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Background: Persistent low-grade immune-inflammatory processes, oxidative and nitrosative stress (O&NS), and hypothalamic- pituitary-adrenal axis activation are integral to the pathophysiology of major depressive disorder (MDD). The microbiome, intestinal compositional changes, and resultant bacterial translocation add a new element to the bidirectional interactions of the gut-brain axis; new evidence implicates these pathways in the patho-aetiology of MDD. In addition, abnormalities in the gut-brain axis are associated with several chronic non-communicable disorders, which frequently co-occur in individuals with MDD, including but not limited to irritable bowel syndrome (IBS), chronic fatigue syndrome (CFS), obesity, and type 2 diabetes mellitus (T2DM). Methods: We searched the PubMed/MEDLINE database up until May 1, 2016 for studies which investigated intestinal dysbiosis and bacterial translocation (the ‘leaky gut’) in the pathophysiology of MDD and co-occurring somatic comorbidities with an emphasis on IBS, CFS, obesity, and T2DM. Results: The composition of the gut microbiota is influenced by several genetic and environmental factors (e.g. diet). Several lines of evidence indicate that gut-microbiota-diet interactions play a significant pathophysiological role in MDD and related medical comorbidities. Gut dysbiosis and the leaky gut may influence several pathways implicated in the biology of MDD, including but not limited to immune activation, O&NS, and neuroplasticity cascades. However, methodological inconsistencies and limitations limit comparisons across studies. Conclusions: Intestinal dysbiosis and the leaky gut may constitute a key pathophysiological link between MDD and its medical comorbidities. This emerging literature opens relevant preventative and therapeutic perspectives. [ABSTRACT FROM AUTHOR]

Background: Depression is an inflammatory disorder while many authors declare myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) to be a functional disorder. The aim of the present study is to compare inflammatory and cell-mediated immune (CMI) responses between depression and ME/CFS. Methods: We measured two proinflammatory cytokines (PICs) in plasma, interleukin-1 (IL-1) and tumor necrosis factor-α (TNF-α), with enzyme-linked immunosorbent assays, and serum neopterin with a radioimmunoassay in controls, ME/CFS and depressive patients. Results: Plasma PICs were significantly higher in ME/CFS than in depression and higher in both patient groups than in controls. Increased PIC levels in depression were attributable to the presence of fatigue and physio-somatic symptoms. Serum neopterin did not differ significantly between depression and ME/CFS but was higher in both patient groups than in controls. The significant positive correlations between neopterin and either IL-1 or TNF-α were significantly greater in depression than in ME/CFS. Conclusions: Since PICs cause depression-like behaviors and fatigue/malaise, we suggest that inflammation may play a role in the pathophysiology of ME/CFS and depression. Increased neopterin also seems to contribute to the pathophysiology of both disorders. This study has detected a shared 'pathway phenotype', i.e. disorders in inflammatory and CMI pathways, which underpins both ME/CFS and depression and, therefore, may explain the co-occurrence of both disorders. ME/CFS and depression are discriminated from each other by increased PICs in ME/CFS and differences in the immune cell communication networks. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The aims of this study were to examine the late components of the auditory event-related potentials (AERPs), i.e. N[sub 100] , P[sub 200] and P[sub 300] , in recently detoxified alcohol-dependent patients compared to normal controls and to investigate whether there is a relationship between alterations in these AERPs and signs of activation of the inflammatory response system (IRS). The study subjects consisted of 14 healthy volunteers and 14 recently detoxified alcohol-dependent patients. All subjects performed a two-tone auditory discrimination task, using a standard ‘oddball’ paradigm. The alcohol-dependent patients had their blood sampled to examine IRS markers, such as erythrocyte sedimentation rate (ESR), serum copper concentrations and the number of leukocytes. The P[sub 300] latency was significantly greater in recently detoxified alcohol-dependent patients than in normal controls. There were significant correlations between the P[sub 300] latency and the ESR (r = 0.84, p = 0.009), serum copper concentrations (r = 0.73, p = 0.01) and number of monocytes (r = 0.71, p = 0.006). It is concluded that the P[sub 300] latency is prolonged in detoxified, chronic alcohol-dependent patients and is positively related to indicators of IRS activation. It is hypothesized that activation of the IRS may play a role in the delayed P[sub 300] latency in recently detoxified, alcohol-dependent patients.Copyright © 2001 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The aim of this study was to determine platelet α[sub 2] -adrenergic receptor (α[sub 2] -AR) binding sites in fibromyalgia both before and after treatment with sertraline or placebo. The maximum number of binding sites (B[sub max] ) and their affinity (K[sub d] ) for [[sup 3] H]rauwolscine, a selective α[sub 2] -AR antagonist, were measured in 13 normal volunteers and 22 fibromyalgia patients. Severity of illness was evaluated by means of the Hamilton Depression Rating Scale (HDRS) and dolorimetric assessments of tenderness at tender points. Fibromyalgia patients had repeated measurements of [[sup 3] H]rauwolscine binding characteristics both before and after subchronic treatment with sertraline or placebo for 12 weeks. [[sup 3] H]rauwolscine binding K[sub d] values were significantly higher in fibromyalgia patients than in normal volunteers. There were significant inverse correlations between [[sup 3] H]rauwolscine binding K[sub d] values and duration of illness, age and lower energy. Significantly higher [[sup 3] H]rauwolscine binding K[sub d] values were found in fibromyalgia patients in an early phase of illness (<3 years) than in fibromyalgia patients with a protracted illness (>3 years). Repeated administration of sertraline had no significant effects on [[sup 3] H]rauwolscine binding B[sub max] or K[sub d] values. The results suggest that fibromyalgia and, in particular, fibromyalgia in an early phase of illness, is accompanied by lowered affinity of platelet α[sub 2] -ARs. [ABSTRACT FROM AUTHOR]

The aim of the present study was to examine the effects of academic examination stress on leukocyte subset distribution in university students. Thirty-eight university students had repeated blood collections for white blood cell differentiation and flow cytometric assay of lymphocytic subsets a few weeks before and after (i.e. two baseline conditions) as well as the day before a difficult academic examination (i.e. stress condition). Flow cytometry was used to determine the number of peripheral blood mononuclear cells (PBMC). In students, who were reactors to psychological stress (criterion based on changes in the Perceived Stress Scale, PSS), but not in stress non-reactors, a significant increase in the number of neutrophils, monocytes, CD8[sup +] , CD2[sup +] CD26[sup +] , and CD2[sup +] HLA-DR[sup +] T cells and CD19[sup +] B cells, and significant reductions in the CD4[sup +] /CD8[sup +] T cell ratio were observed in the stress condition. There were significant and positive relationships between the stress-induced changes in perceived stress (PSS scale) and number of leukocytes, neutrophils, CD2[sup +] , CD2[sup +] CD26[sup +] and CD2[sup +] HLADR[sup +] T cells, and CD19[sup +] B cells. There were significant and negative relationships between the stress-induced changes in the CD4[sup +] /CD8[sup +] ratio and the stress-induced changes in the PSS scale. Female students taking oral contraceptives showed significantly higher stress-induced responses in number of leukocytes, neutrophils and CD19[sup +] B cells than male and female students without use of oral contraceptives. The results suggest that academic examination stress induces changes in the distribution of PBMC, which indicate immune activation and which are probably orchestrated by a stress-induced production of cytokines. [ABSTRACT FROM AUTHOR]

Background: The Montreal Cognitive Assessment (MoCA) is an effective and applicable screening instrument to confirm the diagnosis of amnestic mild cognitive impairment (aMCI) from patients with Alzheimer's disease (AD) and healthy controls (HCs). Objectives: This study aimed to determine the reliability and validity of the following: (a) Thai translation of the MoCA (MoCA-Thai) and (b) delineate the key features of aMCI based on the MoCA subdomains. Methods: This study included 60 HCs, 61 aMCI patients, and 60 AD patients. The MoCA-Thai shows adequate psychometric properties including internal consistency, concurrent validity, test-retest validity, and inter-rater reliability. Results: The MoCA-Thai may be employed as a diagnostic criterion to make the diagnosis of aMCI, whereby aMCI patients are discriminated from HC with an area under the receiver-operating characteristic (AUC-ROC) curve of 0.813 and from AD patients with an AUC-ROC curve of 0.938. The best cutoff scores of the MoCA-Thai to discriminate aMCI from HC is ≤24 and from AD > 16. Neural network analysis showed that (a) aberrations in recall was the most important feature of aMCI versus HC with impairments in language and orientation being the second and third most important features and (b) aberrations in visuospatial skills and executive functions were the most important features of AD versus aMCI and that impairments in recall, language, and orientation but not attention, concentration, and working memory, further discriminated AD from aMCI. Conclusions: The MoCA-Thai is an appropriate cognitive assessment tool to be used in the Thai population for the diagnosis of aMCI and AD. [ABSTRACT FROM AUTHOR]

Background: Postoperative delirium in elderly people with hip fracture is associated with various adverse clinical outcomes. Nevertheless, the pathophysiological processes underpinning delirium have remained elusive. Objectives: The aim of this study was to explore the associations between delirium and its features and immune-inflammatory and blood gas biomarkers. Methods: In this prospective study, we examined 65 patients who underwent a hip fracture surgery and assessed the Confusion Assessment Method for the Intensive Care Unit, Richmond Agitation-Sedation Scale (RASS), and Delirium Rating Scale Revised-98 (DRS-R-98) before and during 4 days after the surgery. Complete blood count and venous blood gas markers were obtained at the same time points. Results: Delirium was observed in 19 patients and was accompanied by significantly increased pO2, number of white blood cells, neutrophil percentage, and neutrophil/lymphocyte ratio, and lower mean platelet volume (MPV) after adjusting for age, central nervous system (CNS) disease, blood loss during surgery, sleep disorders, and body mass index. The severity of delirium was associated with lowered number of platelets and MPV. Psychomotor disorders were associated with lower bicarbonate levels. The requirement of physical restraint of the patients was predicted by increased percentages of neutrophils and lymphocytes. Prior CNS disease was together with these biomarkers a significant predictor of delirium and severity of delirium. Conclusion: Delirium and psychomotor disorders following hip fracture and surgery may be caused by immune-inflammatory and oxidative stress pathways probably attributable to an aseptic inflammatory process. [ABSTRACT FROM AUTHOR]

Major depressive disorder (MDD) is a complex mental illness with unmet therapeutic needs. The antidepressant effects of ω-3 polyunsaturated fatty acids (n-3 PUFAs) have been widely reported. The subcommittee of the International Society for Nutritional Psychiatry Research organized an expert panel and conducted a literature review and a Delphi process to develop a consensus-based practice guideline for clinical use of n-3 PUFAs in MDD. The guideline focuses on 5 thematic areas: general concepts, acute treatment strategy, depression recurrence monitoring and prevention, use in special populations, and potential safety issues. The key practice guidelines contend that: (1) clinicians and other practitioners are advised to conduct a clinical interview to validate clinical diagnoses, physical conditions, and measurement-based psychopathological assessments in the therapeutic settings when recommending n-3 PUFAs in depression treatment; (2) with respect to formulation and dosage, both pure eicosapentaenoic acid (EPA) or an EPA/docosahexaenoic acid (DHA) combination of a ratio higher than 2 (EPA/DHA >2) are considered effective, and the recommended dosages should be 1-2 g of net EPA daily, from either pure EPA or an EPA/DHA (>2:1) formula; (3) the quality of n-3 PUFAs may affect therapeutic activity; and (4) potential adverse effects, such as gastrointestinal and dermatological conditions, should be monitored, as well as obtaining comprehensive metabolic panels. The expert consensus panel has agreed on using n-3 PUFAs in MDD treatment for pregnant women, children, and the elderly, and prevention in high-risk populations. Personalizing the clinical application of n-3 PUFAs in subgroups of MDD with a low Omega-3 Index or high levels of inflammatory markers might be regarded as areas that deserve future research. [ABSTRACT FROM AUTHOR]

Background: The Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) developed a neuropsychological battery (CERAD-NP) to screen patients with Alzheimer’s dementia. Mild cognitive impairment (MCI) has received attention as a pre-dementia stage. Objectives: To delineate the CERAD-NP features of MCI and their clinical utility to externally validate MCI diagnosis. Methods: The study included 60 patients with MCI, diagnosed using the Clinical Dementia Rating, and 63 normal controls. Data were analysed employing receiver operating characteristic analysis, Linear Support Vector Machine, Random Forest, Adaptive Boosting, Neural Network models, and t-distributed stochastic neighbour embedding (t-SNE). Results: MCI patients were best discriminated from normal controls using a combination of Wordlist Recall, Wordlist Memory, and Verbal Fluency Test. Machine learning showed that the CERAD features learned from MCI patients and controls were not strongly predictive of the diagnosis (maximal cross-validation 77.2%), whilst t-SNE showed that there is a considerable overlap between MCI and controls. Conclusions: The most important features of the CERAD-NP differentiating MCI from normal controls indicate impairments in episodic and semantic memory and recall. While these features significantly discriminate MCI patients from normal controls, the tests are not predictive of MCI. [ABSTRACT FROM AUTHOR]

Background: Increased oxidative damage to DNA is one of the pathways involved in Alzheimer's disease (AD). Insufficient base excision repair (BER) is in part responsible for increased oxidative DNA damage. The aim of the present study was to assess the effect of polymorphic variants of BER-involved genes and the peripheral markers of DNA damage and repair in patients with AD. Material and Methods: Comet assays and TaqMan probes were used to assess DNA damage, BER efficiency and polymorphic variants of 12 BER genes in blood samples from 105 AD patients and 130 controls. The DNA repair efficacy (DRE) was calculated according to a specific equation. Results: The levels of endogenous and oxidative DNA damages were higher in AD patients than controls. The polymorphic variants of XRCC1 c.580C>T XRCC1 c.1196A>G and OGG1 c.977C>G are associated with increased DNA damage in AD. Conclusion: Our results show that oxidative stress and disturbances in DRE are particularly responsible for the elevated DNA lesions in AD. The results suggest that oxidative stress and disruption in DNA repair may contribute to increased DNA damage in AD patients and risk of this disease. In addition, disturbances in DRE may be associated with polymorphisms of OGG1 and XRCC1 . [ABSTRACT FROM AUTHOR]

Background: One of the factors that contribute to Alzheimer's disease (AD) is the DNA damage caused by oxidative stress and inflammation that occurs in nerve cells. It has been suggested that the risk of AD may be associated with an agedependent reduction of the DNA repair efficiency. Base excision repair (BER) is, among other things, a main repair system of oxidative DNA damage. One of the reasons for the reduced efficiency of this system may be single-nucleotide polymorphisms (SNP) of the genes encoding its proteins. Methods: DNA for genotyping was obtained from the peripheral blood of 281 patients and 150 controls. In the present study, we evaluated the impact of 8 polymorphisms of 6 BER genes on the AD risk. We analyzed the following SNP: c.-468T>G and c.444T>G of APEX1, c. * 50C>T and c. * 83A>C of LIG3, c.977C>G of OGG1, c. * 283C>G of NEIL1, c.-441G>A of FEN1, and c.-7C>T of LIG1. Results: We showed that the LIG1 c.-7C>T A/A and LIG3 c. * 83A>C A/C variants increased, while the APEX1 c.444T>G G/T, LIG1 c.-7C>T G/, LIG3 c. * 83A>C C/C variants reduced, the AD risk. We also evaluated the relation between gene-gene interactions and the AD risk. We showed that combinations of certain BER gene variants such as c.977C>G×c. * 50C>T CC/CT, c.444T>G×c. * 50C>T GG/CT, c.-468T>G×c. * 50C>T GG/CT, c.-441G>Ac. * 50C>T×c. * 50C>T GG/CT, c. * 83A>C× c. * 50C>T CT/AC, and c.-7C>T×c. * 50C>T CT/GG can substantially positively modulate the risk of AD. Conclusions: In conclusion, we revealed that polymorphisms of BER genes may have a significant effect on the AD risk, and the presence of polymorphic variants may be an important marker for AD. [ABSTRACT FROM AUTHOR]

Background: Many clinical studies have shown that oxidative stress pathways and the efficiency of the oxidative DNA damage base excision repair (BER) system are associated with the pathogenesis of Alzheimer's disease (AD). Reduced BER efficiency may result from polymorphisms of BER-related genes. In the present study, we examine whether single nucleotide polymorphisms (SNPs) of BER genes are associated with increased risk of AD. Methods: SNP genotyping was carried out on DNA isolated from peripheral blood mononuclear cells obtained from 120 patients with AD and 110 healthy volunteers. Samples were genotyped for the presence of BER-related SNPs, i.e. XRCC1-rs1799782, rs25487; MUTYH-rs3219489, and PARP1-rs1136410. Results: We found a positive association between AD risk and the presence of G/A genotype variant of the XRCC1 rs25487 polymorphism [odds ratio (OR) = 3.762, 95% CI: 1.793-7.891]. The presence of the A/A genotype of this polymorphism reduced the risk of AD (OR = 0.485, 95% CI: 0.271-0.870). In cases of the PARP1 gene rs1136410 polymorphism, we observed that the T/C variant increases (OR = 4.159, 95% CI: 1.978-8.745) while the T/T variant reduces risk (OR = 0.240, 95% CI: 0.114-0.556) of AD. Conclusions: We conclude that BER gene polymorphisms may play an important role in the etiology of AD. Diagnosing the presence or absence of particular genetic variants may be an important marker of AD. Further research on a larger population is needed. There is also a need to examine polymorphisms of other BER in the context of AD risk. © 2015 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Recent studies have revealed that recurrent depressive disorders (rDD) are linked with dysregulation of the immune system. Previous studies have found that manganese superoxide dismutase (MnSOD, SOD2) may be a key inflammatory enzyme involved in this disorder. The purpose of this study was to determine the mRNA and protein levels of MnSOD in patients with rDD and to define the relationship between serum MnSOD levels and cognitive performance. Methods: The study comprised 236 subjects, which included patients with rDD (n = 131) and healthy subjects (n = 105, healthy control group, HC). Assessment of cognitive function was based on performance on the Trail Making test (TMT), the Stroop test, the Verbal Fluency test (VFT) and the Auditory Verbal Learning test (AVLT). Results: MnSOD gene expression at mRNA and protein level was significantly lower in rDD patients than in the HC group (p < 0.01). In the rDD and HC groups separately, there were no statistically significant associations between mRNA and protein expression levels of the MnSOD and psychological tests. In the total study group (n = 236), there was a statistically significant correlation between both MnSOD gene levels and the following tests (p < 0.01): the TMT parts A and B (negative correlation), the Stroop test parts RCNb (reading color names in black) and NCWd (naming color of word - different; negative correlation), the VFT (positive correlation) and the AVLT (positive correlation). Conclusions: Our study provides evidence that the MnSOD enzyme-coding gene and MnSOD expression are important for the regulation of cognitive functioning. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Objective: To evaluate the possible biological aspects of ‘unexplained physical symptoms’, this study examined serotonergic and noradrenergic monoamino acids in somatoform disorders and/or depression. Methods: Blood samples of 150 subjects from 4 groups (somatization syndrome; depression; depression and somatization; controls) were analyzed for amino acids contributing to the serotonergic and noradrenergic system and peripheral muscle energy balance (tryptophan, valine, leucine, isoleucine, phenylalanine and tyrosine). Results: Tryptophan, branched chain amino acids and other serotonergic amino acids were decreased in patients with somatoform symptoms, even when no depression was present. Conclusions: We conclude that serotonergic amino acids are biological correlates of multiple unexplained symptoms. Ways of action do not only involve brain mechanisms, but also energy metabolism in peripheral muscles. Copyright © 2004 S. Karger AG, Basel. [ABSTRACT FROM AUTHOR]

Background/Aim: There is now some evidence that autism may be accompanied by abnormalities in the inflammatory response system (IRS). Products of the IRS, such as proinflammatory cytokines, may induce some of the behavioral symptoms of autism, such as social withdrawal, resistance to novelty and sleep disturbances. The main aim of the present study was to examine whether autism is accompanied by an activation of the IRS. Methods: We measured the production of interleukin (IL)-6, IL-10, the IL-1 receptor antagonist (IL-1RA), interferon (IFN)-γ and tumor necrosis factor (TNF)-α by whole blood and the serum concentrations of IL-6, the IL-2 receptor (IL-2R) and IL-1RA. Results: This study showed a significantly increased production of IFN-γ and IL-1RA and a trend toward a significantly increased production of IL-6 and TNF-α by whole blood of autistic children. There were no significant differences in the serum concentrations of IL-6, IL-2R and IL-1RA between autistic and normal children. Conclusions: These results suggest that autism may be accompanied by an activation of the monocytic (increased IL-1RA) and Th-1-like (increased IFN-γ) arm of the IRS. It is hypothesized that increased production of proinflammatory cytokines could play a role in the pathophysiology of autism.Copyright © 2002 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Recently, it was reported that there may be an activation of the inflammatory response system in detoxified alcohol-dependent patients without apparent liver disease (AWLD). The aims of the present study were to examine serum zinc (Zn) concentrations, total serum protein (TSP) and patterns obtained in the electrophoretically separated protein fractions in relation to serum interleukin-6 (IL-6) and IL-8 concentrations in detoxified AWLD patients. Zn, TSP, SP electrophoresis, and serum IL-6 and IL-8 concentrations were determined in detoxified AWLD patients and age-matched healthy volunteers. Serum Zn, TSP and the serum concentrations of albumin (Alb) and the β fraction were significantly lower in detoxified AWLD patients than in healthy volunteers. The percentage of the α[sub 2] fraction was significantly higher in detoxified AWLD patients. Lower serum Zn in detoxified AWLD patients was attributable to lowered serum Alb. Lower serum Alb was significantly and negatively correlated to increased serum IL-8. The percentage of the α[sub 1] and α[sub 2] fractions were significantly and positively related to serum IL-6 and IL-8. The results show that there is an in vivo activation of the inflammatory response system in detoxified AWLD patients and that lower serum Zn may be causally related to lower serum Alb. [ABSTRACT FROM AUTHOR]