Alterations in lipid profile and enzymes paraoxonase and butyrylcholinesterase in CBS-deficient patients

Homocystinuria is an inborn error of metabolism most frequently caused by cystathionine β-synthase (CBS) deficiency. Homocysteine (Hcy), methionine (Met) and other metabolites of Hcy accumulate in the body of affected patients, leading to clinical manifestations such as dislocation of the optic lents, osteoporosis, mental retardation, and thromboembolism. Despite the fact that thromboembolism represent the major cause of morbidity and the most frequent cause of death in CBS-deficient patients, the cause of cardiovascular changes found in homocystinuria remain unclear. In this work, we evaluated the lipid profile (total cholesterol, HDL cholesterol, LDL cholesterol, oxidized LDL cholesterol, apolipoprotein A-1) and the activities of the enzymes paraoxonase (PON1) and butyrylcholinesterase (BuChE) in plasma of patients with homocystinuria due CBS deficiency, at diagnosis and during the treatment. It was verified a significant decrease in HDL cholesterol and apolipoprotein A1 levels in the both groups of CBS-deficient patients (at diagnosis and under treatment) when compared to controls. PON1 activity was also significantly lower in the both groups of CBS-deficient patients when compared to controls which may be related with an Hcy-dependent oxidation of any group important to catalytic activity of the enzyme that favors the atherogenesis. BuChE activity was significantly increased only in CBS-deficient patients at diagnosis and it is known that this enzymatic activity is positively associated with cardiovascular risk factors. Evaluated together, our results demonstrated that treated or not CBS-deficient patients presented important alterations in lipid metabolism. This work contributes to the understanding of the responsible mechanisms of vascular lesions in CBS-deficient patients.Apoio: CNPq, FAPERGS, CAPES, FIPE/HCP

COMT Val158Met polymorphism and socioeconomic status interact to predict attention deficit/hyperactivity problems in children aged 10–14

The functional Val158Met COMT polymorphism appears to affect a host of behaviours mediated by the pre-frontal cortex, and has been found associated to the risk for disruptive behaviours including ADHD. Parental socioeconomic status (SES) has also been reported as a predictor for the same childhood disorders. In a general population sample of 575 Italian pre-adolescents aged 10–14, we examined the association of the functional Val158Met COMT polymorphism and SES—both as linear and interactive effects—with oppositional defiant problems, conduct problems, and attention deficit/hyperactivity problems, as defined by the newly established Child Behaviour Check-List/6-18 DSM oriented scales. Multivariate- and subsequent univariate-analysis of covariance showed a significant association of COMT × SES interaction with CBCL 6/18 DOS attention deficit/hyperactivity problems (p = 0.004), and revealed higher scores among those children with Val/Val COMT genotype who belonged to low-SES families. We also found a significant association of SES with attention deficit/hyperactivity problems and conduct problems DOS (p = 0.04 and 0.01, respectively). Our data are consistent with a bulk of recent literature suggesting a role of environmental factors in moderating the contribution of specific genetic polymorphisms to human variability in ADHD. While future investigations will refine and better clarify which specific environmental and genetic mechanisms are at work in influencing the individual risk to ADHD in pre-adolescence, these data may contribute to identify/prevent the risk for ADHD problems in childhood

Clinical Effects of an ACT-Group Training in Children and Adolescents with Attention-Deficit/Hyperactivity Disorder

Abstract Objective The aim of the present study is evaluate the effectiveness of an Acceptance and Commitment Therapy (ACT)-based training protocol, in adjunct to token economy and previous parent training, in a sample of children with Attention-Deficit/Hyperactivity Disorder (ADHD). By promoting the reduction of immediate responses to thoughts and feelings, we aimed to reduce the impulsive behaviour of children and to improve their self-regulation. Methods The protocol was centred on awareness of the present moment, defusion and acceptance of feelings and emotions. Behavioural (Conners' Parent Rating Scale -Revised: Long version, CPRS-R:L) and severity measures (Clinical Global Impression -Severity, CGI-S) were assessed before and after treatment in a clinical sample of 31 children aged 8–13 years. Results At the end of the ACT protocol, children showed significant improvement in global functioning and behavioural symptoms. There were significant improvements in the CPRS subscales Cognitive Problems (p = 0.005), Hyperactivity (p = 0.006), Perfectionism (p = 0.017), ADHD Index (p = 0.023), Global Index: Restless–Impulsive (p = 0.023), Global Index: Total (p = 0.036), DSM IV Inattentive (p = 0.029), DSM IV Hyperactive–Impulsive (p = 0.016), and DSM IV Total (p = 0.003). When controlling for the confounding effect of pharmacological therapy, comorbidities and socio-economic status, treatment maintained a significant effect on the CPRS subscales Perfectionism (partial η2 = 0.31, p < 0.01), Global Index: Restless–Impulsive (partial η2 = 0.29, p < 0.01), Global Index: Total (partial η2 = 0.31, p < 0.01), DSM IV Hyperactive–Impulsive (partial η2 = 0.20, p = 0.02). Symptom severity as rated by CGI-S scores decreased in 74.2% of the children. Conclusions This preliminary work on an Acceptance and Commitment Therapy-based child training in children affected by ADHD resulted in significant improvements, measured by a rating scale specific for ADHD

Globotriaosylceramide is correlated with oxidative stress and inflammation in Fabry patients treated with enzyme replacement therapy

AbstractFabry disease is an X-linked inborn error of glycosphingolipid catabolism due to deficient activity of α-galactosidase A that leads to accumulation of the enzyme substrates, mainly globotriaosylceramide (Gb3), in body fluids and lysosomes of many cell types. Some pathophysiology hypotheses are intimately linked to reactive species production and inflammation, but until this moment there is no in vivo study about it. Hence, the aim of this study was to investigate oxidative stress parameters, pro-inflammatory cytokines and Gb3 levels in Fabry patients under treatment with enzyme replacement therapy (ERT) and finally to establish a possible relation between them. We analyzed urine and blood samples of patients under ERT (n=14) and healthy age-matched controls (n=14). Patients presented decreased levels of antioxidant defenses, assessed by reduced glutathione (GSH), glutathione peroxidase (GPx) activity and increased superoxide dismutase/catalase (SOD/CAT) ratio in erythrocytes. Concerning to the damage to biomolecules (lipids and proteins), we found that plasma levels of malondialdehyde (MDA) and protein carbonyl groups and di-tyrosine (di-Tyr) in urine were increased in patients. The pro-inflammatory cytokines IL-6 and TNF-α were also increased in patients. Urinary Gb3 levels were positively correlated with the plasma levels of IL-6, carbonyl groups and MDA. IL-6 levels were directly correlated with di-Tyr and inversely correlated with GPx activity. This data suggest that pro-inflammatory and pro-oxidant states occur, are correlated and seem to be induced by Gb3 in Fabry patients

Lipid, Oxidative and Inflammatory Profile and Alterations in the Enzymes Paraoxonase and Butyrylcholinesterase in Plasma of Patients with Homocystinuria Due CBS Deficiency: The Vitamin B12 and Folic Acid Importance

Cystathionine-β-synthase (CBS) deficiency is the main cause of homocystinuria. Homocysteine (Hcy), methionine, and other metabolites of Hcy accumulate in the body of affected patients. Despite the fact that thromboembolism represents the major cause of morbidity in CBS-deficient patients, the mechanisms of cardiovascular alterations found in homocystinuria remain unclear. In this work, we evaluated the lipid and inflammatory profile, oxidative protein damage, and the activities of the enzymes paraoxonase (PON1) and butyrylcholinesterase (BuChE) in plasma of CBS-deficient patients at diagnosis and during the treatment (protein-restricted diet supplemented with pyridoxine, folic acid, betaine, and vitamin B12). We also investigated the effect of folic acid and vitamin B12 on these parameters. We found a significant decrease in HDL cholesterol and apolipoprotein A1 (ApoA-1) levels, as well as in PON1 activity in both untreated and treated CBS-deficient patients when compared to controls. BuChE activity and IL-6 levels were significantly increased in not treated patients. Furthermore, significant positive correlations between PON1 activity and sulphydryl groups and between IL-6 levels and carbonyl content were verified. Moreover, vitamin B12 was positively correlated with PON1 and ApoA-1 levels, while folic acid was inversely correlated with total Hcy concentration, demonstrating the importance of this treatment. Our results also demonstrated that CBS-deficient patients presented important alterations in biochemical parameters, possibly caused by the metabolites of Hcy, as well as by oxidative stress, and that the adequate adherence to the treatment is essential to revert or prevent these alterations.This work was supported in part by grants from CAPES, CNPq, and FIPE/HCPA-Brazil

Espécies reativas ao ácido tiobarbitúrico e reatividade antioxidante total em plasma de pacientes com adrenomieloneuropatia e de mulheres portadoras de adrenoleucodistrofia ligada ao x

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Disinfection byproducts formed during drinking water treatment reveal an export control point for dissolved organic matter in a subalpine headwater stream

Changes in climate, season, and vegetation can alter organic export from watersheds. While an accepted tradeoff to protect public health, disinfection processes during drinking water treatment can adversely react with organic compounds to form disinfection byproducts (DBPs). By extension, DBP monitoring can yield insights into hydrobiogeochemical dynamics within watersheds and their implications for water resource management. In this study, we analyzed temporal trends from a water treatment facility that sources water from Coal Creek in Crested Butte, Colorado. These trends revealed a long-term increase in haloacetic acid and trihalomethane formation over the period of 2005-2020. Disproportionate export of dissolved organic carbon and formation of DBPs that exceeded maximum contaminant levels were consistently recorded in association with late spring freshet. Synoptic sampling of the creek in 2020 and 2021 identified a biogeochemical hotspot for organic carbon export in the upper domain of the watershed that contained a prominent fulvic acid-like fluorescent signature. DBP formation potential analyses from this domain yielded similar ratios of regulated DBP classes to those formed at the drinking water facility. Spectrometric qualitative analyses of pre and post-reacted waters with hypochlorite indicated lignin-like and condensed hydrocarbon-like molecules were the major reactive chemical classes during chlorine-based disinfection. This study demonstrates how drinking water quality archives combined with synoptic sampling and targeted analyses can be used to identify and understand export control points for dissolved organic matter. This approach could be applied to identify and characterize analogous watersheds where seasonal or climate-associated organic matter export challenge water treatment disinfection and by extension inform watershed management and drinking water treatment

Espécies reativas ao ácido tiobarbitúrico e reatividade antioxidante total em plasma de pacientes com adrenomieloneuropatia e de mulheres portadoras de adrenoleucodistrofia ligada ao x

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