Functional Analysis of Missense Mutations in Kv8.2 Causing Cone Dystrophy with Supernormal Rod Electroretinogram

Mutations in KCNV2 have been proposed as the molecular basis for cone dystrophy with supernormal rod electroretinogram. KCNV2 codes for the modulatory voltage-gated potassium channel α-subunit, Kv8.2, which is incapable of forming functional channels on its own. Functional heteromeric channels are however formed with Kv2.1 in heterologous expression systems, with both α-subunit genes expressed in rod and cone photoreceptors. Of the 30 mutations identified in the KCNV2 gene, we have selected three missense mutations localized in the potassium channel pore and two missense mutations localized in the tetramerization domain for analysis. We characterized the differences between homomeric Kv2.1 and heteromeric Kv2.1/Kv8.2 channels and investigated the influence of the selected mutations on the function of heteromeric channels. We found that two pore mutations (W467G and G478R) led to the formation of nonconducting heteromeric Kv2.1/Kv8.2 channels, whereas the mutations localized in the tetramerization domain prevented heteromer generation and resulted in the formation of homomeric Kv2.1 channels only. Consequently, our study suggests the existence of two distinct molecular mechanisms involved in the disease pathology

Mechanical Properties of End-crosslinked Entangled Polymer Networks using Sliplink Brownian Dynamics Simulations

The mechanical properties of a polymeric network containing both crosslinks and sliplinks (entanglements) are studied using a multi-chain Brownian dynamics simulation. We coarse-grain at the level of chain segments connecting consecutive nodes (cross- or sliplinks), with particular attention to the Gaussian statistics of the network. Affine displacement of nodes is not imposed: their displacement as well as sliding of monomers through sliplinks is governed by force balances. The simulation results of stress in uniaxial extension and the full stress tensor in simple shear including the (non-zero) second normal stress difference are presented for monodisperse chains with up to 18 entanglements between two crosslinks. The cases of two different force laws of the subchains (Gaussian chains and chains with finite extensibility) for two different numbers of monomers in a subchain (no = 50 and no = 100) are examined. It is shown that the additivity assumption of slip- and crosslink contribution holds for sufficiently long chains with two or more entanglements, and that it can be used to construct the strain response of a network of infinitely long chains. An important consequence is that the contribution of sliplinks to the small-strain shear modulus is about ⅔ of the contribution of a crosslink

Metallic atomically-thin layered silicon epitaxially grown on silicene/ZrB2

Using low energy electron diffraction (LEED) and scanning tunnelling microscopy (STM), we observe a new two-dimensional (2D) silicon crystal that is formed by depositing additional Si atoms onto spontaneously-formed epitaxial silicene on a ZrB2 thin film. From scanning tunnelling spectroscopy (STS) studies, we find that this atomically-thin layered silicon has distinctly different electronic properties. Angle resolved photoelectron spectroscopy (ARPES) reveals that, in sharp contrast to epitaxial silicene, the layered silicon exhibits significantly enhanced density of states at the Fermi level resulting from newly formed metallic bands. The 2D growth of this material could allow for direct contacting to the silicene surface and demonstrates the dramatic changes in electronic structure that can occur by the addition of even a single monolayer amount of material in 2D systems

Supersymmetric Charged Clouds in AdS_5

We consider supersymmetric holographic flows that involve background gauge fields dual to chemical potentials in the boundary field theory. We use a consistent truncation of gauged N=8 supergravity in five dimensions and we give a complete analysis of the supersymmetry conditions for a large family of flows. We examine how the well-known supersymmetric flow between two fixed points is modified by the presence of the chemical potentials and this yields a new, completely smooth, solution that interpolates between two global AdS spaces of different radii and with different values of the chemical potential. We also examine some black-hole-like singular flows and a new non-supersymmetric black hole solution. We comment on the interpretation of our new solutions in terms of giant gravitons and discuss the implications of our work for finding black-hole solutions in AdS geometries.Comment: 31 pages, 6 figures; minor corrections, updated reference

Damage to Broca's area does not contribute to long-term speech production outcome after stroke

Broca’s area in the posterior half of the left inferior frontal gyrus has long been thought to be critical for speech production. The current view is that long-term speech production outcome in patients with Broca’s area damage is best explained by the combination of damage to Broca’s area and neighbouring regions including the underlying white matter, which was also damaged in Paul Broca’s two historic cases. Here, we dissociate the effect of damage to Broca’s area from the effect of damage to surrounding areas by studying long-term speech production outcome in 134 stroke survivors with relatively circumscribed left frontal lobe lesions that spared posterior speech production areas in lateral inferior parietal and superior temporal association cortices. Collectively, these patients had varying degrees of damage to one or more of nine atlas-based grey or white matter regions: Brodmann areas 44 and 45 (together known as Broca’s area), ventral premotor cortex, primary motor cortex, insula, putamen, the anterior segment of the arcuate fasciculus, uncinate fasciculus and frontal aslant tract. Spoken picture description scores from the Comprehensive Aphasia Test were used as the outcome measure. Multiple regression analyses allowed us to tease apart the contribution of other variables influencing speech production abilities such as total lesion volume and time post-stroke. We found that, in our sample of patients with left frontal damage, long-term speech production impairments (lasting beyond 3 months post-stroke) were solely predicted by the degree of damage to white matter, directly above the insula, in the vicinity of the anterior part of the arcuate fasciculus, with no contribution from the degree of damage to Broca’s area (as confirmed with Bayesian statistics). The effect of white matter damage cannot be explained by a disconnection of Broca’s area, because speech production scores were worse after damage to the anterior arcuate fasciculus with relative sparing of Broca’s area than after damage to Broca’s area with relative sparing of the anterior arcuate fasciculus. Our findings provide evidence for three novel conclusions: (i) Broca’s area damage does not contribute to long-term speech production outcome after left frontal lobe strokes; (ii) persistent speech production impairments after damage to the anterior arcuate fasciculus cannot be explained by a disconnection of Broca’s area; and (iii) the prior association between persistent speech production impairments and Broca’s area damage can be explained by co-occurring white matter damage, above the insula, in the vicinity of the anterior part of the arcuate fasciculus

Re-evaluation of the diagnosis of porphyria cutanea tarda in Admiral Sir Francis Beaufort

OBJECTIVES: Two biographies of Admiral Francis Beaufort (1774-1857) have stated that, aged 20-25 years, he suffered from porphyria cutanea tarda (PCT) that was 'cured' following severe blood loss during a naval skirmish. We have examined the evidence concerning the nature of his skin disease.  DESIGN: Primary records, most notably Beaufort's correspondence with his family, his journals and his father's diaries were sought out and analysed.  SETTING: This case report is discussed in the context of 18th-century naval medicine and concepts and treatment of skin disease.  RESULTS: The description of his lesions, their age of onset, their progression and response to treatment, particularly topical tar and associated features are quite inconsistent with a diagnosis of PCT. His mother, Mary Waller Beaufort (1739-1821), consulted Dr Robert Darwin in 1803 about a painful skin disease affecting her legs. Detailed description of the lesions and a contemporary diagnosis are not available but possible diagnoses include chronic psoriasis and stasis eczema.  CONCLUSIONS: A more tenable diagnosis is that Francis Beaufort had chronic plaque psoriasis remitted by bed rest and convalescence in the sunny Mediterranean climate with cessation of alcohol consumption and improved nutrition as well as topical and oral medications

Towards condom skills: a cross-sectional study of the association between condom proficiency, condom problems and STI risk amongst MSM

<p>Abstract</p> <p>Background</p> <p>Condom use problems are common amongst Scotland’s men who have sex with men (MSM). To date condom errors have been associated with the likelihood of sexually transmitted infections in heterosexual sexually transmitted infection (STI) clinic attendees but not in MSM and direct evidence of a link between condom problems and STI acquisition in MSM have been lacking. This study investigated the possibility of an independent association between condom proficiency, condom problems and STI acquisition in MSM in Scotland.</p> <p>Methods</p> <p>An exploratory observational design employed cross-sectional surveys in both STI clinic and community settings. Respondents completed self-report measures of socio-demographic variables, scales of condom proficiency and condom problems and numbers of different partners with whom men have had unprotected anal intercourse (UAI partners) in the preceding year. Self-report data was corroborated with clinical STI diagnosis where possible. Analysis included chi-squared and Mann–Whitney tests and multiple logistic regression.</p> <p>Results</p> <p>792 respondents provided data with an overall response rate of 70% (n = 459 clinic sample, n = 333 community sample). Number of UAI partners was the strongest predictor of self-reported STI acquisition over the previous 12 months (p < 0.001 in both clinic and community samples). Demographic characteristics were not associated with self-reported STI diagnosis. However, condom proficiency score was associated with self-reported STI acquisition (p < 0.05 in both samples). Condom problem score was also associated with self-reported STI diagnosis in the clinic (p = 0.001) but not the community sample. Condom problem score remained associated with self-reported STI diagnosis in the clinic sample after adjusting for number of UAI partners with logistic regression.</p> <p>Conclusions</p> <p>This exploratory study highlights the potential importance of targeted condom use skills interventions amongst MSM. It demands further research examining the utility of condom problem measures in wider populations, across prospective and experimental research designs, and a programme of research exploring their feasibility as a tool determining candidacy for brief interventions.</p

A survey of staffing levels in paediatric diabetes services throughout the UK

AIMS: To assess staffing levels of healthcare professionals involved in the care of children and young people with diabetes in the UK. METHODS: A web-based questionnaire was distributed to lead consultant paediatricians from all paediatric diabetes services in the UK between October and December 2014. Data on staffing levels and other aspects of diabetes services were collected and differences between the four nations of the UK and across the 10 English diabetes networks were explored. RESULTS: Some 175 services (93%) caring for 29 711 children and young people aged ≤ 24 years with diabetes participated in the survey. Northern Ireland and Wales had the lowest ratio of total staff to patient population. Nursing caseloads per one whole-time equivalent (WTE) nurse ranged from 71 patients in England to 110 patients in Northern Ireland with only 52% of the UK services meeting the Royal College of Nursing recommended nurse-to-patient ratio of < 1 : 70. Scotland and Northern Ireland had the highest ratio of consultants and fully trained doctors per 1000 patients (3.5 WTE). Overall, 17% of consultants had a Certificate of Completion of Training in Endocrinology and Diabetes. Some 44% of dietitians were able to adjust insulin dose. Only 43% of services provided 24-h access to advice from the diabetes team and 82% of services had access to a psychologist. Staffing levels adjusted for volume were not directly related to glycaemic performance of services in England and Wales. CONCLUSIONS: Wide variations in staffing levels existed across the four nations of the UK and important gaps were present in key areas

The Effects of Overexpression of Histamine Releasing Factor (HRF) in a Transgenic Mouse Model

Asthma is a disease that affects all ages, races and ethnic groups. Its incidence is increasing both in Westernized countries and underdeveloped countries. It involves inflammation, genetics and environment and therefore, proteins that exacerbate the asthmatic, allergic phenotype are important. Our laboratory purified and cloned a histamine releasing factor (HRF) that was a complete stimulus for histamine and IL-4 secretion from a subpopulation of allergic donors' basophils. Throughout the course of studying HRF, it was uncovered that HRF enhances or primes histamine release and IL-13 production from all anti-IgE antibody stimulated basophils. In order to further delineate the biology of HRF, we generated a mouse model.We constructed an inducible transgenic mouse model with HRF targeted to lung epithelial cells, via the Clara cells. In antigen naïve mice, overproduction of HRF yielded increases in BAL macrophages and statistical increases in mRNA levels for MCP-1 in the HRF transgenic mice compared to littermate controls. In addition to demonstrating intracellular HRF in the lung epithelial cells, we have also been able to document HRF's presence extracellularly in the BAL fluid of these transgenic mice. Furthermore, in the OVA challenged model, we show that HRF exacerbates the allergic, asthmatic responses. We found statistically significant increases in serum and BAL IgE, IL-4 protein and eosinophils in transgenic mice compared to controls.This mouse model demonstrates that HRF expression enhances allergic, asthmatic inflammation and can now be used as a tool to further dissect the biology of HRF

Design of the Quality of Life in Motion (QLIM) study: a randomized controlled trial to evaluate the effectiveness and cost-effectiveness of a combined physical exercise and psychosocial training program to improve physical fitness in children with cancer

<p>Abstract</p> <p>Background</p> <p>Childhood cancer and its treatment have considerable impact on a child's physical and mental wellbeing. Especially long-term administration of chemotherapy and/or radiotherapy impairs physical fitness both during and after therapy, when children often present with muscle weakness and/or low cardiorespiratory fitness. Physical exercise can improve these two elements of physical fitness, but the positive effects of physical exercise might be further increased when a child's wellbeing is simultaneously enhanced by psychosocial training. Feeling better may increase the willingness and motivation to engage in sports activities. Therefore, this multi-centre study evaluates the short and long-term changes in physical fitness of a child with a childhood malignancy, using a combined physical exercise and psychosocial intervention program, implemented during or shortly after treatment. Also examined is whether positive effects on physical fitness reduce inactivity-related adverse health problems, improve quality of life, and are cost-effective.</p> <p>Methods</p> <p>This multi-centre randomized controlled trial compares a combined physical and psychosocial intervention program for children with cancer, with care as usual (controls). Children with cancer (aged 8-18 years) treated with chemotherapy and/or radiotherapy, and who are no longer than 1 year post-treatment, are eligible for participation. A total of 100 children are being recruited from the paediatric oncology/haematology departments of three Dutch university medical centres. Patients are stratified according to pubertal stage (girls: age ≤10 or >10 years; boys: ≤11 or >11 years), type of malignancy (haematological or solid tumour), and moment of inclusion into the study (during or after treatment), and are randomly assigned to the intervention or control group.</p> <p>Discussion</p> <p>Childhood cancer patients undergoing long-term cancer therapy may benefit from a combined physical exercise and psychosocial intervention program since it may maintain or enhance their physical fitness and increase their quality of life. However, the feasibility, patient need, and effectiveness of such a program should be established before the program can be implemented as part of standard care.</p> <p>Trial registration number</p> <p>NTR1531 (The Netherlands National Trial Register)</p