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Mass spectrometric multiple reaction monitoring detection of protein glycation, oxidation and nitration adducts and amino acids. Table S2. Correlation analysis – plasma protein glycation, oxidation and nitration adduct residues. Table S3. Correlation analysis – plasma protein glycation, oxidation and nitration free adducts. Table S4. Correlation analysis – plasma amino acids. Table S5. Correlation analysis – urinary protein glycation, oxidation and nitration free adducts. Table S6. Correlation analysis – Urinary amino acids. Table S7. Confusion matrix of algorithm to identify autistic spectrum disorder. (DOCX 80 kb)

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.

Down Syndrome (DS) is characterized by a wide spectrum of clinical signs, which include segmental premature aging of central nervous and immune systems. Although it is well established that the causative defect of DS is the trisomy of chromosome 21, the molecular bases of its phenotype are still largely unknown. We used the Infinium HumanMethylation450 BeadChip to investigate DNA methylation patterns in whole blood from 29 DS persons, using their relatives (mothers and unaffected siblings) as controls. This family-based model allowed us to monitor possible confounding effects on DNA methylation patterns deriving from genetic and environmental factors. Although differentially methylated regions (DMRs) displayed a genome-wide distribution, they were enriched on chromosome 21. DMRs mapped in genes involved in developmental functions, including embryonic development (HOXA family) and haematological (RUNX1 and EBF4) and neuronal (NCAM1) development. Moreover, genes involved in the regulation of chromatin structure (PRMD8, KDM2B, TET1) showed altered methylation. The data also showed that several pathways are affected in DS, including PI3K-Akt signaling. In conclusion, we identified an epigenetic signature of DS that sustains a link between developmental defects and disease phenotype, including segmental premature aging.

Friedreich’s ataxia is an autosomal recessive disorder characterized by impaired mitochondrial function, resulting in oxidative stress. In this study, we aimed at evaluating whether tocotrienol, a phytonutrient that diffuses easily in tissues with saturated fatty layers, could complement the current treatment with idebenone, a quinone analogue with antioxidant properties. Five young Friedreich’s ataxia patients received a low-dose tocotrienol supplementation (5 mg/kg/day), while not discontinuing idebenone treatment. Several oxidative stress markers and biological parameters related to oxidative stress were evaluated at the time of initiation of treatment and 2 and 12 months post-treatment. Some oxidative stress-related parameters and some inflammation indices were altered in Friedreich’s ataxia patients taking idebenone alone and tended to be normal values following tocotrienol supplementation; likewise, a cardiac magnetic resonance study showed some improvement following one-year tocotrienol treatment. The pathway by which tocotrienol affects the Nrf2 modulation of hepcidin gene expression, a peptide involved in iron handling and in inflammatory responses, is viewed in the light of the disruption of the iron intracellular distribution and of the Nrf2 anergy characterizing Friedreich’s ataxia. This research provides a suitable model to analyze the efficacy of therapeutic strategies able to counteract the excess free radicals in Friedreich’s ataxia, and paves the way to long-term clinical studies. Impact statement Oxidative stress is involved in the pathogenesis of Friedreich's ataxia (FRDA), a genetic disorder causing neurodegeneration due to the dramatic reduction in the expression of frataxin. To date, no cure is available for FRDA patients. In some countries, FRDA patients assume idebenone in order to counteract the effects of frataxin deficiency. We demonstrate that idebenone treatment alone is not able to abrogate oxidative stress in FRDA patients, whereas the combined treatment with tocotrienols might be more efficient and perhaps produce clinical improvement. In fact, a decrease in oxidative stress and inflammation markers can be seen after two months and is more pronounced after one year of treatment. This is, in our opinion, valuable information for clinicians, since idebenone is the treatment of choice for FRDA patients in some countries.

Aims/hypothesis: To assess thiamine and related metabolite status by analysis of plasma and urine in autistic children and healthy controls, correlations to clinical characteristics and link to plasma protein markers of oxidative damage. Methods: 27 children with autism (21 males and 6 females) and 21 (15 males and 6 females) age-matched healthy control children were recruited. The concentration of thiamine and related phosphorylated metabolites in plasma and urine and plasma protein content of dityrosine, N-formylkynurenine and 3-nitrotyrosine was determined. Results: Plasma thiamine and thiamine monophosphate concentrations were similar in both study groups (median [lower–upper quartile]): autistic children–6.60 nM (4.48–8.91) and 7.00 nM (5.51–8.55), and healthy controls–6.82 nM (4.47–7.02) and 6.82 nM (5.84–8.91), respectively. Thiamine pyrophosphate (TPP) was decreased 24% in autistic children compared to healthy controls: 6.82 nM (5.81–8.52) versus 9.00 nM (8.41–10.71), p

none 8 no Autism Spectrum Disorders (ASD) are a heterogeneous group of neurodevelopmental disorders. Recognized causes of ASD include genetic factors, metabolic diseases, toxic and environmental factors, and a combination of these. Available tests fail to recognize genetic abnormalities in about 70% of ASD children, where diagnosis is solely based on behavioral signs and symptoms, which are difficult to evaluate in very young children. Although it is advisable that specific psychotherapeutic and pedagogic interventions are initiated as early as possible, early diagnosis is hampered by the lack of nongenetic specific biological markers. In the past ten years, the scientific literature has reported dozens of neurophysiological and biochemical alterations in ASD children; however no real biomarker has emerged. Such literature is here reviewed in the light of Receiver Operating Characteristic (ROC) analysis, a very valuable statistical tool, which evaluates the sensitivity and the specificity of biomarkers to be used in diagnostic decision making. We also apply ROC analysis to some of our previously published data and discuss the increased diagnostic value of combining more variables in one ROC curve analysis. We also discuss the use of biomarkers as a tool for advancing our understanding of nonsyndromic ASD. Abruzzo, Provvidenza M.; Ghezzo, Alessandro; Bolotta, Alessandra; Ferreri, Carla; Minguzzi, Renato; Vignini, Arianna; Visconti, Paola; Marini, Marina Abruzzo, Provvidenza M.; Ghezzo, Alessandro; Bolotta, Alessandra; Ferreri, Carla; Minguzzi, Renato; Vignini, Arianna; Visconti, Paola; Marini, Marina

The number of children affected by Autism Spectrum Disorders (ASD) is dramatically increasing as well as the studies aimed at understanding the risk factors associated with the development of ASD. Since the etiology of ASD is partly genetic and partly environmental, factors (i.e., heavy metals, pesticides) as well as lifestyle seem to have a key role in the development of the disease. ASD and Control (CTR) children, aged 5–12 years, were compared. Gas chromatography coupled with trap mass detector was used to measure the level of 3-PBA, the main pyrethroid metabolite in urine in a group of ASD patients, while optical emission spectrometry analysis was employed to estimate the level of metals and microelements in hair in a different group of ASD children. The presence of 3-PBA in urine seems to be independent of age in ASD children, while a positive correlation between 3-PBA and age was observed in the control group of the same age range. Urine concentration of 3-BPA in ASD children had higher values than in the control group, which were marginally significant (p = 0.054). Mg results were significantly decreased in ASD with respect to controls, while V, S, Zn, and Ca/Mg were marginally increased, without reaching statistical significance. Results of Principal Component (PC) analysis of metals and microelements in hair were not associated with either age or health status. In conclusion, 3-PBA in urine and Mg in hair were changed in ASD children relative to control ones.

Within the MARK-AGE project, a population study (3337 subjects) was conducted to identify a set of biomarkers of ageing which, as a combination of parameters with appropriate weighting, would measure biological age better than any single marker. The MARK-AGE project involves 14 European countries and a total of 26 research centres. In such a study, standard operating procedures (SOPs) are an essential task, which are binding for all MARK-AGE Beneficiaries. The SOPs cover all aspects of subject's recruitment, collection, shipment and distribution of biological samples (blood and its components, buccal mucosa cells or BMC and urine) as well as the anthropometric measurements and questionnaires. published