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Background Adults with attention deficit/hyperactivity disorder (ADHD) or autism spectrum disorder (ASD) face multiple challenges in obtaining and maintaining employment. Aims To identify and describe how adults with ADHD or ASD experienced their ability to work and what factors affected their ability to find a sustainable work situation over time. Methods Individual in-depth interviews were performed with 20 purposively sampled participants with ADHD/ASD. Data were analysed inductively using reflexive thematic analysis.ResultsThree themes were identified, describing (1) one’s own cognitive abilities and challenges, (2) enablement by flexibility and acceptance in the work environment, and (3) accumulated stress that makes the work situation unsustainable over time. Conclusions Over time, a lack of continuity and predictability of support measures caused great stress and exhaustion, with severe consequences for working life and in life in general. Adaptations needed to be individually tailored and include nonoccupational factors. Significance The study shows that adults with ADHD/ASD need long-term interventions that flexibly adapt to individual needs, as they vary over time. The findings suggest that occupational therapists and other health care providers, employers, employment services and other involved agencies should pay a greater deal of attention to stability and predictability over time. Funding: Medical Research Council of Southeast Sweden [FORSS-910651, FORSS-931117]; Swedish Research Council [2018-02131]

Background The research on the role of father in the foetal programming of health and behaviour has received increasing attention. However, the influences of paternal depressive symptoms and couple relationship satisfaction during pregnancy – potentially mediated via maternal well-being – on the offspring's risk of infections in early life is still seldom assessed. Aims The aim was to investigate if paternal psychological distress during pregnancy is associated with elevated risk of recurrent respiratory infections (RRIs) for offspring at 12 months of age, and whether maternal distress mediates the association between paternal distress and offspring RRIs. Method The study population was drawn from the nested case–control cohort of the FinnBrain Birth Cohort Study. Children with RRIs (n = 50) were identified by maternal reports at the age of 12 months, whereas mothers did not report RRIs for the comparison group (n = 716). Parental depressive symptoms were measured with the Edinburgh Postnatal Depression Scale and couple relationship satisfaction was measured with the Revised Dyadic Adjustment Scale. Results The association between paternal depressive symptoms during pregnancy and offspring RRIs was mediated by maternal prenatal depressive symptoms. Additionally, paternal poorer relationship satisfaction was associated with child RRIs independently of maternal distress. Conclusions The results suggest different pathways through which paternal distress during pregnancy may contribute to elevated risk of offspring RRIs, and more research is needed to study their underlying mechanisms. Paternal distress and couple relationship satisfaction during pregnancy should be assessed and screened as a contributor to offspring health.

In their latest survey from 2017/18, the Public Health Agency in Sweden reported an increase in multiple mental health complaints among children and adolescents. The study is part of a collaborative WHO project that started in 1985/86 and collects data every four years. With this background, a working group was commissioned by the Swedish Medical Association to identify areas for improvement within the school system and to work out proposals for effective interventions. In this report, we summarize research data on evidence-based knowledge within five areas. How to promote daily physical activity at school to enhance wellbeing and cognitive abilities; how to balance time on the internet; what is known about school-based intervention programs to promote mental health; the need to adapt knowledge requirements in the national curriculum to children's development and cognitive abilities, and to describe specific risk groups for impaired mental health. Finally, we describe competence-enhancing initiatives and emphasize the need for collaboration between school health, child and adolescent mental health services, pediatrics and the social services.

Background To examine health and health-related behaviors in migrant and refugee individuals who identify as sexual or gender minority, and in comparison to their heterosexual peers. Methods The study included 168,952 individuals (aged 16-84 years, males: 45.9%, sexual or gender minorities: 3.1%) who answered the Swedish National Public Health Survey in 2018 and 2020. Participants were grouped into Swedish-and Western-born (White) heterosexual, White sexual- or gender minority, migrant heterosexual, migrant sexual- or gender minority, refugee heterosexual, and refugee sexual- or gender minority. Outcomes included mental health (for example suicidal ideation, wellbeing), general health, risky behaviors (risk alcohol use, risk gambling, and substance use), and experiences of violence. Associations between 1) sexual- or gender -ethnic identities and 2) gender-ethnic identities and all outcomes were analyzed using logistic and linear regression adjusting for sex, age, and educational level. Findings Being a sexual- or gender minority, regardless of ethnic minority status, was associated with worse general health and mental ill-health compared to heterosexual peers including suicidal ideation in refugee sexual- or gender minority individuals (OR 2.42, 95 % CI 1.44-4.08). Ethnic minorities (heterosexual and sexual- or gender minority migrants and refugees) had lower odds of drug and risk alcohol use compared to White heterosexual peers but higher odds of risk gambling (1.88, 1.49-2.37 for refugee heterosexuals). Transgender refugees had high odds for risk gambling (8.62, 1.94-38.40) and exposure to physical violence (7.46, 2.97-18.70). Interpretation In this national population-based study, sexual and gender minority individuals have worse mental and general health regardless of ethnic minority status. We did not find evidence for worse health in sexual- or gender minority refugees in comparison to migrant, and White sexual- or gender minorities and their heterosexual peers. Transgender individuals (White and ethnic minority) experienced significantly higher levels of physical violence. Public health policy should emphasize preventive measures to reduce exposure to violence and discrimination in sexual- and gender minority individuals, increase access and use of mental healthcare services and sensitise healthcare professionals about higher rates of health and related issues faced by sexual- and gender minority individuals including those with multiple minority identities. Funding: Linkoping University; Save the Children Sweden

is missing (Short communication)

IntroductionChildhood sexual abuse (CSA) is a global public health problem with potentially severe health and mental health consequences. Healthcare professionals (HCPs) should be familiar with risk factors and potential indicators of CSA, and able to provide appropriate medical management. The WHO issued global guidelines for the clinical care of children with CSA, based on rigorous review of the evidence base. The current systematic review identifies existing CSA guidelines issued by government agencies and academic societies in the European Region and assesses their quality and clarity to illuminate strengths and identify opportunities for improvement.Methods and analysisThis 10-database systematic review will be conducted according to the Centre for Reviews and Dissemination guidelines and will be reported according to The Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Guidance for HCPs regarding CSA, written by a national governmental agency or academic society of HCPs within 34 COST Action 19106 Network Countries (CANC) and published in peer-reviewed or grey literature between January 2012 and November 2022, is eligible for inclusion. Two independent researchers will search the international literature, screen, review and extract data. Included guidelines will be assessed for completeness and clarity, compared with the WHO 2017/2019 guidelines on CSA, and evaluated for consistency between the CANC guidelines. The Appraisal of Guidelines for Research and Evaluation II tool and Grading of Recommendations Assessment, Development and Evaluation methodology will be used to evaluate CANC guidelines. Descriptive statistics will summarise content similarities and differences between the WHO guidelines and national guidelines; data will be summarised using counts, frequencies, proportions and per cent agreement between country-specific guidelines and the WHO 2017/2019 guidelines.Ethics and disseminationThere are no individuals or protected health information involved and no safety issues identified. Results will be published in a peer-reviewed medical journal.PROSPERO registration numberCRD42022320747.

The Nordic welfare model is often used as an example for the promotion of health and wellbeing, even in vulnerable groups of children, such as refugees. Nonetheless, there are no published reviews on resilience and/or risk and protective factors for physical and mental health among refugee children living in Nordic countries. In this systematic review, we identified 5181 studies on the topic, screened titles, and abstracts, viewed 632, and finally included 26 studies. These studies described 18 samples with a total of 34,080 individuals ranging in ages 0–18 years. Overall, the studies were of good quality. Nearly all studies assessed adversity. Six studies reported physical health outcomes and all studies mental health outcomes, most often post-traumatic stress disorder and anxiety. None explicitly studied resilience. While we found that age and sex are the most frequently studied risk- and protective factors, findings are inconclusive, since the direction of the associations was different in the different studies. This systematic review indicates that there is still a need for well-designed and -powered studies using clear definitions of key study concepts to examine health outcomes and resilience among refugee children in Nordic countries. Funding: Open access funding provided by Linköping University. FORTE (Dnr 2019–12-01).

Disruptive behavior disorders (DBD), including oppositional defiant disorder (ODD) and conduct disorder (CD), are some of the most common psychiatric conditions in childhood. Despite this, there has been limited research on DBDs. We examined the incidence, comorbidity and gender differences of DBDs diagnosed by specialist services. This was a nationwide register study of 570,815 children and adolescents born in 1996–2005. The 7050 individuals diagnosed with DBD by specialist healthcare services were matched to 26,804 controls. By the age of 15, the cumulative incidence of diagnosed DBDs was 3.5% for boys and 1.4% for girls. The yearly incidence rate increased for girls after 13 years of age, while the incidence for boys was relatively stable between 8 and 15 years of age. When we compared subjects born between 1996–1998 and 1999–2001, we found that by the age of 12, the cumulative incidence per 100 people had increased from 0.56 to 0.68 among girls and from 2.3 to 2.6 among boys. This indicated a minor increase in treated incidence. The parents of children diagnosed with DBDs had lower educational levels than the parents of controls. Children with DBD were also more likely to have been diagnosed with other psychiatric disorders. Although DBDs were 3.5 times more common among boys during the whole follow-up period, the yearly incidence during adolescence was fairly similar between boys and girls. DBD existed alongside various psychiatric disorders at a relatively young age and only a minor increase in treated incidence was found during childhood.

Background Genetic heterogeneity in type I interferon (IFN)–related gene IFI44L may account for variable susceptibility to respiratory tract infections (RTIs) in children. Methods In 2 prospective, population-based birth cohorts, the STEPS Study and the FinnBrain Birth Cohort Study, IFI44L genotypes for rs273259 and rs1333969 were determined in relation to the development of RTIs until 1 or 2 years of age, respectively. At age 3 months, whole-blood transcriptional profiles were analyzed and nasal samples were tested for respiratory viruses in a subset of children. Results In the STEPS Study (n = 1135), IFI44L minor/minor gene variants were associated with lower rates of acute otitis media episodes (adjusted incidence rate ratio, 0.77 [95% confidence interval, .61–.96] for rs273259 and 0.74 [.55–.99] for rs1333969) and courses of antibiotics for RTIs (0.76 [.62–.95] and 0.73 [.56–.97], respectively. In the FinnBrain cohort (n = 971), IFI44L variants were associated with lower rates of RTIs and courses of antibiotics for RTIs. In respiratory virus–positive 3-month-old children, IFI44L gene variants were associated with decreased expression levels of IFI44L and several other IFN-related genes. Conclusions Variant forms of IFI44L gene were protective against early-childhood RTIs or acute otitis media, and they attenuated IFN pathway activation by respiratory viruses.

Background Exposure to prenatal maternal psychological distress may contribute to the development of childhood atopic disorders. Little is known about the importance of distress severity and its duration for the risk. Our aim was to investigate how chronic maternal depressive and anxiety symptoms across gestation influence the risk of wheezing and eczema at child age 24 months. Methods The study population was drawn from the FinnBrain Birth Cohort Study, including 1305 mother-infant dyads followed across gestation until the child age of 24 months when the outcomes were mother-reported wheezing ever and doctor-diagnosed eczema. To investigate the risk of wheezing phenotypes, wheezing with and without eczema were separated. Maternal distress was assessed with the Edinburgh Postnatal Depression Scale for depressive and the Symptom Checklist-90 for anxiety symptoms three times during pregnancy, and the chronicity was demonstrated using symptom trajectories composed by Latent Growth Mixture Modeling. Results Of the children, 219/1305 (17%) had wheezing ever and 285/1276 (22%) had eczema. Risk of wheezing ever was elevated with maternal consistently high depressive symptoms (adjusted odds ratio 2.74; 95% confidence interval 1.37-5.50) or moderate and increasing anxiety symptoms (1.94; 1.06-3.54, respectively). Similarly, wheezing without eczema was associated with consistently high depressive (3.60; 1.63-7.94, respectively) and moderate and increasing anxiety symptoms (2.43; 1.21-4.91, respectively). Conclusions Maternal chronic psychological distress across gestation was associated with toddler wheezing and especially wheezing without other atopic features (eczema). This finding supports the theory of intrauterine programming effect by maternal psychological distress on offspring immune system and respiratory morbidity.

BACKGROUND Neurodevelopmental difficulties with various emotional and behavioral symptoms increase the risk of mental health problems later in life. Although we know that early detection and interventions are effective, there is a lack of intersectoral, integrative, and evidence-based working models to provide these services for preschool children and their parents. PLUSS (Psykisk hälsa Lärande Utveckling Samverkan kring Små barn; English translation: mental health, learning, development, collaboration around preschool children) is a collaborative “one way in” model involving parents, health care providers, preschools, social services, and researchers. PLUSS provides coordinated services to screen, evaluate, and support toddlers with neurodevelopmental problems. It also offers parental interventions and education for preschool teachers. OBJECTIVE The model will be studied in a research project that aims to investigate (1) using a quasi-experimental study on longitudinal trajectories of neurodevelopmental difficulties and ability to function among participating preschoolers, (2) user satisfaction, and (3) implementation of the model and its effectiveness. The long-term goal is to provide evidence-based, coordinated services to reduce problems related to neurodevelopmental difficulties among preschool children and promote well-being and functioning in everyday life. METHODS The population of interest is children aged 1.5-5 years, whom the child health care nurse refers for further assessment due to suspected neurodevelopmental problems. Data are collected using questionnaires and semistructured interviews. Measures include sociodemographic data, longitudinal data on neurodevelopmental problems, parental well-being and satisfaction, the effectiveness of parental and preschool teacher training and implementation of the model, and fostered multisectoral collaborations. Data will be analyzed with qualitative and quantitative methods. RESULTS The PLUSS model has been approved by the National Ethics Review Board (2019–04839). This study was supported by FUTURUM grants 910161 and 910441. Data collection started in April 2019, with the data collection period planned to end in May 2024. CONCLUSIONS PLUSS is an integrative working model with multiprofessional competence and intersectoral collaboration capacity to help preschool children with neurodevelopmental problems and their parents. It will be studied using quasi-experimental cross-sectional and longitudinal study designs. Data will be collected from parents, health care providers, and preschool teachers, and will be analyzed using quantitative and qualitative methods. The study will run in one Swedish county, and generalizability needs to be studied separately. Loss of follow-up could impact the longitudinal analysis. CLINICALTRIAL ClinicalTrials.gov NCT04815889; https://clinicaltrials.gov/ct2/show/NCT04815889 INTERNATIONAL REGISTERED REPORT DERR1-10.2196/34969

Neurodevelopmental difficulties with various emotional and behavioral symptoms increase the risk of mental health problems later in life. Although we know that early detection and interventions are effective, there is a lack of intersectoral, integrative, and evidence-based working models to provide these services for preschool children and their parents. PLUSS (Psykisk hälsa Lärande Utveckling Samverkan kring Små barn; English translation: mental health, learning, development, collaboration around preschool children) is a collaborative "one way in" model involving parents, health care providers, preschools, social services, and researchers. PLUSS provides coordinated services to screen, evaluate, and support toddlers with neurodevelopmental problems. It also offers parental interventions and education for preschool teachers.The model will be studied in a research project that aims to investigate (1) using a quasi-experimental study on longitudinal trajectories of neurodevelopmental difficulties and ability to function among participating preschoolers, (2) user satisfaction, and (3) implementation of the model and its effectiveness. The long-term goal is to provide evidence-based, coordinated services to reduce problems related to neurodevelopmental difficulties among preschool children and promote well-being and functioning in everyday life.The population of interest is children aged 1.5-5 years, whom the child health care nurse refers for further assessment due to suspected neurodevelopmental problems. Data are collected using questionnaires and semistructured interviews. Measures include sociodemographic data, longitudinal data on neurodevelopmental problems, parental well-being and satisfaction, the effectiveness of parental and preschool teacher training and implementation of the model, and fostered multisectoral collaborations. Data will be analyzed with qualitative and quantitative methods.The PLUSS model has been approved by the National Ethics Review Board (2019-04839). This study was supported by FUTURUM grants 910161 and 910441. Data collection started in April 2019, with the data collection period planned to end in May 2024.PLUSS is an integrative working model with multiprofessional competence and intersectoral collaboration capacity to help preschool children with neurodevelopmental problems and their parents. It will be studied using quasi-experimental cross-sectional and longitudinal study designs. Data will be collected from parents, health care providers, and preschool teachers, and will be analyzed using quantitative and qualitative methods. The study will run in one Swedish county, and generalizability needs to be studied separately. Loss of follow-up could impact the longitudinal analysis.ClinicalTrials.gov NCT04815889; https://clinicaltrials.gov/ct2/show/NCT04815889.DERR1-10.2196/34969.

Background: Neurodevelopmental difficulties are frequent in preschoolers and constitute a risk for later negative consequences. This article describes the development of a multi-professional and multi-agency model, PLUSS, to facilitate care and interventions for preschoolers with neurodevelopmental difficulties. Methods: The PLUSS-model was developed for children aged 1.5-5 years with a need for a further assessment of neurodevelopmental symptoms. The model is evaluated using a quasi-experimental study design along with qualitative interviews. Outcomes of interest are a) implementation, b) effectiveness related to processes and multi-agency collaboration, c) capacity building among professionals, d) child-related outcomes with a longitudinal follow-up as well as d) parental wellbeing and satisfaction. Results: The model was launched in 2019 and so far, approximately 130 children have been assessed. Results from a pilot study with 62 children (27-72 months; boys: girls 2.65:1) show, using the strengths and difficulties questionnaire (SDQ), that the included children have clinically significant problems. The total mean SDQ score in parental rating was 15 +/- 6 and in preschool teacher ratings 14 +/- 7, exceeding the Swedish cut-off of 12. 54 parents have participated in parental training and rate high levels of satisfaction (mean score 4.5, max 5.0). In addition, 74 pre-school professionals have been trained in early signs of neurodevelopmental difficulties to facilitate early detection. Feedback from these educational activities is encouraging (mean score 4.2, max 5.0). Conclusions: The PLUSS-model enables early detection and interventions for preschool children and their families, without a set diagnosis. The pilot study shows that the screening procedure can detect children with clinically significant problems. In addition, encouraging results have been obtained from both parent- and preschool teacher training. The longitudinal study approach enables both child follow-up and evaluation of interventions provided by the working model. Trial registration: Clinical Trials 2021, PLUSS identifier, NCT04815889. First registration 25/03/2021.

Background Altered hypothalamic-pituitary-adrenal axis (HPA) functioning is one of the potential mechanisms bridging exposure to maternal prenatal psychological distress (PPD) and later risk for offspring psychiatric illness. Research on infant cortisol stress reactivity, on scarcely studied recovery and their associations with maternal PPD is needed to clarify these mechanisms. Knowledge on sex differences in prospective settings is largely lacking. We aimed at filling these gaps by building upon our previous report showing that exposure to maternal prenatal depressive and anxiety symptoms associates with slower cortisol recovery among 10-week-old female infants. Methods In all, 363, 205 and 263 infants at 10 weeks, six and 14 months of age from the FinnBrain Birth Cohort Study participated in a stress test comprising of venipuncture and nasopharynx sampling. Five saliva cortisol samples were collected during each visit to measure cortisol reactivity and recovery. PPD was assessed from maternal self-reports for depressive, anxiety and pregnancy-related anxiety symptoms at gestational weeks 14, 24 and 34. Results An 11% enhanced recovery among 14-month-old females was associated with higher depressive and anxiety symptoms (95% CI=1-23%) and pregnancy-related anxiety symptoms (2-21%). No alterations in the female cortisol reactivity or male cortisol stress responses were observed. Conclusions The opposite directions in the associations between the PPD exposure and infant cortisol recovery among 10-week-old and 14-month-old females suggest sex- and age-dependent associations between HPA axis functioning and PPD exposure among healthy infants. Follow-up is needed to characterize the impact of this altered negative feedback mechanism on later health.

Background: Enterovirus (EV) infections, being among the most prevalent viruses worldwide, have been associated with reduced risk of allergic diseases. We sought to determine the association between EVs and allergic sensitization and disease in early childhood. Methods: The study was carried out in a nested case-control setting within a prospective birth cohort in Finland. We included 138 case children who had specific IgE (s-IgE) sensitization at the age of 5 years and 138 control children without s-IgE sensitization. Allergic disease was recorded at study visits and identified with the ISAAC questionnaire. We screened for the presence of serotype-specific antibodies against 41 EVs at 1–5 years of age and assessed their association with allergic sensitization and disease. Results: The overall number of EV infections did not differ between s-IgE–sensitized children and non-sensitized control children. However, there was a tendency of case children with an allergic disease having less EV infections than their controls. This observation was statistically significant for species A EVs in case children with atopic dermatitis vs. control children: OR 0.6 (95% CI 0.36–0.99), p = .048. Conclusion: This study supports the evidence that EV exposure and development of allergic disease are inversely associated. Interestingly, the inverse association was not observed for bare atopic IgE sensitization, but for IgE sensitization coupled with clinical atopic disease. This suggests that environmental factors influencing IgE sensitization may differ from those influencing progression to clinical allergic disease.

Background Emergence delirium is a complex behaviour of perceptual disturbances that may occur after general anaesthesia in children. These children often exhibit delusions, confusion, restlessness and involuntary physical activity. They cry and are almost impossible to console. Research has mainly focused on comparing different medication agents in the occurrence of and dealing with emergence delirium. However, less is known about parents experiences of emergence delirium during the recovery process, and there is hardly any research concerning the childrens experiences. Aims The primary aim of this study was to describe parents experiences and reflections during their childs emergence delirium behaviour when recovering from anaesthesia. A secondary aim was to describe childrens experiences of having been in this condition. Method A qualitative research approach with thematic analysis was applied. The study was conducted at two county hospitals in southern Sweden. A total of 16 parents and one child were interviewed. Results Watching their child demonstrate emergence delirium made parents feel as if they were encountering an incomprehensible scenario. They experienced fear and insecurity and had feelings of powerlessness and guilt. Information and previous experience turned out to offer relief, and being seen by the healthcare staff when they, in their vulnerability, failed to reach or console their child, gave hope and energy. The child confirmed the unexpected and uncontrolled behaviour described by parents. She clearly remembered being wild and out of control. Conclusion Emergence delirium must be extensively considered in children undergoing general anaesthesia. It is of great importance for healthcare staff to be aware of the parental difficulties it may cause and what is experienced as relieving, such as receiving information and staff members being available, responsive and supportive during the wake-up period. Funding Agencies|Medical Research Council of Southeast SwedenUK Research & Innovation (UKRI)Medical Research Council UK (MRC) [FORSS 469201, 648131]

Genetic variants may predispose children to recurrent respiratory infections (RRIs) but studies on genotype-environment interaction are rare. We hypothesized that the risk for RRIs is elevated in children with innate immune gene variants, and that prenatal exposure to maternal psychological distress further increases the risk. In a birth cohort, children with RRIs (n = 96) were identified by the age of 24 months and compared with the remaining cohort children (n = 894). The risk for RRIs in children with preselected genetic variants and the interaction between maternal distress during pregnancy and child genotype were assessed with logistic regression. The IL6 minor allele G was associated with elevated risk for RRIs (OR 1.55; 95% CI 1.14–2.12). Overall, there was no interaction between maternal psychological distress and child genotype. Exploratory analyses showed that, the association between the variant type of IL6 and the risk for RRIs was dependent on prenatal exposure to maternal psychological distress in males (OR 1.96; 95% CI 1.04–3.67). Our study didn’t find genotype-environment interaction between prenatal maternal distress and child genotype. Exploratory analyses suggest sex differences in gene-environment interaction related to susceptibility to RRIs.

Background: Prenatal environment has been shown to influence child's risk of atopic diseases. Laboratory-confirmed data about the role of maternal infections during pregnancy is scarce. Objective: The aim of this study was to determine the associations between serologically confirmed maternal infections during pregnancy and atopic disease in the offspring. Methods: This was a nested case-control study within a prospective birth cohort study. Altogether 202 atopic case children and 333 matched non-atopic control children were included. Atopic outcome was defined as having an atopic disease and IgE sensitization by the age of 5 years. We analysed serologically acute enterovirus (EV), influenza virus A (IAV) and Mycoplasma pneumoniae (M. pneumoniae) infections during pregnancy, and mother's seropositivity against human cytomegalovirus (CMV) and Helicobacter pylori. Results: Maternal EV infection during pregnancy was inversely associated with atopic outcome in the offspring (odds ratio 0.43; 95% confidence interval: 0.23-0.80, P = 0.008). Acute IAV or M. pneumoniae infections or seropositivity against CMV or Helicobacter pylori were not associated with the atopic outcome. Conclusions and Clinical Relevance: Our results suggest that maternal EV infections during pregnancy are inversely associated with atopic disease in the offspring. Our finding provides further support to the previous studies suggesting an important role of the in utero environment in the development of atopic diseases.

Background: Enterovirus (EV) infections, being among the most prevalent viruses worldwide, have been associated with reduced risk of allergic diseases. We sought to determine the association of EVs with allergic sensitization and disease in early childhood. Methods: The study was carried out in a nested case-control setting within a prospective birth cohort in Finland. We included 138 case children who had specific IgE (s-IgE) sensitization at the age of 5 years and 138 control children without s-IgE sensitization. Allergic disease was recorded at study visits and asked with ISAAC questionary. We screened for the presence of serotype specific antibodies against 41 EVs at 1 to 5 years of age and assessed their association with allergic sensitization and disease. Results: The overall number of EV infections did not differ between s-IgE-sensitized children and non-sensitized control children. However, there was a tendency of case children with an allergic disease having less EV infections than their controls. This observation was statistically significant for species A EVs in case children with atopic dermatitis vs. control children: OR 0.6 (95 % CI 0.36-0.99), P = 0.048. Conclusion: This study supports the evidence that EV exposure and development of allergic disease are inversely associated. Interestingly, the inverse association was not observed for bare atopic IgE sensitization, but for IgE sensitization coupled with clinical atopic disease. This suggests that environmental factors influencing IgE sensitization may differ from those influencing progression to clinical allergic disease.

There is a need for unified guidance on the management of ocular manifestations of atopic dermatitis and ocular manifestations associated with dupilumab in the Nordic region (Denmark, Finland, Norway and Sweden). This initiative gathered Nordic dermatologists and ophthalmologists to identify consensus in this area using a modified Delphi process. The initiative was led by a Nordic expert panel who developed a questionnaire that was circulated to a wider group. The results informed an agenda consisting of 24 statements to be voted on using a 5-point Likert scale at a meeting in Copenhagen on 24 April 2019. A facilitator moderated discussion and revised statements according to expert feedback for a second vote when required to reach consensus. Consensus was reached for 23 statements regarding the diagnosis, treatment and referral of these patients, which we hope will improve patient management in the Nordic region.

Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) is a master regulator of mitochondria biogenesis and cell stress playing a role in metabolic and degenerative diseases. In the brain PGC-1α expression has been localized mainly to GABAergic interneurons but its overall role is not fully understood. We observed here that the protein levels of γ-aminobutyric acid (GABA) type A receptor-α2 subunit (GABARα2) were increased in hippocampus and brain cortex in transgenic (Tg) mice overexpressing PGC-1α in neurons. Along with this, GABARα2 expression was enhanced in the hippocampus of the PGC-1α Tg mice, as shown by quantitative PCR. Double immunostaining revealed that GABARα2 co-localized with the synaptic protein gephyrin in higher amounts in the striatum radiatum layer of the hippocampal CA1 region in the Tg compared with Wt mice. Electrophysiology revealed that the frequency of spontaneous and miniature inhibitory postsynaptic currents (mIPSCs) was increased in the CA1 region in the Tg mice, indicative of an augmented GABAergic transmission. Behavioral tests revealed an increase for anxiety-like behavior in the PGC-1α Tg mice compared with controls. To study whether drugs acting on PPARγ can affect GABARα2, we employed pioglitazone that elevated GABARα2 expression in primary cultured neurons. Similar results were obtained using the specific PPARγ agonist, N-(2-benzoylphenyl)-O-[2-(methyl-2-pyridinylamino) ethyl]-L-tyrosine hydrate (GW1929). These results demonstrate that PGC-1α regulates GABARα2 subunits and GABAergic neurotransmission in the hippocampus with behavioral consequences. This indicates further that drugs like pioglitazone, widely used in the treatment of type 2 diabetes, can influence GABARα2 expression via the PPARγ/PGC-1α system.

Previous research suggests that maternal prenatal psychological distress (PPD) is related to altered cortisol reactivity in the exposed child. There are indications for the sex differences in vulnerability for prenatal adversities that depend on the exposure and child outcome. Still, it is not known whether the association between maternal PPD and infant cortisol stress response is moderated by sex. In addition, the recovery phase of the cortisol stress response has not been given as much attention as reactivity. Our aim was to study the sex differences in the associations between self-reported maternal prenatal depressive-, anxiety- and pregnancy-related anxiety symptoms through gestational weeks 14, 24 and 34 and the saliva cortisol reactivity to and recovery from the acute stress among 10-week-old infants. The study population comprised of 363 mother-infant pairs from the FinnBrain Birth Cohort Study. We found evidence for sex-dependent associations between PPD exposure and infant cortisol response. A less steep recovery slope (-10 % per one SD increase in PPD [95 % CI = -18 to -2 %] and -8 % [-16 to 0 %] depending on the exposure) and a possibly less steep reactivity slope (-14 % [95 % CI = -25 to 0 %] and -10 % [-21 to 3 %]) were associated with higher PPD exposure in females. Of the PPD measures, the strongly intercorrelated, and thus combined, depressive and anxiety symptom score provided the most robust prediction of infant cortisol recovery. Our results demonstrate sexually dimorphic alterations in the functioning of the infant hypothalamus-pituitary-adrenal axis and especially in the functioning of the negative feedback loop of the axis after prenatal PPD exposure among healthy babies.

Disruptive behavior disorders (DBD), including oppositional defiant disorder (ODD) and conduct disorder (CD), are some of the most common psychiatric conditions in childhood. Despite this, there has been limited research on DBDs. We examined the incidence, comorbidity and gender differences of DBDs diagnosed by specialist services.This was a nationwide register study of 570,815 children and adolescents born in 1996-2005. The 7050 individuals diagnosed with DBD by specialist healthcare services were matched to 26,804 controls.By the age of 15, the cumulative incidence of diagnosed DBDs was 3.5% for boys and 1.4% for girls. The yearly incidence rate increased for girls after 13 years of age, while the incidence for boys was relatively stable between 8 and 15 years of age. When we compared subjects born between 1996-1998 and 1999-2001, we found that by the age of 12, the cumulative incidence per 100 people had increased from 0.56 to 0.68 among girls and from 2.3 to 2.6 among boys. This indicated a minor increase in treated incidence. The parents of children diagnosed with DBDs had lower educational levels than the parents of controls. Children with DBD were also more likely to have been diagnosed with other psychiatric disorders.Although DBDs were 3.5 times more common among boys during the whole follow-up period, the yearly incidence during adolescence was fairly similar between boys and girls. DBD existed alongside various psychiatric disorders at a relatively young age and only a minor increase in treated incidence was found during childhood.

Similarities and differences in the everyday clinical management of moderate-to-severe atopic dermatitis in Nordic countries are unknown. Using a modified Delphi approach, 15 dermatologists from Denmark, Finland, Norway and Sweden completed face-to-face and online questionnaires and participated in summary discussions to map expert opinion on the clinical management of moderate-to-severe atopic dermatitis in these Nordic countries. Through discussions, 6 adult patient profiles, reflecting common disease presentations of atopic dermatitis, were identified. Using these case profiles, diagnostic work-up, treatment goals, patient education and treatment approaches were discussed. Patient education was identified as essential for effective management. A treatment sequence of moderate-to-potent topical glucocorticosteroids and emollients, followed by systemic treatment, was recommended, allowing 3 months to ascertain systemic treatment response before switching, if necessary. Consensus was not reached on systemic treatment choice, reflecting differences in clinical practice and reimbursement between countries. Practical, case-based clinical recommendations were developed for optimal patient care.

SummaryBackground In 2016, dermatologists in Finland suspected contact allergy in several patients using moisturizers under the trade name Apobase®. Following a formulation change, Phenostat™, which is a mixture of phenoxyethanol, caprylhydroxamic acid, and methylpropanediol, was used as a preservative in Apobase® moisturizers in Finland. Objectives To confirm the suspected contact allergy to Apobase® cream, oily cream, and/or lotion, and to identify the specific contact allergen and define its optimal patch test concentration. Methods Thirty-nine patients with suspected contact allergy to Apobase® creams or lotion were patch tested in four Finnish dermatological clinics. The patch tests included old and new Apobase® formulas and their preservative agents: phenoxyethanol, methylpropanediol, and dilution series of Phenostat™ and caprylhydroxamic acid or its potassium salt. Results The patch tests showed positive reactions to the new Apobase® formulas, Phenostat™, and caprylhydroxamic acid or its potassium salt, but not to the old Apobase® formulas, methylpropanediol, or phenoxyethanol. Conclusions We found a new contact allergen, caprylhydroxyamic acid, which caused an epidemic of allergic contact dermatitis in patients using moisturizers containing this preservative. Whether the sensitizing capacity of caprylhydroxamic acid depends on the other chemicals used in Apobase® moisturizers needs further investigation.

Peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) is a transcriptional coactivator involved in the regulation of mitochondrial biogenesis and cell defense. The functions of PGC-1α in physiology of brain mitochondria are, however, not fully understood. To address this we have studied wild-type and transgenic mice with a two-fold overexpression of PGC-1α in brain neurons. Data showed that the relative number and basal respiration of brain mitochondria were increased in PGC-1α transgenic mice compared with wild-type mitochondria. These changes occurred concomitantly with altered levels of proteins involved in oxidative phosphorylation (OXPHOS) as studied by proteomic analyses and immunoblottings. Cultured hippocampal neurons from PGC-1α transgenic mice were more resistant to cell degeneration induced by the glutamate receptor agonist kainic acid. In vivo kainic acid induced excitotoxic cell death in the hippocampus at 48 h in wild-type mice but significantly less so in PGC-1α transgenic mice. However, at later time points cell degeneration was also evident in the transgenic mouse hippocampus, indicating that PGC-1α overexpression can induce a delay in cell death. Immunoblotting showed that X-linked inhibitor of apoptosis protein (XIAP) was increased in PGC-1α transgenic hippocampus with no significant changes in Bcl-2 or Bcl-X. Collectively, these results show that PGC-1α overexpression contributes to enhanced neuronal viability by stimulating mitochondria number and respiration and increasing levels of OXPHOS proteins and the anti-apoptotic protein XIAP.

Low-density lipoprotein receptors (LDLRs) mediate the uptake of lipoprotein particles into cells, as studied mainly in peripheral tissues. Here, we show that nerve growth factor (NGF) increases LDLR levels in PC6.3 cells and in cultured septal neurons from embryonic rat brain. Study of the mechanisms showed that NGF enhanced transcription of the LDLR gene, acting mainly via Tropomyosin receptor kinase A receptors. Simvastatin, a cholesterol-lowering drug, also increased the LDLR expression in PC6.3 cells. In addition, pro-NGF and pro-brain-derived neurotrophic factor, acting via the p75 neurotrophin receptor (p75NTR) also increased LDLRs. We further observed that Myosin Regulatory Light Chain-Interacting Protein/Inducible Degrader of the LDLR (Mylip/Idol) was down-regulated by pro-NGF, whereas the other LDLR regulator, proprotein convertase subtilisin kexin 9 (PCSK9) was not significantly changed. On the functional side, NGF and pro-NGF increased lipoprotein uptake by neuronal cells as shown using diacetyl-labeled LDL. The addition of serum-derived lipoprotein particles in conjunction with NGF or simvastatin enhanced neurite outgrowth. Collectively, these results show that NGF and simvastatin are able to stimulate lipoprotein uptake by neurons with a positive effect on neurite outgrowth. Increases in LDLRs and lipoprotein particles in neurons could play a functional role during brain development, in neuroregeneration and after brain injuries. Nerve growth factor (NGF) and pro-NGF induce the expression of low-density lipoprotein receptors (LDLRs) in neuronal cells leading to increased LDLR levels. Pro-NGF also down-regulated myosin regulatory light chain-interacting protein/inducible degrader of the LDLR (Mylip/Idol) that is involved in the degradation of LDLRs. NGF acts mainly via Tropomyosin receptor kinase A (TrkA) receptors, whereas pro-NGF stimulates p75 neurotrophin receptor (p75NTR). Elevated LDLRs upon NGF and pro-NGF treatments enhanced lipoprotein uptake by neurons. Addition of LDL particles further led to the stimulation of neurite outgrowth in PC6.3 cells after NGF or simvastatin treatments, suggesting a stimulatory role of lipoproteins on neuronal differentiation. In contrast, pro-NGF had no effect on neurite outgrowth either in the absence or presence of LDL particles. The precise mechanisms by which increased lipoproteins uptake can affect neurite outgrowth warrant further studies.

In 2016, dermatologists in Finland suspected contact allergy in several patients using moisturizers under the trade name Apobase®. Following a formulation change, Phenostat™, which is a mixture of phenoxyethanol, caprylhydroxamic acid, and methylpropanediol, was used as a preservative in Apobase® moisturizers in Finland.To confirm the suspected contact allergy to Apobase® cream, oily cream, and/or lotion, and to identify the specific contact allergen and define its optimal patch test concentration.Thirty-nine patients with suspected contact allergy to Apobase® creams or lotion were patch tested in four Finnish dermatological clinics. The patch tests included old and new Apobase® formulas and their preservative agents: phenoxyethanol, methylpropanediol, and dilution series of Phenostat™ and caprylhydroxamic acid or its potassium salt.The patch tests showed positive reactions to the new Apobase® formulas, Phenostat™, and caprylhydroxamic acid or its potassium salt, but not to the old Apobase® formulas, methylpropanediol, or phenoxyethanol.We found a new contact allergen, caprylhydroxyamic acid, which caused an epidemic of allergic contact dermatitis in patients using moisturizers containing this preservative. Whether the sensitizing capacity of caprylhydroxamic acid depends on the other chemicals used in Apobase® moisturizers needs further investigation.

Non

Objective To assess the relation between maternal prenatal psychological distress, comprising depression and anxiety symptoms and relationship quality, and the risk of recurrent respiratory infections (RRIs) in children up to 2 years of age. Children with RRIs frequently use health care services and antibiotics. Prenatal maternal psychological distress can be one, previously unidentified risk factor for RRIs. Study design The study population was drawn from a population-based pregnancy cohort in Finland ( www.finnbrain.fi ). Children with RRIs (n = 204) and a comparison group (n = 1014) were identified by maternal reports at the child age of 12 or 24 months. The Edinburgh Postnatal Depression Scale, Symptom Checklist-90 anxiety subscale, the Pregnancy-Related Anxiety Questionnaire–Revised 2, and the Revised Dyadic Adjustment Scale were used to assess maternal symptoms and parental relationship quality at 34 weeks of gestation. Adjustment for maternal postnatal depressive and anxiety symptoms was performed. Results Maternal prenatal Edinburgh Postnatal Depression Scale (OR, 1.24; 95% CI, 1.08-1.44), Symptom Checklist-90/Anxiety (OR, 1.40; 95% CI, 1.01-1.76), Pregnancy-Related Anxiety Questionnaire–Revised 2 (OR, 1.28; 95% CI, 1.11-1.47), and Revised Dyadic Adjustment Scale (OR, 1.32; 95% CI, 1.01-1.58) total sum scores were associated with child RRIs by the age of 24 months. Greater number of siblings, shorter duration of breastfeeding, and the level of maternal education were also identified as risk factors for child RRIs. Conclusions Maternal prenatal psychological distress is linked with a higher risk for child RRIs.

BDNF positively influences various aspects of neuronal migration, maturation, and survival in the developing brain. Reelin in turn mediates inhibitory signals to migrating neuroblasts, which is crucial for brain development. The interplay between BDNF and Reelin signaling in neurodevelopment is not fully understood. We show here that BDNF increased the levels of the Reelin receptor (VLDL receptor (VLDLR)) in hippocampal neurons by increasing gene expression. In contrast, Reelin decreased VLDLRs, which was accompanied by an increase in the levels of the E3 ligase Mylip/Idol in neurons. Down-regulation of Mylip/Idol using shRNAs abrogated the decrease in VLDLRs induced by Reelin. These results show that VLDLRs are tightly regulated in hippocampal neurons by both transcriptional and post-transcriptional mechanisms. The regulation of VLDLR by BDNF and Reelin may affect the migration of neurons and contribute to neurodevelopmental disorders in the nervous system.

Treatment paths in psychiatry may extend from infancy to old age, particularly in neuropsychiatric patients. In the diagnostics and treatment it is important to consider the variations in the symptoms and focuses of rehabilitation during the different periods of the life cycle. Good care and its provision require a perspective extending through the lifespan and assurance of continuity. In our case report we describe a treatment path of 20 years' duration of our neuropsychiatric patient

PACAP is a neuropeptide with a multitude of functions on different cell types and organs including brain tissue. PACAP is relatively highly expressed in embryonic brain indicating a role in neuronal development. Particularly PACAP is expressed in the subventricular zone of lateral ventricles and in the dentate gyrus of hippocampus harboring the neural stem/progenitor cells (NPCs) that give rise to new neurons and glial cells in the developing brain. PACAP is known to stimulate the PACAP-1 receptors (PAC1R) that are expressed by the progenitor and other cells in the brain. Here we will shortly discuss the current view about the role of PACAP in NPCs and how PACAP affects cell proliferation, differentiation, specification, migration and survival of these cells as have been studied mainly in rodent brain. Available data suggests that PACAP acts in concert with other peptides, growth factors and other signaling molecules in governing the behavior of the NPCs both during development and in the adult brain. A better understanding about the action of PACAP in stem cells and its interactions with other factors will be helpful for the potential use of PACAP in treatment of different brain disorders and for understanding of neural repair mechanisms.

Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) is a transcriptional coactivator that favorably affects mitochondrial function. This concept is supported by an increasing amount of data including studies in PGC-1α gene-deleted mice, suggesting that PGC-1α is a rescue factor capable of boosting cell metabolism and promoting cell survival. However, this view has now been called into question by a recent study showing that adeno-associated virus-mediated PGC-1α overexpression causes overt cell degeneration in dopaminergic neurons. How is this to be understood, and can these seemingly conflicting findings tell us something about the role of PGC-1α in cell stress and in control of neuronal homeostasis?

The LDLR is a critical factor in the regulation of blood cholesterol levels that are altered in different human diseases. The level of LDLR in the cell is regulated by both transcriptional and post-transcriptional events. The E3 ubiquitin ligase, myosin regulatory light chain-interacting protein (Mylip)/inducible degrader of the LDL-R (Idol) was shown to induce degradation of LDLR via protein ubiquitination. We have here studied novel factors and mechanisms that may regulate Mylip/Idol in human hepatocyte cells and in mouse macrophages. We observed that FGF21 that is present in serum in different conditions reduced Mylip/Idol at the RNA and protein level, and increased LDLR levels and stability in the cells. FGF21 also enhanced expression of Canopy2 (Cnpy2)/MIR-interacting Saposin-like protein (Msap) that is known to interact with Mylip/Idol. Overexpression of Cnpy2/Msap increased LDLRs, and knockdown experiments showed that Cnpy2/Msap is crucial for the FGF21 effect on LDLRs. Experiments using DiI-labeled LDL particles showed that FGF21 increased lipoprotein uptake and the effect of FGF21 was additive to that of statins. Our results are consistent with an important role of FGF21 and Cnpy2/Msap in the regulation of LDLRs in cultured cells, which warrants further studies using human samples.

Increased protein aggregation and altered cell signaling accompany many neurodegenerative diseases including Huntington's disease (HD). Cell stress is counterbalanced by signals mediating cell repair but the identity of these are not fully understood. We show here that the mammalian target of rapamycin (mTOR) pathway is inhibited and cytoprotective autophagy is activated in neuronal PC6.3 cells at 24 h after expression of mutant huntingtin proteins. Tuberous sclerosis complex (TSC) 1/2 interacted with growth arrest and DNA damage protein 34 (GADD34), which caused TSC2 dephosphorylation and induction of autophagy in mutant huntingtin expressing cells. However, GADD34 and autophagy decreased at later time points, after 48 h of transfection with the concomitant increase in mTOR activity. Overexpression of GADD34 counteracted these effects and increased cytoprotective autophagy and cell survival. These results show that GADD34 plays an important role in cell protection in mutant huntingtin expressing cells. Modulation of GADD34 and the TSC pathway may prove useful in counteracting cell degeneration accompanying HD and other neurodegenerative diseases.

Mitochondrial dysfunction and oxidative stress occur in Parkinson’s disease (PD), but little is known about the molecular mechanisms controlling these events. Peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α) is a transcriptional coactivator that is a master regulator of oxidative stress and mitochondrial metabolism. We show here that transgenic mice overexpressing PGC-1α in dopaminergic neurons are resistant against cell degeneration induced by the neurotoxin MPTP. The increase in neuronal viability was accompanied by elevated levels of mitochondrial antioxidants SOD2 and Trx2 in the substantia nigra of transgenic mice. PGC-1α overexpression also protected against MPTP-induced striatal loss of dopamine, and mitochondria from PGC-1α transgenic mice showed an increased respiratory control ratio compared with wild-type animals. To modulate PGC-1α, we employed the small molecular compound, resveratrol (RSV) that protected dopaminergic neurons against the MPTP-induced cell degeneration almost to the same extent as after PGC-1α overexpression. As studied in vitro, RSV activated PGC-1α in dopaminergic SN4741 cells via the deacetylase SIRT1, and enhanced PGC-1α gene transcription with increases in SOD2 and Trx2. Taken together, the results reveal an important function of PGC-1α in dopaminergic neurons to combat oxidative stress and increase neuronal viability. RSV and other compounds acting via SIRT1/PGC-1α may prove useful as neuroprotective agents in PD and possibly in other neurological disorders.

Increased levels of glutamate causing excitotoxic damage accompany neurological disorders such as ischemia/stroke, epilepsy and some neurodegenerative diseases. Cyclin-dependent kinase-5 (Cdk5) is important for synaptic plasticity and is deregulated in neurodegenerative diseases. However, the mechanisms by which kainic acid (KA)-induced excitotoxic damage involves Cdk5 in neuronal injury are not fully understood. In this work, we have thus studied involvement of Cdk5 in the KA-mediated degeneration of glutamatergic synapses in the rat hippocampus. KA induced degeneration of mossy fiber synapses and decreased glutamate receptor (GluR)6/7 and post-synaptic density protein 95 (PSD95) levels in rat hippocampus in vivo after intraventricular injection of KA. KA also increased the cleavage of Cdk5 regulatory protein p35, and Cdk5 phosphorylation in the hippocampus at 12 h after treatment. Studies with hippocampal neurons in vitro showed a rapid decline in GluR6/7 and PSD95 levels after KA treatment with the breakdown of p35 protein and phosphorylation of Cdk5. These changes depended on an increase in calcium as shown by the chelators 1,2-bis(o-aminophenoxy)ethane-N,N,N ′,N′-tetraacetic acid acetoxymethyl ester (BAPTA-AM) and glycol-bis (2-aminoethylether)-N,N,N ′,N ′-tetra-acetic acid. Inhibition of Cdk5 using roscovitine or employing dominant-negative Cdk5 and Cdk5 silencing RNA constructs counteracted the decreases in GluR6/7 and PSD95 levels induced by KA in hippocampal neurons. The dominant-negative Cdk5 was also able to decrease neuronal degeneration induced by KA in cultured neurons. The results show that Cdk5 is essentially involved in the KA-mediated alterations in synaptic proteins and in cell degeneration in hippocampal neurons after an excitotoxic injury. Inhibition of pathways activated by Cdk5 may be beneficial for treatment of synaptic degeneration and excitotoxicity observed in various brain diseases.

Accumulation of abnormal proteins and endoplasmic reticulum stress accompany neurodegenerative diseases including Huntington's disease. We show that the expression of mutant huntingtin proteins with extended polyglutamine repeats differentially affected endoplasmic reticulum signaling cascades linked to the inositol-requiring enzyme-1 (IRE1) pathway. Thus, the p38 and c-Jun N-terminal kinase pathways were activated, while the levels of the nuclear factor-kappaB-p65 (NF-kappaB-p65) protein decreased. Downregulation of NF-kappaB signaling was linked to decreased antioxidant levels, increased oxidative stress, and enhanced cell death. Concomitantly, calpain was activated, and treatment with calpain inhibitors restored NF-kappaB-p65 levels and increased cell viability. The calpain regulator, calpastatin, was low in cells expressing mutant huntingtin, and overexpression of calpastatin counteracted the deleterious effects caused by N-terminal mutant huntingtin proteins. These results show that calpastatin and an altered NF-kappaB-p65 signaling are crucial factors involved in oxidative stress and cell death mediated by mutant huntingtin proteins.

The HERG (KCNH2) channel is a voltage-sensitive potassium channel mainly expressed in cardiac tissue, but has also been identified in other tissues like neuronal and smooth muscle tissue, and in various tumours and tumour cell lines. The function of HERG has been extensively studied, but it is still not clear what mechanisms regulate the surface expression of the channel. In the present report, using human embryonic kidney cells stably expressing HERG, we show that diacylglycerol potently inhibits the HERG current. This is mediated by a protein kinase C-evoked endocytosis of the channel protein, and is dependent on the dynein-dynamin complex. The HERG protein was found to be located only in early endosomes and not lysosomes. Thus, diacylglycerol is an important lipid participating in the regulation of HERG surface expression and function.

X chromosome-linked inhibitor of apoptosis protein (XIAP) is an anti-apoptotic protein enhancing cell survival. Brain-derived neurotrophic factor (BDNF) also promotes neuronal viability but the links between XIAP and BDNF have remained unclear. We show here that the overexpression of XIAP increases BDNF in transgenic mice and cultured rat hippocampal neurons, whereas downregulation of XIAP by silencing RNA decreased BDNF. XIAP also stimulated BDNF signaling, as shown by increased phosphorylation of the TrkB receptor and the downstream molecule, cAMP response element-binding protein. The mechanism involved nuclear factor-kappaB (NF-kappaB) activation and blocking of NF-kappaB signaling inhibited the increased activities of BDNF promoters I and IV by XIAP. In neuronal cultures XIAP also upregulated interleukin (IL)-6, which is an NF-kappaB-responsive gene. The addition of IL-6 elevated whereas incubation with IL-6-blocking antibodies reduced BDNF in the neurons. BDNF itself activated NF-kappaB in the neurons at higher concentrations. The data show that XIAP has trophic effects on hippocampal neurons by increasing BDNF and TrkB activity. The results reveal a cytokine network in the brain involving BDNF, IL-6 and XIAP interconnected via the NF-kappaB system.