The S100B protein was identified in the mid-1960s as a protein fraction which -on the basis of chromatographic and electrophoretic methods available at that time -was detectable in the brain but not in non-neural extracts, and was named S100 because of its solubility in a 100% saturated solution with ammonium sulphate (Moore 1965). At present, owing to the discovery of a series of proteins exhibiting structural similarities, the term S100 is used to embrace a multigenic family of mostly dimeric calcium-binding proteins comprising more than 20 members with different degrees of homology to each other at the amino acid level, and representing the largest subgroup within the EF-hand superfamily. The genes encoding the majority of human S100 proteins are organized in a cluster within the chromosomal region 1q21, while some genes coding individual S100 proteins are located in other chromosomal regions, including 21q22 where, in particular, the gene for the S100B protein is located. Each monomer is approximately 10-12 kDa and is characterized by two calcium-binding regions, each comprising two alpha helices with an intervening calcium-binding loop forming a conserved pentagonal arrangement around the calcium ion (EF-hand motif).The binding of calcium to EF-hand domains triggers conformational changes that allow interactions with other proteins, so Abstract S100B is a calcium-binding protein concentrated in glial cells, although it has also been detected in definite extra-neural cell types. Its biological role is still debated. When secreted, S100B is believed to have paracrine/autocrine trophic effects at physiological concentrations, but toxic effects at higher concentrations. Elevated S100B levels in biological fluids (CSF, blood, urine, saliva, amniotic fluid) are thus regarded as a biomarker of pathological conditions, including perinatal brain distress, acute brain injury, brain tumors, neuroinflammatory/neurodegenerative disorders, psychiatric disorders. In the majority of these conditions, high S100B levels offer an indicator of cell damage when standard diagnostic procedures are still silent. The key question remains as to whether S100B is merely leaked from injured cells or is released in concomitance with both physiological and pathological conditions, participating at high concentrations in the events leading to cell injury. In this respect, S100B levels in biological fluids have been shown to increase in physiological conditions characterized by stressful physical and mental activity, suggesting that it may be physiologically regulated and raised during conditions of stress, with a putatively active role. This possibility makes this protein a candidate not only for a biomarker but also for a potential therapeutic target.

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; PϽ0.04). 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 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.

1These authors contributed equally to this study.Abbreviations used: CAT, catalase; CM, conditioned medium; EAE, experimental autoimmune encephalomyelitis; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; GFAP, glial fibrillary acid protein; GST, glutathione-S-transferase; MOG, myelin oligodendrocyte glycoprotein peptide; MS, multiple sclerosis; MSC, mesenchimal stem cell; MT, metallothionein; NeuN, neuronal nuclei; PARP-1, poly(ADP-ribose) polymerase-1; PBS, phosphate-buffered saline; RPMI, Royal Park Memorial Institute; SOD, superoxide dismutase. AbstractExperimental autoimmune encephalomyelitis (EAE), an animal model for human multiple sclerosis, is characterized by demyelination, inflammation and neurodegeneration of CNS in which free radicals play a role. Recently, the efficacy of murine mesenchimal stem cells (MSCs) as treatment of EAE induced in mice by the encephalitogenic peptide MOG(35-55) was demonstrated. The present study analyzed some markers of oxidative stress, inflammation/degeneration and apoptosis such as metallothioneins (MTs), antioxidant enzymes (superoxide dismutase, catalase and glutathione-S-transferase), poly(ADP-ribose) polymerase-1 and p53 during EAE progression and following MSC treatment. Expression of the three brain MT isoforms increased significantly in EAE mice compared with healthy controls, but while expression of MT-1 and MT-3 increased along EAE course, MT-2 was up-regulated at the onset, but returned to levels similar to those of controls in chronic phase. The changes in the transcription and activity of the antioxidant enzymes and in expression of poly(ADP-ribose) polymerase-1 and p53 showed the same kinetics observed for MT-1 and MT-3 during EAE. Interestingly, i.v. administration of MSCs reduced the EAE-induced increases in levels/activities of all these proteins. These results support an antioxidant and neuroprotective activity for MSCs that was also confirmed in vitro on neuroblastoma cells exposed to an oxidative insult.

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The purpose of this article is to study one of the most significant causes of neonatal morbidity and mortality: neonatal sepsis. This pathology is due to a bacterial or fungal infection acquired during the perinatal period. Neonatal sepsis has been categorized into two groups: early onset if it occurs within 3-6 days and late onset after 4-7 days. Due to the not-specific clinical signs, along with the inaccuracy of available biomarkers, the diagnosis is still a major challenge. In this regard, the use of a combined approach based on both nuclear magnetic resonance ( 1 H-NMR) and gas-chromatography-mass spectrometry (GC-MS) techniques, coupled with a multivariate statistical analysis, may help to uncover features of the disease that are still hidden. The objective of our study was to evaluate the capability of the metabolomics approach to identify a potential metabolic profile related to the neonatal septic condition. The study population included 25 neonates (15 males and 10 females): 9 (6 males and 3 females) patients had a diagnosis of sepsis and 16 were healthy controls (9 males and 7 females). This study showed a unique metabolic profile of the patients affected by sepsis compared to non-affected ones with a statistically significant difference between the two groups (p = 0.05).

Introduction:The abundant expression of leukotrienes (LTs) and their receptors in adenotonsillar tissues of children with obstructive sleep apnea (OSA) suggest that LT antagonists could be useful in treating OSA. Methods: The effects of LTD4 and of LT receptor antagonists zileuton, montelukast, and BAY u9773 were examined on mixed cell cultures prepared from dissociated tonsils or adenoids harvested intraoperatively from children with polysomnographically diagnosed OSA. Proliferation was assessed by 3 [H]-thymidine incorporation, and inflammatory cytokine production (tumor necrosis factor [TNF]-␣, interleukin [IL]-6, IL-8, IL-10, and IL-12) was assessed in supernatants using enzyme-linked immunosorbent assay.Results: LTD4 elicited dose-dependent increases in adenotonsillar cell proliferation (p < 0.001; n ‫؍‬ 12). All LT antagonists exhibited dose-dependent reductions in adenotonsillar cellular proliferation rates, with montelukast more than BAY u9773 more than zileuton (n ‫؍‬ 14/group; p < 0.001). However, BAY u9773 showed partial agonist effects and increased cellular proliferation at higher concentrations (10 ؊4 mmol/L; p < 0.01; n ‫؍‬ 12). LTD4 effects were partially blocked by montelukast and BAY u9773 but not by zileuton. All three antagonists reduced TNF-␣, IL-6, and IL-12 concentrations, with selective changes in IL-8 and no effects on IL-10 levels. Conclusions: LT pathways mediate intrinsic proliferative and inflammatory signaling pathways in adenotonsillar tissues from children with OSA, and targeted pharmacologic disruption of these pathways may provide nonsurgical alternatives for prevention and treatment of this disease.

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.