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

A core outcome set for localised prostate cancer effectiveness trials : protocol for a systematic review of the literature and stakeholder involvement through interviews and a Delphi survey

Acknowledgements We would like to thank Professor Craig Ramsay, Professor Luke Vale, and Professor Vikki Entwistle for their comments on earlier drafts of the protocol. This study is funded by the Cancer Research Aberdeen and North East Scotland (CRANES) charity. Paula Williamson would like to acknowledge funding from the European Union Seventh Framework Programme (FP7/2007-2013, FP7/2007-2011) under grant agreement number 305081 for the COMET initiative, which provided support for this work.Peer reviewedPublisher PD

Active sites for ice nucleation differ depending on nucleation mode

The nucleation of ice crystals in clouds is poorly understood, despite being of critical importance for our planet's climate. Nucleation occurs largely at rare "active sites" present on airborne particles such as mineral dust, but the nucleation pathway is distinct under different meteorological conditions. These give rise to two key nucleation pathways where a particle is either immersed in a supercooled liquid water droplet (immersion freezing mode) or suspended in a supersaturated vapor (deposition mode). However, it is unclear if the same active sites are responsible for nucleation in these two modes. Here, we directly compare the sites that are active in these two modes by performing immersion freezing and deposition experiments on the same thin sections of two atmospherically important minerals (feldspar and quartz). For both substrates, we confirm that nucleation is dominated by a limited number of sites and show that there is little correlation between the two sets of sites operating in each experimental method: across both materials, only six out of 73 sites active for immersion freezing nucleation were also active for deposition nucleation. Clearly, different properties determine the activity of nucleation sites for each mode, and we use the pore condensation and freezing concept to argue that effective deposition sites have size and/or geometry requirements not of relevance to effective immersion freezing sites. Hence, the ability to nucleate is pathway dependent, and the mode of nucleation has to be explicitly considered when applying experimental data in cloud models. [Abstract copyright: Copyright © 2021 the Author(s). Published by PNAS.

Effect of prior general anesthesia or sedation and antiseizure drugs on the diagnostic utility of wireless video electroencephalography in dogs

Background Ambulatory wireless video electroencephalography (AEEG) is the method of choice to discriminate epileptic seizures from other nonepileptic episodes. However, the influence of prior general anesthesia (GA), sedation, or antiseizure drug (ASD) on the diagnostic ability of AEEG is unknown. Hypothesis/Objectives The use of sedation/GA or ASD treatment before AEEG recording may affect the diagnostic ability of AEEG and the time to first abnormality on AEEG. Animals A total of 108 client-owned dogs undergoing ambulatory AEEG for paroxysmal episodes. Methods Retrospective cohort study. Proportions of diagnostic AEEG and time to first abnormality were compared between dogs that received sedation/GA or neither for instrumentation as well as dogs receiving at least 1 ASD and untreated dogs. Results Ambulatory EEG was diagnostic in 60.2% of all dogs including 49% of the sedation/GA dogs and 68% of dogs that received neither (odds ratio [OR], 2.25; 95% confidence interval [CI], 1.02-5.00;P= .05). The AEEG was diagnostic in 51% of dogs receiving at least 1 ASD and 66% of untreated dogs (OR, 1.95; 95% CI, 0.9-4.3;P= .11). No difference was found in time to first abnormality between sedation/GA or neither or ASD-treated or untreated dogs (P= .1 andP= .3 respectively). Ninety-five percent of dogs had at least 1 abnormality within 277 minutes. Conclusion and Clinical Importance Sedation/GA and concurrent ASD administration were not identified as confounding factors for decreasing AEEG diagnostic capability nor did they delay the time to first abnormality. A 4-hour minimal recording period is recommended.Peer reviewe

Containment - exploring the concept of agency in children’s statutory encounters with social workers

This article examines children’s agency in their interactions with social workers during statutory encounters in a child protection context. It draws from a UK wide ethnographic study. It finds that much of social workers’ responses to children’s agency in this context are best understood as a form of ‘containment’. In doing so, it offers an original and significant contribution to the theoretical understanding of children’s agency, as well as its application in social work practice

A Galaxy at z = 6.545 and Constraints on the Epoch of Reionization

We report the discovery of a Lyman-alpha-emitting galaxy at redshift z=6.545 serendipitously identified in the course of spectroscopic follow-up of hard X-ray sources on behalf of the Serendipitous Extragalactic X-Ray Source Identification (SEXSI) survey. The line flux of the galaxy, 2.1e-17 erg/cm2/s, is similar to line fluxes probed by narrow-band imaging surveys; the 5.2 square-arcminutes surveyed implies a surface density of z~6.5 Lyman-alpha emitters somewhat higher than that inferred from narrow-band surveys. This source marks the sixth Lyman-alpha-emitting galaxy identified at z~6.5, a redshift putatively beyond the epoch of reionization when the damping wings of the neutral hydrogen of the intergalactic medium is capable of severely attenuating Lyman-alpha emission. By comparing the Lyman-alpha emitter luminosity functions at z~5.7 and z~6.5, we infer that the intergalactic medium may remain largely reionized from the local universe out to z~6.5.Comment: 16 pages, 4 figures; submitted to the Astrophysical Journa

Acquisition of Maternal Education and its Relation to Single Word Reading in Middle Childhood: An Analysis of the Millennium Cohort Study

Maternal education captured at a single time point is commonly employed as a predictor of a child's cognitive development. In this paper we ask what bearing the acquisition of additional qualifications has upon reading performance in middle childhood. This was a secondary analysis of the UK's Millennium Cohort Study, a birth cohort of 18,000 children born in 2000. Our outcome variable was Single Word Reading from the British Abilities Scales at 7 years. Predictors included maternal age and education, relative poverty and parity. Increasing maternal education over time was associated with improved child outcomes with a 2 month developmental advantage for children whose mothers had increased education over those whose mothers had not. Parity was important but conditional on this, there was no evidence of child attainment reducing for the children of older mothers. A time-varying education level model is consistent with an input quality mechanism for language development.casl63pub4328pub

Distribution and characterisation of Glucagon-like peptide-1 receptor expressing cells in the mouse brain.

OBJECTIVE: Although Glucagon-like peptide 1 is a key regulator of energy metabolism and food intake, the precise location of GLP-1 receptors and the physiological relevance of certain populations is debatable. This study investigated the novel GLP-1R-Cre mouse as a functional tool to address this question. METHODS: Mice expressing Cre-recombinase under the Glp1r promoter were crossed with either a ROSA26 eYFP or tdRFP reporter strain to identify GLP-1R expressing cells. Patch-clamp recordings were performed on tdRFP-positive neurons in acute coronal brain slices from adult mice and selective targeting of GLP-1R cells in vivo was achieved using viral gene delivery. RESULTS: Large numbers of eYFP or tdRFP immunoreactive cells were found in the circumventricular organs, amygdala, hypothalamic nuclei and the ventrolateral medulla. Smaller numbers were observed in the nucleus of the solitary tract and the thalamic paraventricular nucleus. However, tdRFP positive neurons were also found in areas without preproglucagon-neuronal projections like hippocampus and cortex. GLP-1R cells were not immunoreactive for GFAP or parvalbumin although some were catecholaminergic. GLP-1R expression was confirmed in whole-cell recordings from BNST, hippocampus and PVN, where 100 nM GLP-1 elicited a reversible inward current or depolarisation. Additionally, a unilateral stereotaxic injection of a cre-dependent AAV into the PVN demonstrated that tdRFP-positive cells express cre-recombinase facilitating virally-mediated eYFP expression. CONCLUSIONS: This study is a comprehensive description and phenotypic analysis of GLP-1R expression in the mouse CNS. We demonstrate the power of combining the GLP-1R-CRE mouse with a virus to generate a selective molecular handle enabling future in vivo investigation as to their physiological importance

Acquisition of Growth-Inhibitory Antibodies against Blood-Stage Plasmodium falciparum

Background: Antibodies that inhibit the growth of blood-stage Plasmodium falciparum may play an important role in acquired and vaccine-induced immunity in humans. However, the acquisition and activity of these antibodies is not well understood. Methods: We tested dialysed serum and purified immunoglobulins from Kenyan children and adults for inhibition of P. falciparum blood-stage growth in vitro using different parasite lines. Serum antibodies were measured by ELISA to bloodstage parasite antigens, extracted from P. falciparum schizonts, and to recombinant merozoite surface protein 1 (42 kDa Cterminal fragment, MSP1-42). Results: Antibodies to blood-stage antigens present in schizont protein extract and to recombinant MSP1-42 significantly increased with age and were highly correlated. In contrast, growth-inhibitory activity was not strongly associated with age and tended to decline marginally with increasing age and exposure, with young children demonstrating the highest inhibitory activity. Comparison of growth-inhibitory activity among samples collected from the same population at different time points suggested that malaria transmission intensity influenced the level of growth-inhibitory antibodies. Antibodies to recombinant MSP1-42 were not associated with growth inhibition and high immunoglobulin G levels were poorly predictive of inhibitory activity. The level of inhibitory activity against different isolates varied. Conclusions: Children can acquire growth-inhibitory antibodies at a young age, but once they are acquired they do not appear to be boosted by on-going exposure. Inhibitory antibodies may play a role in protection from early childhood malaria

Chandra Detection of a TypeII Quasar at z=3.288

We report on observations of a TypeII quasar at redshift z=3.288, identified as a hard X-ray source in a 185 ks observation with the Chandra X-ray Observatory and as a high-redshift photometric candidate from deep, multiband optical imaging. CXOJ084837.9+445352 (hereinafter CXO52) shows an unusually hard X-ray spectrum from which we infer an absorbing column density N(H) = (4.8+/-2.1)e23 / cm2 (90% confidence) and an implied unabsorbed 2-10 keV rest-frame luminosity of L(2-10) = 3.3e44 ergs/s, well within the quasar regime. Hubble Space Telescope imaging shows CXO52 to be elongated with slight morphological differences between the WFPC2 F814W and NICMOS F160W bands. Optical and near-infrared spectroscopy of CXO52 show high-ionization emission lines with velocity widths ~1000 km/s and flux ratios similar to a Seyfert2 galaxy or radio galaxy. The latter are the only class of high-redshift TypeII luminous AGN which have been extensively studied to date. Unlike radio galaxies, however, CXO52 is radio quiet, remaining undetected at radio wavelengths to fairly deep limits, f(4.8GHz) < 40 microJy. High-redshift TypeII quasars, expected from unification models of active galaxies and long-thought necessary to explain the X-ray background, are poorly constrained observationally with few such systems known. We discuss recent observations of similar TypeII quasars and detail search techniques for such systems: namely (1) X-ray selection, (2) radio selection, (3) multi-color imaging selection, and (4) narrow-band imaging selection. Such studies are likely to begin identifying luminous, high-redshift TypeII systems in large numbers. We discuss the prospects for these studies and their implications to our understanding of the X-ray background.Comment: 28 pages, 5 figures; to appear in The Astrophysical Journa