Towards a new model and classification of mood disorders based on risk resilience, neuro-affective toxicity, staging, and phenome features using the nomothetic network psychiatry approach.

Current diagnoses of mood disorders are not cross validated. The aim of the current paper is to explain how machine learning techniques can be used to a) construct a model which ensembles risk/resilience (R/R), adverse outcome pathways (AOPs), staging, and the phenome of mood disorders, and b) disclose new classes based on these feature sets. This study was conducted using data of 67 healthy controls and 105 mood disordered patients. The R/R ratio, assessed as a combination of the paraoxonase 1 (PON1) gene, PON1 enzymatic activity, and early life time trauma (ELT), predicted the high-density lipoprotein cholesterol - paraoxonase 1 complex (HDL-PON1), reactive oxygen and nitrogen species (RONS), nitro-oxidative stress toxicity (NOSTOX), staging (number of depression and hypomanic episodes and suicidal attempts), and phenome (the Hamilton Depression and Anxiety scores and the Clinical Global Impression; current suicidal ideation; quality of life and disability measurements) scores. Partial Least Squares pathway analysis showed that 44.2% of the variance in the phenome was explained by ELT, RONS/NOSTOX, and staging scores. Cluster analysis conducted on all those feature sets discovered two distinct patient clusters, namely 69.5% of the patients were allocated to a class with high R/R, RONS/NOSTOX, staging, and phenome scores, and 30.5% to a class with increased staging and phenome scores. This classification cut across the bipolar (BP1/BP2) and major depression disorder classification and was more distinctive than the latter classifications. We constructed a nomothetic network model which reunited all features of mood disorders into a mechanistically transdiagnostic model.

Evaluation of hepatic and renal effects in rat dams and their offspring after exposure to paracetamol during gestation and lactation.

Paracetamol (PAR) is the analgesic and antipyretic of choice for pregnant and nursing women. PAR may reach the fetus and/or neonate through the placenta and/or milk and effect development. This study evaluated possible hepatic and renal effects in rat dams and their offspring exposed to PAR using a human-relevant route of administration and doses from Gestational Day 6 to Postnatal Day (PND) 21. Dams were gavaged daily with PAR (35 or 350mg kg-1) or water (CON). Dams and pups were killed on PND21 and 22 respectively, and blood was collected for biochemical analysis (aspartate aminotransferase (AST), alanine aminotransferase (ALT), urea and creatinine). The kidneys and liver were isolated and processed for histopathological assessment and evaluation of oxidative stress markers. Compared with the CON groups, pups exposed to 350mg kg-1 PAR had increased renal reduced glutathione (GSH), whereas dams exposed to both doses of PAR increased serum AST. PAR administration did not affect parameters of general toxicity or renal and hepatic oxidative stress. In conclusion, maternal exposure to human-relevant doses of PAR by gavage was not associated with hepatic or renal toxicity in the pups or dams, but PAR was not devoid of effects. Exposure to PAR increased renal GSH in pups, which could suggest an adaptive antioxidant response, and affected maternal serum AST activity.

Influence of Spray-Drying and Room Temperature Storage on the Anti- and Prooxidant Properties of Fermented Juçara Pulp.

Many fruits and vegetables contain compounds with antioxidant properties, but the processing and storage conditions of the food industry may damage these beneficial compounds and produce free radicals that are associated with oxidative stress. This study aims to evaluate in vitro the antioxidant capacity and prooxidant effects of juçara pulp fermented with Lactobacillus reuteri or Lactobacillus plantarum before and after spray-drying with maltodextrin, gum arabic or gelatin and stored at 25 °C for 90 days. The antioxidant capacity was assessed by measuring the ability to scavenge reactive oxygen species (ROS) in the neutrophil respiratory burst and free radical 2,2-diphenyl-1-picryl-hydrazyl (DPPH), and by determining the total phenolic content. The prooxidant effects were analyzed as free radical formation measured by electronic paramagnetic resonance (EPR). Fermentation by both bacteria increased the antioxidant activity, while the spray-drying process decreased the content of phenolic compounds (65-85%) and the DPPH scavenging ability, depending on the carrier usage. All of the samples inhibited ROS in the neutrophil burst, and the juçara pulp fermented by L. reuteri and dried with gum arabic exhibited the best performance. Spray-drying did not influence the intensity or type of free radicals detected by EPR. However, storage at room temperature decreased the antioxidant capacity and increased free radical formation.

Interferon-gamma in mobilized stem cells: A possible prognostic marker in early post-transplant management in multiple myeloma.

INTRODUCTION: A complex network of cytokines in the bone marrow microenvironment has been implicated as an important factor in the pathogenesis of multiple myeloma (MM). Different cytokines have been studied in MM, both in peripheral blood and/or bone marrow, but there are few data correlating cytokines in leukapheresis product with post-transplant response depth to treatment. MATERIALS AND METHODS: In a retrospective cross-sectional study, levels of tumor necrosis factor alpha (TNF-α), transforming growth factor beta-1 (TGF-ß1) and interferon gamma (IFN-γ) in peripheral hematopoietic stem cells/leukapheresis product (PHSC) of patients with MM eligible for transplantation were evaluated. Association of these cytokines with certain factors such as mobilized CD34 + cells/kg, staging, response to treatment and outcome were analyzed. RESULTS: The median baseline IFN-γ level was 826.4 pg/mL. IFN-γ levels in the leukapheresis product were significantly lower in patients who achieved complete response (CR) three months post-transplant when compared to patients with very good partial response (VGPR) (674.75 ±â€¯80.32 pg/mL versus 939.6 ±â€¯106.8 pg/mL, p = 0.02), respectively. Patients who lost depth of response at the third-month post-transplant had a median level of IFN-γ 1133, being considered "high-expressors" of IFN-γ, while those reaching improved response were called "low-expressors" (median level IFN-γ 485 pg/mL). Overall and progression-free survival did not have a statistically significant correlation with TNF-α, TGF-ß1 or IFN-γ, as well as TNF-α and TGF-ß1 levels in post-transplant response assessment. CONCLUSION: IFN-γ in PHSC seems to be an important biomarker of loss of response in MM, suggesting a role in early post-transplant therapeutic management.

In major affective disorders, early life trauma predict increased nitro-oxidative stress, lipid peroxidation and protein oxidation and recurrence of major affective disorders, suicidal behaviors and a lowered quality of life.

Early life trauma (ELT) may increase the risk towards bipolar disorder (BD) and major depression (MDD), disorders associated with activated neuro-oxidative and neuro-nitrosative stress (O&NS) pathways. It has remained elusive whether ELTs are associated with O&NS and which ELTs are associated with distinct affective disorder phenotypes. This case-control study examined patients with BD (n = 68) and MDD (n = 37) and healthy controls (n = 66). The Child Trauma Questionnaire (CTQ) was used to assess specific ELT. We measured malondialdehyde (MDA), lipid hydroperoxides (LOOH), superoxide dismutase (SOD), catalase, advanced oxidation protein products (AOPP); NO metabolites (NOx), paraoxonase 1 activity, zinc, albumin, high density lipoprotein cholesterol and -SH groups and computed z-unit weighted composite scores. Physical neglect significantly predicts higher z-unit weighted composite scores of LOOH+SOD, LOOH+SOD+NOx, LOOH+SOD+NOx + MDA and LOOH+SOD+NOx + AOPP. Sexual abuse was associated with a significantly lower composite score of zinc+albumin+SH. Emotional abuse was associated with severity of depression and anxiety, number of depressive and manic episodes, alcohol and hypnotics use, lifetime suicidal behavior and lowered quality of life. Sexual abuse was associated with an increased risk towards BD, but not MDD. ELT, especially physical neglect, may drive increased (nitro-)oxidative stress coupled with lipid and protein oxidation, which - together with emotional abuse - may play a role in severity of illness, lowered quality of life and MDD. ELTs are also associated with the onset of BD, but this link did not appear to be related to activated O&NS pathways. These novel findings deserve confirmation in prospective studies.

Chronic Blood Pressure Reductions and Increments in Plasma Nitric Oxide Bioavailability.

This study analyzed the effects of 12 weeks of resistance training (RT) on resting blood pressure (BP) and plasma levels of nitric oxide metabolites (NOx) in pre- and hypertensive older women, and evaluated the relationship between these 2 parameters. Thirty-five older women (68.2±5.7 years, 70.0±14.4 kg, 157.1±6.4 cm, 28.3±5.0 kg.m-2) were randomly allocated into a training group (TG; n=17), which performed a 12-week RT program, and a control group (CG; n=18), which did not perform any physical exercise. Anthropometry, one repetition maximum (1RM), body composition analysis by dual energy X-ray absorptiometry, blood samples, and resting BP were measured. There was a significant interaction for all variables analyzed, in which reductions of systolic BP (-8.5%), diastolic BP (-8.4%), and mean arterial pressure (-8.5%), and increases of NOx (+35.2%) were observed only for the TG. Moreover, a negative and significant correlation was observed (P<0.05; r=-0.63) between NOx and systolic BP in the TG. Results suggest that a 12-week RT program is sufficient to induce reductions in BP in pre- and hypertensive older women and that the decrease in systolic BP is associated with an increase in plasma NOx concentration.

Employing photoacoustic spectroscopy in the evaluation of the skin permeation profile of emulsion containing antioxidant phenolic-rich extract of Melochia arenosa.

CONTEXT: Oxidative stress is an important factor modulating skin alterations. Melochia arenosa Benth. (Malvaceae) is a Brazilian plant with antimicrobial activity and antioxidant potential. OBJECTIVE: The objective of this study is to develop a topical formulation containing antioxidant phenolic-rich extract of M. arenosa and to evaluate its skin permeation profile. MATERIALS AND METHODS: Response surface methodology was used to maximize the total phenolic (TP) content of the extract and its antioxidant activity was evaluated by 2,2-diphenyl-1-picryl-hydrazyl (DPPH), 2,2'-azinobis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), and respiratory burst methods. An emulsion containing 1% optimized extract (OE) was developed and employed photoacoustic spectroscopy (PAS) for the determination of its skin permeation profile. The morphology of the skin was studied in histological sections stained with hematoxylin-eosin. RESULTS AND DISCUSSION: The optimum conditions predicted for the major extractive efficiency of the phenolics with 100% ethanol led extraction time 101 h and plant:solvent proportion 1:13.5 (w/v). OE presented TP = 724.6 ± 8.2 mg GAE/g extract and scavenging capacity of DPPH (IC50 value = 11.43 ± 0.14 µg/mL) and ABTS radicals (IC50 value = 35.42 ± 0.48 µg/mL). The production of ROS by neutrophils after stimulation with phorbol miristate acetate was lower when the OE was present in the reaction medium, endorsing its high antioxidant capacity. The data obtained by PAS indicated that the OE present in the emulsion has permeated and was distributed in the whole skin. No histopathological alterations were observed in the histological analysis. CONCLUSION: The formulation developed is a promising tool for skin care and could prevent the damage caused by oxidative stress.

A Novel Pathway Phenotype of Temporal Lobe Epilepsy and Comorbid Psychiatric Disorders: Results of Precision Nomothetic Medicine.

No precision medicine models of temporal lobe epilepsy (TLE) and associated mental comorbidities have been developed to date. This observational study aimed to develop a precision nomothetic, data-driven comorbid TLE model with endophenotype classes and pathway phenotypes that may have prognostic and therapeutical implications. We recruited forty healthy controls and 108 TLE patients for this research and assessed TLE and psychopathology (PP) features as well as oxidative stress (OSTOX, e.g., malondialdehyde or MDA, lipid hydroperoxides, and advanced oxidation protein products) and antioxidant (paraoxonase 1 or PON1 status, -SH groups, and total radical trapping potential or TRAP) biomarkers. A large part (57.2%) of the variance in a latent vector (LV) extracted from the above TLE and PP features was explained by these OSTOX and antioxidant biomarkers. The PON1 Q192R genetic variant showed indirect effects on this LV, which were completely mediated by PON1 activity and MDA. Factor analysis showed that a common core could be extracted from TLE, PP, OSTOX and antioxidant scores, indicating that these features are manifestations of a common underlying construct, i.e., a novel pathway phenotype of TLE. Based on the latter, we constructed a new phenotype class that is characterized by increased severity of TLE, PP and OSTOX features and lowered antioxidant defenses. A large part of the variance in episode frequency was explained by increased MDA, lowered antioxidant, and nitric oxide metabolite levels. In conclusion, (a) PP symptoms belong to the TLE phenome, and the signal increased severity; and (b) cumulative effects of aldehyde formation and lowered antioxidants determine epileptogenic kindling.

Reduced paraoxonase 1 activities may explain the comorbidities between temporal lobe epilepsy and depression, anxiety and psychosis.

BACKGROUND: Temporal lobe epilepsy (TLE) is the most common focal epilepsy subtype in adults and is frequently accompanied by depression, anxiety and psychosis. Aberrations in total paraoxonase 1 (PON1) status may occur in TLE and these psychiatric conditions. AIM: To examine PON1 status, namely Q192R PON1 genotypes and PON1 enzymatic activities, in TLE. METHODS: We recruited 40 normal controls and 104 TLE patients, 27 without comorbidities and 77 with comorbidities including mood disorders (n = 25), anxiety disorders (n = 27) and psychosis (n = 25). RESULTS: Four-(chloromethyl)phenyl acetate hydrolysis (CMPAase) and arylesterase activities were significantly lower in TLE and mesial temporal sclerosis (MTS) with and without psychiatric comorbidities than those in normal controls. The areas under the receiver operating characteristic curve of CMPAase were 0.893 (0.037) for TLE and 0.895 (± 0.037) for MTS. Partial least squares path analysis showed that there were specific indirect effects of PON1 genotype on TLE severity (P < 0.0001) and psychopathology (P < 0.0001), which were both mediated by lowered CMPAase activity, while arylesterase activity was not significant. The severity of TLE was significantly associated with psychopathology scores. Furthermore, PON1 CMPAase activity was inversely associated with Mini Mental State Examination score. CONCLUSION: The severity of TLE and comorbidities are to a large extent explained by reduced PON1 enzyme activities and by effects of the Q192R genotype, which are mediated by reduced CMPAase activity. Total PON1 status plays a key role in the pathophysiology of TLE, MTS and psychiatric comorbidities by increasing the risk of oxidative toxicity. PON1 enzyme activities are new drug targets in TLE to treat seizure frequency and psychiatric comorbidities.

Association of parents' physical activity and weight status with obesity and metabolic risk of their offspring.

Our aim was to analyze the joint association of parental characteristics and offspring obesity indicators with metabolic risk in adolescents. A cross-sectional study was carried out with 972 adolescents and their parents. We observed that overweight adolescents who have a normal weight mother show lower metabolic risk in comparison with their counterparts with overweight mothers. In conclusion, mother's weight status moderates the relationship between offspring' obesity indicators and metabolic risk in adolescents.

Increased nitro-oxidative toxicity in association with metabolic syndrome, atherogenicity and insulin resistance in patients with affective disorders.

BACKGROUND: There is a strong comorbidity between mood disorders and metabolic syndrome (MetS). Increased levels of reactive oxygen and nitrogen species (RONS) and nitro-oxidative stress toxicity (NOSTOX) partially underpin this comorbidity. AIMS: To examine the associations of RONS/NOSTOX biomarkers with MetS after adjusting for the significant effects of mood disorders (major depression, and bipolar type 1 and 2), generalized anxiety disorder (GAD), tobacco use disorder (TUD), and male sex. METHODS: The study included subjects with (n=65) and without (n=107) MetS and measured levels of superoxide dismutase 1 (SOD1), lipid hydroperoxides (LOOH), nitric oxide metabolites (NOx), malondialdehyde (MDA), and advanced oxidation protein products (AOPP) and computed z unit-weighted composite scores which reflect RONS/NOSTOX. The study included 105 patients with mood disorders, 46 with GAD, and 95 with TUD. RESULTS: MetS was associated with increased levels of MDA and AOPP, independently from mood disorders, TUD, sex and GAD. Atherogenicity and insulin resistance (IR) were significantly associated with a NOSTOX composite score. Mood disorders, TUD, GAD, male sex and MetS independently contribute to increased RONS/NOSTOX. The RONS/NOSTOX profile of MetS was different from that of GAD, which showed increased SOD1 and NOx levels. TUD was accompanied by increased SOD1, LOOH and MDA, and male sex by increased LOOH and AOPP. CONCLUSIONS: MetS is characterized by increased lipid peroxidation with aldehyde formation and chlorinative stress, and atherogenicity and IR are strongly mediated by RONS/NOSTOX. Partially shared RONS/NOSTOX pathways underpin the comorbidity of MetS with mood disorders, GAD, and TUD.

Perinatal exposure to paracetamol: Dose and sex-dependent effects in behaviour and brain's oxidative stress markers in progeny.

Paracetamol (PAR) has been employed worldwide for pain and fever treatment during pregnancy and lactation. Epidemiologic studies have shown that exposure to PAR can increase the risk for developmental disorders, such as attention-deficit hyperactive disorder and autism spectrum disorder. This study aimed to investigate if gestational and lactational exposure to human-relevant doses of PAR could alter behavioural and brain oxidative stress parameters in the rat`s offspring. Wistar dams were gavaged daily with water or PAR (35 mg/kg/ or 350 mg/kg) during gestational day 6 to weaning (postnatal day 21). Behavioural assessments occurred at post-natal days 10 (nest seeking test), 27 (behavioural stereotypy) and 28 (three chamber sociability test and open field). Concentration of advanced oxidation protein products (AOPP), reduced glutathione (GSH), lipid hydroperoxides (LOOH) and activity of superoxide dismutase (SOD) were estimate in prefrontal cortex, hippocampus, striatum and cerebellum of 22-day-old rats. Compared to CON animals, males exposed to PAR during pregnancy and lactation augmented apomorphine-induced stereotyped behaviour (350 mg/kg) and ambulation in open-field test (35 mg/kg). Reduced exploratory behaviour in three chamber sociability test was observed in pups exposed to PAR at 350 mg/kg in both sexes. PAR treatment decreased hippocampal GSH level and striatal SOD activity in males exposed to 35 mg/kg, suggesting the vulnerability of these areas in PAR-induced developmental neurotoxicity. Findings suggest PAR use during pregnancy and lactation as a potential risk factor for neurodevelopmental disorders with males being more susceptible.

A Randomized Trial of Short-term Treatment with Folic Acid to Reduce the Oxidative Stress of Patients with Chronic Kidney Disease.

BACKGROUND: Increased generation of reactive oxygen and nitrogen species in chronic kidney disease (CKD) patients leads to increased oxidative stress. The antioxidant capacity of folic acid has been shown to scavenge radicals efficiently. OBJECTIVE: The current study was carried out to examine the effects of folic acid treatment on biochemical and oxidative stress biomarkers in patients in different stages of CKD. METHODS: This was a randomized, non-blinded, clinical trial that assessed the effects of 3 months of treatment with 5 mg of folic acid daily or no treatment in 113 outpatients within CKD stages 3a and 3b. At the end of the intervention, we analyzed the data of 66 patients treated with folic acid and 47 in the control group. Serum homocysteine levels and biochemical and oxidative/nitrosative stress biomarkers were analyzed in all patients. RESULTS: In most patients, folic acid treatment normalized homocysteine levels and increased antioxidant enzyme activity (paraoxonase 1) and decreased sulfhydryl (SH) groups. In addition, oxidative biomarkers (products of nitric oxide and lipid hydroperoxide) were significantly lower post-treatment compared to baseline in the active intervention group. In the no active intervention group, no statistically significant effects were found on the oxidative and biochemical biomarkers. CONCLUSION: Folic acid treatment in stages 3a-4 CKD patients effectively ameliorated their hyperhomocysteinemia and increased the activity of antioxidant enzymes, as well as decreased the levels of pro-oxidant biomarkers in stage G3a and G3b CKD patients. Folic acid treatment attenuated oxidative/nitrosative stress and may be considered as a possible strategy to improve redox status and diminish the damages associated with oxidative/nitrosative stress in CKD patients. Further studies are needed to confirm these findings. Clinical Trials Registration No.: This study is registered in the Brazilian Record of Clinical Trials (ReBEC), under reference RBR-2bfthr.

NOVEL antioxidant and oxidant biomarkers related to sarcopenia in COPD.

BACKGROUND: The relation between oxidative stress (OS) and sarcopenia in COPD remains unknown. OBJECTIVE: To analyze OS levels and its association with sarcopenia in COPD. METHODS: Thirty-nine individuals with COPD (69±7years; 41%female) and thirty-five for the control group (69±7years; 43%female) were included. Advanced oxidation protein products (AOPP), paraoxonase-1 (PON1), superoxide dismutase activity (SOD), catalase dismutase activity (CAT), sulfhydryl group (SH), nitric oxide metabolites (NOX), total radical trapping antioxidant parameter (TRAP) were analysed. OS markers were correlated with handgrip and quadriceps strength, gait speed, skeletal muscle mass index, fat-free mass index, maximum inspiratory and expiratory pressure. European criteria were used to identify sarcopenia. RESULTS: In COPD, antioxidant capacity was correlated with muscle mass and strength (r from 0.5 to 0.64) P<0.05 for all. TRAP≤ 850 µM/trolox and AOPP≤65 µM/l were associated with sarcopenia (OR:8.3; 95% CI: 1.4-49.6 and OR:14; 95%CI: 2.2-87.1, respectively; P<0.05 for both). CONCLUSION: OS is associated with sarcopenia in COPD.

Increased nitro-oxidative stress toxicity as a major determinant of increased blood pressure in mood disorders.

BACKGROUND: Hypertension, atherogenicity and insulin resistance are major risk factors of cardiovascular disorder (CVD), which shows a strong comorbidity with major depression (MDD) and bipolar disorder (BD). Activated oxidative and nitrosative stress (O&NS), inflammatory pathways, and increased atherogenicity are shared pathways underpinning CVD and mood disorders. METHODS: The current study examined the effects of lipid hydroperoxides (LOOH), superoxide dismutase (SOD), nitric oxide metabolites (NOx), advanced oxidation protein products (AOPP), and malondialdehyde (MDA) on systolic (SBP) and diastolic (DBP) blood pressure in 96 mood disordered patients and 60 healthy controls. RESULTS: A large part of the variance in SBP (31.6%) was explained by the regression on a z unit-weighted composite score (based on LOOH, AOPP, SOD, NOx) reflecting nitro-oxidative stress toxicity (NOSTOX), coupled with highly sensitive C-reactive protein, body weight and use of antihypertensives. Increased DBP was best predicted (23.8%) by body mass index and NOSTOX. The most important O&NS biomarkers predicting an increased SBP were in descending order of significance: LOOH, AOPP and SOD. Higher levels of the atherogenic index of plasma, HOMA2 insulin resistance index and basal thyroid-stimulating hormone also contributed to increased SBP independently from NOSTOX. Although there were no significant changes in SBP/DBP in mood disorders, the associations between NOSTOX and blood pressure were significant in patients with mood disorders but not in healthy controls. CONCLUSIONS: Activated O&NS pathways including increased lipid peroxidation and protein oxidation, which indicates hypochlorous stress, are the most important predictors of an increased BP, especially in patients with mood disorders.

Association of -94 ATTG insertion/deletion NFkB1 and c.*126G>A NFkBIA genetic polymorphisms with oxidative and nitrosative stress biomarkers in Brazilian subjects with Parkinson's Disease.

Parkinson's disease (PD) is a complex neurodegenerative disorder, resulting dopaminergic neuronal cell death in the substantia nigra. The disease is characterized by major motor impairment, being bradykinesia, rest tremor, rigidity and loss of postural reflexes the most common, while autonomic dysfunctions, sleep disturbances and psychiatric disorders are some of the wide range of non-motor symptoms. Several processes have been identified to be associated with disease development, such as mitochondrial dysfunction, oxidative/nitrosative stress and neuroinflammation. NF-κB is an important transcription factor that regulates several inflammatory elements and pathways, and polymorphisms on NFKB1 and NFKBIA genes can potentially influence redox balance towards a pro-oxidative frame, modulating disease progression. Evaluation of these polymorphisms in the redox status of PD subjects could provide new insights on the pathogenesis of this disorder. The study aimed to test associations of -94 in./del ATTG NFKB1 (rs28362491) and c.*126G > A NFKBIA (rs696) polymorphisms with PD development, and to test the influence of both polymorphisms on oxidative/nitrosative stress (OS/NS) parameters. A total of 110 Brazilian individuals were enrolled, being 55 subjects recruited from University Hospital of Londrina as the PD group, and 55 subjects matched for age, sex and ethnicity composed the healthy control (HC) group. NFkB1 and NFkBIA polymorphisms were genotyped by PCR-RFLP. Lipid hydroperoxides (LOOH), nitric oxide metabolites (NOx), advanced oxidation protein products (AOPP), sulfhydryl groups (SH), total radical trapping antioxidant parameter (TRAP) and paraoxonase-1 activity (PON-1) were assessed. Despite no association of polymorphisms on disease development was observed, in PD subjects the NFKB1 del/del genotype was associated with higher levels of LOOH, while NFkBIA GA and AA genotypes were associated with higher NOx levels, suggesting that NFkB plays a role in PD susceptbility. In conclusion, the prospect of genetic polymorphisms of elements involved in inflammation and OS/NS might be a new approach to unravel PD etiology.

Increased oxidative stress, decreased total antioxidant capacity, and iron overload in untreated patients with chronic hepatitis C.

The aim of this study was to determine oxidative stress in patients with untreated chronic hepatitis C (CHC), relating the obtained results with iron status and disease activity markers. Two groups (CHC patients and controls) were studied. CHC patients presented significantly higher values than the control group in some parameters: ALT, AST, GGT, iron, ferritin, and transferrin saturation, and also in tert-butyl hydroperoxide initiate chemiluminescence and thiobarbituric acid-reactive substances (TBARS) as well as lower values in total radical-trapping antioxidant parameter (TRAP). TBARS showed a significant correlation with serum AST and with transferrin saturation, whereas TRAP correlated inversely with serum albumin. Serum ferritin correlated with ALT and GGT, whereas serum iron did so with GGT. In conclusion, lower antioxidant capacity, higher levels of pro-oxidants activity, and iron overload occur in untreated patients with CHC. This greater oxidative activity could play an important role in pathogenesis and evolution of hepatitis C and thus further investigations.

Vitamin D deficiency is not associated with increased oxidative stress in chronic kidney disease pre-dialysis patients.

INTRODUCTION: The progressive decline in 25-hydroxyvitamin D [25(OH)D] in chronic kidney disease (CKD) limits the kidney ability of synthesizing the vitamin. Vitamin D deficiency as defined by KDIGO (25(OH)D <20 ng/mL) is prevalent in CKD patients and associated to oxidative stress (OS). We studied a possible association between vitamin D deficiency and OS in pre-dialysis patients. METHODS: A cross-sectional study with 206 CKD patients was carried out. Laboratory tests for 25(OH)D, 1,25(OH)2D, inflammatory markers, and OS were added to routine tests including creatinine, albumin, calcium, phosphorus, alkaline phosphatase, iPTH, glucose, hemoglobin, uric acid, total cholesterol, LDL, HDL, and triglycerides. RESULTS: Vitamin D deficiency was present in 55 CKD patients and normal vitamin D levels were seen in 149 patients. There was a significant association between vitamin D and estimated glomerular filtration rate (eGRF). Homocysteine levels were best predicted by eGRF, sex, and age; high sensitivity C-reactive protein (hsCRP) by staging and BMI; nitric oxide metabolites (NOx) were increased in late disease; leptin was influenced by BMI and higher in women than man; and adiponectin levels were higher in women. CONCLUSIONS: OS biomarkers were not correlated with vitamin D deficiency but increased NOx were seen in stages 4-5 CKD patients. Even though a relatively large number of CKD patients was included and a broad number of OS and inflammatory biomarkers were used in this studied we failed to find an association between vitamin D levels and eGRF. More studies are needed to evaluate the influence of vitamin D status in OS in pre-dialysis CKD patients.

Silver serum levels in burned patients treated with silver sulfadiazine and its toxicity on inflammatory cells.

BACKGROUND: Silver sulfadiazine (SSD) has been widely used in burned patients for the prevention of local infections. To be biologically active and exert antimicrobial properties, silver needs to be present in the form of silver ions (Ag1+) that bind to negatively charged proteins, namely, the RNA and DNA in microorganisms. However, previous published studies conducted with SSD in the 1990s reported a high level of silver absorption through damaged skin and noted the potential cytotoxicity of Ag1+ to human cells. SSD toxicity, however, had been described in cell cultures using arbitrary silver concentrations. In the present study, we determined the serum silver levels in burned patients treated with SSD and, taking into account the molar Ag1+ concentrations found in these patients, we evaluated the Ag1+ toxicity effects on inflammatory cells (ROS and cytokine production) in vitro. METHODS: Twenty patients with an average burned body surface area of 27.68% were included in this study. RESULTS: Patients' Ag1+ serum levels reached up to 558 times those of the unexposed controls. Ag1+ was then added to inflammatory cells in vitro at levels up to 2000 times the level of the control, and there was no effect on the viability of the cells nor on the rate of apoptosis. We observed a decrease in reactive oxygen species production by mononuclear (MN) and polymorphonuclear (PMN) cells, as well as a substantial decrease in cytokines IL-1ß, IL-6, IL-8, IL-10, and TNF-α production by leukocytes (MN and PNM). CONCLUSION: These findings suggest that Ag1+ may contribute to negative outcomes after burns, decreasing the primary defense mechanism (respiratory burst) and altering cytokine production.

Gestational exposure to paracetamol in rats induces neurofunctional alterations in the progeny.

Paracetamol (PAR) is an over-the-counter medicine used as analgesic or antipyretic by 40-50% of the pregnant women in different countries. Epidemiologic studies have been associating maternal use of PAR with neurodevelopmental disruption and special attention has been given to its potential to increase the odds for neurodevelopmental disorders, such as attention-deficit hyperactive disorder and autism spectrum disorder. Population-based research do not allow the establishment of causal relationships because variable control is weak. We aimed to evaluate the potential of PAR to induce developmental neurotoxicity in rats. Pregnant Wistar rats were gavaged with PAR (350 mg/kg/day) or water from gestational day 6 until delivery. General toxicity endpoints included dams' body weight and food intake as well as pups' body weight until weaning. Behavioral evaluation occurred at post-natal days 10 (nest seeking test), 27 (behavioral stereotypy), 28 (three chamber sociability test and open field) and 29 (hot plate and elevated plus-maze). Moreover, lipid hidroperoxide (LOOH), reduced glutathione (GSH) and brain derived neurotrophic factor (BDNF) levels were quantified in prefrontal cortex and hippocampus of 22-days-old rats. Gestational exposure to PAR impaired nest seeking behavior, augmented apomorphine-induced behavioral stereotypy and decreased rostral grooming in the elevated plus maze. Exposed female pups presented elevated vertical exploration in the open field test. No alterations were observed in LOOH, GSH or BDNF levels in the prefrontal cortex or hippocampus. Exposure regimen did not affect general toxicity parameters or pups' behavior in the hot plate and sociability tests. These data suggest PAR as a developmental neurotoxicant. Observed alterations may be relevant for neurodevelopmental disorders.