Predicting language change between three and five years and its implications for early identification

BACKGROUND AND OBJECTIVE: Early language delays across the preschool period have important implications for children, parents, and services raising the significance of early identification. Screening tests are an appealing solution but have proved problematic. A combined risk model would seem promising but has yet to be tested. The goal of this study was to examine the factors that predict language change in a nationally representative sample of children between 3 and 5 years when most children are identified as being in need of services. METHODS: By using data from children (n = 13 016) in the Millennium Cohort Study (a national UK birth cohort), linear regression was used to predict 5-year performance from 3-year test performance data coupled with sociodemographic and within-child factors and indicators of parental concern. Patterns of change were identified and logistic regression was used to predict the difference between children for whom profiles change and those for whom they do not. RESULTS: The final model (predicting 32% of the variance) included maternal education, pattern construction, behavior, language concerns, and 3-year vocabulary. Four change patterns were identified: one consistently low (n = 201), one consistently high (n = 12 066), a group that is resilient (n = 572), and one with a declining profile (n = 177). The models accurately predicted 71% of the declining group and 99% of the resilient group. Maternal education (odds ratio: 0.49) and behavior (odds ratio: 0.9) were significant predictors for the former and maternal education (odds ratio: 0.6) and pattern construction (odds ratio: 1.03) the latter. CONCLUSIONS: Early identification of delayed language remains problematic but, once identified, there are key indicators that predict which children are likely to be more or less at risk across time. The implications are discussed in terms of policy and practice. Copyright 2012 by the American Academy of Pediatrics.CIHR130pub279

Novel SCN9A mutations underlying extreme pain phenotypes: unexpected electrophysiological and clinical phenotype correlations.

The importance of NaV1.7 (encoded by SCN9A) in the regulation of pain sensing is exemplified by the heterogeneity of clinical phenotypes associated with its mutation. Gain-of-function mutations are typically pain-causing and have been associated with inherited erythromelalgia (IEM) and paroxysmal extreme pain disorder (PEPD). IEM is usually caused by enhanced NaV1.7 channel activation, whereas mutations that alter steady-state fast inactivation often lead to PEPD. In contrast, nonfunctional mutations in SCN9A are known to underlie congenital insensitivity to pain (CIP). Although well documented, the correlation between SCN9A genotypes and clinical phenotypes is still unclear. Here we report three families with novel SCN9A mutations. In a multiaffected dominant family with IEM, we found the heterozygous change L245 V. Electrophysiological characterization showed that this mutation did not affect channel activation but instead resulted in incomplete fast inactivation and a small hyperpolarizing shift in steady-state slow inactivation, characteristics more commonly associated with PEPD. In two compound heterozygous CIP patients, we found mutations that still retained functionality of the channels, with two C-terminal mutations (W1775R and L1831X) exhibiting a depolarizing shift in channel activation. Two mutations (A1236E and L1831X) resulted in a hyperpolarizing shift in steady-state fast inactivation. To our knowledge, these are the first descriptions of mutations with some retained channel function causing CIP. This study emphasizes the complex genotype-phenotype correlations that exist for SCN9A and highlights the C-terminal cytoplasmic region of NaV1.7 as a critical region for channel function, potentially facilitating analgesic drug development studies.J.J.C. and A.M.H. were supported by an MRC Research Career Development fellowship. F.M.G., F.R., and E.C.E. were supported by Wellcome Trust Senior Fellowships WT088357/Z/09/Z and WT084210/Z/07/Z and MRC Grant MC_UU_12012/3. C.G.W. was supported by the Cambridge Biomedical Research Campus.This is the final published version. It first appeared at http://www.jneurosci.org/content/35/20/7674.short

Exploring the links between star formation and minor companions around isolated galaxies

Previous studies have shown that galaxies with minor companions exhibit an elevated star formation rate. We reverse this inquiry, constructing a volume-limited sample of \simL\star (Mr \leq -19.5 + 5 log h) galaxies from the Sloan Digital Sky Survey that are isolated with respect to other luminous galaxies. Cosmological simulations suggest that 99.8% of these galaxies are alone in their dark matter haloes with respect to other luminous galaxies. We search the area around these galaxies for photometric companions. Matching strongly star forming (EW(H{\alpha})\geq 35 \AA) and quiescent (EW(H{\alpha})< 35 \AA) samples for stellar mass and redshift using a Monte Carlo resampling technique, we demonstrate that rapidly star-forming galaxies are more likely to have photometric companions than other galaxies. The effect is relatively small; about 11% of quiescent, isolated galaxies have minor photometric companions at radii \leq 60 kpc h$^{-1}$ kpc while about 16% of strongly star-forming ones do. Though small, the cumulative difference in satellite counts between strongly star-forming and quiescent galaxies is highly statistically significant (PKS = 1.350 \times10$^{-3}$) out to to radii of \sim 100 h$^{-1}$ kpc. We discuss explanations for this excess, including the possibility that \sim 5% of strongly star-forming galaxies have star formation that is causally related to the presence of a minor companion.Comment: 7 pages, 6 figures, submitted to MNRA

A probabilistic analysis of argument cogency

This paper offers a probabilistic treatment of the conditions for argument cogency as endorsed in informal logic: acceptability, relevance, and sufficiency. Treating a natural language argument as a reason-claim-complex, our analysis identifies content features of defeasible argument on which the RSA conditions depend, namely: change in the commitment to the reason, the reason’s sensitivity and selectivity to the claim, one’s prior commitment to the claim, and the contextually determined thresholds of acceptability for reasons and for claims. Results contrast with, and may indeed serve to correct, the informal understanding and applications of the RSA criteria concerning their conceptual dependence, their function as update-thresholds, and their status as obligatory rather than permissive norms, but also show how these formal and informal normative approachs can in fact align

A novel NGF mutation clarifies the molecular mechanism and extends the phenotypic spectrum of the HSAN5 neuropathy

Background Nerve growth factor beta (NGF beta) and tyrosine kinase receptor type A (TRKA) are a well studied neurotrophin/receptor duo involved in neuronal survival and differentiation. The only previously reported hereditary sensory neuropathy caused by an NGF mutation, c.661C>T (HSAN5), and the pathology caused by biallelic mutations in the TRKA gene (NTRK1) (HSAN4), share only some clinical features. A consanguineous Arab family, where five of the six children were completely unable to perceive pain, were mentally retarded, did not sweat, could not discriminate temperature, and had a chronic immunodeficiency, is reported here. The condition is linked to a new homozygous mutation in the NGF gene, c. [680C>A]+[681_682delGG].Methods Genetic linkage and standard sequencing techniques were used to identify the causative gene. Using wild-type or mutant over-expression constructs transfected into PC12 and COS-7 cells, the cellular and molecular consequences of the mutations were investigated.Results The mutant gene produced a precursor protein V232fs that was unable to differentiate PC12 cells. V232fs was not secreted from cells as mature NGF beta.Conclusions Both the clinical and cellular data suggest that the c.[680C>A]+[ 681 682delGG] NGF mutation is a functional null. The HSAN5 phenotype is extended to encompass HSAN4-like characteristics. It is concluded that the HSAN4 and HSAN5 phenotypes are parts of a phenotypic spectrum caused by changes in the NGF/ TRKA signalling pathway

How Do Disks Survive Mergers?

We develop a physical model for how galactic disks survive and/or are destroyed in interactions. Based on dynamical arguments, we show gas primarily loses angular momentum to internal torques in a merger. Gas within some characteristic radius (a function of the orbital parameters, mass ratio, and gas fraction of the merging galaxies), will quickly lose angular momentum to the stars sharing the perturbed disk, fall to the center and be consumed in a starburst. A similar analysis predicts where violent relaxation of the stellar disks is efficient. Our model allows us to predict the stellar and gas content that will survive to re-form a disk in the remnant, versus being violently relaxed or contributing to a starburst. We test this in hydrodynamic simulations and find good agreement as a function of mass ratio, orbital parameters, and gas fraction, in simulations spanning a wide range in these properties and others, including different prescriptions for gas physics and feedback. In an immediate sense, the amount of disk that re-forms can be understood in terms of well-understood gravitational physics, independent of details of ISM gas physics or feedback. This allows us to explicitly quantify the requirements for such feedback to (indirectly) enable disk survival, by changing the pre-merger gas content and distribution. The efficiency of disk destruction is a strong function of gas content: we show how and why sufficiently gas-rich major mergers can, under general conditions, yield systems with small bulges (B/T<0.2). We provide prescriptions for inclusion of our results in semi-analytic models.Comment: 32 pages, 16 figures, accepted to ApJ (minor revisions to match accepted version

Congenital Insensitivity to Pain: Novel SCN9A Missense and In-Frame Deletion Mutations

SCN9A encodes the voltage-gated sodium channel Nav1.7, a protein highly expressed in pain-sensing neurons. Mutations in SCN9A cause three human pain disorders: bi-allelic loss of function mutations result in Channelopathy-associated Insensitivity to Pain (CIP), whereas activating mutations cause severe episodic pain in Paroxysmal Extreme Pain Disorder (PEPD) and Primary Erythermalgia (PE). To date, all mutations in SCN9A that cause a complete inability to experience pain are protein truncating and presumably lead to no protein being produced. Here, we describe the identification and functional characterization of two novel non-truncating mutations in families with CIP: a homozygously-inherited missense mutation found in a consanguineous Israeli Bedouin family (Nav1.7-R896Q) and a five amino acid in-frame deletion found in a sporadic compound heterozygote (Nav1.7-ΔR1370-L1374). Both of these mutations map to the pore region of the Nav1.7 sodium channel. Using transient transfection of PC12 cells we found a significant reduction in membrane localization of the mutant protein compared to the wild type. Furthermore, voltage clamp experiments of mutant-transfected HEK293 cells show a complete loss of function of the sodium channel, consistent with the absence of pain phenotype. In summary, this study has identified critical amino acids needed for the normal subcellular localization and function of Nav1.7. © 2010 Wiley-Liss, Inc

Galaxy Pairs in the Sloan Digital Sky Survey - III: Evidence of Induced Star Formation from Optical Colours

We have assembled a large, high quality catalogue of galaxy colours from the Sloan Digital Sky Survey Data Release 7, and have identified 21,347 galaxies in pairs spanning a range of projected separations (r_p < 80 h_{70}^{-1} kpc), relative velocities (\Delta v < 10,000 km/s, which includes projected pairs that are essential for quality control), and stellar mass ratios (from 1:10 to 10:1). We find that the red fraction of galaxies in pairs is higher than that of a control sample matched in stellar mass and redshift, and demonstrate that this difference is likely due to the fact that galaxy pairs reside in higher density environments than non-paired galaxies. We detect clear signs of interaction-induced star formation within the blue galaxies in pairs, as evidenced by a higher fraction of extremely blue galaxies, along with blueward offsets between the colours of paired versus control galaxies. These signs are strongest in close pairs (r_p < 30 h_{70}^{-1} kpc and \Delta v < 200 km/s), diminish for more widely separated pairs (r_p > 60 h_{70}^{-1} kpc and \Delta v < 200 km/s) and disappear for close projected pairs (r_p < 30 h_{70}^{-1} kpc and \Delta v > 3000 km/s). These effects are also stronger in central (fibre) colours than in global colours, and are found primarily in low- to medium-density environments. Conversely, no such trends are seen in red galaxies, apart from a small reddening at small separations which may result from residual errors with photometry in crowded fields. When interpreted in conjunction with a simple model of induced starbursts, these results are consistent with a scenario in which close peri-centre passages trigger induced star formation in the centres of galaxies which are sufficiently gas rich, after which time the galaxies gradually redden as they separate and their starbursts age.Comment: 17 pages. Accepted for publication in MNRA

Galaxy Pairs in the Sloan Digital Sky Survey - II: The Effect of Environment on Interactions

We use a sample of close galaxy pairs selected from the Sloan Digital Sky Survey Data Release 4 (SDSS DR4) to investigate in what environments galaxy mergers occur and how the results of these mergers depend on differences in local galaxy density. The galaxies are quantified morphologically using two-dimensional bulge-plus-disk decompositions and compared to a control sample matched in stellar mass, redshift and local projected density. Lower density environments have fractionally more galaxy pairs with small projected separations (r_p) and relative velocities (Delta v), but even high density environments contain significant populations of pairs with parameters that should be conducive to interactions. Metrics of asymmetry and colour are used to identify merger activity and triggered star formation. The location of star formation is inferred by distinguishing bulge and disk colours and calculating bulge fractions from the SDSS images. Galaxies in the lowest density environments show the largest changes in star formation rate, asymmetry and bulge-total fractions at small separations, accompanied by bluer bulge colours. At the highest local densities, the only galaxy property to show an enhancement in the closest pairs is asymmetry. We interpret these results as evidence that whilst interactions (leading to tidal distortions) occur at all densities, triggered star formation is seen only in low-to-intermediate density environments. We suggest that this is likely due to the typically higher gas fractions of galaxies in low density environments. Finally, by cross-correlating our sample of galaxy pairs with a cluster catalogue, we investigate the dependence of interactions on clustercentric distance. It is found that for close pairs the fraction of asymmetric galaxies is highest in the cluster centres.Comment: Accepted by MNRAS, 15 page

Am J Hum Genet

Fuhrmann syndrome and the Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome are considered to be distinct limb-malformation disorders characterized by various degrees of limb aplasia/hypoplasia and joint dysplasia in humans. In families with these syndromes, we found homozygous missense mutations in the dorsoventral-patterning gene WNT7A and confirmed their functional significance in retroviral-mediated transfection of chicken mesenchyme cell cultures and developing limbs. The results suggest that a partial loss of WNT7A function causes Fuhrmann syndrome (and a phenotype similar to mouse Wnt7a knockout), whereas the more-severe limb truncation phenotypes observed in Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome result from null mutations (and cause a phenotype similar to mouse Shh knockout). These findings illustrate the specific and conserved importance of WNT7A in multiple aspects of vertebrate limb development