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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.

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.

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.

X chromosome-linked inhibitor of apoptosis protein is an endogenous inhibitor of caspases and is an important regulator of cell death. XIAP can also influence cell signaling, but downstream proteins affected are largely unknown. We show here using neuronal PC6.3 cells that XIAP increases the levels of antioxidants, particularly superoxide dismutase-2 that is localized to mitochondria. Studies using reporter constructs and NF-kappaB Rel-A deficient mouse embryonic fibroblasts showed that NF-kappaB signaling is required for the induction of Sod2 by XIAP. XIAP also reduced oxidative stress in the PC6.3 cells as shown by decreased production of reactive oxygen species. These findings disclose a novel role for XIAP in control of oxidative stress and mitochondrial antioxidants that may contribute to cell protection after various injuries.

Amyotrophic lateral sclerosis (ALS) is characterized by the selective degeneration of motor neurons. The cause for nerve cell demise is not clear but involves activation of the caspase family of cysteine proteases. We have shown that ER stress and caspase-12 activation occur in ALS transgenic mice carrying the mutant copper/zinc superoxide dismutase (SOD1) gene. In these mice, we found that the antiapoptotic proteins, X-linked Inhibitor of Apoptosis Protein (XIAP) and the related protein, MIAP2 were decreased. To study the role of this, we generated double transgenic mice expressing XIAP in ALS spinal cord neurons using the Thy1 promoter. Overexpression of XIAP inhibited caspase-12 cleavage and reduced calpain activity in the ALS mice. XIAP also reduced the breakdown of calpastatin that is an inhibitor of calpain. In the double transgenic mice, life span was increased by about 12%. These data support the view that XIAP has beneficial effects in ALS and extends survival. The neuroprotective effect of XIAP involves inhibition of caspases and the stabilization of the calpastatin/calpain system that is altered in the ALS mice.

Nine-day-old transgenic XIAP overexpressing (TG-XIAP) and wild-type mice were subjected to left carotid artery ligation and 10% O(2) for 60 min, leading to widespread infarctions in the ipsilateral hemisphere during reperfusion. The activation of caspase-3 and -9 seen in wild-type animals was virtually abolished in TG-XIAP mice. Tissue loss was significantly reduced from 54.4 +/- 4.1 mm(3) (mean +/- SEM) in wild-type mice to 33.1 +/- 2.1 mm(3) in the TG-XIAP mice. Injured neurons displayed stronger XIAP staining during reperfusion, particularly in the nuclei. XIAP was colocalized with XAF-1, Smac, and HtrA2 in injured neurons after hypoxia-ischemia (HI). XIAP was cleaved after HI, and Smac immunoprecipitation co-precipitated a 25-kDa C-terminal fragment of XIAP, indicating that Smac preferentially bound to cleaved XIAP. These findings provide the first evidence that increased XIAP levels protect the neonatal brain against HI.

X-chromosome linked inhibitor of apoptosis protein (XIAP) is a member of the inhibitor of apoptosis protein (IAP) family and known to inhibit death of various cells under different experimental conditions. Although present in brain tissue, little is known about the physiology of the IAPs in nerve cells. Here we report on the establishment of transgenic mice with overexpression of human XIAP in brain neurons. The mice developed normally, and were more resistant to brain injury caused by transient forebrain ischemia after occlusion of the middle cerebral artery compared to control mice. The XIAP transgenic animals exhibited significantly smaller brain damage, as shown by TUNEL labelling, less reduction in brain protein synthesis, and less active caspase-3 after ischemia compared with controls. Upregulation of RhoB, which is an early indicator of neurological damage, was markedly reduced in the XIAP-overexpressing mice, which had also a better neurological outcome than control animals. This together with the increase in XIAP in normal mouse brain in regions surviving the infarct demonstrates that XIAP is an important factor promoting neuronal survival after ischemia. The results suggest that interference with the levels and the activity of XIAP in neurons may provide targets for the development of drugs limiting neuronal death after ischemia, and possibly in other brain injuries.

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.

Estrogen has profound effects on function and plasticity of the nervous system. Receptors for estrogen (ERs) are expressed by neurons in several areas of the brain. Here we demonstrate that embryonic and adult rat neural stem cells (NSC) express ERalpha and ERbeta, 17beta-Estradiol treatment decreased the proliferation of NSC stimulated by epidermal growth factor (EGF), which was due to the upregulation of the cyclin-dependent kinase (CDK) inhibitor, p21(Cip1). The modulatory effect of 17beta-estradiol on EGF was more pronounced in adult NSC. However, 17beta-estradiol alone increased the proliferation of embryonic, but not adult, NSC. The effect of 17beta-estradiol was inhibited by the ER antagonist, ICI-182780, showing an involvement of ERs. 17beta-Estradiol also increased the ratio of neurons to glia cells in embryonic NSC, but not in adult NSC, suggesting an influence on neurogenesis during embryonic development. The data show that estrogen, via ER, affects the proliferation and differentiation of NSC cells, probably acting in conjunction with other factors governing NSC development.

Hepatocyte growth factor (HGF) is a secreted cytokine which is expressed in the central nervous system (CNS) together with its specific receptor MET. Since HGF exerts strong neurotrophic activity including motoneurons, we have further analysed whether the HGF/MET axis is defective in patients with amyotrophic lateral sclerosis (ALS). Intrathecal HGF-secretion was measured in cerebrospinal fluid (CSF) from patients with amyotrophic lateral sclerosis and in controls without neurological diseases using a specific sandwich immunoassay (ELISA). MET-expression was analysed by immunohistology in spinal cord cross-sections of ALS patients and unaffected controls. The HGF concentrations in CSF were moderately but significantly increased in ALS patients compared to healthy controls (580 pg/ml vs 348 pg/ml). MET-protein was detectable in spinal cord motoneurons of patients with ALS as well as unaffected controls. The data demonstrate that ALS does not show a lack of the trophic signalling axis, HGF/MET, suggesting that the signalling system itself is not affected. The moderate increase in HGF-secretion may represent a compensatory effect.

XIAP (X-chromosome-linked inhibitor of apoptosis protein) is an antiapoptotic protein which inhibits the activity of caspases and suppresses cell death. However, little is known about the presence and function of XIAP in the nervous system. Here we report that XIAP mRNA is expressed in developing and adult rat brain. Using a specific antibody, we observed XIAP-immunoreactive cells in different brain regions, among others, in the hippocampus and cerebral cortex. Kainic acid, which induces delayed cell death of specific neurons, increased the levels of XIAP in the CA3 region of hippocampus. XIAP was, however, largely absent in cells undergoing cell death, as shown by TUNEL labeling and staining for active caspase-3. In cultured hippocampal neurons, XIAP was initially upregulated by kainic acid and then degraded in a process blocked by the caspase-3 inhibitor DEVD. Similarly, recombinant XIAP is cleaved by active caspase-3 in vitro. The results show that there is biphasic regulation of XIAP in the hippocampus following kainic acid and that XIAP becomes a target for caspase-3 activated during cell death in the hippocampus. The degradation of XIAP by kainic acid contributes to neuronal cell death observed in vulnerable neurons of the hippocampus after caspase activation.

We have previously reported increased concentrations of interleukin (1L)-6 in CSF from patients with tonic-clonic seizures, where increased cytokine production most likely is a consequence of neuronal epileptic activity associated with seizures. The biological effects of IL-6 are mediated by other cytokines, which are studied here in addition to IL-6. The purpose of this study was to analyze levels of soluble cytokines from plasma and CSF from patients with newly developed tonic-clonic seizures. The concentrations of IL-6, IL-1 receptor antagonist (IL-1RA), IL-1beta, tumor necrosis factor (TNFalpha) and nerve growth factor (NGF) were measured from plasma and CSF from 22 patients with newly developed tonic-clonic seizures within 24 h from the seizure and 18 controls. The mean concentrations of IL-6 were significantly increased in CSF (P