Emissions from corrosion protection systems of offshore wind farms: Evaluation of the potential impact on the marine environment.

Offshore wind energy is a fast growing sector of renewable energies worldwide. This will change the marine environment and thus, a wide range of environmental impacts of offshore wind farms are subject of current research. Here we present an overview about chemical emissions from corrosion protection systems, discuss their relevance and potential impact to the marine environment, and suggest strategies to reduce their emissions. Corrosion is a general problem for offshore infrastructures and corrosion protection systems are necessary to maintain the structural integrity. These systems are often in direct contact with seawater and have different potentials for emissions, e.g. galvanic anodes emitting substantial amounts of metals. Organic coatings may release organic substances due to weathering and/or leaching. Current assumptions suggesting a low environmental impact, but monitoring data is not sufficient to assess the environmental impact of this new source.

Prenatal fever and autism risk.

Some studies suggest that prenatal infection increases risk of autism spectrum disorders (ASDs). This study was undertaken in a prospective cohort in Norway to examine whether we could find evidence to support an association of the prenatal occurrence of fever, a common manifestation of infection, with ASD risk. Prospective questionnaires provided maternal exposure data; case status was established from clinical assessments and registry linkages. In a large, prospectively ascertained cohort of pregnant mothers and their offspring, we examined infants born ⩾32 weeks for associations between fever exposure in each trimester and ASD risk using logistic regression. Maternal exposure to second-trimester fever was associated with increased ASD risk, adjusting for presence of fever in other trimesters and confounders (adjusted odds ratio (aOR), 1.40; 95% confidence interval, 1.09-1.79), with a similar, but nonsignificant, point estimate in the first trimester. Risk increased markedly with exposure to three or more fever episodes after 12 weeks' gestation (aOR, 3.12; 1.28-7.63). ASD risk appears to increase with maternal fever, particularly in the second trimester. Risk magnified dose dependently with exposure to multiple fevers after 12 weeks' gestation. Our findings support a role for gestational maternal infection and innate immune responses to infection in the pathogenesis of at least some cases of ASD.

Immune network analysis of cerebrospinal fluid in myalgic encephalomyelitis/chronic fatigue syndrome with atypical and classical presentations.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a persistent and debilitating disorder marked by cognitive and sensory dysfunction and unexplained physical fatigue. Classically, cases present after a prodrome consistent with infection; however, some cases are atypical and have a different presentation and comorbidities that pose challenges for differential diagnosis. We analyzed cerebrospinal fluid (CSF) from 32 cases with classical ME/CFS and 27 cases with atypical ME/CFS using a 51-plex cytokine assay. Atypical subjects differed in cytokine profiles from classical subjects. In logistic regression models incorporating immune molecules that were identified as potential predictor variables through feature selection, we found strong associations between the atypical ME/CFS phenotype and lower CSF levels of the inflammatory mediators, interleukin 17A and CXCL9. Network analysis revealed an absence of inverse inter-cytokine relationships in CSF from atypical patients, and more sparse positive intercorrelations, than classical subjects. Interleukin 1 receptor antagonist appeared to be a negative regulator in classical ME/CFS, with patterns suggestive of disturbances in interleukin 1 signaling and autoimmunity-type patterns of immune activation. Immune signatures in the central nervous system of ME/CFS patients with atypical features may be distinct from those with more typical clinical presentations.

Prenatal immune programming of the sex-dependent risk for major depression.

Maternal immune functioning during pregnancy contributes to sex-dependent deficits in neurodevelopment and to behaviors associated with affective traits in preclinical studies, and has been indirectly associated with offspring depression in epidemiologic studies. We therefore investigated the association between immune activity during pregnancy and the risk of depression among male and female offspring. We conducted a case-control study of depression (n=484 cases and n=774 controls) using data from the New England Family Study, a pregnancy cohort enrolled between 1959 and 1966 that assessed psychiatric outcomes in adult offspring (mean age=39.7 years). We assayed concentrations of three pro-inflammatory cytokines, interleukin (IL)-1ß, IL-6 and tumor necrosis factor (TNF)-α, and the anti-inflammatory cytokine, IL-10, in maternal serum collected at the end of the second and beginning of the third trimesters. High maternal TNF-α was associated with reduced odds of depression among both male and female offspring (odds ratio (OR)=0.68; confidence interval (CI)=0.48, 0.98). However, when considering the TNF-α to IL-10 ratio, a measure of the ratio of pro- to anti-inflammatory loading, maternal immune effects on offspring depression differed significantly by sex (χ(2)=13.9, degrees of freedom=4, P=0.008). Among females, higher maternal TNF-α:IL-10 was associated with reduced odds of depression (OR=0.51; CI=0.32, 0.81), whereas, among males, high maternal TNF-α:IL-10 was associated with elevated odds of depression (OR=1.86; CI=1.02, 3.39). Thus, the balance between TNF-α and IL-10 in maternal prenatal serum was associated with depression in a sex-dependent manner. These findings are consistent with the role of TNF-α in the maturation of the sexually dimorphic fetal brain circuitry that regulates stress and affective responses, and support a prenatal stress-immune model of depression pathogenesis.

ViPAR: a software platform for the Virtual Pooling and Analysis of Research Data.

BACKGROUND: Research studies exploring the determinants of disease require sufficient statistical power to detect meaningful effects. Sample size is often increased through centralized pooling of disparately located datasets, though ethical, privacy and data ownership issues can often hamper this process. Methods that facilitate the sharing of research data that are sympathetic with these issues and which allow flexible and detailed statistical analyses are therefore in critical need. We have created a software platform for the Virtual Pooling and Analysis of Research data (ViPAR), which employs free and open source methods to provide researchers with a web-based platform to analyse datasets housed in disparate locations. METHODS: Database federation permits controlled access to remotely located datasets from a central location. The Secure Shell protocol allows data to be securely exchanged between devices over an insecure network. ViPAR combines these free technologies into a solution that facilitates 'virtual pooling' where data can be temporarily pooled into computer memory and made available for analysis without the need for permanent central storage. RESULTS: Within the ViPAR infrastructure, remote sites manage their own harmonized research dataset in a database hosted at their site, while a central server hosts the data federation component and a secure analysis portal. When an analysis is initiated, requested data are retrieved from each remote site and virtually pooled at the central site. The data are then analysed by statistical software and, on completion, results of the analysis are returned to the user and the virtually pooled data are removed from memory. CONCLUSIONS: ViPAR is a secure, flexible and powerful analysis platform built on open source technology that is currently in use by large international consortia, and is made publicly available at [http://bioinformatics.childhealthresearch.org.au/software/vipar/].

Cytokine network analysis of cerebrospinal fluid in myalgic encephalomyelitis/chronic fatigue syndrome.

Myalgic encephalomyelitis/chronic fatigue syndrome is an unexplained debilitating disorder that is frequently associated with cognitive and motor dysfunction. We analyzed cerebrospinal fluid from 32 cases, 40 subjects with multiple sclerosis and 19 normal subjects frequency-matched for age and sex using a 51-plex cytokine assay. Group-specific differences were found for the majority of analytes with an increase in cases of CCL11 (eotaxin), a chemokine involved in eosinophil recruitment. Network analysis revealed an inverse relationship between interleukin 1 receptor antagonist and colony-stimulating factor 1, colony-stimulating factor 2 and interleukin 17F, without effects on interleukin 1α or interleukin 1ß, suggesting a disturbance in interleukin 1 signaling. Our results indicate a markedly disturbed immune signature in the cerebrospinal fluid of cases that is consistent with immune activation in the central nervous system, and a shift toward an allergic or T helper type-2 pattern associated with autoimmunity.

Autism risk associated with parental age and with increasing difference in age between the parents.

Advancing paternal and maternal age have both been associated with risk for autism spectrum disorders (ASD). However, the shape of the association remains unclear, and results on the joint associations is lacking. This study tests if advancing paternal and maternal ages are independently associated with ASD risk and estimates the functional form of the associations. In a population-based cohort study from five countries (Denmark, Israel, Norway, Sweden and Western Australia) comprising 5 766 794 children born 1985-2004 and followed up to the end of 2004-2009, the relative risk (RR) of ASD was estimated by using logistic regression and splines. Our analyses included 30 902 cases of ASD. Advancing paternal and maternal age were each associated with increased RR of ASD after adjusting for confounding and the other parent's age (mothers 40-49 years vs 20-29 years, RR=1.15 (95% confidence interval (CI): 1.06-1.24), P-value<0.001; fathers⩾50 years vs 20-29 years, RR=1.66 (95% CI: 1.49-1.85), P-value<0.001). Younger maternal age was also associated with increased risk for ASD (mothers <20 years vs 20-29 years, RR=1.18 (95% CI: 1.08-1.29), P-value<0.001). There was a joint effect of maternal and paternal age with increasing risk of ASD for couples with increasing differences in parental ages. We did not find any support for a modifying effect by the sex of the offspring. In conclusion, as shown in multiple geographic regions, increases in ASD was not only limited to advancing paternal or maternal age alone but also to differences parental age including younger or older similarly aged parents as well as disparately aged parents.

Prenatal maternal immune disruption and sex-dependent risk for psychoses.

BACKGROUND: Previous studies suggest that abnormalities in maternal immune activity during pregnancy alter the offspring's brain development and are associated with increased risk for schizophrenia (SCZ) dependent on sex. METHOD: Using a nested case-control design and prospectively collected prenatal maternal sera from which interleukin (IL)-1ß, IL-8, IL-6, tumor necrosis factor (TNF)-α and IL-10 were assayed, we investigated sex-dependent associations between these cytokines and 88 psychotic cases [SCZ = 44; affective psychoses (AP) = 44] and 100 healthy controls from a pregnancy cohort followed for > 40 years. Analyses included sex-stratified non-parametric tests adjusted for multiple comparisons to screen cytokines associated with SCZ risk, followed by deviant subgroup analyses using generalized estimating equation (GEE) models. RESULTS: There were higher prenatal IL-6 levels among male SCZ than male controls, and lower TNF-α levels among female SCZ than female controls. The results were supported by deviant subgroup analyses with significantly more SCZ males with high IL-6 levels (>highest quartile) compared with controls [odd ratio (OR)75 = 3.33, 95% confidence interval (CI) 1.13-9.82], and greater prevalence of low TNF-α levels (

Absence of evidence for bornavirus infection in schizophrenia, bipolar disorder and major depressive disorder.

In 1983, reports of antibodies in subjects with major depressive disorder (MDD) to an as-yet uncharacterized infectious agent associated with meningoencephalitis in horses and sheep led to molecular cloning of the genome of a novel, negative-stranded neurotropic virus, Borna disease virus (BDV). This advance has enabled the development of new diagnostic assays, including in situ hybridization, PCR and serology based on recombinant proteins. Since these assays were first implemented in 1990, more than 80 studies have reported an association between BDV and a wide range of human illnesses that include MDD, bipolar disorder (BD), schizophrenia (SZ), anxiety disorder, chronic fatigue syndrome, multiple sclerosis, amyotrophic lateral sclerosis, dementia and glioblastoma multiforme. However, to date there has been no blinded case-control study of the epidemiology of BDV infection. Here, in a United States-based, multi-center, yoked case-control study with standardized methods for clinical assessment and blinded serological and molecular analysis, we report the absence of association of psychiatric illness with antibodies to BDV or with BDV nucleic acids in serially collected serum and white blood cell samples from 396 subjects, a study population comprised of 198 matched pairs of patients and healthy controls (52 SZ/control pairs, 66 BD/control pairs and 80 MDD/control pairs). Our results argue strongly against a role for BDV in the pathogenesis of these psychiatric disorders.

Sex-specific impact of maternal-fetal risk factors on depression and cardiovascular risk 40 years later.

Major depressive disorder (MDD) and cardiovascular disease (CVD) represent leading causes of morbidity and mortality worldwide. We tested the hypothesis that growth restriction and preeclampsia (referred to as fetal risk) are significant predictors of these conditions, with women at higher risk in adulthood. Adult offspring exposed to fetal risk factors and their discordant siblings were from two prenatal cohorts, whose mothers were followed through pregnancy and whom we recruited as adults 40 years later (n = 538; 250 males and 288 females). Subjects were psychiatrically diagnosed and underwent a stress challenge during which parasympathetic regulation was assessed by electrocardiogram, operationalized as high-frequency R-R interval variability (HF-RRV). Linear mixed models and generalized estimating equations were used to examine the relationship of fetal risk on HF-RRV, MDD and comorbidity of low HF-RRV (lowest 25th percentile) and MDD, including interactions with sex and socioeconomic status (SES). Fetal risk was significantly associated with low HF-RRV response (F = 3.64, P = 0.05), particularly among low SES (interaction: F = 4.31, P < 0.04). When stratified by MDD, the fetal risk impact was three times greater among MDD compared with non-MDD subjects (effect size: 0.21 v. 0.06). Females had a significantly higher risk for the comorbidity of MDD and low HF-RRV than males (relative risk (RR) = 1.36, 95% CI: 1.07-1.73), an association only seen among those exposed to fetal risk (RR = 1.38, 95% CI: 1.04-1.83). Findings suggest that these are shared fetal antecedents to the comorbidity of MDD and CVD risk 40 years later, an association stronger in females than in males.

The Autism Birth Cohort: a paradigm for gene-environment-timing research.

The reported prevalence of autism spectrum disorders (ASDs) has increased by 5- to 10-fold over the past 20 years. Whether ASDs are truly more frequent is controversial; nonetheless, the burden is profound in human and economic terms. Although autism is among the most heritable of mental disorders, its pathogenesis remains obscure. Environmental factors are proposed; however, none is implicated. Furthermore, there are no biomarkers to screen for ASD or risk of ASD. The Autism Birth Cohort (ABC) was initiated to analyze gene x environment x timing interactions and enable early diagnosis. It uses a large, unselected birth cohort in which cases are prospectively ascertained through population screening. Samples collected serially through pregnancy and childhood include parental blood, maternal urine, cord blood, milk teeth and rectal swabs. More than 107,000 children are continuously screened through questionnaires, referral, and a national registry. Cases are compared with a control group from the same cohort in a 'nested case-control' design. Early screening and diagnostic assessments and re-assessments are designed to provide a rich view of longitudinal trajectory. Genetic, proteomic, immunologic, metagenomic and microbiological tools will be used to exploit unique biological samples. The ABC is a paradigm for analyzing the role of genetic and environmental factors in complex disorders.

Passive transfer of streptococcus-induced antibodies reproduces behavioral disturbances in a mouse model of pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection.

Streptococcal infections can induce obsessive-compulsive and tic disorders. In children, this syndrome, frequently associated with disturbances in attention, learning and mood, has been designated pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS). Autoantibodies recognizing central nervous system (CNS) epitopes are found in sera of most PANDAS subjects, but may not be unique to this neuropsychiatric subset. In support of a humoral immune mechanism, clinical improvement often follows plasmapheresis or intravenous immunoglobulin. We recently described a PANDAS mouse model wherein repetitive behaviors correlate with peripheral anti-CNS antibodies and immune deposits in brain following streptococcal immunization. These antibodies are directed against group A beta-hemolytic streptococcus matrix (M) protein and cross-react with molecular targets complement C4 protein and alpha-2-macroglobulin in brain. Here we show additional deficits in motor coordination, learning/memory and social interaction in PANDAS mice, replicating more complex aspects of human disease. Furthermore, we demonstrate for the first time that humoral immunity is necessary and sufficient to induce the syndrome through experiments wherein naive mice are transfused with immunoglobulin G (IgG) from PANDAS mice. Depletion of IgG from donor sera abrogates behavior changes. These functional disturbances link to the autoimmunity-related IgG1 subclass but are not attributable to differences in cytokine profiles. The mode of disrupting blood-brain barrier integrity differentially affects the ultimate CNS distribution of these antibodies and is shown to be an additional important determinant of neuropsychiatric outcomes. This work provides insights into PANDAS pathogenesis and may lead to new strategies for identification and treatment of children at risk for autoimmune brain disorders.

The molecular mechanism of the inhibition by licofelone of the biosynthesis of 5-lipoxygenase products.

BACKGROUND AND PURPOSE: Licofelone is a dual inhibitor of the cyclooxygenase and 5-lipoxygenase (5-LO) pathway, and has been developed for the treatment of inflammatory diseases. Here, we investigated the molecular mechanisms underlying the inhibition by licofelone of the formation of 5-LO products. EXPERIMENTAL APPROACH: The efficacy of licofelone to inhibit the formation of 5-LO products was analysed in human isolated polymorphonuclear leukocytes (PMNL) or transfected HeLa cells, as well as in cell-free assays using respective cell homogenates or purified recombinant 5-LO. Moreover, the effects of licofelone on the subcellular redistribution of 5-LO were studied. KEY RESULTS: Licofelone potently blocked synthesis of 5-LO products in Ca(2+)-ionophore-activated PMNL (IC(50)=1.7 microM) but was a weak inhibitor of 5-LO activity in cell-free assays (IC(50)>>10 microM). The structures of licofelone and MK-886, an inhibitor of the 5-LO-activating protein (FLAP), were superimposable. The potencies of both licofelone and MK-886 in ionophore-activated PMNL were impaired upon increasing the concentration of arachidonic acid, or under conditions where 5-LO product formation was evoked by genotoxic, oxidative or hyperosmotic stress. Furthermore, licofelone prevented nuclear redistribution of 5-LO in ionophore-activated PMNL, as had been observed for FLAP inhibitors. Finally, licofelone as well as MK-886 caused only moderate inhibition of the synthesis of 5-LO products in HeLa cells, unless FLAP was co-transfected. CONCLUSIONS AND IMPLICATIONS: Our data suggest that the potent inhibition of the biosynthesis of 5-LO products by licofelone requires an intact cellular environment and appears to be due to interference with FLAP.

Neurotoxic effects of postnatal thimerosal are mouse strain dependent.

The developing brain is uniquely susceptible to the neurotoxic hazard posed by mercurials. Host differences in maturation, metabolism, nutrition, sex, and autoimmunity influence outcomes. How population-based variability affects the safety of the ethylmercury-containing vaccine preservative, thimerosal, is unknown. Reported increases in the prevalence of autism, a highly heritable neuropsychiatric condition, are intensifying public focus on environmental exposures such as thimerosal. Immune profiles and family history in autism are frequently consistent with autoimmunity. We hypothesized that autoimmune propensity influences outcomes in mice following thimerosal challenges that mimic routine childhood immunizations. Autoimmune disease-sensitive SJL/J mice showed growth delay; reduced locomotion; exaggerated response to novelty; and densely packed, hyperchromic hippocampal neurons with altered glutamate receptors and transporters. Strains resistant to autoimmunity, C57BL/6J and BALB/cJ, were not susceptible. These findings implicate genetic influences and provide a model for investigating thimerosal-related neurotoxicity.

Trans-placental exposure of neonates to acrylamide--a pilot study.

OBJECTIVES: Acrylamide (AA) (CAS No 79-06-1) has most recently been identified as a food-borne toxicant generated during the heating process of starch-containing foods. It was the aim of the present study to investigate the trans-placental exposure of newborn infants to this possible human carcinogen by analysis of the specific haemoglobin adduct of AA ( N-2-carbamoylethylvaline, AAV) in the blood of mothers and the corresponding umbilical cord blood of neonates as a parameter of biochemical effects. METHODS: We investigated the blood of 11 women advanced in pregnancy (one smoker, ten non-smokers) and the corresponding umbilical cord blood of neonates for the N-terminal haemoglobin adducts of AA (AAV) and the smoking-specific adduct of acrylonitrile (CAS No 107-13-1) ( N-cyanoethylvaline, CEV). The limit of detection (LOD) was 5 pmol/g globin for AAV and 4 pmol/g globin for CEV. RESULTS: AAV could be determined in all blood samples of the mothers (median 21 pmol/g globin, range 18-104 pmol/g globin) as well as in the umbilical cord blood of neonates (median 10 pmol/g globin, range 6-43 pmol/g globin). The highest values were detected in the blood of the smoking mother and her child. CEV was detected only in the blood of the smoking mother (185 pmol/g globin) and the corresponding umbilical cord blood (69 pmol/g globin). DISCUSSION: AAV adduct levels in non-smoking mothers and neonates showed a good correlation (r=0.859). The concentration of AA adducts in the blood of neonates is approximately 50% of the adduct level found in the blood of the mother. In view of the shorter life span of neonatal erythrocytes and the lower body weight of newborn infants, the relative internal dose of AA in neonates (in microgrammes per kilogramme body weight) must be assumed to be at least equal to that of the mother. Because of the high cell-replication rates during foetal development, trans-placental exposure of neonates to AA might raise concerns. Neonates of smoking mothers take up much higher doses of AA than those of non-smoking mothers.

Infectious and immune factors in the pathogenesis of neurodevelopmental disorders: epidemiology, hypotheses, and animal models.

Both genetic and environmental factors contribute to the pathogenesis of a wide variety of neurodevelopmental disorders, including autism, mental retardation, and schizophrenia. Some heritable disorders approach 100% penetrance; nonetheless, even in these disorders, subtle aspects of clinical disease expression may be influenced by the environment. In other disorders with genetic influences, exogenous factors, and the timepoint(s) during nervous system development at which they are introduced, modulate expression of disease. Elucidation of the mechanisms guiding this intricate interplay between host response genes, environmental agents, and the neurodevelopmental context within which these interactions occur, is necessary to understand the continuum of clinical outcomes. This chapter will review the evidence that infectious and immune factors may contribute to the pathogenesis of neurodevelopmental disorders, describe an animal model of neurodevelopmental disorders based upon viral infection, identify processes by which neural circuitry may be compromised, and outline areas for future research.

Borna disease virus and neuropsychiatric disease--a reappraisal.

Despite progress in understanding the molecular biology and pathobiology of Borna disease virus, its epidemiology and role in human disease remain controversial. The challenges encountered in this field are a paradigm for the investigation of diseases potentially linked to complex host-microorganism interactions.

Bornavirus tropism and targeted pathogenesis: virus-host interactions in a neurodevelopmental model.

Animal models provide unique opportunities to explore interactions between host and environment. Two models have been established based on Bornavirus infection that provide new insights into mechanisms by which neurotropic agents and/or immune factors may impact developing or mature CNS circuitry to effect complex disturbances in movement and behavior. Distinct losses in DA pathways in the adult infection model, and the associated dramatic movement disorder that accompanies it, make it an intriguing model for tardive dyskinesia and dystonic syndromes. The neuropathologic, physiologic, and neurobehavioral features of BDV infection of neonates indicate that it not only provides a useful model for exploring the mechanisms by which viral and immune factors may damage developing neurocircuitry, but also has significant links to the range of biologic, neurostructural, locomotor, cognitive, and social deficits observed in serious neuropsychiatric illnesses such as autism.

Borna disease virus infection of adult and neonatal rats: models for neuropsychiatric disease.

Animal models provide unique opportunities to explore interactions between host and environment. Two models have been established based on Borna disease virus infection that provide new insights into mechanisms by which neurotropic agents and/or immune factors may impact developing or mature CNS circuitry to effect complex disturbances in movement and behavior. Note in press: Since this chapter was submitted, several manuscripts have been published that extend findings reported here and support the relevance of BDV infections of neonatal Lewis rats as models for investigating mechanisms of neurodevelopmental damage in autism. Behavioral abnormalities, including disturbed play behavior and chronic emotional overactivity, have been described by Pletnikov et al. (1999); inhibition of responses to novel stimuli were described by Hornig et al. (1999); loss of Purkinje cells following neonatal BDV infection has been demonstrated by Eisenman et al. (1999), Hornig et al. (1999), and Weissenböck et al. (2000); and alterations in cytokine gene expression have been reported by Hornig et al. (1999), Plata-Salaman et al. (1999) and Sauder et al. (1999).