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Find video protocols related to scientific articles indexed in Pubmed.
Chronic infection of Toxoplasma gondii downregulates miR-132 expression in multiple brain regions in a sex-dependent manner.
Parasitology
PUBLISHED: 10-30-2014
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SUMMARY MicroRNA-132 (miR-132) has been demonstrated to affect multiple neuronal functions and its dysregulation is linked to several neurological disorders. We previously showed that acute Toxoplasma gondii infection induces miR-132 expression both in vitro and in vivo. To investigate the impact of chronic infection on miR-132, we infected mice with T. gondii PRU strain and performed assessment 5 months later in six brain regions (cortex, hypothalamus, striatum, cerebellum, olfactory bulb and hippocampus) by qPCR. We found that while acute infection of T. gondii increases the expression of miR-132, chronic infection has the opposite effect. The effect varied amongst different regions of the brain and presented in a sex-dependent manner, with females exhibiting more susceptibility than males. MiR-132 and brain-derived neurotrophic factor (BDNF, an inducer of miR-132) were not co-varies in the brain areas of infected mice. T. gondii DNA/RNA was found in all tested brain regions and a selective tropism towards the hippocampus, based on bradyzoite density, was observed in both males and females. However, the expressions of miR-132 or BDNF were poorly reflected by the density of T. gondii in brain areas. Our findings highlight the importance of investigating the miR-132-mediated neuronal function in mice infected with T. gondii.
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Chlorovirus ATCV-1 is part of the human oropharyngeal virome and is associated with changes in cognitive functions in humans and mice.
Proc. Natl. Acad. Sci. U.S.A.
PUBLISHED: 10-27-2014
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Chloroviruses (family Phycodnaviridae) are large DNA viruses known to infect certain eukaryotic green algae and have not been previously shown to infect humans or to be part of the human virome. We unexpectedly found sequences homologous to the chlorovirus Acanthocystis turfacea chlorella virus 1 (ATCV-1) in a metagenomic analysis of DNA extracted from human oropharyngeal samples. These samples were obtained by throat swabs of adults without a psychiatric disorder or serious physical illness who were participating in a study that included measures of cognitive functioning. The presence of ATCV-1 DNA was confirmed by quantitative PCR with ATCV-1 DNA being documented in oropharyngeal samples obtained from 40 (43.5%) of 92 individuals. The presence of ATCV-1 DNA was not associated with demographic variables but was associated with a modest but statistically significant decrease in the performance on cognitive assessments of visual processing and visual motor speed. We further explored the effects of ATCV-1 in a mouse model. The inoculation of ATCV-1 into the intestinal tract of 9-11-wk-old mice resulted in a subsequent decrease in performance in several cognitive domains, including ones involving recognition memory and sensory-motor gating. ATCV-1 exposure in mice also resulted in the altered expression of genes within the hippocampus. These genes comprised pathways related to synaptic plasticity, learning, memory formation, and the immune response to viral exposure.
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One minute ultraviolet exposure inhibits Toxoplasma gondii tachyzoite replication and cyst conversion without diminishing host humoral-mediated immune response.
Exp. Parasitol.
PUBLISHED: 08-14-2014
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We developed a protocol to inactivate Toxoplasma gondii (T. gondii) tachyzoites employing 1 min of ultraviolet (UV) exposure. We show that this treatment completely inhibited parasite replication and cyst formation in vitro and in vivo but did not affect the induction of a robust IgG response in mice. We propose that our protocol can be used to study the contribution of the humoral immune response to rodent behavioral alterations following T. gondii infection.
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Toxoplasma gondii and anxiety disorders in a community-based sample.
Brain Behav. Immun.
PUBLISHED: 08-12-2014
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A growing body of literature suggests that exposure to the neurotropic parasite Toxoplasma gondii (T. gondii) is associated with increased risk of mental disorders, particularly schizophrenia. However, a potential association between T. gondii exposure and anxiety disorders has not been rigorously explored. Here, we examine the association of T. gondii infection with both anxiety and mood disorders. Participants (n=484) were drawn from the Detroit Neighborhood Health Study, a population-representative sample of Detroit residents. Logistic regression was used to examine the associations between T. gondii exposure (defined by seropositivity and IgG antibody levels) and three mental disorders: generalized anxiety disorder (GAD), posttraumatic stress disorder (PTSD) and depression. We found that T. gondii seropositivity was associated with a 2 times greater odds of GAD (odds ratio (OR), 2.25; 95% confidence interval (CI), 1.11-4.53) after adjusting for age, gender, race, income, marital status, and medication. Individuals in the highest antibody level category had more than 3 times higher odds of GAD (OR, 3.35; 95% CI, 1.41-7.97). Neither T. gondii seropositivity nor IgG antibody levels was significantly associated with PTSD or depression. Our findings indicate that T. gondii infection is strongly and significantly associated with GAD. While prospective confirmation is needed, T. gondii infection may play a role in the development of GAD.
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Cytomegalovirus Infection and Risk of Alzheimer Disease in Older Black and White Individuals.
J. Infect. Dis.
PUBLISHED: 08-08-2014
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?Human cytomegalovirus (CMV) is prevalent in older adults and has been implicated in many chronic diseases of aging. This study investigated the relation between CMV and the risk of Alzheimer disease (AD).
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Antibodies to Toxoplasma gondii and cognitive functioning in schizophrenia, bipolar disorder, and nonpsychiatric controls.
J. Nerv. Ment. Dis.
PUBLISHED: 07-11-2014
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Increased rates of exposure to Toxoplasma gondii have been found in individuals with schizophrenia and bipolar disorder, but the association between Toxoplasma and cognitive functioning has not previously been examined. We measured IgG and IgM class antibodies to Toxoplasma in 408 nonelderly individuals with schizophrenia, 347 with bipolar disorder, and 352 nonpsychiatric controls. Cognitive functioning was measured with the Repeatable Battery for the Assessment of Neuropsychological Status. Multivariate linear and regression analyses showed significant associations between Toxoplasma IgM antibody level and cognitive scores within the control group and the bipolar disorder group but not the schizophrenia group. Within the control group, having an elevated Toxoplasma IgM antibody level, greater than or equal to the 50th and 75th levels of the control group, was associated with significantly elevated odds of a low total cognitive score. Exposure to Toxoplasma may confer risk for lower cognitive functioning in persons without a psychiatric disorder and those with bipolar disorder.
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IgG dynamics of dietary antigens point to cerebrospinal fluid barrier or flow dysfunction in first-episode schizophrenia.
Brain Behav. Immun.
PUBLISHED: 06-20-2014
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Schizophrenia is a complex brain disorder that may be accompanied by idiopathic inflammation. Classic central nervous system (CNS) inflammatory disorders such as viral encephalitis or multiple sclerosis can be characterized by incongruent serum and cerebrospinal fluid (CSF) IgG due in part to localized intrathecal synthesis of antibodies. The dietary antigens, wheat gluten and bovine milk casein, can induce a humoral immune response in susceptible individuals with schizophrenia, but the correlation between the food-derived serological and intrathecal IgG response is not known. Here, we measured IgG to wheat gluten and bovine milk casein in matched serum and CSF samples from 105 individuals with first-episode schizophrenia (n=75 antipsychotic-naïve), and 61 controls. We found striking correlations in the levels of IgG response to dietary proteins between serum and CSF of schizophrenia patients, but not controls (schizophrenia, R(2)=0.34-0.55, p?0.0001; controls R(2)=0.05-0.06, p>0.33). A gauge of blood-CSF barrier permeability and CSF flow rate, the CSF-to-serum albumin ratio, was significantly elevated in cases compared to controls (p?0.001-0.003). Indicators of intrathecal IgG production, the CSF IgG index and the specific Antibody Index, were not significantly altered in schizophrenia compared to controls. Thus, the selective diffusion of bovine milk casein and wheat gluten antibodies between serum and CSF in schizophrenia may be the function of a low-level anatomical barrier dysfunction or altered CSF flow rate, which may be transient in nature.
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The urban risk and migration risk factors for schizophrenia: Are cats the answer?
Schizophr. Res.
PUBLISHED: 05-27-2014
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Being born in and/or raised in an urban area is a proven risk factor for developing schizophrenia. Migrating from countries such as Jamaica or Morocco to countries such as England or the Netherlands is also a proven risk factor for developing schizophrenia. The transmission of Toxoplasma gondii oocysts to children is reviewed and proposed as a partial explanation for both of these risk factors.
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Herpesviruses, inflammatory markers and incident depression in a longitudinal study of Detroit residents.
Psychoneuroendocrinology
PUBLISHED: 04-30-2014
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Depression is predicted to become the leading cause of disability worldwide by 2030 and moreover, socioeconomic inequalities in depression persist. Herpesviruses, which are more prevalent among socioeconomically disadvantaged populations, subject to stress-induced reactivation and are associated with increased levels of pro-inflammatory cytokines implicated in the etiology of depression, may serve as novel risk factors for depression onset.
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Inflammatory molecular signature associated with infectious agents in psychosis.
Schizophr Bull
PUBLISHED: 04-17-2014
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Schizophrenia (SZ) is a devastating mental condition with onset in young adulthood. The identification of molecular biomarkers that reflect illness pathology is crucial. Recent evidence suggested immune and inflammatory cascades in conjunction with infection may play a role in the pathology. To address this question, we investigated molecular changes in cerebrospinal fluid (CSF) from antipsychotic-naïve patients with SZ and at risk mental status for psychosis (ARMS), in comparison with healthy controls (HCs). We measured 90 analytes using a broad multiplex platform focusing on immune and inflammatory cascades then selected 35 with our quality reporting criteria for further analysis. We also examined Toxoplasma gondii (TG) and herpes simplex virus 1 antibody levels in CSF. We report that expression of 15 molecules was significantly altered in the patient groups (SZ and ARMS) compared with HCs. The majority of these molecular changes (alpha-2-macroglobulin [?2M], fibrinogen, interleukin-6 receptor [IL-6R], stem cell factor [SCF], transforming growth factor alpha [TGF?], tumor necrosis factor receptor 2 [TNFR2], IL-8, monocyte chemotactic protein 2 [MCP-2/CCL8], testosterone [for males], angiotensin converting enzyme [ACE], and epidermal growth factor receptor) were consistent between SZ and ARMS patients, suggesting these may represent trait changes associated with psychotic conditions in general. Interestingly, many of these analytes (?2M, fibrinogen, IL-6R, SCF, TGF?, TNFR2, IL-8, MCP-2/CCL8, and testosterone [for males]) were exacerbated in subjects with ARMS compared with subjects with SZ. Although further studies are needed, we optimistically propose that these molecules may be good candidates for predictive markers for psychosis from an early stage. Lastly, reduction of IL-6R, TGF?, and ACE was correlated with positivity of TG antibody in the CSF, suggesting possible involvement of TG infection in the pathology.
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Autoimmune diseases, gastrointestinal disorders and the microbiome in schizophrenia: more than a gut feeling.
Schizophr. Res.
PUBLISHED: 03-31-2014
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Autoimmunity, gastrointestinal (GI) disorders and schizophrenia have been associated with one another for a long time. This paper reviews these connections and provides a context by which multiple risk factors for schizophrenia may be related. Epidemiological studies strongly link schizophrenia with autoimmune disorders including enteropathic celiac disease. Exposure to wheat gluten and bovine milk casein also contribute to non-celiac food sensitivities in susceptible individuals. Co-morbid GI inflammation accompanies humoral immunity to food antigens, occurs early during the course of schizophrenia and appears to be independent from antipsychotic-generated motility effects. This inflammation impacts endothelial barrier permeability and can precipitate translocation of gut bacteria into systemic circulation. Infection by the neurotropic gut pathogen, Toxoplasma gondii, will elicit an inflammatory GI environment. Such processes trigger innate immunity, including activation of complement C1q, which also functions at synapses in the brain. The emerging field of microbiome research lies at the center of these interactions with evidence that the abundance and diversity of resident gut microbiota contribute to digestion, inflammation, gut permeability and behavior. Dietary modifications of core bacterial compositions may explain inefficient gluten digestion and how immigrant status in certain situations is a risk factor for schizophrenia. Gut microbiome research in schizophrenia is in its infancy, but data in related fields suggest disease-associated altered phylogenetic compositions. In summary, this review surveys associative and experimental data linking autoimmunity, GI activity and schizophrenia, and proposes that understanding of disrupted biological pathways outside of the brain can lend valuable information regarding pathogeneses of complex, polygenic brain disorders.
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Persistent Infection by HSV-1 Is Associated With Changes in Functional Architecture of iPSC-Derived Neurons and Brain Activation Patterns Underlying Working Memory Performance.
Schizophr Bull
PUBLISHED: 03-14-2014
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Background: Herpes simplex virus, type 1 (HSV-1) commonly produces lytic mucosal lesions. It invariably initiates latent infection in sensory ganglia enabling persistent, lifelong infection. Acute HSV-1 encephalitis is rare and definitive evidence of latent infection in the brain is lacking. However, exposure untraceable to encephalitis has been repeatedly associated with impaired working memory and executive functions, particularly among schizophrenia patients. Methods: Patterns of HSV-1 infection and gene expression changes were examined in human induced pluripotent stem cell (iPSC)-derived neurons. Separately, differences in blood oxygenation level-dependent (BOLD) responses to working memory challenges using letter n-back tests were investigated using functional magnetic resonance imaging (fMRI) among schizophrenia cases/controls. Results: HSV-1 induced lytic changes in iPSC-derived glutamatergic neurons and neuroprogenitor cells. In neurons, HSV-1 also entered a quiescent state following coincubation with antiviral drugs, with distinctive changes in gene expression related to functions such as glutamatergic signaling. In the fMRI studies, main effects of schizophrenia (P = .001) and HSV-1 exposure (1-back, P = 1.76 × 10(-) (4); 2-back, P = 1.39 × 10(-) (5)) on BOLD responses were observed. We also noted increased BOLD responses in the frontoparietal, thalamus, and midbrain regions among HSV-1 exposed schizophrenia cases and controls, compared with unexposed persons. Conclusions: The lytic/quiescent cycles in iPSC-derived neurons indicate that persistent neuronal infection can occur, altering cellular function. The fMRI studies affirm the associations between nonencephalitic HSV-1 infection and functional brain changes linked with working memory impairment. The fMRI and iPSC studies together provide putative mechanisms for the cognitive impairments linked to HSV-1 exposure.
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Effect of probiotic supplementation on schizophrenia symptoms and association with gastrointestinal functioning: a randomized, placebo-controlled trial.
Prim Care Companion CNS Disord
PUBLISHED: 02-13-2014
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A range of immune system abnormalities have been associated with schizophrenia. Probiotic compounds modulate the immune response and offer a potential treatment strategy for schizophrenia. Probiotic compounds have also been observed to improve gastrointestinal dysfunction, which is a common problem in individuals with schizophrenia. We performed a randomized, double-blind, placebo-controlled trial to examine whether probiotic supplementation can reduce symptom severity in patients with schizophrenia receiving antipsychotic treatment and also whether probiotics are associated with bowel functioning.
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A thiazole derivative of artemisinin moderately reduces Toxoplasma gondii cyst burden in infected mice.
J. Parasitol.
PUBLISHED: 02-13-2014
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Toxoplasmosis continues to be a public health problem, causing significant morbidity worldwide. Currently available medications, effective for acute toxoplasmosis, are nonetheless problematic due to adverse side effects in many patients. In addition, no medication is able to completely eradicate the parasite cysts, rendering infected individuals at risk for reactivation upon becoming immunocompromised. We examined the anti- T. gondii activity of 2 derivatives of artemisinin. In vitro metabolic stability tests revealed that both derivatives are stable in mouse plasma but only the thiazole CPH4-136 is stable in the presence of mouse microsomes. When tested in a mouse model of acute toxoplasmosis, both derivatives showed modest efficacy dependent upon the compound dose and the solvent vehicle. Finally, in a mouse model of chronic T. gondii infection, CPH4-136 at 3 mg/kg once per day for 32 days moderately but significantly decreased mouse brain cyst burden. Collectively, our findings suggest that artemisinin derivatives are partially effective in treating experimental T. gondii infections.
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A longitudinal study of cognitive functioning in schizophrenia: clinical and biological predictors.
Schizophr. Res.
PUBLISHED: 02-09-2014
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Cognitive deficits are a central feature of schizophrenia but it is not certain how cognitive functioning changes over time. The purpose of this prospective longitudinal study was to determine the temporal change of cognitive functioning and the predictors of cognitive performance from among demographic, clinical, and biological variables.
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Transcriptional derepression of the ERVWE1 locus following influenza A virus infection.
J. Virol.
PUBLISHED: 01-29-2014
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Syncytin-1, a fusogenic protein encoded by a human endogenous retrovirus of the W family (HERV-W) element (ERVWE1), is expressed in the syncytiotrophoblast layer of the placenta. This locus is transcriptionally repressed in adult tissues through promoter CpG methylation and suppressive histone modifications. Whereas syncytin-1 appears to be crucial for the development and functioning of the human placenta, its ectopic expression has been associated with pathological conditions, such as multiple sclerosis and schizophrenia. We previously reported on the transactivation of HERV-W elements, including ERVWE1, during influenza A/WSN/33 virus infection in a range of human cell lines. Here we report the results of quantitative PCR analyses of transcripts encoding syncytin-1 in both cell lines and primary fibroblast cells. We observed that spliced ERVWE1 transcripts and those encoding the transcription factor glial cells missing 1 (GCM1), acting as an enhancer element upstream of ERVWE1, are prominently upregulated in response to influenza A/WSN/33 virus infection in nonplacental cells. Knockdown of GCM1 by small interfering RNA followed by infection suppressed the transactivation of ERVWE1. While the infection had no influence on CpG methylation in the ERVWE1 promoter, chromatin immunoprecipitation assays detected decreased H3K9 trimethylation (H3K9me3) and histone methyltransferase SETDB1 levels along with influenza virus proteins associated with ERVWE1 and other HERV-W loci in infected CCF-STTG1 cells. The present findings suggest that an exogenous influenza virus infection can transactivate ERVWE1 by increasing transcription of GCM1 and reducing H3K9me3 in this region and in other regions harboring HERV-W elements.
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Maternal complement C1q and increased odds for psychosis in adult offspring.
Schizophr. Res.
PUBLISHED: 01-24-2014
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The presence of maternal antibodies to food and infectious antigens may confer an increased risk of developing schizophrenia and psychosis in adult offspring. Complement factor C1q is an immune molecule with multiple functions including clearance of antigen-antibody complexes from circulation and mediation of synaptic pruning during fetal brain development. To determine if maternal C1q was associated with offspring schizophrenia and psychosis, we evaluated 55 matched case-control maternal serum pairs from the National Collaborative Perinatal Project. Sample pairs were composed of mothers whose offspring developed psychoses as adults and those whose offspring were free from psychiatric disease. Matching criteria for offspring included birth date, delivery hospital, race, and gender, with further matching based on mother's age. IgG markers of C1q, bovine milk casein, egg ovalbumin, and wheat gluten were measured with enzyme-linked immunosorbent assays. C1q levels were compared to food antigen IgG and to previously generated data for C-reactive protein, adenovirus, herpes simplex viruses, influenza viruses, measles virus, and Toxoplasma gondii. C1q was significantly elevated in case mothers with odds ratios of 2.66-6.31 (conditional logistic regressions, p ? 0.008-0.05). In case mothers only, C1q was significantly correlated with antibodies to both food and infectious antigens: gluten (R(2)=0.26, p ? 0.004), herpes simplex virus type 2 (R(2)=0.21, p ? 0.02), and adenovirus (R(2)=0.25, p ? 0.006). In conclusion, exposure to maternal C1q activity during pregnancy may be a risk factor for the development of schizophrenia and psychosis in offspring. Prenatal measurement of maternal C1q may be an important and convergent screening tool to identify potentially deleterious immune activation from multiple sources.
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Multiplex immunoassay analysis of plasma shows prominent upregulation of growth factor activity pathways linked to GSK3? signaling in bipolar patients.
J Affect Disord
PUBLISHED: 01-14-2014
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Our understanding of bipolar disorder (BD) aetiology has advanced in recent years but our ability to translate this to improve patient care in the clinic is still limited.
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Genome-wide genetic and transcriptomic investigation of variation in antibody response to dietary antigens.
Genet. Epidemiol.
PUBLISHED: 01-13-2014
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Increased immunoglobulin G (IgG) response to dietary antigens can be associated with gastrointestinal dysfunction and autoimmunity. The underlying processes contributing to these adverse reactions remain largely unknown, and it is likely that genetic factors play a role. Here, we estimate heritability and attempt to localize genetic factors influencing IgG antibody levels against food-derived antigens using an integrative genomics approach. IgG antibody levels were determined by ELISA in >1,300 Mexican Americans for the following food antigens: wheat gliadin; bovine casein; and two forms of bovine serum albumin (BSA-a and BSA-b). Pedigree-based variance components methods were used to estimate additive genetic heritability (h(2) ), perform genome-wide association analyses, and identify transcriptional signatures (based on 19,858 transcripts from peripheral blood lymphocytes). Heritability estimates were significant for all traits (0.15-0.53), and shared environment (based on shared residency among study participants) was significant for casein (0.09) and BSA-a (0.33). Genome-wide significant evidence of association was obtained only for antibody to gliadin (P = 8.57 × 10(-8) ), mapping to the human leukocyte antigen II region, with HLA-DRA and BTNL2 as the best candidate genes. Lack of association of known celiac disease risk alleles HLA-DQ2.5 and -DQ8 with antigliadin antibodies in the studied population suggests a separate genetic etiology. Significant transcriptional signatures were found for all IgG levels except BSA-b. These results demonstrate that individual genetic differences contribute to food antigen antibody measures in this population. Further investigations may elucidate the underlying immunological processes involved.
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Association between exposure to HSV1 and cognitive functioning in a general population of adolescents. The TRAILS study.
PLoS ONE
PUBLISHED: 01-01-2014
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Infections with different herpes viruses have been associated with cognitive functioning in psychiatric patients and healthy adults. The aim of this study was to find out whether antibodies to different herpes viruses are prospectively associated with cognitive functioning in a general adolescent population.
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Association between cytomegalovirus antibody levels and cognitive functioning in non-elderly adults.
PLoS ONE
PUBLISHED: 01-01-2014
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Elevated levels of antibodies to Cytomegalovirus (CMV) have been associated with cognitive impairment, but the quantitative relationship between CMV antibody levels and domains of cognitive functioning in younger adults has not been established.
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Mortality in Schizophrenia: Clinical and Serological Predictors.
Schizophr Bull
PUBLISHED: 08-13-2013
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Persons with schizophrenia have a reduced life expectancy largely due to death from natural causes. Factors that have been previously associated with excess mortality include cigarette smoking and antipsychotic medication. The role of other environmental factors such as exposure to infectious agents has been the subject of only limited investigation. We prospectively assessed a cohort of persons with schizophrenia with a clinical evaluation and a blood sample from which antibodies to human herpes viruses and Toxoplasma gondii were measured. Mortality was determined with data from the National Death Index following a period of up to 11 years. We examined the role of demographic, serological, and clinical factors on mortality. A total of 25 (5%) of 517 persons died of natural causes. The standardized mortality ratio was 2.80 (95% CI 0.89, 6.38). After adjusting for age and gender, mortality from natural causes was predicted in separate models by cigarette smoking (relative risk [RR] = 4.66, P = .0029); lower cognitive score (RR = 0.96, P = .013); level of antibodies to Epstein-Barr virus (RR = 1.22, P = .0041) and to Herpes Simplex virus type 1 (RR = 1.19, P = .030); immunologic disease (RR = 3.14, P = .044); and genitourinary disease (RR = 2.70; P = .035). Because cigarette smoking confers an almost 5-fold risk of mortality, smoking cessation is an urgent priority. Having an elevated level of antibodies to Epstein-Barr virus and to Herpes Simplex virus type 1 are also significant predictors of death from natural causes.
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Seroreactive marker for inflammatory bowel disease and associations with antibodies to dietary proteins in bipolar disorder.
Bipolar Disord
PUBLISHED: 08-01-2013
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Immune sensitivity to wheat glutens and bovine milk caseins may affect a subset of individuals with bipolar disorder. Digested byproducts of these foods are exorphins that have the potential to impact brain physiology through action at opioid receptors. Inflammation in the gastrointestinal (GI) tract might accelerate exposure of food antigens to systemic circulation and help explain elevated gluten and casein antibody levels in individuals with bipolar disorder.
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Association between antibodies to multiple infectious and food antigens and new onset schizophrenia among US military personnel.
Schizophr. Res.
PUBLISHED: 06-18-2013
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Multiple studies have documented immune activation in many individuals with schizophrenia suggesting that antigens capable of generating a prolonged immune response may be important environmental factors in many cases of this disorder. While existing studies have found single-agent associations of antibodies to food and neurotropic infectious agents with schizophrenia, a simultaneous examination of multiple agents may shed light on agent interactions or possible etiopathogenic pathways.
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Toxoplasma oocysts as a public health problem.
Trends Parasitol.
PUBLISHED: 04-25-2013
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Waterborne outbreaks of Toxoplasma gondii have focused attention on the importance of oocysts shed in the feces of infected cats. Cat feces deposited annually into the environment in the United States total approximately 1.2 million metric tons. The annual oocyst burden measured in community surveys is 3 to 434 oocysts per square foot and is greater in areas where cats selectively defecate. Because a single oocyst can possibly cause infection, this oocyst burden represents a major potential public health problem. The proper disposal of cat litter, keeping cats indoors, reducing the feral cat population, and protecting the play areas of children might potentially reduce the oocyst burden.
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Discordant patterns of bacterial translocation markers and implications for innate immune imbalances in schizophrenia.
Schizophr. Res.
PUBLISHED: 03-08-2013
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The origin of inflammation in psychiatric disorders is not well understood. The translocation of commensal microbiota across the gastrointestinal barrier can result in a persistent state of low-grade immune activation and/or inflammation. We measured serological surrogate markers of bacterial translocation (soluble CD14 (sCD14) and lipopolysaccharide binding protein (LBP)) in two psychiatric cohorts and compared these levels to C-reactive protein (CRP), body mass index (BMI), and food-related and autoimmune antibodies. The two cohorts were composed of the following: (1) n=141 schizophrenia, n=75 bipolar disorder, n=78 controls; (2) n=78 antipsychotic-naïve first-episode schizophrenia, n=38 medicated first-episode schizophrenia. sCD14 seropositivity conferred a 3.1-fold increased odds of association with schizophrenia (multivariate regressions, OR=3.09, p<0.0001) compared to controls. Case-control differences in sCD14 were not matched by LBP. Quantitative levels of LBP, but not sCD14, correlated with BMI in schizophrenia (R(2)=0.21, p<0.0001). sCD14 and LBP also exhibited some congruency in schizophrenia with both significantly correlated with CRP (R(2)=0.26-0.27, p<0.0001) and elevated in females compared to males (p<0.01). Antipsychotic treatment generally did not impact sCD14 or LBP levels except for significant correlations, especially sCD14, with gluten antibodies in antipsychotic-naïve schizophrenia (R(2)=0.27, p<0.0001). In bipolar disorder, sCD14 levels were significantly correlated with anti-tissue transglutaminase IgG (R(2)=0.37, p<0.001). In conclusion, these bacterial translocation markers produced discordant and complex patterns of activity, a finding that may reflect an imbalanced, activated innate immune state. Whereas both markers may upregulate following systemic exposure to Gram-negative bacteria, non-lipopolysaccharide-based monocyte activation, autoimmunity and metabolic dysfunction may also contribute to the observed marker profiles.
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Exposure to herpes simplex virus, type 1 and reduced cognitive function.
J Psychiatr Res
PUBLISHED: 03-07-2013
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Herpes simplex virus, type 1 (HSV-1) causes cold sores, keratitis and rarely, fatal encephalitis. The infection is lifelong, with sensory ganglia serving as reservoirs of latent infection. Recently, exposure to HSV-1 has also been repeatedly associated with reduced cognitive function among healthy individuals without prior encephalitis. Though HSV-1 does not elevate risk for schizophrenia (SZ) per se, exposure is likewise associated with impaired cognitive functions among SZ patients. The range of cognitive changes observed in HSV-1 exposed persons has not been investigated systematically, nor is it known whether interaction between HSV-1 exposure and SZ related factors contributes to the impairment among SZ patients. Persons with or without schizophrenia/schizophreniform disorder (N = 298 total, DSM IV criteria) were assessed for HSV-1 exposure using serum HSV-1 antibody titers. The Penn Computerized Neurocognitive battery was used to assess eight cognitive domains with respect to accuracy and speed. There were no significant case-control differences in HSV-1 exposure. The SZ/schizophreniform disorder cases were significantly impaired in all cognitive domains compared with the controls. HSV-1 exposure was also associated with reduced cognitive function in the entire sample, but the magnitude of the effects and their patterns differed from the SZ related changes. Further, statistically significant interactions between HSV-1 exposure and SZ case status were not detected. HSV-1 exposure does not elevate risk for SZ, but it is associated with reduced function in specific cognitive domains regardless of SZ diagnostic status. An epidiagnostic model for the association is proposed to explain the results.
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Elevated C-reactive protein and cognitive deficits in individuals with bipolar disorder.
J Affect Disord
PUBLISHED: 02-27-2013
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Some individuals with bipolar disorder have cognitive deficits even when euthymic. In previous studies, we found an association between elevated levels of C-reactive protein (CRP), a marker of inflammation, and reduced cognitive functioning in schizophrenia. This issue has not been examined in bipolar disorder.
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Abnormalities of neurotransmitter and neuropeptide systems in human neuroepithelioma cells infected by three Toxoplasma strains.
J Neural Transm
PUBLISHED: 02-22-2013
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Since Toxoplasma gondii can establish a persistent infection in the central nervous system in humans, we studied its effects on a hosts neurotransmitter and neuropeptide systems (NNS). Using microarray technology, we have screened the expression of genes coding for NNS in human neuroepithelioma cells in response to representative strains of Toxoplasma to identify potential target genes. Transcripts that displayed expression levels distinct from uninfected controls were examined by RT-PCR and Western blot. Our results indicate the presence of disturbed NNS upon Toxoplasma infection and the extent of this disturbance varies considerably among the three strains. In cells infected by type I strain, three neurotransmitter systems (dopamine, glutamate and serotonin) and two neuropeptides (PROK2 and TAC1) displayed abnormalities relative to controls. Type III infection led to the change of a critical enzyme, TDO2, in the kynurenine pathway. No significant effects of type II infection were found in the NNS. These data may have implications for understanding the pathogenesis and heterogeneity of neurologic disturbances in toxoplasmosis.
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Antibodies to Toxoplasma gondii in individuals with mania.
Bipolar Disord
PUBLISHED: 02-17-2013
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Increased rates of infection with Toxoplasma gondii have been found in individuals with schizophrenia as compared to control groups but this issue has not been studied in mania.
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HLA associations in schizophrenia: Are we re-discovering the wheel?
Am. J. Med. Genet. B Neuropsychiatr. Genet.
PUBLISHED: 02-15-2013
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Associations between human leukocyte antigen (HLA) polymorphisms on chromosome 6p and schizophrenia (SZ) risk have been evaluated for over five decades. Numerous case-control studies from the candidate gene era analyzed moderately sized samples and reported nominally significant associations with several loci in the HLA region (sample sizes, n?=?100-400). The risk conferred by individual alleles was modest (odds ratios?
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Application of meta-analysis methods for identifying proteomic expression level differences.
Proteomics
PUBLISHED: 01-22-2013
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We present new statistical approaches for identification of proteins with expression levels that are significantly changed when applying meta-analysis to two or more independent experiments. We showed that the Euclidean distance measure has reduced risk of false positives compared to the rank product method. Our ?-ranking method has advantages over the traditional fold-change approach by incorporating both the fold-change direction as well as the p-value. In addition, the second novel method, ?-ranking, considers the ratio of the fold-change and thus integrates all three parameters. We further improved the latter by introducing our third technique, ?-ranking, which combines all three parameters in a balanced nonparametric approach.
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A genome-wide integrative genomic study localizes genetic factors influencing antibodies against Epstein-Barr virus nuclear antigen 1 (EBNA-1).
PLoS Genet.
PUBLISHED: 01-10-2013
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Infection with Epstein-Barr virus (EBV) is highly prevalent worldwide, and it has been associated with infectious mononucleosis and severe diseases including Burkitt lymphoma, Hodgkin lymphoma, nasopharyngeal lymphoma, and lymphoproliferative disorders. Although EBV has been the focus of extensive research, much still remains unknown concerning what makes some individuals more sensitive to infection and to adverse outcomes as a result of infection. Here we use an integrative genomics approach in order to localize genetic factors influencing levels of Epstein Barr virus (EBV) nuclear antigen-1 (EBNA-1) IgG antibodies, as a measure of history of infection with this pathogen, in large Mexican American families. Genome-wide evidence of both significant linkage and association was obtained on chromosome 6 in the human leukocyte antigen (HLA) region and replicated in an independent Mexican American sample of large families (minimum p-value in combined analysis of both datasets is 1.4×10(-15) for SNPs rs477515 and rs2516049). Conditional association analyses indicate the presence of at least two separate loci within MHC class II, and along with lymphocyte expression data suggest genes HLA-DRB1 and HLA-DQB1 as the best candidates. The association signals are specific to EBV and are not found with IgG antibodies to 12 other pathogens examined, and therefore do not simply reveal a general HLA effect. We investigated whether SNPs significantly associated with diseases in which EBV is known or suspected to play a role (namely nasopharyngeal lymphoma, Hodgkin lymphoma, systemic lupus erythematosus, and multiple sclerosis) also show evidence of associated with EBNA-1 antibody levels, finding an overlap only for the HLA locus, but none elsewhere in the genome. The significance of this work is that a major locus related to EBV infection has been identified, which may ultimately reveal the underlying mechanisms by which the immune system regulates infection with this pathogen.
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Elevated gliadin antibody levels in individuals with schizophrenia.
World J. Biol. Psychiatry
PUBLISHED: 01-03-2013
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We aimed to replicate, in a larger sample and in a different geographical location, the previously reported elevation of anti-gliadin IgG antibodies in schizophrenia.
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Cigarette smoking among persons with schizophrenia or bipolar disorder in routine clinical settings, 1999-2011.
Psychiatr Serv
PUBLISHED: 01-03-2013
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This study examined the prevalence of cigarette smoking and the quantity of cigarettes consumed by individuals with schizophrenia or bipolar disorder and by those with no psychiatric disorder in the period 1999-2011.
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A combined marker of inflammation in individuals with mania.
PLoS ONE
PUBLISHED: 01-01-2013
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Markers of immune activation have been associated with mania but have not been examined in combination. We studied the association between mania and an inflammation score based on four immune markers.
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Advances in bipolar disorder: selected sessions from the 2011 International Conference on Bipolar Disorder.
Ann. N. Y. Acad. Sci.
PUBLISHED: 12-24-2011
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Recently, the 9(th) International Conference on Bipolar Disorder (ICBD) took place in Pittsburgh, PA, June 9-11, 2011. The conference focused on a number of important issues concerning the diagnosis of bipolar disorders across the life span, advances in neuroscience, treatment strategies for bipolar disorders, early intervention, and medical comorbidity. Several of these topics were discussed in four plenary sessions. This meeting report describes the major points of each of these sessions and included (1) strategies for moving biology forward; (2) bipolar disorder and the forthcoming new DSM-5 nomenclature; (3) management of bipolar disorders-both theory and intervention, with an emphasis on the medical comorbidities; and, (4) a review of several key task force reports commissioned by the International Society for Bipolar Disorder (ISBD).
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Neonatal antibodies to infectious agents and risk of bipolar disorder: a population-based case-control study.
Bipolar Disord
PUBLISHED: 11-17-2011
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There is a substantial evidence base linking prenatal exposure to infectious agents and an increased risk of schizophrenia. However, there has been less research examining the potential for these exposures to also contribute to risk for bipolar disorder. The aim of this study was to examine the association between neonatal markers of selected prenatal infections and risk for bipolar disorder.
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Establishing the baseline level of repetitive element expression in the human cortex.
BMC Genomics
PUBLISHED: 10-10-2011
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Although nearly half of the human genome is comprised of repetitive sequences, the expression profile of these elements remains largely uncharacterized. Recently developed high throughput sequencing technologies provide us with a powerful new set of tools to study repeat elements. Hence, we performed whole transcriptome sequencing to investigate the expression of repetitive elements in human frontal cortex using postmortem tissue obtained from the Stanley Medical Research Institute.
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Identification of a blood-based biological signature in subjects with psychiatric disorders prior to clinical manifestation.
World J. Biol. Psychiatry
PUBLISHED: 09-22-2011
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To determine whether a molecular signature is present in blood of patients with psychiatric disorders before manifestation of symptoms.
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Additive effects of elevated C-reactive protein and exposure to Herpes Simplex Virus type 1 on cognitive impairment in individuals with schizophrenia.
Schizophr. Res.
PUBLISHED: 07-28-2011
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We investigated the effect of elevated levels of C-reactive protein (CRP) and exposure to Herpes simplex virus type 1 (HSV-1) on the severity of cognitive impairment in individuals with schizophrenia.
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Toxoplasma gondii antibody titers and history of suicide attempts in patients with schizophrenia.
Schizophr. Res.
PUBLISHED: 07-15-2011
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Toxoplasma gondii (T. gondii) a widespread neurotropic parasite, has been previously associated with schizophrenia and more recently with suicidal behavior. However, no previous study has examined the association of T. gondii with suicidal behavior in schizophrenia patients. 950 individuals diagnosed with schizophrenia by SCID were recruited from the Munich area of Germany. Solid-enzyme immunoassay methods were used to measure IgG plasma antibodies to T. gondii, other neurotropic pathogens and gliadin. Logistic regression models were developed to analyze the association of T. gondii seropositivity or serointensity with history of suicidal behavior. In those younger than the median age of the sample, 38, T. gondii serointensity was associated with history of suicidal behavior (p = 0.02), while in the older patients the relationship was not significant (p = 0.21). Seropositivity was also associated with history of suicide attempt in younger patients, odds ratio 1.59 (95% CI 1.06 to 2.40), p = 0.03. Seropositivity for CMV (p = 0.22), HSV-1 (p = 0.36) and gliadin (p = 0.92) was not related to history of suicide attempt in the entire sample or any age subgroup. T. gondii serology might become, with interaction with vulnerability genes, a candidate biomarker for a subgroup of schizophrenia patients prone to attempting suicide.
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Impaired functioning in euthymic patients with bipolar disorder--HSV-1 as a predictor.
Prog. Neuropsychopharmacol. Biol. Psychiatry
PUBLISHED: 07-05-2011
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There is a possible association between infectious agents and psychiatric disorders. Previous studies in the US provided evidence for cognitive impairment correlated with Herpes simplex virus type 1 (HSV-1) infection. For a replication study in Europe we chosed individuals diagnosed with bipolar disorder to analyse the correlation with HSV-1 infection. Antibody prevalence was analyzed by using solid phase immunoassay techniques. Cognitive functioning was tested with the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Form A, the Trail Making Test A&B, and two subtests from the WAIS III: the Letter Number Sequencing Task and the subtest on information. History and psychopathology was assessed using structured interviews and validated rating scales (SCID, HRSD-21, YMRS, PANSS). Additionally, we investigated social functioning and quality of life using self-assessment-scales (SAS, LQLP). Prevalence rates of antibodies against diverse infectious agents did not differ significantly between patients and controls. We found a significant correlation between cognitive impairment in patients with bipolar disorder and the prevalence of antibodies directed against HSV-1. Cognitive functions were significantly impaired including language, attention, and immediate memory. The results of this study confirm previous findings suggesting that HSV-1 affects cognitive functions in patients with bipolar disorder. This may also result in more impaired functioning, less quality of life and difficulties in social adjustment.
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Seroprevalence of 13 common pathogens in a rapidly growing U.S. minority population: Mexican Americans from San Antonio, TX.
BMC Res Notes
PUBLISHED: 06-20-2011
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Infection risks vary among individuals and between populations. Here we present information on the seroprevalence of 13 common infectious agents in a San Antonio-based sample of Mexican Americans. Mexican Americans represent the largest and most rapidly growing minority population in the U.S., and they are also considered a health disparities population.
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Progressive gray matter loss and changes in cognitive functioning associated with exposure to herpes simplex virus 1 in schizophrenia: a longitudinal study.
Am J Psychiatry
PUBLISHED: 06-01-2011
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Longitudinal changes in gray matter volume and cognitive performance were evaluated among individuals exposed to neurotropic herpes simplex virus subtype 1 (HSV1). There is a replicable association of HSV1 exposure with smaller prefrontal volumes and cognitive impairments in schizophrenia.
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Genetic factors influence serological measures of common infections.
Hum. Hered.
PUBLISHED: 04-27-2011
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Antibodies against infectious pathogens provide information on past or present exposure to infectious agents. While host genetic factors are known to affect the immune response, the influence of genetic factors on antibody levels to common infectious agents is largely unknown. Here we test whether antibody levels for 13 common infections are significantly heritable.
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Antibodies to infectious agents and the positive symptom dimension of subclinical psychosis: The TRAILS study.
Schizophr. Res.
PUBLISHED: 02-23-2011
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Infections have been suggested to play a role in the etiology of schizophrenia, but the evidence for this has been inconsistent. Schizophrenia patients have an increased risk of infections as a result of hospitalizations or life style factors. Therefore a study on early subclinical manifestations of psychosis in relation to virus infections is warranted. We examined whether serum antibodies against human Herpes viruses and Toxoplasma gondii were associated with subclinical symptoms of psychosis in adolescents. Data were collected as part of the TRacking Adolescents Individual Lives Survey (TRAILS) cohort, a large prospective cohort of Dutch adolescents. A total of 1176 participants with an available Community Assessment of Psychic Experiences (CAPE) and an available blood sample were included in this analysis. Solid-enzyme immunoassay methods were used to measure the presence of immunoglobulin G (IgG) antibodies in serum to the Herpes virus family and to T. gondii. There was no significant association between serologic evidence of infection with human Herpes viruses or T. gondii and the risk of subclinical positive experience of psychosis. Subjects with a positive serological reaction to Epstein-Barr Virus (EBV) had higher scores on the positive dimension of psychosis measured by CAPE (b=0.03, P=0.02). This significant association was observed in males, but not in females. The current study suggests that there is no significant association between serological evidence of infection to human Herpes viruses and positive subclinical experience of psychosis, whereas there was an association between EBV infection and subclinical psychotic symptoms in boys.
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Markers of gluten sensitivity and celiac disease in bipolar disorder.
Bipolar Disord
PUBLISHED: 02-16-2011
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Increased immune sensitivity to dietary gluten proteins has been reported in schizophrenia but has not been studied in bipolar disorder. In this study, we examine the levels of antibody reactivity to gliadin, deamidated gliadin, and tissue transglutaminase (tTG) in individuals with bipolar disorder and compare these levels to those in individuals who do not have any history of psychiatric disorder.
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Artemisinin reduces the level of antibodies to gliadin in schizophrenia.
Schizophr. Res.
PUBLISHED: 02-11-2011
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To investigate if adjunctive artemisinin, an anti-malarial compound with in vivo activity against Toxoplasma gondii, reduces symptoms or antibodies in schizophrenia.
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Association between bovine casein antibody and new onset schizophrenia among US military personnel.
Schizophr. Res.
PUBLISHED: 02-01-2011
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Schizophrenia is a pervasive neuropsychiatric disorder of uncertain etiology. Multiple studies have documented immune activation in individuals with schizophrenia. One antigen capable of inducing a prolonged immune response is bovine casein derived from ingested milk products. Increased levels of casein antibodies have been found in individuals with schizophrenia after diagnosis. This study was directed at determining the potential association between schizophrenia and pre-illness onset levels of immunoglobulin G (IgG) antibodies to bovine casein. Parallel analyses for casein antibody levels with bipolar disorder were included as comparison. Cases were service members who received medical discharges from the military with a schizophrenia diagnosis from 1992 to 2005. Serum specimens were selected for 855 cases and 1165 matched healthy controls. IgG antibodies to bovine whole-casein were measured by solid phase enzyme-linked immunosorbent assays (ELISAs). Hazard ratios (HR) were calculated to examine the associations of casein IgG level with risk of schizophrenia by time to diagnosis and by subjects initial level. Increasing casein IgG antibody levels among those with a high initial level, drawn before diagnosis, was associated with an 18% increase in the hazard risk of schizophrenia per unit increase (value of low-positive standard) in IgG antibody levels (HR=1.18; 95% CI 1.04, 1.34). This is the first report to identify an association between the risk of schizophrenia and elevated antibodies to bovine casein prior to disease onset. Additional research is required to elucidate the complex genetic environmental interactions involved in the pathogenesis of schizophrenia and to identify potentially modifiable risk factors.
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Association of GRIN1 and GRIN2A-D with schizophrenia and genetic interaction with maternal herpes simplex virus-2 infection affecting disease risk.
Am. J. Med. Genet. B Neuropsychiatr. Genet.
PUBLISHED: 01-27-2011
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N-methyl-D-aspartate (NMDA) receptors are very important for proper brain development and several lines of evidence support that hypofunction of the NMDA receptors are involved in the pathophysiology of schizophrenia. Gene variation and gene-environmental interactions involving the genes encoding the NMDA receptors are therefore likely to influence the risk of schizophrenia. The aim of this study was to determine (1) whether SNP variation in the genes (GRIN1, GRIN2A, GRIN2B, GRIN2C, and GRIN2D) encoding the NMDA receptor were associated with schizophrenia; (2) whether GRIN gene variation in the offspring interacted with maternal herpes simplex virus-2 (HSV-2) seropositivity during pregnancy influencing the risk of schizophrenia later in life. Individuals from three independently collected Danish case control samples were genotyped for 81 tagSNPs (in total 984 individuals diagnosed with schizophrenia and 1,500 control persons) and antibodies against maternal HSV-2 infection were measured in one of the samples (365 cases and 365 controls). Nine SNPs out of 30 in GRIN2B were significantly associated with schizophrenia. One SNP remained significant after Bonferroni correction (rs1806194, P(nominal) ?= 0.0008). Significant interaction between maternal HSV-2 seropositivity and GRIN2B genetic variation in the offspring were observed for seven SNPs and two remained significant after Bonferroni correction (rs1805539, P(nominal) ?= 0.0001 and rs1806205, P(nominal) ?= 0.0008). The significant associations and interactions were located at the 3 region of GRIN2B suggesting that genetic variation in this part of the gene may be involved in the pathophysiology of schizophrenia.
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Serological evidence of exposure to Herpes Simplex Virus type 1 is associated with cognitive deficits in the CATIE schizophrenia sample.
Schizophr. Res.
PUBLISHED: 01-25-2011
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Cognitive impairment is a core feature of schizophrenia. Previous studies have indicated that exposure to neurotropic infectious agents such as Herpes Simplex Virus type 1 may contribute to cognitive deficits and neuroanatomical abnormalities in individuals with schizophrenia. We examined the association between exposure to neurotropic infectious agents and cognitive function in 1308 participants in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) trial. This sample included all of the individuals in the CATIE trial for whom baseline blood samples were available. Cognition was evaluated at baseline by a test battery which yielded composite scores in the domains of processing speed, verbal memory, vigilance, reasoning, and working memory as well as a summary neurocognitive score. Solid phase immunoassay techniques were used to measure IgG class antibodies to Herpes Simplex Virus type 1 (HSV-1), Herpes Simplex Virus type 2 (HSV-2), Cytomegalovirus (CMV), and to Toxoplasma gondii (T gondii) in the sera of the study individuals. We found a significant association between the neurocognitive summary score and antibodies to HSV-1 but not to HSV-2, CMV, or T. gondii. There was also a significant association between HSV-1 exposure and the Verbal Memory, Vigilance, and Processing Speed composite scores. HSV-1 may modulate the neurocognitive function of individuals with schizophrenia through its ability to establish latency in the central nervous system and undergo periodic reactivation. A better understanding of the role of HSV-1 may lead to better methods of treatment for the cognitive impairments associated with schizophrenia.
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A systematic evaluation of expression of HERV-W elements; influence of genomic context, viral structure and orientation.
BMC Genomics
PUBLISHED: 01-12-2011
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One member of the W family of human endogenous retroviruses (HERV) appears to have been functionally adopted by the human host. Nevertheless, a highly diversified and regulated transcription from a range of HERV-W elements has been observed in human tissues and cells. Aberrant expression of members of this family has also been associated with human disease such as multiple sclerosis (MS) and schizophrenia. It is not known whether this broad expression of HERV-W elements represents transcriptional leakage or specific transcription initiated from the retroviral promoter in the long terminal repeat (LTR) region. Therefore, potential influences of genomic context, structure and orientation on the expression levels of individual HERV-W elements in normal human tissues were systematically investigated.
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No difference in antibody titers against xenotropic MLV related virus in prostate cancer cases and cancer-free controls.
Mol. Cell. Probes
PUBLISHED: 01-11-2011
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New ELISA assays were developed to measure immunoreactivity for XMRV. Antibody titers were measured in a cohort of prostate cancer cases and cancer free controls from the central United States. No statistically significant differences were observed in immunoreactivity between cases and controls for either the XMRV-env or the XMRV-gag antigen.
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Dietary antigens, epitope recognition, and immune complex formation in recent onset psychosis and long-term schizophrenia.
Schizophr. Res.
PUBLISHED: 01-06-2011
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Peptides derived from dietary antigens such as bovine milk caseins are opioid receptor ligands and contribute to schizophrenia-associated hyperpeptidemia and hyperpeptiduria. The IgG antibody response to bovine caseins is increased in schizophrenia and recent onset psychosis. To identify specific casein peptide sequences that are antigenic in patients vs controls, we measured serum IgG binding to 10-26 amino acid long linear epitopes of casein with immunoassays for the entire group (n=95 recent onset psychosis; n=103 long-term schizophrenia; n=65 control), and with peptide microarray libraries in a casein-sensitive subset (n=14 recent onset; n=10 control). In the entire group, we compared anti-casein peptide IgG vs anti-whole casein IgG and evaluated whether peptide immune complexes contributed to IgG binding results. Anti-whole casein IgG levels correlated with anti-casein peptide IgG in controls only (R2=0.17-0.25, p?0.002-0.03). In recent onset psychosis, IgG binding to linear peptide sequences was significantly decreased 3.8-5.7-fold compared to controls in immunoassays (OR 0.18-0.26, p?0.0001-0.001). In peptide microarrays, recent onset patients again showed significantly reduced IgG binding and fewer epitopes than controls (p?0.00001-0.05). Anti-peptide IgG levels did not differ between patients with long-term schizophrenia and controls. Finally, significantly more recent onset individuals had casein peptide-IgG immune complexes than controls (OR 4.96, p?0.001). These findings suggest an immunological specificity that differs in early vs later stages of neuropsychiatric diseases and an IgG saturation by casein-derived peptides that may in part explain the reduced IgG binding to small linear epitopes observed in these patients.
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Prenatal depression and anxiety in Toxoplasma gondii-positive women.
Am. J. Obstet. Gynecol.
PUBLISHED: 01-03-2011
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This study analyzed a relationship between prenatal mood states and serologic evidence of immune response to Toxoplasma gondii. A secondary aim was to determine whether thyroid peroxidase autoantibody status was related to T gondii status.
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Immune activation by casein dietary antigens in bipolar disorder.
Bipolar Disord
PUBLISHED: 12-24-2010
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? Inflammation and other immune processes are increasingly linked to psychiatric diseases. Antigenic triggers specific to bipolar disorder are not yet defined. We tested whether antibodies to bovine milk caseins were associated with bipolar disorder, and whether patients recognized different epitopes of the casein protein than control individuals.
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Differential effects of three canonical Toxoplasma strains on gene expression in human neuroepithelial cells.
Infect. Immun.
PUBLISHED: 12-13-2010
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Strain type is one of the key factors suspected to play a role in determining the outcome of Toxoplasma infection. In this study, we examined the transcriptional profile of human neuroepithelioma cells in response to representative strains of Toxoplasma by using microarray analysis to characterize the strain-specific host cell response. The study of neural cells is of interest in light of the ability of Toxoplasma to infect the brain and to establish persistent infection within the central nervous system. We found that the extents of the expression changes varied considerably among the three strains. Neuroepithelial cells infected with Toxoplasma type I exhibited the highest level of differential gene expression, whereas type II-infected cells had a substantially smaller number of genes which were differentially expressed. Cells infected with type III exhibited intermediate effects on gene expression. The three strains also differed in the individual genes and gene pathways which were altered following cellular infection. For example, gene ontology (GO) analysis indicated that type I infection largely affects genes related to the central nervous system, while type III infection largely alters genes which affect nucleotide metabolism; type II infection does not alter the expression of a clearly defined set of genes. Moreover, Ingenuity Pathways Analysis (IPA) suggests that the three lineages differ in the ability to manipulate their host; e.g., they employ different strategies to avoid, deflect, or subvert host defense mechanisms. These observed differences may explain some of the variation in the neurobiological effects of different strains of Toxoplasma on infected individuals.
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Toxoplasma gondii strain-dependent effects on mouse behaviour.
Folia Parasitol.
PUBLISHED: 07-09-2010
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Toxoplasma gondii reportedly manipulates rodent behaviour to increase transmission to its definitive feline host. We compared the effects of mouse infection by two Type II strains of T. gondii, Prugniaud (PRU) and ME49, on attraction to cat odour, locomotor activity, anxiety, sensorimotor gating, and spatial working and recognition memory 2 months post-infection (mpi). Attraction to cat odour was reassessed 7 mpi. At 2 mpi, mice infected with either strain exhibited significantly more attraction to cat odour than uninfected animals did, but only PRU-infected mice exhibited this behaviour 7 mpi. PRU-infected mice had significantly greater body weights and hyperactivity, while ME49-infected mice exhibited impaired spatial working memory. No differences in parasite antibody titres were seen between PRU- and ME49-infected mice. The present data suggest the effect of T. gondii infection on mouse behaviour is parasite strain-dependent.
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A Danish National Birth Cohort study of maternal HSV-2 antibodies as a risk factor for schizophrenia in their offspring.
Schizophr. Res.
PUBLISHED: 05-26-2010
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Several studies have implicated early infections, including maternal infection with herpes simplex virus 2 (HSV-2), as an environmental risk factor for schizophrenia.
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Validation of a blood-based laboratory test to aid in the confirmation of a diagnosis of schizophrenia.
Biomark Insights
PUBLISHED: 05-12-2010
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We describe the validation of a serum-based test developed by Rules-Based Medicine which can be used to help confirm the diagnosis of schizophrenia. In preliminary studies using multiplex immunoassay profiling technology, we identified a disease signature comprised of 51 analytes which could distinguish schizophrenia (n = 250) from control (n = 230) subjects. In the next stage, these analytes were developed as a refined 51-plex immunoassay panel for validation using a large independent cohort of schizophrenia (n = 577) and control (n = 229) subjects. The resulting test yielded an overall sensitivity of 83% and specificity of 83% with a receiver operating characteristic area under the curve (ROC-AUC) of 89%. These 51 immunoassays and the associated decision rule delivered a sensitive and specific prediction for the presence of schizophrenia in patients compared to matched healthy controls.
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Neonatally measured immunoglobulins and risk of autism.
Autism Res
PUBLISHED: 04-11-2010
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Previous studies indicate that prenatal exposure to infections is a possible pathway through which autism spectrum disorders (ASD) could be initiated. We investigated whether immunoglobulin levels in archived specimens obtained from newborns subsequently diagnosed with ASD are different from levels in newborn specimens from controls. Children with ASD born in six California counties in 1994 were ascertained through records of the California Department of Developmental Services (DDS) and Kaiser Permanente; controls were randomly selected using birth certificates. Archived newborn blood specimens were obtained from the California Genetic Disease Screening Program (GDSP) for N = 213 cases and N = 265 controls and assayed to determine levels of total IgG, antigen-specific IgG to selected common pathogens, total IgM, total IgA, and C-reactive protein (CRP). We did not find measurable levels of total IgM or IgA in any neonate and measurable CRP was present in only a few. No antigen-specific IgG antibodies were elevated in cases compared to controls and total IgG levels were lower. In adjusted models, a 10-unit increase in total IgG yielded an OR = 0.72 (95% CI 0.56, 0.91); a significantly decreasing trend in risk of ASD was observed across increasing exposure quartiles of total IgG (P = 0.01). The finding of lower IgG in cases may indicate maternal immune dysfunction during gestation and/or impaired transplacental transfer of immunoglobulins. Further investigation of IgG levels in newborns and the mechanisms by which they might be associated with ASD are warranted.
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Thiazole, oxadiazole, and carboxamide derivatives of artemisinin are highly selective and potent inhibitors of Toxoplasma gondii.
J. Med. Chem.
PUBLISHED: 04-09-2010
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We have prepared 23 new dehydroartemisinin (DART) trioxane derivatives (11 thiazoles, 2 oxadiazoles, and 10 carboxamides) and have screened them for in vitro activity in the Toxoplasma lytic cycle. Fifteen (65%) of the derivatives were noncytotoxic to host cells (TD(50) > or = 320 microM). Eight thiazole derivatives and two carboxamide derivatives displayed effective inhibition of Toxoplasma growth (IC(50) = 0.25-0.42 microM), comparable in potency to artemether (IC(50) = 0.31 microM) and >100 times more inhibitory than the currently employed front-line drug trimethoprim (IC(50) = 46 microM). The thiazoles as a group were more effective than the other derivatives at inhibiting growth of extracellular as well as intracellular parasites. Unexpectedly, two thiazole trioxanes (5 and 6) were parasiticidal; both inhibited parasite replication irreversibly after parasite exposure to 10 microM of drug for 24 h, whereas the standard trioxane drugs artemisinin and artemether were not parasiticidal. Some of the new derivatives of artemisinin described here represent effective anti-Toxoplasma trioxanes as well as molecular probes for elucidating the mechanism of action of the DART class of artemisinin derivatives.
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Association of seropositivity for influenza and coronaviruses with history of mood disorders and suicide attempts.
J Affect Disord
PUBLISHED: 03-23-2010
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Anecdotal reports of mood disorder following infection with common respiratory viruses with neurotropic potential have been in existence since the last century. Nevertheless, systematic studies on the association between these viruses and mood disorders are lacking.
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Markers of gluten sensitivity and celiac disease in recent-onset psychosis and multi-episode schizophrenia.
Biol. Psychiatry
PUBLISHED: 01-15-2010
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Increased immune sensitivity to gluten has been reported in schizophrenia. However, studies are inconsistent about this association.
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Neuroanatomic and cognitive abnormalities related to herpes simplex virus type 1 in schizophrenia.
Schizophr. Res.
PUBLISHED: 01-14-2010
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Herpes simplex virus 1 (HSV-1) tends to replicate in the temporal cortex and can damage the limbic system. The presence of serum antibodies to HSV-1 is associated with cognitive impairment in adults with schizophrenia, suggesting that cerebral gray matter abnormalities might distinguish patient subgroups defined by HSV-1 exposure. We assessed 43 adult outpatients with schizophrenia. The assessment included clinical interviews, neurocognitive testing, anatomic brain magnetic resonance imaging and measures of serum IgG antibodies specific to herpes simplex viruses 1 and 2. We then compared 25 patients who tested positive for antibodies to HSV-1 with 15 who were seronegative for both HSV-1 and HSV-2. The seropositive patients performed significantly worse than the seronegative patients on four neuropsychological measures of psychomotor speed, executive functioning, and explicit verbal memory. Voxel-based morphometric analyses revealed that the same patients showed reduced gray matter volume in the anterior cingulate and areas of the cerebellum. Finally, performance on the test of psychomotor speed and executive functioning that showed the largest between- group effect size correlated with reduced gray matter volume in some of the same brain regions (cingulate and cerebellum) that distinguished the two HSV-1 subgroups. In these outpatients with schizophrenia, HSV-1 seropositivity and performance on a cognitive test that is highly sensitive to it co-localize to closely overlapping brain regions.
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Subunit and whole molecule specificity of the anti-bovine casein immune response in recent onset psychosis and schizophrenia.
Schizophr. Res.
PUBLISHED: 01-13-2010
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Previous studies show increased antibody levels to bovine casein in some individuals with schizophrenia. The immunogenicity of specific domains of bovine casein varies among people with milk sensitivities and thus could vary among different neuropsychiatric disorders. Using ELISAs and immunoblotting, we characterized IgG class antibody specificity to whole bovine casein and to the alpha(s), beta, and kappa subunits in individuals with recent onset psychosis (n=95), long-term schizophrenia (n=103), and non-psychiatric controls (n=65). In both patient groups, we found elevated IgG to casein proteins, particularly to whole casein and the alpha(s) subunit (p
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Grey matter changes associated with host genetic variation and exposure to Herpes Simplex Virus 1 (HSV1) in first episode schizophrenia.
Schizophr. Res.
PUBLISHED: 01-04-2010
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We previously reported reduced prefrontal cortex (PFC) grey matter volume among first episode, antipsychotic-naïve schizophrenia subjects (SZ) exposed to HSV1 but not among healthy subjects (HS) (Prasad et al., 2007). Independently, rs1051788, an exonic polymorphism of the MHC Class I polypeptide-related sequence B (MICB) gene was associated with HSV1 seropositivity, as well as SZ risk. In this study, we examined whether PFC grey matter changes associated with HSV1 exposure varied against the background of MICB genotypes.
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Antibodies to measles in individuals with recent onset psychosis.
Schizophr. Res.
PUBLISHED: 01-03-2010
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Measles virus is a highly prevalent neurotropic virus capable of causing persistent infections within the central nervous system.
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JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

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In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.