Gut microbiota, dietary intakes and intestinal permeability reflected by serum zonulin in women.

PURPOSE: Increased gut permeability causes the trespass of antigens into the blood stream which leads to inflammation. Gut permeability reflected by serum zonulin and diversity of the gut microbiome were investigated in this cross-sectional study involving female study participants with different activity and BMI levels. METHODS: 102 women were included (BMI range 13.24-46.89 kg m-2): Anorexia nervosa patients (n = 17), athletes (n = 20), normal weight (n = 25), overweight (n = 21) and obese women (n = 19). DNA was extracted from stool samples and subjected to 16S rRNA gene analysis (V1-V2). Quantitative Insights Into Microbial Ecology (QIIME) was used to analyze data. Zonulin was measured with ELISA. Nutrient intake was assessed by repeated 24-h dietary recalls. We used the median of serum zonulin concentration to divide our participants into a "high-zonulin" (> 53.64 ng/ml) and "low-zonulin" (< 53.64 ng/ml) group. RESULTS: The alpha-diversity (Shannon Index, Simpson Index, equitability) and beta-diversity (unweighted and weighted UniFrac distances) of the gut microbiome were not significantly different between the groups. Zonulin concentrations correlated significantly with total calorie-, protein-, carbohydrate-, sodium- and vitamin B12 intake. Linear discriminant analysis effect size (LEfSe) identified Ruminococcaceae (LDA = 4.163, p = 0.003) and Faecalibacterium (LDA = 4.151, p = 0.0002) as significantly more abundant in the low zonulin group. CONCLUSION: Butyrate-producing gut bacteria such as Faecalibacteria could decrease gut permeability and lower inflammation. The diversity of the gut microbiota in women does not seem to be correlated with the serum zonulin concentration. Further interventional studies are needed to investigate gut mucosal permeability and the gut microbiome in the context of dietary factors.

Ultra-endurance exercise induces stress and inflammation and affects circulating hematopoietic progenitor cell function.

Although amateur sports have become increasingly competitive within recent decades, there are as yet few studies on the possible health risks for athletes. This study aims to determine the impact of ultra-endurance exercise-induced stress on the number and function of circulating hematopoietic progenitor cells (CPCs) and hematological, inflammatory, clinical, metabolic, and stress parameters in moderately trained amateur athletes. Following ultra-endurance exercise, there were significant increases in leukocytes, platelets, interleukin-6, fibrinogen, tissue enzymes, blood lactate, serum cortisol, and matrix metalloproteinase-9. Ultra-endurance exercise did not influence the number of CPCs but resulted in a highly significant decline of CPC functionality after the competition. Furthermore, Epstein-Barr virus was seen to be reactivated in one of seven athletes. The link between exercise-induced stress and decline of CPC functionality is supported by a negative correlation between cortisol and CPC function. We conclude that ultra-endurance exercise induces metabolic stress and an inflammatory response that affects not only mature hematopoietic cells but also the function of the immature hematopoietic stem and progenitor cell fraction, which make up the immune system and provide for regeneration.

[Oxidative stress in bipolar affective disorder]. / Oxidativer Stress bei bipolar affektiver Störung. (corrected).

The results of mortality studies have indicated that medical conditions, such as cardiovascular disease, obesity and diabetes are the most important causes of mortality among patients with bipolar disorder. The reasons for the increased incidence and mortality are not fully understood. Oxidative stress and an inadequate antioxidative system might be one missing link and could also help to further elucidate the pathophysiological basis of bipolar disorder. This article provides a comprehensive review of oxidative stress in general and about the existing data for bipolar disorder. In addition information is given about possible therapeutic strategies to reduce oxidative stress and the use in bipolar disorder.

Smoking denial in cardiovascular disease studies.

Assessment of self-reported smoking behavior in cardiovascular studies may lead to inaccurate measures of nicotine exposure. A more objective measurement of nicotine exposure can be done by measurement of plasma cotinine levels. The aim of the present study was to define the rate of discordance between the self-reported smoking behavior and biochemically defined smoking status. Data from 3,316 patients hospitalized for coronary angiography, who completed a questionnaire on smoking behavior, were analyzed. As a biochemical assessment of smoking status we used a cut-off serum cotinine level of 15 µg/l. Smoking denial, defined as a discrepancy between high cotinine levels and self-reported never- or ex-smoking status, was observed in 3.7 % of the study participants. In a logistic regression analysis with a step-wise inclusion of sex, age, CAD, previous MI, and educational level, only male sex (odds ratio male/female: 2.00, 95 % CI 1.22-3.33; p = 0.007) and age (odds ratio per year: 0.79, 95 % confidence interval 0.66-0.94, p = 0.008) were associated with smoking denial. In conclusion, a misclassification rate of 3.7 % in the evaluation of such an important risk factor may lead to blurred effects and favor false negative results. The results of the present study substantiate the importance of biochemical markers for smoking assessment in cardiovascular studies.

The association between anti-inflammatory effects of long-term lithium treatment and illness course in Bipolar Disorder.

INTRODUCTION: Altered levels of acute-phase proteins are often described in different conditions in BD. Nevertheless, data on the association between lithium treatment and inflammatory markers in the long-term course of BD are still missing. The aim of the study was to examine the long-term course of BD concerning long-term lithium treatment, chronic inflammatory processes and symptom progression. Furthermore, the association between duration of lithium treatment and levels of hsCRP was explored. METHODS: 267 individuals (males= 139, females= 128) with BD were included. Duration of lithium treatment as well as symptom progression, defined as the increase in severity of symptoms, number of episodes a year and duration of episodes within a period of 1.5 years in the past and hsCRP were evaluated. RESULTS: Male individuals with symptom progression over time had significantly lower duration of lithium treatment compared to individuals without symptoms progression (U= 47.4, p=.037). There were significantly higher levels of hsCRP in male individuals with symptom progression compared to males without symptom progression (U= 47.5, p=.027). Further, there was a significant negative correlation between the duration of lithium treatment and hsCRP levels in the whole sample (r= -.276, p<.05). CONCLUSION: Our results show that an altered inflammatory state may be associated with a more severe illness course in BD. Further, a longer duration of lithium treatment may be associated with lower symptom progression. The shown association between hsCRP-levels and lithium treatment duration suggests a potential anti-inflammatory effect of lithium as a mediator of its significant positive outcome effect in BD.

Sex differences in zonulin in affective disorders and associations with current mood symptoms.

INTRODUCTION: The bidirectional connection between the brain and the gut within psychiatric entities has gained increasing scientific attention over the last years. As a regulator of intestinal permeability, zonulin acts as a key player on the interface of this interplay. Like several psychiatric disorders, intestinal permeability was associated with inflammation in previous findings. METHODS: In this study we explored differences in zonulin serum levels in currently depressed (n = 55) versus currently euthymic (n = 37) individuals with an affective disorder. Further, we explored sex differences and possible influences on zonulin and affective symptoms like medication, age, body mass index, and smoking status. RESULTS: Serum zonulin was significantly higher in females than in men independent from affective status (z = -2.412, p = .016). More specifically, females in the euthymic subgroup had higher zonulin levels than euthymic men (z = -2.114, p = .035). There was no difference in zonulin serum levels in individuals taking or not taking a specific psychopharmacotherapy. We found no correlation between zonulin serum levels and depression severity. DISCUSSION: Increased serum zonulin levels as a proxy for increased intestinal permeability in women may indicate a state of elevated susceptibility for depression-inducing stimuli.

Obesity reduces the bioavailability of nitric oxide in juveniles.

OBJECTIVE: There is growing evidence that nitric oxide (NO) is critically involved in obesity and its clinical consequences like cardiovascular disease, hypertension and diabetes. We hypothesize that NO is already involved in the pathophysiology of juvenile obesity. We here determined the role of NO, its metabolites arginine and citrulline in obese and normal weight children. DESIGN: We investigated 57 obese and 57 normal weight age- and gender-matched juveniles. Various clinical parameters as well as body measurements and intima media thickness were determined. RESULTS: Obese juveniles revealed highly significant alterations in the NO pathway. NOX and citrulline were decreased in obese compared to normal weight juveniles and negatively correlated with body weight. Arginine was increased in obese juveniles and positively correlated with body weight. We found a significant negative correlation between NOX and oxidized low-density lipoprotein. Analysis of gamma-aminobutyric acid (GABA) revealed correlations with the NO pathway as NOX and citrulline were negatively correlated with GABA and arginine showed a positive correlation. CONCLUSION: We show here that NO and its metabolites arginine and citrulline are already involved in juvenile obesity that may contribute to atherogenesis via reduced bioavailability of NO. Moreover, we identify GABA as a new parameter in the mechanism of obesity-related NO reduction.

IgG antibodies against food antigens are correlated with inflammation and intima media thickness in obese juveniles.

OBJECTIVE: Systemic low grade inflammation may contribute to the development of obesity, insulin resistance, diabetes mellitus and atherosclerotic vascular disease. Food intolerance reflected by immunoglobulin G (IgG) antibodies may predispose to low grade inflammation and atherogenesis. We examined the relationship between IgG antibodies specific for food components, low grade inflammation and early atherosclerotic lesions in obese and normal weight juveniles. RESEARCH METHODS AND PROCEDURES: We determined IgG antibodies directed against food antigens, C-reactive protein (CRP) and the thickness of the intima media layer (IMT) of the carotid arteries in 30 obese children and in 30 normal weight children. RESULTS: Obese juveniles showed a highly significant increase in IMT (p=0.0001), elevated CRP values (p=0.0001) and anti-food IgG antibody concentrations (p=0.0001) compared to normal weight juveniles. Anti-food IgG showed tight correlations with CRP (p=0.001/r=0.546) and IMT (p=0.0001/r=0.513) and sustained highly significant in a multiple regression model. DISCUSSION: We show here, that obese children have significantly higher IgG antibody values directed against food antigens than normal weight children. Anti- food IgG antibodies are tightly associated with low grade systemic inflammation and with the IMT of the common carotid arteries. These findings raise the possibility, that anti-food IgG is pathogenetically involved in the development of obesity and atherosclerosis.

Asymmetric dimethylarginine (ADMA) is tightly correlated with growth in juveniles without correlations to obesity related disorders.

BACKGROUND: Asymmetrical dimethylarginine (ADMA) was found to be increased in conditions associated with atherosclerosis and metabolic disorders. We investigated ADMA in obese juveniles with pre-atherosclerotic symptoms and in normal weight juveniles. DESIGN: To elucidate correlations of ADMA in juveniles with obesity related disorders such as insulin resistance, low grade inflammation, hypertension and pre-atherosclerosis, we analysed ADMA by high performance liquid chromatography (HPLC) in 68 obese and 68 healthy, age and gender matched juveniles. RESULTS: ADMA levels are slightly, but significantly increased (p=0.04) in obese (0.78+/-0.01 micromol/l), compared to normal weight juveniles (0.74+/-0.01 micromol/l). There are no robust correlations of ADMA with obesity related disorders, like dyslipidemia, hypertension, low-grade inflammation and pre-atherosclerosis. Age, body length and alkaline phosphatase, as markers of growth are correlated with ADMA. Multiple testing revealed that, alkaline phosphatase turned out as highly significant positively correlated with ADMA in normal weight (r=0.45/p<0.0001) and obese (r=0.59/p<0.0001) children. CONCLUSIONS: We show here, that ADMA is slightly increased in obese juveniles without any robust correlations to obesity related disorders. ADMA is tightly correlated with alkaline phosphatase as a marker of growth in obese and normal weight, healthy juveniles.

The role of tryptophan metabolism and food craving in the relationship between obesity and bipolar disorder.

BACKGROUND & AIMS: Individuals with bipolar disorder (BD) have a significantly increased risk of obesity-related conditions. The imbalance between food intake and energy expenditure is assumed to be a major risk factor for obesity in BD. This study analyzed food craving in relation to anthropometric, metabolic, and neurobiological parameters in a well-characterized cohort of euthymic individuals with BD. METHODS: One-hundred-thirty-five patients completed the Food-Craving Inventory assessing four categories of food craving (fat, fast-food, sweets and carbohydrate craving). Additionally, clinical, metabolic and anthropometric parameters were assessed. RESULTS: Higher levels of fat craving were observed in males, versus females, with BD. High levels of carbohydrate craving positively correlated with kynurenine and the kynurenine-to-tryptophan ratio. Higher serum nitrite and neopterin levels were related to fat craving. Parameters of fat metabolism (triglycerides, high-density lipoprotein) were associated with fat and fast-food craving. Anthropometric measures of obesity (e.g. body mass index, waist-to-hip-ratio) were not related to food craving. CONCLUSIONS: Overweight/obese individuals with BD show an increased driving of tryptophan down the kynurenine pathways, as indicated by an increase in the serum kynurenine-to-tryptophan ratio. The driving of tryptophan down the kynurenine pathway is mediated by immune-inflammatory activity and stress. The correlation of increased kynurenine with food craving, especially carbohydrate craving, probably indicates a regulatory deficit in the maintenance of chronic inflammatory processes in obesity and BD. Food craving seems to be of clinical importance in the treatment of metabolic disturbances in BD, although not associated with anthropometric measures of obesity. Rather, food craving correlates with blood metabolic parameters and an increased activation of the kynurenine pathway, both of which are linked to higher affective symptomatology and the development of cardiovascular diseases.

Visfatin/pre-B-cell colony-enhancing factor: a protein with various suggested functions.

Pre-B-cell colony-enhancing factor (PBEF) was recently found in high levels in visceral fat, and was therefore renamed visfatin. This new adipocytokine exerts insulin-mimetic effects in mice and in cultured cells by binding to and activating the insulin receptor. Despite some recent studies on this topic, the proposed role of visfatin in metabolism remains largely unknown. Initially, PBEF/visfatin was discovered as a cytokine for the differentiation of B-cells. Pre-B-cell colony-enhancing factor was also shown to inhibit apoptosis of neutrophils in sepsis and was discussed as a novel biomarker for acute lung injury (ALI). Although PBEF is missing a signal sequence, its secretion and function as a molecule involved in the regulation of inflammatory processes was reported in several studies. Investigations of PBEF/visfatin in gestational membranes suggest a function in the physiologic and pathologic pathways leading to labor. Furthermore, it was found upregulated in colorectal cancer and was brought into connection with the regulation of the cell cycle. Intra-cellular, PBEF/visfatin acts as a cytosolic enzyme involved in nicotinamide adenine dinucleotide (NAD) synthesis. This activity was shown to be important for vascular smooth muscle cell (SMC) maturation, indicating a possible involvement in vascular pathology. The important physiologic role of PBEF/visfatin is also underlined by its evolutionary highly conserved gene in different species. This review summarizes the current knowledge of the various functions of PBEF/visfatin towards involvements in pathophysiology of several diseases.

Implementation of buffy-coat-derived pooled platelet concentrates for internal quality control of light transmission aggregometry: a proof of concept study.

Essentials In platelet function testing, standardized internal controls (IQC) are not commercially provided. Platelet function testing was performed daily on aliquoted pooled platelet concentrates. Pooled platelet concentrates showed stability for control purposes from Monday to Friday. Pooled platelet concentrates provide the necessary steadiness to serve as IQC material. SUMMARY: Background Standardized commercially available control material for internal quality control (IQC) of light transmission aggregometry (LTA) is still lacking. Moreover, the availability of normal blood donors to provide fresh platelets is difficult in small laboratories, where 'volunteers' may be in short supply. Objectives To evaluate the implementation of buffy-coat-derived pooled platelet concentrates (PCs) for IQC material for LTA. Methods We used buffy-coat-derived pooled PCs from the blood bank as IQC material for LTA. On each weekend one PC was prepared (> 200 mL) and aliquoted from the original storage bag on a daily basis in four baby bags (40-50 mL), which were delivered from Monday to Friday to our laboratory. The IQC measurements of at least 85 work-weeks (from Monday to Friday) were evaluated with this new IQC material. LTA was performed on a four-channel Chronolog 700 Aggregometer (Chronolog Corporation, Havertown, PA, USA) (agonists: collagen, adenosine diphosphate [ADP], arachidonic acid [AA] and thrombin receptor activator peptide-6 [TRAP-6]). Results The medians of platelet aggregation from IQC measurements with collagen, ADP and AA from Monday to Friday were 68.0-59.5, 3.0-2.0 and 51.0-50.0%, respectively, and the mean of platelet aggregation with TRAP-6 was 71.2-66.4%. Conclusions Buffy-coat-derived pooled PCs serve as a reliable and robust IQC material for LTA measurements and would be beneficial for the whole laboratory procedure and employees' safety.

Non-coding RNAs in pancreatic cancer: challenges and opportunities for clinical application.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with a dismal prognosis for which new therapeutic strategies are desperately needed. Non-coding RNAs (ncRNAs), especially microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), may yield new therapeutic concepts for the treatment of PDAC. A vast number of miRNAs, including the well-studied miR-21, miR-155 and miR-34, has been shown to regulate PDAC growth, invasion and metastasis in vitro and in vivo by targeting members of key signaling pathways. In addition, other miRNAs and lncRNAs, such as HOTTIP and MALAT-1, have been shown to influence the malignant behavior of PDAC cells. METHODS: Here, we discuss several ncRNAs that may be used either as new therapeutic agents or as targets of new therapeutic agents. Furthermore, we discuss the problem of proper delivery of nucleotide-based agents and novel methods that may be used to circumvent this problem. CONCLUSIONS: Although the number of reports addressing the role of ncRNAs in PDAC virtually grows by the day, there are still many steps to be taken before the application of ncRNA-based therapies will become reality in clinical practice.

Assessment of vitamin D status and serum CrossLaps levels in adults with primary lactose malabsorption.

BACKGROUND/OBJECTIVES: Primary adult-type lactose malabsorption (PALM) is a widespread inherited autosomal recessive condition, which is considered to be associated with osteoporosis. This prospective study aimed at assessing the 25-hydroxy-vitamin D (25(OH)D) status and serum CrossLaps levels in individuals with PALM and normal controls. SUBJECTS/METHODS: All participants (n=210) underwent genotyping for the LCT C/T-13910 polymorphism, 25(OH)D and CrossLaps measurements and clinical examinations. In addition, the anthropometric data (that is, height, weight and body mass index) were determined. RESULTS: Fifty-five individuals with PALM (that is, LCT C/C-13910 homozygotes) showed lower 25(OH)D (mean: 24.95±10.04 vs 28.59±9.56 ng/ml, P=0.018) and higher CrossLaps serum levels (mean: 0.46±0.31 vs 0.43±0.49 ng/ml, P=0.251) compared with 155 normal controls (that is, LCT C/T-13910 hetero- or T/T-13910 homozygotes). Anthropometric data were similar between PALM probands and controls. CONCLUSIONS: Individuals with PALM were found to have lower 25(OH)D and higher CrossLaps serum levels compared with normal controls. In order to preserve life-long bone health, routine 25(OH)D and CrossLaps serum measurements should be performed in individuals with PALM.

Abdominal obesity is associated with impaired cognitive function in euthymic bipolar individuals.

OBJECTIVES: Overweight/obesity has been implicated to play a role in cognitive deficits in bipolar disorder (BD). This study aims to identify the relationship between body fat distribution and different domains of cognition in BD during euthymia. METHODS: A sample of 100 euthymic individuals with BD was measured with a cognitive test battery (i.e., Trail Making Test-A-B/TM-A/B, d2 Test of Attention, Stroop test, California Verbal Learning Test/CVLT) and an anthropometric measures set (body mass index, waist circumference, hip circumference, waist-to-hip-ratio, waist-to-height-ratio, and lipometry). Patient data were compared with a healthy control group (n = 64). RESULTS: Results show that overweight patients with BD exhibit lower performance in the TMT-A/B as well as in the free recall performance of the CVLT compared to normal-weight patients with BD and controls. In bipolar individuals, (abdominal) obesity was significantly associated with a poor cognitive performance. In bipolar females, associations with measures of verbal learning and memory were found; in bipolar males, associations with poor performance in the TMT-A/B and in the Stroop interference task were demonstrated. In controls, no associations were found. CONCLUSIONS: There are several possible pathways moderating the association between obesity and cognition in BD. Anthropometric and lipometry data underline the substantial mediating impact of body fat distribution on cognition in BD.

Insulin is an independent correlate of plasma homocysteine levels in obese children and adolescents.

OBJECTIVE: The aim of the study was to investigate whether anthropometric and metabolic risk factors for coronary heart disease (CHD) contribute to the variation in homocysteine levels in obese children and adolescents. RESEARCH DESIGN AND METHODS: A total of 84 children and adolescents were assessed for fasting total homocysteine, methylenetetrahydrofolate reductase polymorphism (C677T mutation), folate and vitamin B12 status, and anthropometric and metabolic risk factors for CHD. RESULTS: No significant sex differences were found for all available anthropometric and metabolic characteristics except for homocysteine, which was significantly higher in boys than in girls (7.1 vs. 6.3 micromol/l; P<0.05). After adjustment for age and sex, homocysteine correlated significantly with BMI, fat mass, percentage of fat mass, and insulin and showed an inverse correlation with folate levels. Homocysteine did not correlate with vitamin B12; total cholesterol; LDL, HDL, and VLDL; triglycerides; and glucose. BMI and fat mass correlated significantly with insulin and showed a significant inverse correlation with folate. We found no association between homocysteine and the C677T mutation. In multiple regression analyses, insulin was found to be the main correlate of homocysteine. CONCLUSIONS: Our study demonstrates for the first time that insulin is a main correlate of homocysteine in obese children and adolescents and suggests that fat mass-associated hyper-insulinism may contribute to impairment of homocysteine metabolism in childhood obesity

Oxidative stress: Determination of 4-hydroxy-2-nonenal by gas chromatography/mass spectrometry in human and rat plasma.

The lipid peroxidation product 4-hydroxynonenal (HNE) is a biomarker of oxidative stress which is essentially involved in the pathophysiology of many diseases. The analysis of HNE is challenging because this aldehyde is extremely reactive and thus unstable. Hence, we adopted a gas chromatography-mass spectrometry (GC-MS) method based on derivatization of HNE with pentafluorobenzyl-hydroxylamine-HCl followed by trimethylsilylation to trimethylsilyl ethers. Ions representative for a negative ion chemical ionization mode were recorded at m/z = 152 for HNE and at m/z = 162 for the deuterated analogon (HNE-d11) as internal standard. This excellent stable and precise GC-MS method was carefully validated for HNE, and showed good linearity (r(2) = 0.998), and high specificity and sensitivity. Within-day precisions were 4.4-6.1% and between-day precisions were 5.2-10.2%. Accuracies were between 99% and 104% for the whole calibration range (2.5-250 nmol/L) of HNE. To examine the versatility of this modified GC-MS method, we analyzed HNE in ethylenediaminetetraacetic acid (EDTA) plasma in a well-defined collective of migraine patients; recently published. The results underline our former observations that women with migraine are afflicted with increased levels of HNE. Patients with thyroidal dysfunction showed no significant HNE alterations. This was confirmed by normal HNE EDTA plasma levels in hyper- und hypothyroid Sprague-Dawley rats. Taken together, the GC-MS method presented herein is of excellent quality to record oxidative stress-related bioactive HNE levels. This is important for a reorientation of oxidative stress analytics in other human diseases first of atherosclerosis and cancer.

Patatin-like phospholipase 3 (rs738409) gene polymorphism is associated with increased liver enzymes in obese adolescents and metabolic syndrome in all ages.

BACKGROUND: Obesity is associated with non-alcoholic fatty liver disease (NAFLD), and the patatin-like phospholipase 3 (PNPLA3) rs738409 (Ile148Met, C>G) gene polymorphism is one of the most important genetic determinants of NAFLD. Carriers have been reported to better respond to lifestyle modification. AIM: To investigate the effect of rs738409 on overweight/obese adolescents and adults with and without metabolic syndrome (MetS). METHODS: Two hundred and eighty-eight overweight/obese and 209 normal weight participants of the STYJOBS/EDECTA cohort (NCT00482924) were analysed for PNPLA3 genotypes. RESULTS: Compared to overweight/obese without MetS, in overweight/obese study participants with MetS, the presence of the G allele (148Met) was significantly higher (CC: 5.0% vs. 9.2%, Spearman's correlation, 0.12; P = 0.038). Persons with CG (heterozygote for the risk allele) and with GG (homozygote for the risk allele) genotypes showed significantly higher ALT levels than those with CC genotypes. Even young individuals aged below 20 years had significantly increased ALT levels if they were homozygote with the G allele. CONCLUSIONS: The PNPLA3 rs738409 polymorphism is associated already in youths with increased ALT, and is more frequent in obese with MetS of all ages. Hence, overweight/obese rs738409 carriers should be identified early in life and treated with a rigorous life style intervention.

Peripheral markers of oxidative stress and antioxidative defense in euthymia of bipolar disorder--Gender and obesity effects.

INTRODUCTION: Oxidative and nitrosative stress are implicated in the pathogenesis of uni- and bipolar disorder. Herein we primarily sought to characterize markers of oxidative/nitrosative stress during euthymia in adults with bipolar disorder (BD). Oxidative markers were further evaluated in this BD sample in synopsis with excess overweight or obesity and/or comorbid metabolic syndrome (MetS). METHODS: Peripheral markers of oxidative stress [i.e. thiobarbituric acid reactive substance, (TBARS), malondialdehyde (MDA), and carbonyl proteins] and antioxidant markers [e.g. total antioxidative capacity (TAC), superoxide dismutase (SOD), glutathione S-transferase (GST)] were obtained in a cohort of euthymic adults with BD (N=113) and compared to healthy controls (CG) (N=78). Additionally, anthropometric measures included the body mass index (BMI) [kg/m(2)], waist and hip circumference [cm], waist-to-hip-ratio (WHR), waist to height ratio (WtHR) as well as the IDF-defined MetS. RESULTS: The major finding was a significantly decreased TAC in BD compared to the CG (p<0.01; BD: M 1.18, SD 0.47; CG: M 1.39, SD 0.49). MDA was significantly and TBARS by trend higher in the CG compared to the euthymic bipolar test persons (MDA: p<0.01, BD: M 0.70, SD 0.18; CG: M 0.81, SD 0.25; TBARS: p<0.1, BD: M 0.78, SD 0.28; CG: M 0.76, SD 0.30). The antioxidative enzyme GST was significantly elevated in both patients and controls (BD: M 298.24, SD 133.02; CG: M 307.27 SD 118.18). Subgroup analysis revealed that the CG with concurrent MetS and obesity had significantly elevated TAC when compared to CG without concurrent MetS (p<0.05, no MetS: M 1.33, SD 0.50; MetS: M 1.67, SD 0.32), as well as persons with BD with or without current MetS (no MetS: M 1.18, SD 0.44; MetS: M 1.15, SD 0.49). Significant correlations between GST and anthropometric variables were found in male study participants. Multivariate analysis indicated a significant gender effect concerning TBARS values in all patients and CG (p<0.01, females: M 0.73, SD 0.29; males: M 0.83, SD 0.28). CONCLUSION: Euthymic bipolar adults exhibit peripheral evidence of a disturbed biosignature of oxidative stress and antioxidative defense. Male test persons showed significantly higher peripheral markers of oxidative stress than women- female sex may exert protective effects. Furthermore, the biosignature of oxidative stress obtained herein was more pronounced in males with concurrent metabolic disorders. Our results further extend knowledge by introducing the moderating influence of gender and obesity on oxidative stress and BD.