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

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

S100B Protein Maternal and Fetal bloodstreams gradient in Healthy and Small for Gestational Age Pregnancies

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 patho-physiological 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 (P0.05) 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 (P0.05) 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 suggesting that non-invasive fetal brain monitoring is becoming possible opening a new cue on further investigations on S100B fetal/maternal gradient changes under pathological conditions

Perinatal asphyxia: kidney failure does not affect S100B urine concentrations.

BACKGROUND: S100B protein is a well-established marker of brain damage. Its importance in urine assessment is the convenience of a collection and sampling procedure that can be repeated without risk for the newborn. Since S100B is mainly eliminated by the kidneys and perinatal asphyxia (PA) is often associated with kidney failure we investigated whether S100B release might be kidney-mediated, thereby modifying the protein's reliability as a brain-damage marker. METHODS: We examined a cohort of healthy (n=432) and asphyxiated newborns (n=32) in whom kidney function parameters (blood urea and creatinine concentrations and urine gravity) and urine S100B concentrations were assessed in the first hours after birth. Data were analyzed by multiple logistic regression analysis with S100B as independent variable among a variety of clinical and laboratory monitoring parameters. RESULTS: S100B urine concentrations were significantly higher (P0.05, for all) between total urine S100B levels and kidney function parameters such as creatinine (r=0.03), urea (r=0.04) and urine gravity (r=0.06) were found. Multiple logistic regression analysis of a series of clinical and laboratory monitoring parameters (odds ratio at sampling: 9.47) with S100B as independent variable showed a positive significant correlation only between S100B levels (P<0.001) and the occurrence of PA. CONCLUSION: The present study shows that altered kidney function is not an adverse and/or confounding factor in urine S100B assessment and marks a new step towards the introduction of longitudinal monitoring of brain constituents in clinical practice

Perinatal asphyxia: Kidney failure does not affect S100B urine concentrations

BACKGROUND: S100B protein is a well-established marker of brain damage. Its importance in urine assessment is the convenience of a collection and sampling procedure that can be repeated without risk for the newborn. Since S100B is mainly eliminated by the kidneys and perinatal asphyxia (PA) is often associated with kidney failure we investigated whether S100B release might be kidney-mediated, thereby modifying the protein's reliability as a brain-damage marker. METHODS: We examined a cohort of healthy (n=432) and asphyxiated newborns (n=32) in whom kidney function parameters (blood urea and creatinine concentrations and urine gravity) and urine S100B concentrations were assessed in the first hours after birth. Data were analyzed by multiple logistic regression analysis with S100B as independent variable among a variety of clinical and laboratory monitoring parameters. RESULTS: S100B urine concentrations were significantly higher (P0.05, for all) between total urine S100B levels and kidney function parameters such as creatinine (r=0.03), urea (r=0.04) and urine gravity (r=0.06) were found. Multiple logistic regression analysis of a series of clinical and laboratory monitoring parameters (odds ratio at sampling: 9.47) with S100B as independent variable showed a positive significant correlation only between S100B levels (P<0.001) and the occurrence of PA. CONCLUSION: The present study shows that altered kidney function is not an adverse and/or confounding factor in urine S100B assessment and marks a new step towards the introduction of longitudinal monitoring of brain constituents in clinical practice

Urinary H-1-NMR and GC-MS metabolomics predicts early and late onset neonatal sepsis

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)

The S100B protein in biological fluids: more than a lifelong biomarker of brain distress

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