Integrative genomics reveals pathogenic mediator of valproate-induced neurodevelopmental disability

Prenatal exposure to the anti-seizure medication sodium valproate (VPA) is associated with an increased risk of adverse postnatal neurodevelopmental outcomes, including lowered intellectual ability, autism spectrum disorder and attention-deficit hyperactivity disorder. In this study, we aimed to clarify the molecular mechanisms underpinning the neurodevelopmental consequences of gestational VPA exposure using integrative genomics. First, we assessed the effect of gestational VPA on fetal brain gene expression using a validated rat model of valproate teratogenicity that mimics the human scenario of chronic oral valproate treatment during pregnancy at doses which are therapeutically relevant to the treatment of epilepsy. Two different rat strains were studied - inbred Genetic Absence Epilepsy Rats from Strasbourg (GAERS), a model of genetic generalized epilepsy, and inbred Non-Epileptic Control rats. Female rats were fed standard chow or VPA mixed in standard chow for 2 weeks prior to conception and then mated with same-strain males. In the VPA-exposed rats maternal oral treatment was continued throughout pregnancy. Fetuses were extracted via C-section on gestational day 21 (one day prior to birth) and fetal brains were snap frozen and genome-wide gene expression data generated. We found that gestational VPA exposure via chronic maternal oral dosing was associated with substantial drug-induced differential gene expression in the pup brains, including dysregulated splicing, and observed that this occurred in the absence of evidence for significant neuronal gain or loss. The functional consequences of VPA-induced gene expression were explored using pathway analysis and integration with genetic risk data for psychiatric disease and behavioural traits. The set of genes down-regulated by VPA in the pup brains were significantly enriched for pathways related to neurodevelopment and synaptic function, and significantly enriched for heritability to human intelligence, schizophrenia and bipolar disorder. Our results provide a mechanistic link between chronic fetal VPA exposure and neurodevelopmental disability mediated by VPA-induced transcriptional dysregulation

The ASSIST Study - The BD Odon Device for assisted vaginal birth: a safety and feasibility study.

BACKGROUND: Assisted vaginal birth is a vital health intervention that can result in better outcomes for mothers and their babies when complications arise in the second stage of labour. Unfortunately, instruments for assisted vaginal birth (forceps and ventouse) are often not utilised in settings where there is most clinical need, resulting in maternal and neonatal morbidity and mortality which could have been prevented. The BD Odon Device is a new device for assisted vaginal birth that may be able to address this unmet need. However, before dissemination, the device requires evaluation in robust clinical trials. A feasibility study to investigate the clinical impact, safety, and acceptability of the BD Odon Device for assisted vaginal birth is therefore planned. This will provide further information on acceptability, recruitment, and the outcome data required to design a future randomised controlled trial of the BD Odon Device versus Kiwi ventouse. METHODS: Forty women who require an assisted vaginal birth for a recognised clinical indication will have the birth assisted with the BD Odon Device. The primary outcome is successful vaginal birth completed with the BD Odon Device. Secondary clinical outcomes include maternal and neonatal outcomes, and maternal and practitioner satisfaction. Safety data will be reviewed following every birth. DISCUSSION: A future randomised controlled trial of the BD Odon Device versus the current standard instrument (the Kiwi ventouse) is planned. The findings of the ASSIST Study will inform the randomised controlled trial design. TRIAL REGISTRATION: ISRCTN, ISRCTN10203171 . Prospectively registered on 27 July 2018

Muscle loss following a single high-dose intramuscular injection of corticosteroids to treat disease flare in patients with rheumatoid arthritis.

OBJECTIVE: Adverse changes in body composition, specifically decreased muscle mass (MM) and increased fat mass, characterize rheumatoid arthritis (RA). These changes, termed rheumatoid cachexia (RC), are important contributors to the disability and elevated co-morbidity risk of RA. Recently, we observed substantial muscle loss (~2 kg) in a patient with RA following a single intramuscular (IM) corticosteroid (CS) injection to treat a disease flare. The aim of the current study is to determine whether this apparent iatrogenic effect of IM CS is typical, i.e., does this routine, recommended treatment contribute to RC? METHODS: Body composition was assessed by dual-energy X-ray absorptiometry (DXA) in eight patients with established RA who received a 120 mg IM methylprednisolone injection to treat a disease flare. DXA scans estimated appendicular lean mass (ALM; a surrogate measure of MM), total lean mass (LM), and total and regional adiposity at baseline (injection day) and 4 weeks and 6-9 months post-injection. Statistical analysis was performed using one-way ANOVA. RESULTS: There was significant loss of ALM (-0.93 kg, p=0.001, 95% CI [-0.49, -1.36]) and a trend toward reduced LM (-1.10 kg, p=0.165, 95% CI [0.58, -2.79]) at 4 weeks relative to baseline. At 6-9 months despite control of inflammation and disease activity, these losses remained. CONCLUSION: Substantial muscle loss occurred in patients with RA following IM CS injection to treat a disease flare. Thus, this recommended treatment appears to exacerbate RC, thereby potentially increasing disability and co-morbidity risk. If this effect is confirmed by larger studies, the role of one-off high-dose CS in the treatment of RA should be reviewed

In Vivo Measurement of Hippocampal GABAA/cBZR Density with [18F]-Flumazenil PET for the Study of Disease Progression in an Animal Model of Temporal Lobe Epilepsy

PURPOSE: Imbalance of inhibitory GABAergic neurotransmission has been proposed to play a role in the pathogenesis of temporal lobe epilepsy (TLE). This study aimed to investigate whether [(18)F]-flumazenil ([(18)F]-FMZ) PET could be used to non-invasively characterise GABA(A)/central benzodiazepine receptor (GABA(A)/cBZR) density and affinity in vivo in the post-kainic acid status epilepticus (SE) model of TLE. METHODS: Dynamic [(18)F]-FMZ -PET scans using a multi-injection protocol were acquired in four male wistar rats for validation of the partial saturation model (PSM). SE was induced in eight male Wistar rats (10 weeks of age) by i.p. injection of kainic acid (7.5–25 mg/kg), while control rats (n = 7) received saline injections. Five weeks post-SE, an anatomic MRI scan was acquired and the following week an [(18)F]-FMZ PET scan (3.6–4.6 nmol). The PET data was co-registered to the MRI and regions of interest drawn on the MRI for selected structures. A PSM was used to derive receptor density and apparent affinity from the [(18)F]-FMZ PET data. KEY FINDINGS: The PSM was found to adequately model [(18)F]-FMZ binding in vivo. There was a significant decrease in hippocampal receptor density in the SE group (p<0.01), accompanied by an increase in apparent affinity (p<0.05) compared to controls. No change in cortical receptor binding was observed. Hippocampal volume reduction and cell loss was only seen in a subset of animals. Histological assessment of hippocampal cell loss was significantly correlated with hippocampal volume measured by MRI (p<0.05), but did not correlate with [(18)F]-FMZ binding. SIGNIFICANCE: Alterations to hippocampal GABA(A)/cBZR density and affinity in the post-kainic acid SE model of TLE are detectable in vivo with [(18)F]-FMZ PET and a PSM. These changes are independent from hippocampal cell and volume loss. [(18)F]-FMZ PET is useful for investigating the role that changes GABA(A)/cBZR density and binding affinity play in the pathogenesis of TLE

Dermatosis neglecta in a case of multiple fractures, shoulder dislocation and radial nerve palsy in a 35-year-old man: a case report

<p>Abstract</p> <p>Introduction</p> <p>Dermatosis neglecta is an often misdiagnosed and under-diagnosed condition. In dermatosis neglecta, a progressive accumulation of sebum, sweat, keratin and other dirt and debris, occurs due to inadequate local hygiene resulting in a localized hyperpigmented patch or a verrucous plaque. Vigorous rubbing with alcohol-soaked gauze or soap and water results in a complete resolution of the lesion. This is the first case of dermatosis neglecta reported in a patient with multiple traumatic injuries.</p> <p>Case presentation</p> <p>We report a case of a 35-year-old male Caucasian of Pakistani origin, with multiple fractures, neurological deficit and immobility sustained in a fall, leading to the development of dermatosis neglecta of the left hand.</p> <p>Conclusion</p> <p>Early and prompt clinical recognition of this condition eliminates the need for aggressive diagnostic and therapeutic procedures.</p

Astrophysical Fluids of Novae: High Resolution Pre-decay X-ray spectrum of V4743 Sagittarii

Eight X-ray observations of V4743 Sgr (2002), observed with Chandra and XMM-Newton are presented. The nova turned off some time between days 301.9 and 371, and the X-ray flux subsequently decreased from day 301.9 to 526 following an exponential decline time scale of $(96 \pm 3)$ days. We use the absorption lines present in the SSS spectrum for diagnostic purposes, and characterize the physics and the dynamics of the expanding atmosphere during the explosion of the nova. The information extracted from this first stage is then used as input for computing full photoionization models of the ejecta in V4743 Sgr. The SSS spectrum is modeled with a simple black-body and multiplicative Gaussian lines, which provides us of a general kinematical picture of the system, before it decays to its faint phase (Ness et al. 2003). In the grating spectra taken between days 180.4 and 370, we can resolve the line profiles of absorption lines arising from H-like and He-like C, N, and O, including transitions involving higher principal quantum numbers. Except for a few interstellar lines, all lines are significantly blue-shifted, yielding velocities between 1000 and 6000 km/s which implies an ongoing mass loss. It is shown that significant expansion and mass loss occur during this phase of the explosion, at a rate $\dot{M} \approx (3-5) \times 10^{-4} ~ (\frac{L}{L_{38}}) ~ M_{\odot}/yr$. Our measurements show that the efficiency of the amount of energy used for the motion of the ejecta, defined as the ratio between the kinetic luminosity $L_{\rm kin}$ and the radiated luminosity $L_{\rm rad}$, is of the order of one.Comment: 25 pages, 9 figures. Accepted in book: Recent Advances in Fluid Dynamics with Environmental Applications, pp.365-39

X-Ray Emitting Blast Wave from the Recurrent Nova RS Ophiuchi

Stellar explosions such as novae and supernovae produce most of the heavy elements in the Universe. Although the onset of novae from runaway thermonuclear fusion reactions on the surface of a white dwarf in a binary star system is understood[1], the structure, dynamics, and mass of the ejecta are not well known. In rare cases, the white dwarf is embedded in the wind nebula of a red-giant companion; the explosion products plow through the nebula and produce X-ray emission. Early this year, an eruption of the recurrent nova RS Ophiuchi[2,3] provided the first opportunity to perform comprehensive X-ray observations of such an event and diagnose conditions within the ejecta. Here we show that the hard X-ray emission from RS Ophiuchi early in the eruption emanates from behind a blast wave, or outward-moving shock wave, that expanded freely for less than 2 days and then decelerated due to interaction with the nebula. The X-rays faded rapidly, suggesting that the blast wave deviates from the standard spherical shell structure[4-6]. The early onset of deceleration indicates that the ejected shell had a low mass, the white dwarf has a high mass[7], and that RS Ophiuchi is a progenitor of the type of supernova integral to studies of the expansion of the universe.Comment: To appear in Nature; 7 pages, including 2 color figures; removed incorrect statement of embargo polic

Phenotypic heterogeneity in IGHV-mutated CLL patients has prognostic impact and identifies a subset with increased sensitivity to BTK and PI3Kδ inhibition

The majority of chronic lymphocytic leukemia (CLL) patients are diagnosed with early-stage disease but the currently used prognostic tools appear to be less informative in this group of patients.1 This is especially problematic for patients with mutated immunoglobulin genes (M-CLL) as they have a more diverse clinical course when compared with patients with unmutated immunoglobulin genes (U-CLL).1, 2, 3, 4 Given the emergence of promising targeted, less toxic, therapeutics in CLL,5, 6 there is an increased need to identify patients who might benefit from early treatment with these new agents

Describing the genetic architecture of epilepsy through heritability analysis

Epilepsy is a disease with substantial missing heritability; despite its high genetic component, genetic association studies have had limited success detecting common variants which influence susceptibility. In this paper, we reassess the role of common variants on epilepsy using extensions of heritability analysis. Our data set consists of 1258 UK patients with epilepsy, of which 958 have focal epilepsy, and 5129 population control subjects, with genotypes recorded for over 4 million common single nucleotide polymorphisms. Firstly, we show that on the liability scale, common variants collectively explain at least 26% (standard deviation 5%) of phenotypic variation for all epilepsy and 27% (standard deviation 5%) for focal epilepsy. Secondly we provide a new method for estimating the number of causal variants for complex traits; when applied to epilepsy, our most optimistic estimate suggests that at least 400 variants influence disease susceptibility, with potentially many thousands. Thirdly, we use bivariate analysis to assess how similar the genetic architecture of focal epilepsy is to that of non-focal epilepsy; we demonstrate both significant differences (P = 0.004) and significant similarities (P = 0.01) between the two subtypes, indicating that although the clinical definition of focal epilepsy does identify a genetically distinct epilepsy subtype, there is also scope to improve the classification of epilepsy by incorporating genotypic information. Lastly, we investigate the potential value in using genetic data to diagnose epilepsy following a single epileptic seizure; we find that a prediction model explaining 10% of phenotypic variation could have clinical utility for deciding which single-seizure individuals are likely to benefit from immediate anti-epileptic drug therapy