifically on naïve and memory T cells and sparing effector T cells. Here we characterized IL-17 and IFNγ producing effector CD4 and CD8 positive T cells as well as CD4 positive CD25(high)CD127(low) regulatory T cells in MS patients before and 1 month after treatment was started. We observed that fingolimod did not significantly affect the percentage of CCR6 and CD161 positive T cells in both CD4 and CD8 compartments. In contrast, it significantly reduced the levels of both CD4+ CCR6+ CD161+ and CD8+ CCR6+ CD161+ producing IFNγ alone or in combination with IL-17. The percentage of IL-17 secreting cells in both subsets was affected by the treatment to a lesser extent. Finally, we observed that CD4+ CD25(high)CD127(low) regulatory T cells were decreased in MS patients compared to healthy controls and fingolimod significantly increased their frequencies. All together these findings demonstrate that fingolimod functionally modulates the ability of potentially pathogenic effector cells to produce relevant pro-inflammatory cytokines and increases the number of circulating regulatory T cells possibly contributing in restoring a balance between these populations.

Next generation biomarkers for brain injury.

In perinatal medicine, there is an emerging interest on the potential usefulness of non-invasive brain biochemical monitoring in infants at risk for brain injury. To date, several biomarkers such as neuro-proteins, calcium binding proteins, oxidative stress markers, vasoactive agents, inflammatory mediators, have been investigated. Results showed that hypoxia insult, under different conditions, triggers a biochemical pathophysiological cascade of events leading to brain damage. In this setting, increased biomarkers concentrations in different biological fluids have been found to correlate with the occurrence of brain damage at short-long term both in preterm and term fetuses/newborns. However, before inclusion of any biomarker in guidelines, USA and European institutions have recently stated a panel of criteria that have to be fulfilled. Therefore, the present review offers an overview of the main biomarkers currently studied in perinatal medicine and their progresses according to institutions' criteria.