The biological basis of autism spectrum disorders: evaluation of oxidative stress and erytrocyte membrane alterations

This case-control study involved a total of 29 autistic children (Au) aged 6 to 12 years, and 28 gender and age-matched typically developing children (TD). We evaluated a high number of peripheral oxidative stress parameters, erythrocyte and lymphocyte membrane functional features and membrane lipid composition of erythrocyte. Erythrocyte TBARS, Peroxiredoxin II, Protein Carbonyl Groups and urinary HEL and isoprostane levels were elevated in AU (confirming an imbalance of the redox status of Au); other oxidative stress markers or associated parameters (urinary 8-oxo-dG, plasma Total antioxidant capacity and plasma carbonyl groups, erythrocyte SOD and catalase activities) were unchanged, whilst peroxiredoxin I showed a trend of elevated levels in red blood cells of Au children. A very significant reduction of both erythrocyte and lymphocyte Na+, K+-ATPase activity (NKA), a reduction of erythrocyte membrane fluidity, a reduction of phospatydyl serine exposition on erythrocyte membranes, an alteration in erythrocyte fatty acid membrane profile (increase in MUFA and in ω6/ω3 ratio due to decrease in EPA and DHA) and a reduction of cholesterol content of erythrocyte membrane were found in Au compared to TD, without change in erythrocyte membrane sialic acid content and in lymphocyte membrane fluidity. Some Au clinical features appear to be correlated with these findings; in particular, hyperactivity score appears to be related with some parameters of the lipidomic profile and membrane fluidity, and ADOS and CARS score are inversely related to peroxiredoxin II levels. Oxidative stress and erythrocyte structural and functional alterations may play a role in the pathogenesis of Autism Spectrum Disorders and could be potentially utilized as peripheral biomarkers

Modeling the inter-annual variability of salinity in the lagoon of Venice in relation to the water framework directive typologies

The Water Framework Directive (2000/60/EC) requires member states to classify and enhance the ecological quality of water bodies in accordance with their type. To estimate the effect on type of the natural variability of lagoons, we applied a two-dimensional hydrodynamic model to the lagoon of Venice. The model calculated the mean annual spatial distributions of two variables: salinity and residence time. The standard deviation of salinity was also included, in order to estimate the variation of salinity values around the mean, which is associated with the instability of the mean salinity value. A highly detailed numerical grid was calibrated and high-frequency tributary discharge data were used. The simulations, under realistic forcing conditions, are based on the years 2003 and 2005. The former was characterized by low precipitation, around 30% less than the typical value. A comparison of model results and measurements shows the high reliability of the model in reproducing the spatial distribution and temporal evolution of salinity. We found strong inter-annual variation in salinity, standard deviation of salinity and residence time. The effect on the typing process is that the most representative types shift from one category to another. On the basis of the spatial patterns of the variables and their superposition, we identi fi ed types that described the bulk of the lagoon. This numerical tool offers support for lagoon management on various levels, in terms of both WFD requirements and other applications, by: (1) providing unbiased and objective zoning indications for the basin; (2) evaluating the response of water quality elements; (3) establishing the reference status of a water body; and (4) establishing a hierarchical division of a lagoon that can be used to select an appropriate number of sampling stations for monitoring

Frataxin mRNA isoforms in FRDA patients and normal subjects: effect of tocotrienol supplementation.

Friedreich's ataxia (FRDA) is caused by deficient expression of the mitochondrial protein frataxin involved in the formation of iron-sulphur complexes, and by consequent oxidative stress. We analysed low-dose tocotrienol supplementation effects on the expression of the three splice variant isoforms (FXN-1, FXN-2 and FXN-3) in mononuclear blood cells of FRDA patients and healthy subjects. In FRDA patients, tocotrienol leads to a specific and significant increase of FXN-3 expression, while not affecting FXN-1 and FXN-2 expression. Since no structural and functional details were available for FNX-2 and FXN-3, 3D-models were built. FXN-1, the canonical isoform, was then docked on the human iron-sulphur complex and functional interactions were computed; when FXN-1 was replaced by FXN-2 or FNX-3, we found that the interactions were maintained, thus suggesting a possible biological role for both isoforms in human cells. Finally, in order to evaluate whether tocotrienol enhancement of FXN-3 was mediated by an increase in peroxisome proliferator-activated receptor-\uf067 (PPARG), PPARG expression was evaluated. At low dose of tocotrienol, the increase of FXN-3 expression appeared to be independent of PPARG expression. Our data show that it is possible to modulate the mRNA expression of the minor frataxin isoforms, and that they may have a functional role

Advanced glycation endproducts, dityrosine and arginine transporter dysfunction in autism - a source of biomarkers for clinical diagnosis.

Background: Clinical chemistry tests for autism spectrum disorder (ASD) are currently unavailable. The aim of this study was to explore the diagnostic utility of proteotoxic biomarkers in plasma and urine, plasma protein glycation, oxidation, and nitration adducts, and related glycated, oxidized, and nitrated amino acids (free adducts), for the clinical diagnosis of ASD. Methods: Thirty-eight children with ASD (29 male, 9 female; age 7.6 \ub1 2.0 years) and 31 age-matched healthy controls (23 males, 8 females; 8.6 \ub1 2.0 years) were recruited for this study. Plasma protein glycation, oxidation, and nitration adducts and amino acid metabolome in plasma and urine were determined by stable isotopic dilution analysis liquid chromatography-tandem mass spectrometry. Machine learning methods were then employed to explore and optimize combinations of analyte data for ASD diagnosis. Results: We found that children with ASD had increased advanced glycation endproducts (AGEs), N\u3b5-carboxymethyllysine (CML) and N\u3c9-carboxymethylarginine (CMA), and increased oxidation damage marker, dityrosine (DT), in plasma protein, with respect to healthy controls. We also found that children with ASD had increased CMA free adduct in plasma ultrafiltrate and increased urinary excretion of oxidation free adducts, alpha-aminoadipic semialdehyde and glutamic semialdehyde. From study of renal handling of amino acids, we found that children with ASD had decreased renal clearance of arginine and CMA with respect to healthy controls. Algorithms to discriminate between ASD and healthy controls gave strong diagnostic performance with features: plasma protein AGEs\u2014CML, CMA\u2014and 3-deoxyglucosonederived hydroimidazolone, and oxidative damage marker, DT. The sensitivity, specificity, and receiver operating characteristic area-under-the-curve were 92%, 84%, and 0.94, respectively. Conclusions: Changes in plasma AGEs were likely indicative of dysfunctional metabolism of dicarbonyl metabolite precursors of AGEs, glyoxal and 3-deoxyglucosone. DT is formed enzymatically by dual oxidase (DUOX); selective increase of DT as an oxidative damage marker implicates increased DUOX activity in ASD possibly linked to impaired gutmucosal immunity. Decreased renal clearance of arginine and CMA in ASD is indicative of increased arginine transporter activity which may be a surrogate marker of disturbance of neuronal availability of amino acids. Data driven combination of these biomarkers perturbed by proteotoxic stress, plasma protein AGEs and DT, gave diagnostic algorithms of high sensitivity and specificity for ASD

Modeling the inter-annual variability of salinity in the lagoon of Venice in relation to the Water Framework Directive typologies

The Water Framework Directive (2000/60/EC) requires to classify the water basins in order to reserve their ecological integrity. To estimate the effects of the natural variability on the lagoon classification, as required by, we applied a two-dimensional hydrodynamic model to the Venice lagoon. The model calculated the mean annual spatial distributions of two variables: salinity and residence time. The former is specified by System B of the WFD as obligatory factor and the latter as an optional factor. The standard deviation of salinity was also included, in order to estimate the variation of salinity values around the mean, which is associated with the persistence of the mean salinity value. A highly detailed numerical grid was calibrated and high-frequency discharge data were adopted for the tributaries. The simulations, under realistic forcing conditions, refer to the years 2003 and 2005. The first year was characterized by low precipitation, around 30% less than the typical value. A comparison of model results and measurements shows the high reliability of the model in reproducing the spatial distribution and temporal evolution of salinity. We found strong inter-annual variation in salinity, standard deviation of salinity and residence time. The effect on the typing process is that the most representative types shift from one category to another. We considered the different spatial combinations of the variables and identified types that described the bulk of the lagoon and we proposed a possible division of the lagoon into water bodies.JRC.H.6-Spatial data infrastructure

New Insights into the Hepcidin-Ferroportin Axis and Iron Homeostasis in iPSC-Derived Cardiomyocytes from Friedreich’s Ataxia Patient

Iron homeostasis in the cardiac tissue as well as the involvement of the hepcidin-ferroportin (HAMP-FPN) axis in this process and in cardiac functionality are not fully understood. Imbalance of iron homeostasis occurs in several cardiac diseases, including iron-overload cardiomyopathies such as Friedreich’s ataxia (FRDA, OMIM no. 229300), a hereditary neurodegenerative disorder. Exploiting the induced pluripotent stem cells (iPSCs) technology and the iPSC capacity to differentiate into specific cell types, we derived cardiomyocytes of a FRDA patient and of a healthy control subject in order to study the cardiac iron homeostasis and the HAMP-FPN axis. Both CTR and FRDA iPSCs-derived cardiomyocytes express cardiac differentiation markers; in addition, FRDA cardiomyocytes maintain the FRDA-like phenotype. We found that FRDA cardiomyocytes show an increase in the protein expression of HAMP and FPN. Moreover, immunofluorescence analysis revealed for the first time an unexpected nuclear localization of FPN in both CTR and FRDA cardiomyocytes. However, the amount of the nuclear FPN was less in FRDA cardiomyocytes than in controls. These and other data suggest that iron handling and the HAMP-FPN axis regulation in FRDA cardiac cells are hampered and that FPN may have new, still not fully understood, functions. These findings underline the complexity of the cardiac iron homeostasis