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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: 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.

Introduction: Although figure skating attracts several hundred thousand participants worldwide, there is little knowledge about physical health and sports injuries among young skaters. The present study aimed to describe the health status of a geographically defined Swedish population of licensed competitive figure skaters and to examine injury determinants.Methods: All licensed competitive skaters in the southeastern region of Sweden were in April 2019 invited to participate in a cross-sectional study using an online questionnaire. Multiple binary logistic regression was used for the examination of injury determinants. The primary outcome measure was the 1-year prevalence of a severe sports injury episode (time loss >21 days). The secondary outcome measure was the point prevalence of an ongoing injury. The determinants analyzed were age, skating level, relative energy deficiency indicators, and training habits.Results: In total, 142 (36%) skaters participated, 137 (96%) girls [mean (SD) age: 12.9 (SD 3.0) years]. Participating boys (n = 5) were excluded from further analysis. The 1-year prevalence of a severe sports injury episode was 31%. The most common injury locations for these injuries were the knee (25%), ankle (20%), and hip/groin (15%). In the multiple model, having sustained a severe injury episode was associated with older age (OR 1.2, 95% CI 1.1–1.4; p = 0.002) and an increased number of skipped meals per week (OR 1.1, 95% CI 1.0–1.3; p = 0.014). The point prevalence of an ongoing injury episode was 19%. The most common locations were the knee (24%), ankle (24%), and foot (24%). Having an ongoing injury episode was associated with older age (OR 1.4, 95% CI 1.2–1.7; p < 0.001) and an increased number of skipped meals per week (OR 1.1, 95% CI 1.0–1.3; p = 0.049).Conclusion: One-third of young female Swedish competitive figure skaters had sustained a severe injury episode during the past year, and a fifth reported an ongoing episode. Older age and an increased number of skipped meals per week were associated with a sports injury episode. Long-term monotonous physical loads with increasing intensity and insufficient energy intake appear to predispose for injury in young female figure skaters. Further examination of injury determinants among competitive figure skaters is highly warranted.

Objectives: To evaluate the prevalence and persistence of snoring during the first two years of life in two Finnish birth cohorts and to assess the associated factors. Study design: The study population comprised 947 children from the CHILD-SLEEP (CS) and 1393 children from the FinnBrain (FB) birth cohorts. Questionnaires were provided to both parents when the child was 24 months of age. The questionnaire consisted of parts concerning the child's sleep and environmental factors. Results: The combined prevalence of habitual snoring in the two birth cohorts at the age of 24 months was 2.3% (95% CI 1.5-3.1), which is markedly lower than reported previously. Children suffering from recurrent infections (CS odds ratio (OR) 3.9, 95% CI 1.2-12.5) or asthma (FB OR 4.3, 1.4-13.5) snored habitually more often. Both the mother's (CS OR 3.2, 1.2-9.0) and father's (CS OR 3.4, 1.4-8.0) snoring every night added to the risk of the child snoring. In the multivariate models, parental snoring (CS adjusted odds ratio (ORa) 2.8, 1.1-6.8), the mother's lower level of education (CS ORa 2.9, 1.2-7.5, FB ORa 2.1, 1.0-4.5), and the mother's lower monthly income (FB ORa 2.9, 1.3-6.3) associated with the child's habitual snoring. Conclusions: The prevalence of habitual snoring in two Finnish birth cohorts is lower than reported previously. The independent risk factors for habitual snoring at the age of two years were the parents' snoring and the mother's low income and low education. Objectives: To evaluate the prevalence and persistence of snoring during the first two years of life in two Finnish birth cohorts and to assess the associated factors. Study design: The study population comprised 947 children from the CHILD-SLEEP (CS) and 1393 children from the FinnBrain (FB) birth cohorts. Questionnaires were provided to both parents when the child was 24 months of age. The questionnaire consisted of parts concerning the child's sleep and environmental factors. Results: The combined prevalence of habitual snoring in the two birth cohorts at the age of 24 months was 2.3% (95% CI 1.5-3.1), which is markedly lower than reported previously. Children suffering from recurrent infections (CS odds ratio (OR) 3.9, 95% CI 1.2-12.5) or asthma (FB OR 4.3, 1.4-13.5) snored habitually more often. Both the mother's (CS OR 3.2, 1.2-9.0) and father's (CS OR 3.4, 1.4-8.0) snoring every night added to the risk of the child snoring. In the multivariate models, parental snoring (CS adjusted odds ratio (ORa) 2.8, 1.1-6.8), the mother's lower level of education (CS ORa 2.9, 1.2-7.5, FB ORa 2.1, 1.0-4.5), and the mother's lower monthly income (FB ORa 2.9, 1.3-6.3) associated with the child's habitual snoring. Conclusions: The prevalence of habitual snoring in two Finnish birth cohorts is lower than reported previously. The independent risk factors for habitual snoring at the age of two years were the parents' snoring and the mother's low income and low education. (C) 2021 The Authors. Published by Elsevier B.V.

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.

Neurons are polarized in structure with a cytoplasmic compartment extending into dendrites and a long axon that terminates at the synapse. The high level of compartmentalization imposes specific challenges for protein quality control in neurons making them vulnerable to disturbances that may lead to neurological dysfunctions including neuropsychiatric diseases. Synapse and dendrites undergo structural modulations regulated by neuronal activity involve key proteins requiring strict control of their turnover rates and degradation pathways. Recent advances in the study of the unfolded protein response (UPR) and autophagy processes have brought novel insights into the specific roles of these processes in neuronal physiology and synaptic signaling. In this review, we highlight recent data and concepts about UPR and autophagy in neuropsychiatric disorders and synaptic plasticity including a brief outline of possible therapeutic approaches to influence UPR and autophagy signaling in these diseases. Funding Agencies|Academy of FinlandAcademy of Finland; Finska Lakaresallskapet; Magnus Ehrnrooth Foundation; Liv and Halsa Foundation; Parkinson Foundation Finland; Minerva Foundation; EU H2020-MSCA-RISE-2016European Union (EU) [73479]; Swedish Research CouncilSwedish Research Council [201802623, 2019-05820]; Region Ostergotland [LIO-795611, LIO897641]; Region South-East Sweden [FORSS-807001, FORSS-849051]

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.

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.

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.

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.

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.

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.

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.

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.

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.

Transgenic mice with overexpression of the caspase-inhibitor, X-chromosome-linked inhibitor of apoptosis protein (XIAP) in Purkinje cell (PC) and in retinal bipolar cells (RBCs) were produced to study the regulation of cell death. Unexpectedly, an increased neurodegeneration was observed in the PCs in these L7-XIAP mice after the third postnatal week with the mice exhibiting severe ataxia. The loss of PCs was independent of Bax as shown by crossing the L7-XIAP mice with Bax gene–deleted mice. Electron microscopy revealed intact organelles in PCs but with the stacking of ER cisterns indicative of cell stress. Immunostaining for cell death proteins showed an increased phosphorylation of c-Jun in the PCs, suggesting an involvement in cell degeneration. Apart from PCs, the number of RBCs was decreased in adult retina in line with the expression pattern for the L7 promoter. The data show that overexpression of the anti-apoptotic protein XIAP in vulnerable neurons leads to enhanced cell death. The mechanisms underlying this neurodegeneration can be related to the effects of XIAP on cell stress and altered cell signaling., Supported by Sigrid Juselius Foundation, Academy of Finland, EU Biotech Grant, Liv och Hälsa, Maud Kuistila, Ylppö Foundation, Uppsala University and Minerva Foundation. We thank Dr. Urmas Arumäe for discussions, and Dr. Patrik Ernfors for the Bax KO mice, and Eeva Lehto for technical assistance. L7AUG was a kind gift from Dr. J. Oberdick, Ohio State University, USA.

Mitochondrial dysfunction has been linked to several neurodegenerative diseases such as Parkinson's disease (PD). Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) is a master gene for mitochondrial biogenesis and has been shown to be neuroprotective in models of PD. In this work we have studied the mechanisms by which peroxisome proliferator-activated receptor-γ (PPARγ) selective agonist N-(2-benzoylphenyl)-O-[2-(methyl-2-pyridinylamino)ethyl]-l-tyrosine hydrate (GW1929) acts on human dopaminergic neurons in culture. Data showed that GW1929 increased the viability of human dopaminergic neurons and protected them against oxidative stress induced by H2O2 and the mitochondrial toxin Rotenone. The enhanced resilience of the neurons was attributed to increased levels of mitochondrial antioxidants and of PGC-1α. GW1929 treatment further increased cell respiration, mitochondrial biogenesis and sirtuin-1 (SIRT1) expression in the human dopaminergic neurons. Phosphorylation of cAMP responsive element-binding protein (CREB) was also robustly increased in GW1929-treated cells. Together these results show that the PPARγ agonist GW1929 influences CREB signaling and PGC-1α activities in the human dopaminergic neurons contributing to an increased cell viability. This supports the view that drugs acting on the PPARγ-PGC-1α signaling in neurons may have beneficial effects in PD and possible also in other brain disorders.

XIAP (X chromosome-linked inhibitor of apoptosis protein) has been shown to inhibit cell death in a variety of cells. XIAP binds to active caspases, but XIAP also has a carboxy-terminal RING domain that can regulate cell death via protein degradation. Here we have studied the function of full-length and RING-deleted XIAP in mouse sympathetic neurons microinjected with expression plasmids and in neuroblastoma cells stably overexpressing these proteins. Both full-length and RING-deleted XIAP-protected sympathetic neurons against death induced by nerve growth factor (NGF) withdrawal to about the same extent. However, the two proteins were differentially localized in transfected neurons, with RING-deleted XIAP present in the cytoplasm and full-length XIAP found mostly in cytoplasmic protein aggregates, as revealed by transmission electron microscopy. The occurrence of these aggregates was blocked by lactacystin, a proteasome inhibitor. In neuroblastoma cells, RING-deleted XIAP protected against death induced by staurosporine, thapsigargin, or serum withdrawal, whereas full-length XIAP was without effect. Full-length, but not RING-deleted, XIAP was degraded and ubiquitinated in the neuroblastoma cells. The results show that the presence of the RING domain differentially affected the neuroprotective ability of XIAP in sensory neurons and neuroblastoma cells. The RING domain was essentially required for the proteasomal association of XIAP and for its ubiquitination.

Nerve growth factor (NGF) is a neurotrophic factor, which is expressed both in the nervous system and in peripheral organs. NGF is also present in mast cells, and in B- and T-lymphocytes, and may play a role in the immune cell development and differentiation. Various cytokines have been shown to affect NGF expression, and NGF is elevated in inflammation and in some autoimmune diseases. Here we have studied NGF concentrations in serum of pediatric patients with systemic lupus erythematosus (SLE) using a two-site enzyme-linked immunosorbent assay (ELISA). We have further correlated the levels of NGF to the inflammatory state of the disease. The mean value of serum NGF in SLE patients was significantly increased compared with controls (3346 vs 627pg/ml). There was a correlation between the activity of SLE and the levels of NGF. The results show that NGF is elevated in childhood SLE and that the levels are correlated with disease activity. The present results suggest that NGF may play a role in the pathogenesis of SLE and may have a prognostic value in evaluating the course of the disease and in outlining the medication.

Mitochondrial dysfunctions accompany several neurodegenerative disorders and contribute to disease pathogenesis among others in Parkinson’s disease (PD). Peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) is a major regulator of mitochondrial functions and biogenesis, and was suggested as a therapeutic target in PD. PGC-1α is regulated by both transcriptional and posttranslational events involving also the action of growth factors. Fibroblast growth factor-21 (FGF21) is a regulator of glucose and fatty acid metabolism in the body but little is known about its action in the brain. We show here that FGF21 increased the levels and activity of PGC-1α and elevated mitochondrial antioxidants in human dopaminergic cells in culture. The activation of PGC-1α by FGF21 occurred via the NAD+-dependent deacetylase Sirtuin-1 (SIRT1) subsequent to an increase in the enzyme, nicotinamide phosphoribosyltransferase (Nampt). FGF21 also enhanced mitochondrial respiratory capacity in human dopaminergic neurons as shown in real-time analyses of living cells. FGF21 is present in the brain including midbrain and is expressed by glial cells in culture. These results show that FGF21 activates PGC-1α and increases mitochondrial efficacy in human dopaminergic neurons suggesting that FGF21 could potentially play a role in dopaminergic neuron viability and in PD.

Rett syndrome is now considered to be a neurodevelopmental disease. Its cause is unknown, but it has been suggested that neuronal growth factors and neurotransmitters play important roles. We measured levels of brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor in cerebrospinal fluid, and nerve growth factor and brain-derived neurotrophic factor in serum in child and adolescent patients with Rett syndrome. Levels of brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor in cerebrospinal fluid were below the limit of sensitivity of the methods used. Serum levels of nerve growth factor and brain-derived neurotrophic factor did not differ from control values. In Rett syndrome, the normal serum levels of nerve growth factor together and previously reported low levels of the factor in cerebrospinal fluid indicate that the latter may reflect low levels of nerve growth factor in the central nervous system. (J Child Neurol 1998; 13:429-433).

SummaryBackground Enterovirus infections in childhood have been associated with a reduced risk of atopy in cross-sectional studies. Objective To study the relation between enterovirus infections in the first 2 years of life and atopic disease with IgE sensitization in a prospective study setting. Methods This was a nested case-control study among children who had been followed from birth. Neutralizing antibodies against 12 enterovirus serotypes were analysed at the age of 2 years from 71 atopic children and 142 non-atopic control children. Atopy was defined as having an atopic disease and IgE antibodies against at least one aeroallergen by the age of 5 years. Results Cumulative exposure to different enterovirus serotypes was inversely associated with atopy [odds ratio (OR) 0.73; 95% confidence interval (CI): 0.56-0.96]. The most pronounced protection was seen when echoviruses were analysed as a separate group (OR 0.63; 95%CI: 0.46–0.88). Conclusions and Clinical Relevance We propose that exposure to several different enteroviruses in early childhood is inversely associated with atopic diseases. Our results support the hypothesis that repeated microbial infections in early life may protect from atopic sensitization and atopic diseases.

Treatment with resveratrol (RSV) has been shown to protect vulnerable neurons after various brain injuries and in neurodegenerative diseases. The mechanisms for the effects of RSV in brain are not fully understood, but RSV may affect the expression of various gene products. RSV is structurally related to the synthetic estrogen, diethylstilbestrol so the effects of RSV may be gender-specific. Here we studied the role of RSV in the regulation of dopamine transporter (DAT) in the striatum using male and female mice. The basic levels of DAT in the striatum showed no sex difference, but the levels increased significantly by RSV (20 mg/kg i.p.) in female but not in male mice. Pretreatment of mice with the selective estrogen receptor (ER), ERα- and ERβ antagonist ICI 182,780, led to a complete block of RSV effect on DAT protein levels, suggesting that ERs are involved in the up-regulation of DAT by RSV. Similar data was also obtained in culture using human MESC2.10 and mouse SN4741 dopaminergic cells after treatment with RSV. Data further showed that RSV specifically induced gene transcription of DAT in the dopaminergic cells. These results show that estrogen receptors are involved in the up-regulation of DAT by RSV in the dopaminergic neurons, demonstrating a sex-dependent effect of RSV in the brain that may be of clinical importance. This article is part of a Special Issue entitled 'Post-Traumatic Stress Disorder'.

Resveratrol, a polyphenol derived e.g. from red grapes, has been shown to mediate several positive biological actions such as protection of cells against oxidative stress. It can also influence cell signaling, but the mechanisms behind its antioxidant properties are largely unknown. Here we show that RSV reduces oxidative stress and enhances cell survival in PC6.3 cells depending on the concentration. In these cells, RSV increased the levels of antioxidants, SOD2 and TRX2, and of X chromosome-linked inhibitor of apoptosis protein. RSV also activated NFκB signaling as shown using luciferase reporter constructs. These findings show that RSV regulates oxidative stress and mitochondrial antioxidants in neuronal cells. This may contribute to cell protection in various brain disorders.

Inflammation is part of many neurological disorders and immune reactions may influence neuronal progenitor cells (NPCs) contributing to the disease process. Our knowledge about the interplay between different cell types in brain inflammation are not fully understood. It is important to know the mechanisms and factors involved in order to enhance regeneration and brain repair. We show here that NPCs express receptors for interferon-gamma (IFNgamma), and IFNgamma activates the signal transducer and activator of transcription (STAT) protein-1. IFNgamma reduced cell proliferation in NPCs by upregulation of the cell cycle protein p21 as well as induced cell death of NPCs by activating caspase-3. Studies of putative factors for rescue showed that the neuropeptide, Pituitary adenylate cyclase-activating polypeptide (PACAP) increased cell viability, the levels of p-Bad and reduced caspase-3 activation in the NPCs. Medium from cultured microglia contained IFNgamma and decreased the viability of NPCs, whilst blocking with anti-IFNgamma antibodies counteracted this effect. The results show that NPCs are negatively influenced by IFNgamma whereas PACAP is able to modulate its action. The interplay between IFNgamma released from immune cells and PACAP is of importance in brain inflammation and may affect the regeneration and recruitment of NPCs in immune diseases. The observed effects of IFNgamma on NPCs deserve to be taken into account in human anti-viral therapies particularly in children with higher rates of brain stem cell proliferation.

We have previously identified the E3 ubiquitin ligase-inducible degrader of the low density lipoprotein receptor (LDLR) (Idol) as a post-translational modulator of LDLR levels. Idol is a direct target for regulation by liver X receptors (LXRs), and its expression is responsive to cellular sterol status independent of the sterol-response element-binding proteins. Here we demonstrate that Idol also targets two closely related LDLR family members, VLDLR and ApoE receptor 2 (ApoER2), proteins implicated in both neuronal development and lipid metabolism. Idol triggers ubiquitination of the VLDLR and ApoER2 on their cytoplasmic tails, leading to their degradation. We further show that the level of endogenous VLDLR is sensitive to cellular sterol content, Idol expression, and activation of the LXR pathway. Pharmacological activation of the LXR pathway in mice leads to increased Idol expression and to decreased Vldlr levels in vivo. Finally, we establish an unexpected functional link between LXR and Reelin signaling. We demonstrate that LXR activation results in decreased Reelin binding to VLDLR and reduced Dab1 phosphorylation. The identification of VLDLR and ApoER2 as Idol targets suggests potential roles for this LXR-inducible E3 ligase in the central nervous system in addition to lipid metabolism.

In this review, we highlight recent findings about the role of some mitochondrial proteins in neurological diseases. Studies in mice gene-deleted for Omi/HtrA2 and AIF showed the involvement of these mitochondrial proteins in selective cell degeneration in the spinal cord and brain. In humans, mutations in the mitochondrial protein, Paraplegin, cause an autosomal form of hereditary spastic paraplegia with an enhanced sensitivity to oxidative stress. Reactive oxygen species and decreased respiratory chain activity in mitochondria also contribute to common neurological diseases. The mitochondrial uncoupling protein, Ucp-2, was found to be neuroprotective in experimental stroke and brain trauma. Recent proteomic and profiling studies have revealed the existence of additional mitochondrial proteins with unknown functions. The elucidation of the physiological functions of mitochondrial proteins may lead to new insights into the role of these organelles in cell degeneration and to identification of novel drug targets for the prevention and treatment of different diseases.

Neuronal apoptosis inhibitory protein (NAIP) has been linked to the inherited disease, spinal muscular atrophy (SMA), which occurs in children with degeneration of the motorneurons. In the nervous system, NAIP is expressed by specific classes of neurons including spinal motorneurons. Recently, NAIP was shown to interact with hippocalcin, which belongs to the neuronal calcium sensor (NCS) protein family. Here we have studied this interaction in more detail, using deletions and a mutagenesis of the third baculovirus inhibitory repeat (BIR) motif in NAIP, and functional assays for neuronal death. The results showed that specific amino acids and the zinc finger domain in BIR3 are needed for efficient interaction of NAIP with hippocalcin. Cotransfections of NAIP-BIR3 and hippocalcin resulted in translocation and colocalisation of the two proteins in neuroblastoma cells. This was accompanied by an enhanced resistance towards cell death induced by high levels of calcium. In contrast, expression of NAIP-BIR3 and hippocalcin in sympathetic neurons did not protect against death induced by nerve growth factor (NGF) withdrawal. The results demonstrate a functional interaction of hippocalcin with NAIP-BIR3, which in neuroblastoma cells leads to rescue of cells after high intracellular calcium, but which in sympathetic neurons had no significant effect. The results indicate that NAIP in conjunction with hippocalcin can affect the survival of some, but not all neural cells, and this interaction may play a role in the neurodegenerative processes in SMA, and possible other human disorders.

Nerve growth factor (NGF) in cerebrospinal fluid was measured by ELISA in ten children with postinfectious diseases and in five children with diseases suggested to be of autoimmune etiology. Three groups of patients were studied: (1) those with moderately elevated concentrations (50.67 +/- 17.02 pg/mL, mean and SEM), (2) those with high concentrations (mean 424.25 +/- 125.41 pg/mL, mean and SEM), and (3) those with enormously high concentrations (mean 2,745 +/- 1,819.46 pg/mL, mean and SEM). We suggest that CSF-NGF could be used as an immunologic marker of an ongoing CNS process. Uncontrolled signaling of NGF receptors may lead to long-term inflammatory and autoimmune responses, which in turn can lead to disease.

Background Neural progenitor cells (NPCs) in the developing neuroepithelium are regulated by intrinsic and extrinsic factors. There is evidence that NPCs form a self-supporting niche for cell maintenance and proliferation. However, molecular interactions and cell-cell contacts and the microenvironment within the neuroepithelium are largely unknown. We hypothesized that cellular proteases especially those associated with the cell surface of NPCs play a role in regulation of progenitor cells in the brain. Methodology/Principal Findings In this work, we show that NPCs, isolated from striatal anlage of developing rat brain, express hepatocyte growth factor activator inhibitor-1 and -2 (HAI-1 and HAI-2) that are cell surface-linked serine protease inhibitors. In addition, radial glia cells derived from mouse embryonic stem cells also express HAI-1 and HAI-2. To study the functional significance of HAI-1 and HAI-2 in progenitor cells, we modulated their levels using expression plasmids or silencing RNA (siRNA) transfected into the NPCs. Data showed that overexpression of HAI-1 or HAI-2 decreased cell proliferation of cultured NPCs, whilst their siRNAs had opposite effects. HAI-1 also influenced NPC differentiation by increasing the number of glial fibrillary acidic protein (GFAP) expressing cells in the culture. Expression of HAI-1 in vivo decreased cell proliferation in developing neuroepithelium in E15 old animals and promoted astrocyte cell differentiation in neonatal animals. Studying the regulation of HAI-1, we observed that Bone morphogenetic protein-2 (BMP-2) and BMP-4 increased HAI-1 levels in the NPCs. Experiments using HAI-1-siRNA showed that these BMPs act on the NPCs partly in a HAI-1-dependent manner. Conclusions This study shows that the cell-surface serine protease inhibitors, HAI-1 and HAI-2 influence proliferation and cell fate of NPCs and their expression levels are linked to BMP signaling. Modulation of the levels and actions of HAI-1 in NPCs may be of a potential value in stem cell therapies in various brain diseases.

We wanted to analyze the basis for the distinction between OX(1) and OX(2) orexin receptors by the known agonists, orexin-A, orexin-B and Ala(11), D-Leu(15)-orexin-B, of which the latter two show some selectivity for OX(2). For this, chimaeric OX(1)/OX(2) and OX(2)/OX(1) orexin receptors were generated. The receptors were transiently expressed in HEK-293 cells, and potencies of the agonists to elicit cytosolic Ca(2+) elevation were measured. The results show that the N-terminal regions of the receptor are most important, and the exchange of the area from the C-terminal part of the transmembrane helix 2 to the transmembrane helix 4 is enough to lead to an almost total change of the receptor's ligand profile.