Rotavirus infects human biliary epithelial cells and stimulates secretion of cytokines IL-6 and IL-8 via MAPK pathway

Biliary atresia (BA) is an infantile inflammatory cholangiopathy of unknown etiology although epidemiologic studies and animal models utilizing rotavirus (RV) have suggested a role for viral infection. Proinflammatory and profibrotic cytokines have been detected in infants with BA.The purpose of our study was to investigate the susceptibility of human cholangiocytes (H69 cells) to infection with RRV and to determine if this infection resulted in cytokine secretion. Infection ofH69 cells by RRV was noncytolytic and resulted in a time-dependent increase in the release of both infectious virions and cytokines IL-6 and IL-8 into the supernate. The greatest difference in cytokine supernatant levels between infected and mock-infected cells was noted at 24 hours postinfection (h p.i.) for IL-8, 556 ± 111 versus 77 ± 68 pg/mL ( < 0.0001), and at 48 h p.i. for IL-6, 459 ± 64 versus 67 ± 2 pg/mL ( < 0.0001). Production of both cytokines following RRV infection was significantly reduced by pretreating the H69 cells with inhibitors of mitogen-activated protein kinase (MAPK). Conclusion. RRV can infect human cholangiocytes resulting in the production of proinflammatory and profibrotic cytokines via the MAPK pathway. RRV-infected H69 cells could be a useful model system for investigating the viral hypothesis of BA

Toxoplasma gondii infection and common mental disorders in the Finnish general population

Objective: We investigated whether T. gondii seropositivity is associated with 12-month depressive, anxiety and alcohol use disorders and current depressive symptoms and whether inflammation, measured by C-reactive protein (CRP) level, explains these associations. Method: Health 2000 study (BRIF8901), conducted in years 2000-2001, is based on a nationally representative sample of Finns aged 30 and above, with 7112 participants and 88.6% response rate. DSM-IV depressive, anxiety and alcohol use disorders were assessed with the Composite International Diagnostic Interview and depressive symptoms with the Beck Depressive Inventory (BDI-21). We used logistic regression to investigate the association of T. gondii seropositivity with mental disorders and linear regression with BDI-21 scores. Results: T. gondii seroprevalence was significantly associated with 12-month generalized anxiety disorder but not with other anxiety, depressive or alcohol use disorders. T. gondii seropositivity was associated with higher BDI-21 scores (beta 0.56, 95% CI 0.12-1.00, P = 0.013) and with having a comorbid depressive and anxiety disorder (OR 1.86, 95% CI 1.16-2.97, P = 0.010). Higher CRP levels were associated with these outcomes and with T. gondii seropositivity, but adjusting for CRP did not change the effect of T. gondii seropositivity. Limitations: Cross-sectional study design with no information on the timing of T. gondii infection. Conclusion: T. gondii seropositivity is associated with generalized anxiety disorder, depressive symptoms and comorbid depressive and anxiety disorders, which is not mediated by inflammation.Peer reviewe

Potential Biomarkers Selection for Bipolar Disorder Identification

A biomarker is a measurable indicator of the severity or presence of some disease. A biomarker is anything that can be used as an indicator of a particular disease state or some other physiological state of an organism. The space Decomposition-Gradient-Regression (DGR) method has been developed (Li et al., 2012; Li et al., 2015) to select biomarkers for schizophrenia. This study performs the DGR approach on data for bipolar disorder patients, which contains 56 biomarkers and 8 infectious agent’s antibodies. Serum specimens were collected from 132 United States military service members (118 males and 14 females) with a diagnosis of bipolar disorder from 1992 to 2005 and their matched healthy controls.. Trefoil Factor3 (TFF3), Gliadin, prolactin (PRL), Apolipoprotein A-II (Apo A-II) and Immunoglobulin A (IGA) were found to be significant predictors of Bipolar Disorder (BD) in males. Macrophage-Derived Chemokine (MDC), Alpha-1-Antitrypsin (AAT), Gliadin, Beta-2-Microglobulin (B2M) and Monocyte Chemotactic Protein 2 (MCP-2) might be used to identify bipolar disorder in females. A predictive biomarker panel for BD offers the potential to aid in the diagnosis, initiate treatment earlier and ideally alter the course of disease with reduced morbidity and functional impairment

The association between toxoplasma and the psychosis continuum in a general population setting

Toxoplasma gondii infection is associated with increased risk for psychosis. However, the possible association between T. gondii and psychotic-like symptoms in the general adult population is unknown. We investigated whether T. gondii is associated with psychotic-like symptoms and psychosis diagnoses using data from Health 2000, a large cross-sectional health survey of the Finnish general population aged 30 and above. Seropositivity to toxoplasma was defined as a cutoff of 50 IU/ml of IgG antibodies. Lifetime psychotic-like symptoms were identified with section G of the Composite International Diagnostic Interview, Munich version (M-CIDI). Symptoms were considered clinically relevant if they caused distress or help-seeking or there were at least three of them. Lifetime psychotic disorders were screened from the sample and were diagnosed with DSM-IV using SCID-I interview and information from medical records. All data were available for 5906 participants. We adjusted for variables related to T. gondii seropositivity (age, gender, education, region of residence, cat ownership, and C-reactive protein measuring inflammation) in regression models. We found that T. gondii seropositivity was significantly associated with clinically relevant psychotic-like symptoms (OR 1.77, p = 0.001) and with the number of psychotic-like symptoms (IRR = 1.55, p = 0.001). The association between toxoplasma and diagnosed psychotic disorders did not reach statistical significance (OR 1.45 for schizophrenia). In a large sample representing the whole Finnish adult population, we found that serological evidence of toxoplasma infection predicted psychotic-like symptoms, independent of demographic factors and levels of C-reactive protein. Toxoplasma infection may be a risk factor for manifestation of psychotic-like symptoms. (c) 2017 Elsevier B.V. All rights reserved.Peer reviewe

Inflammation and immunity in schizophrenia: implications for pathophysiology and treatment.

Complex interactions between the immune system and the brain might have important aetiological and therapeutic implications for neuropsychiatric brain disorders. A possible association between schizophrenia and the immune system was postulated over a century ago, and is supported by epidemiological and genetic studies pointing to links with infection and inflammation. Contrary to the traditional view that the brain is an immunologically privileged site shielded behind the blood-brain barrier, studies in the past 20 years have noted complex interactions between the immune system, systemic inflammation, and the brain, which can lead to changes in mood, cognition, and behaviour. In this Review, we describe some of the important areas of research regarding innate and adaptive immune response in schizophrenia and related psychotic disorders that, we think, will be of interest to psychiatric clinicians and researchers. We discuss potential mechanisms and therapeutic implications of these findings, including studies of anti-inflammatory drugs in schizophrenia, describe areas for development, and offer testable hypotheses for future investigations.The work was supported by a doctoral clinical research training fellowship grant from the Wellcome Trust to Golam Khandaker (094790/Z/10/Z; 2010-‘13), grants from the Stanley Medical Research Institute and the National Institutes of Mental Health (grant# MH-94268) to Robert Yolken, and grants from the Wellcome Trust (095844/Z/11/Z & 088869/Z/09/Z), and the NIHR (RP-PG-0606-1335) to Peter Jones.This is the accepted manuscript. The final version is available from Elsevier at http://www.thelancet.com/journals/lanpsy/article/PIIS2215-0366%2814%2900122-9/abstrac

Association of cytomegalovirus and Epstein-Barr virus with cognitive functioning and risk of dementia in the general population : 11-year follow-up study

Background: Earlier studies have documented an association between cytomegalovirus and cognitive impairment, but results have been inconsistent. Few studies have investigated the association of cytomegalovirus and Epstein-Barr virus with cognitive decline longitudinally. Our aim was to examine whether cytomegalovirus and Epstein-Barr virus are associated with cognitive decline, in adults. Method: The study sample is from the Finnish Health 2000 Survey (BRIF8901, n = 7112), which is representative of the Finnish adult population. The sample was followed up after 11 years in the Health 2011 Survey. In addition, persons with dementia were identified from healthcare registers. Results: In the Finnish population aged 30 and over, the seroprevalence of cytomegalovirus was estimated to be 84% and the seroprevalence of Epstein-Barr virus 98%. Seropositivity of the viruses and antibody levels were mostly not associated with cognitive performance. In the middle-aged adult group, cytomegalovirus serointensity was associated with impaired performance in verbal learning. However, the association disappeared when corrected for multiple testing. No interactions between infection and time or between the two infections were significant when corrected for multiple testing. Seropositivity did not predict dementia diagnosis. Conclusions: The results suggest that adult levels of antibodies to cytomegalovirus and Epstein-Barr virus may not be associated with a significant decline in cognitive function or with dementia at population level. (C) 2018 Published by Elsevier Inc.Peer reviewe

Cross-genetic determination of maternal and neonatal immune mediators during pregnancy.

BACKGROUND:The immune system plays a fundamental role in development during pregnancy and early life. Alterations in circulating maternal and neonatal immune mediators have been associated with pregnancy complications as well as susceptibility to autoimmune and neurodevelopmental conditions in later life. Evidence suggests that the immune system in adults not only responds to environmental stimulation but is also under strong genetic control. METHODS:This is the first genetic study of > 700 mother-infant pairs to analyse the circulating levels of 22 maternal mid-gestational serum-derived and 42 neonatal bloodspot-derived immune mediators (cytokines/chemokines) in the context of maternal and fetal genotype. We first estimated the maternal and fetal genome-wide SNP-based heritability (h2g) for each immune molecule and then performed genome-wide association studies (GWAS) to identify specific loci contributing to individual immune mediators. Finally, we assessed the relationship between genetic immune determinants and ASD outcome. RESULTS:We show maternal and neonatal cytokines/chemokines displaying genetic regulation using independent methodologies. We demonstrate that novel fetal loci for immune function independently affect the physiological levels of maternal immune mediators and vice versa. The cross-associated loci are in distinct genomic regions compared with individual-specific immune mediator loci. Finally, we observed an interaction between increased IL-8 levels at birth, autism spectrum disorder (ASD) status, and a specific maternal genotype. CONCLUSIONS:Our results suggest that maternal and fetal genetic variation influences the immune system during pregnancy and at birth via distinct mechanisms and that a better understanding of immune factor determinants in early development may shed light on risk factors for developmental disorders

Exposure to common infections and risk of suicide and self-harm : a longitudinal general population study

Common infectious agents, such as Toxoplasma gondii (T. gondii) and several human herpes viruses, have been linked to increased risk of self-harm. The aim of this study was to investigate the associations between self-harm and seropositivity to T. gondii, Epstein-Barr virus (EBV), Herpes Simplex virus Type 1 (HSV-1), and Cytomegalovirus (CMV). IgM and IgG antibodies to these infections were measured in the Health 2000 project nationally representative of the whole Finnish adult population, and 6250 participants, age 30 and over, were followed for 15 years via registers. In addition, lifetime suicidal ideation and suicide attempts based on medical records and interview were assessed within a subsample of 694 participants screened to a substudy for possible psychotic symptoms or as controls. Among the 6250 participants, 14 individuals died of suicide and an additional 4 individuals had a diagnosis of intentional self-harm during follow-up. Serological evidence of lifetime or acute infections was not found to be associated with these suicidal outcomes. However, in the subsample, those seropositive for CMV had fewer suicide attempts compared to those seronegative, adjusting for gender, age, educational level, childhood family size, regional residence, CRP, and screen status (OR for multiple attempts = 0.40, 95% confidence interval 0.20-0.83, p = 0.014). To conclude, common infections were not associated with risk of death by suicide or with self-harm diagnoses at a 15-year follow-up in the general population sample. Our finding of an increased number of suicide attempts among persons seronegative for CMV calls for further research.Peer reviewe