Relative age in the school year and risk of mental health problems in childhood, adolescence, and young adulthood

Purpose Relative age within the school year (‘relative age’) is associated with increased rates of symptoms and diagnoses of mental health disorders, including ADHD. We aimed to investigate how relative age influences mental health and behaviour before, during and after school (age range: 4–25 years). Method We used a regression discontinuity design to examine the effect of relative age on risk of mental health problems using data from a large UK population-based cohort (Avon Longitudinal Study of Parents and Children (ALSPAC); N = 14,643). We compared risk of mental health problems between ages 4 and 25 years using the parent-rated Strengths and Difficulties Questionnaire (SDQ), and depression using self-rated and parent-rated Short Mood and Feelings Questionnaire (SMFQ) by relative age. Results The youngest children in the school year have greater parent-rated risk of mental health problems, measured using parent-rated SDQ total difficulties scores. We found no evidence of differences before school entry [estimated standardised mean difference (SMD) between those born on 31 August and 1 September: .02 (−.05, .08)]. We found that estimates of effect size for a 1-year difference in relative age were greatest at 11 years [SMD: .22 (.15, .29)], but attenuated to the null at 25 years [SMD: −.02 (−.11, .07)]. We did not find consistent evidence of differences in self-rated and parent-rated depression by relative age. Conclusions Younger relative age is associated with poorer parent-rated general mental health, but not symptoms of depression

Nuclear factor I-A represses expression of the cell adhesion molecule L1

<p>Abstract</p> <p>Background</p> <p>The neural cell adhesion molecule L1 plays a crucial role in development and plasticity of the nervous system. Neural cells thus require precise control of L1 expression.</p> <p>Results</p> <p>We identified a full binding site for nuclear factor I (NFI) transcription factors in the regulatory region of the mouse <it>L1 </it>gene. Electrophoretic mobility shift assay (EMSA) showed binding of nuclear factor I-A (NFI-A) to this site. Moreover, for a brain-specific isoform of NFI-A (NFI-A bs), we confirmed the interaction <it>in vivo </it>using chromatin immunoprecipitation (ChIP). Reporter gene assays showed that in neuroblastoma cells, overexpression of NFI-A bs repressed L1 expression threefold.</p> <p>Conclusion</p> <p>Our findings suggest that NFI-A, in particular its brain-specific isoform, represses <it>L1 </it>gene expression, and might act as a second silencer of L1 in addition to the neural restrictive silencer factor (NRSF).</p

Gene expression analysis of nuclear factor I-A deficient mice indicates delayed brain maturation

BACKGROUND: Nuclear factor I-A (NFI-A), a phylogenetically conserved transcription/replication protein, plays a crucial role in mouse brain development. Previous studies have shown that disruption of the Nfia gene in mice leads to perinatal lethality, corpus callosum agenesis, and hydrocephalus. RESULTS: To identify potential NFI-A target genes involved in the observed tissue malformations, we analyzed gene expression in brains from Nfia(-/- )and Nfia(+/+ )littermate mice at the mRNA level using oligonucleotide microarrays. In young postnatal animals (postnatal day 16), 356 genes were identified as being differentially regulated, whereas at the late embryonic stage (embryonic day 18) only five dysregulated genes were found. An in silico analysis identified phylogenetically conserved NFI binding sites in at least 70 of the differentially regulated genes. Moreover, assignment of gene function showed that marker genes for immature neural cells and neural precursors were expressed at elevated levels in young postnatal Nfia(-/- )mice. In contrast, marker genes for differentiated neural cells were downregulated at this stage. In particular, genes relevant for oligodendrocyte differentiation were affected. CONCLUSION: Our findings suggest that brain development, especially oligodendrocyte maturation, is delayed in Nfia(-/- )mice during the early postnatal period, which at least partly accounts for their phenotype. The identification of potential NFI-A target genes in our study should help to elucidate NFI-A dependent transcriptional pathways and contribute to enhanced understanding of this period of brain formation, especially with regard to the function of NFI-A

Pathology of a mouse mutation in peripheral myelin protein P0 is characteristic of a severe and early onset form of human Charcot-Marie-Tooth type 1B disorder

Mutations in the gene of the peripheral myelin protein zero (P0) give rise to the peripheral neuropathies Charcot-Marie-Tooth type 1B disease (CMT1B), Déjérine-Sottas syndrome, and congenital hypomyelinating neuropathy. To investigate the pathomechanisms of a specific point mutation in the P0 gene, we generated two independent transgenic mouse lines expressing the pathogenic CMT1B missense mutation Ile106Leu (P0sub) under the control of the P0 promoter on a wild-type background. Both P0sub-transgenic mouse lines showed shivering and ultrastructural abnormalities including retarded myelination, onion bulb formation, and dysmyelination seen as aberrantly folded myelin sheaths and tomacula in all nerve fibers. Functionally, the mutation leads to dispersed compound muscle action potentials and severely reduced conduction velocities. Our observations support the view that the Ile106Leu mutation acts by a dominant-negative gain of function and that the P0sub-transgenic mouse represents an animal model for a severe, tomaculous form of CMT1B

Cell surface sialylation and fucosylation are regulated by the cell recognition molecule L1 via PLCγ and cooperate to modulate embryonic stem cell survival and proliferation

AbstractCell surface glycosylation patterns are markers of cell type and status. However, the mechanisms regulating surface glycosylation patterns remain unknown. Using a panel of carbohydrate markers, we have shown that cell surface sialylation and fucosylation are upregulated in L1-transfected embryonic stem cells (L1-ESCs). Consistently, the mRNA levels of sialyltransferase ST6Gal1 and ST3Gal4, and fucosyltransferase FUT9 were significantly increased in L1-transfected ESCs. Activation of L1 signaling promoted cell survival and inhibited cell proliferation. ShRNAs knocking down FUT9, ST6Gal1 and ST3Gal4 blocked these effects. A phospholipase Cγ (PLCγ) inhibitor and shRNA reduced ST6Gal1, ST3Gal4 and FUT9 mRNA levels in the L1-ESCs. Thus, embryonic stem cell surface sialylation and fucosylation are regulated via PLCγ by L1, with which they cooperate to modulate cell survival and proliferation

Assessing the long-term effectiveness of interferon-beta and glatiramer acetate in multiple sclerosis: final 10-year results from the UK multiple sclerosis risk-sharing scheme

Background Because multiple sclerosis (MS) is a chronic disease causing disability over decades, it is crucial to know if the short-term effects of disease-modifying therapies reported in randomised controlled trials reduce long-term disability. This 10-year prospective observational study of disability outcomes (Expanded Disability Status Scale (EDSS) and utility) was set up, in conjunction with a risk-sharing agreement between payers and producers, to investigate this issue. Methods The outcomes of the UK treated patients were compared with a modelled untreated control based on the British Columbia MS data set to assess the long-term effectiveness of these treatments. Two complementary analysis models were used: a multilevel model (MLM) and a continuous Markov model. Results 4862 patients with MS were eligible for the primary analysis (mean and median follow-up times 8.7 and 10 years). EDSS worsening was reduced by 28% (MLM), 7% (Markov) and 24% time-adjusted Markov in the total cohort, and by 31% (MLM) and 14% (Markov) for relapsing remitting patients. The utility worsening was reduced by 23%–24% in the total cohort and by 24%–31% in the RR patients depending on the model used. All sensitivity analyses showed a treatment effect. There was a 4-year (CI 2.7 to 5.3) delay to EDSS 6.0. An apparent waning of treatment effect with time was seen. Subgroup analyses suggested better treatment effects in those treated earlier and with lower EDSS scores. Conclusions This study supports a beneficial effect on long-term disability with first-line MS disease-modifying treatments, which is clinically meaningful. However the waning effect noted requires further study

Residential exposure to radon and DNA methylation across the lifecourse: an exploratory study in the ALSPAC birth cohort [version 2; peer review: 2 approved, 1 not approved]

Background: Radon (and its decay products) is a known human carcinogen and the leading cause of lung cancer in never-smokers and the second in ever-smokers. The carcinogenic mechanism from radiation is a combination of genetic and epigenetic processes, but compared to the genetic mechanisms, epigenetic processes remain understudied in humans. This study aimed to explore associations between residential radon exposure and DNA methylation in the general population. Methods: Potential residential radon exposure for 75-metre area buffers was linked to genome-wide DNA methylation measured in peripheral blood from children and mothers of the Accessible Resource for Integrated Epigenomic Studies subsample of the ALSPAC birth cohort. Associations with DNA methylation were tested at over 450,000 CpG sites at ages 0, 7 and 17 years (children) and antenatally and during middle-age (mothers). Analyses were adjusted for potential residential and lifestyle confounding factors and were determined for participants with complete data (n = 786 to 980). Results: Average potential exposure to radon was associated in an exposure-dependent manner with methylation at cg25422346 in mothers during pregnancy, with no associations at middle age. For children, radon potential exposure was associated in an exposure-dependent manner with methylation of cg16451995 at birth, cg01864468 at age 7, and cg04912984, cg16105117, cg23988964, cg04945076, cg08601898, cg16260355 and cg26056703 in adolescence. Conclusions: Residential radon exposure was associated with DNA methylation in an exposure-dependent manner. Although chance and residual confounding cannot be excluded, the identified associations may show biological mechanisms involved in early biological effects from radon exposure

Residential exposure to radon and DNA methylation across the lifecourse:an exploratory study in the ALSPAC birth cohort

Background: Radon (and its decay products) is a known human carcinogen and the leading cause of lung cancer in never-smokers and the second in ever-smokers. The carcinogenic mechanism from radiation is a combination of genetic and epigenetic processes, but compared to the genetic mechanisms, epigenetic processes remain understudied in humans. This study aimed to explore associations between residential radon exposure and DNA methylation in the general population. Methods: Potential residential radon exposure for 75-metre area buffers was linked to genome-wide DNA methylation measured in peripheral blood from children and mothers of the Accessible Resource for Integrated Epigenomic Studies subsample of the ALSPAC birth cohort. Associations with DNA methylation were tested at over 450,000 CpG sites at ages 0, 7 and 17 years (children) and antenatally and during middle-age (mothers). Analyses were adjusted for potential residential and lifestyle confounding factors and were determined for participants with complete data (n = 786-980). Results: Average potential exposure to radon was associated in an exposure-dependent manner with methylation at cg25422346 in mothers during pregnancy, with no associations at middle age. For children, radon potential exposure was associated in an exposure-dependent manner with methylation of cg16451995 at birth, cg01864468 at age 7, and cg04912984, cg16105117, cg23988964, cg04945076, cg08601898, cg16260355 and cg26056703 in adolescence. Conclusions: Residential radon exposure was associated with DNA methylation in an exposure-dependent manner. Although residual confounding cannot be excluded, the identified associations may show biological mechanisms involved in early biological effects from radon exposure

Accretion-related properties of Herbig Ae/Be stars. Comparison with T Tauris

We look for trends relating the mass accretion rate (Macc) and the stellar ages (t), spectral energy distributions (SEDs), and disk masses (Mdisk) for a sample of 38 HAeBe stars, comparing them to analogous correlations found for classical T Tauri stars. Our goal is to shed light on the timescale and physical processes that drive evolution of intermediate-mass pre-main sequence objects. Macc shows a dissipation timescale \tau = 1.3^{+1.0}_{-0.5} Myr from an exponential law fit, while a power law yields Macc(t) \propto t^{-\eta}, with \eta = 1.8^{+1.4}_{-0.7}. This result is based on our whole HAeBe sample (1-6 Msun), but the accretion rate decline most probably depends on smaller stellar mass bins. The near-IR excess is higher and starts at shorter wavelengths (J and H bands) for the strongest accretors. Active and passive disks are roughly divided by 2 x 10^{-7} Msun/yr. The mid-IR excess and the SED shape from the Meeus et al. classification are not correlated with Macc. We find Macc \propto Mdisk^{1.1 +- 0.3}. Most stars in our sample with signs of inner dust dissipation typically show accretion rates ten times lower and disk masses three times smaller than the remaining objects. The trends relating Macc with the near-IR excess and Mdisk extend those for T Tauri stars, and are consistent with viscous disk models. The differences in the inner gas dissipation timescale, and the relative position of the stars with signs of inner dust clearing in the Macc-Mdisk plane, could be suggesting a slightly faster evolution, and that a different process - such as photoevaporation - plays a more relevant role in dissipating disks in the HAeBe regime compared to T Tauri stars. Our conclusions must consider the mismatch between the disk mass estimates from mm fluxes and the disk mass estimates from accretion, which we also find in HAeBe stars.Comment: 11 pages, 7 figures, 1 appendix. Accepted in A&