Δευτέρα, 27 Νοεμβρίου 2017

Termination of reentrant atrial tachycardia via optogenetic stimulation with optimized spatial targeting: insights from computational models

Abstract

Optogenetics has emerged as a potential alternative to electrotherapy for treating arrhythmia, but feasibility studies have been limited to ventricular defibrillation via epicardial light application. Here, we assess the efficacy of optogenetic atrial tachycardia (AT) termination in human hearts using a strategy that targets for illumination specific regions identified in an automated manner. In three patient-specific models reconstructed from late gadolinium-enhanced MRI scans, we simulated channelrhodopsin-2 (ChR2) expression via gene delivery. In all three models, we attempted to terminate reentrant AT (induced via rapid pacing) via optogenetic stimulation. We compared two strategies: (1) distributed illumination of the endocardium by multi-optrode grids (Nopt = 64, 128, 256) and (2) targeted illumination of the critical isthmus, which was identified via analysis of simulated activation patterns using an algorithm based on flow networks. The illuminated area and input power were smaller for the targeted approach (19–57.8 mm2; 0.6–1.8 W) compared to the sparsest distributed arrays (Nopt = 64; 124.9 ± 6.3 mm2; 3.9 ± 0.2 W). AT termination rates for distributed illumination were low, ranging from <5% for short pulses (1/10 ms-long) to ∼20% for longer stimuli (100/1000 ms). When we attempted to terminate the same AT episodes with targeted illumination, outcomes were similar for short pulses (1/10 ms-long: 0% success) but improved for longer stimuli (100 ms: 54% success; 1000 ms: 90% success). We conclude that simulations in patient-specific models show that light pulses lasting longer than the AT cycle length can efficiently and reliably terminate AT in atria light-sensitized via gene delivery. We show that targeted optogenetic stimulation based on analysis of AT morphology may be a reliable approach for defibrillation and requires less power than distributed illumination.

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Cost-effectiveness analysis of HLA-B*58: 01 genetic testing before initiation of allopurinol therapy to prevent allopurinol-induced Stevens-Johnson syndrome/toxic epidermal necrolysis in a Malaysian population.

Objective: Studies found a strong association between allopurinol-induced Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) and the HLA-B*58:01 allele. HLA-B*58:01 screening-guided therapy may mitigate the risk of allopurinol-induced SJS/TEN. This study aimed to evaluate the cost-effectiveness of HLA-B*58:01 screening before allopurinol therapy initiation compared with the current practice of no screening for Malaysian patients with chronic gout in whom a hypouricemic agent is indicated. Methods: This cost-effectiveness analysis adopted a societal perspective with a lifetime horizon. A decision tree model coupled with Markov models were developed to estimate the costs and outcomes, represented by quality-adjusted life years (QALYs) gained, of three treatment strategies: (a) current practice (allopurinol initiation without HLA-B*58:01 screening); (b) HLA-B*58:01 screening before allopurinol initiation; and (c) alternative treatment (probenecid) without HLA-B*58:01 screening. The model was populated with data from literature review, meta-analysis, and published government documents. Cost values were adjusted for the year 2016, with costs and health outcomes discounted at 3% per annum. A series of sensitivity analysis including probabilistic sensitivity analysis were carried out to determine the robustness of the findings. Results: Both HLA-B*58:01 screening and probenecid prescribing were dominated by current practice. Compared with current practice, HLA-B*58:01 screening resulted in 0.252 QALYs loss per patient at an additional cost of USD 322, whereas probenecid prescribing resulted in 1.928 QALYs loss per patient at an additional cost of USD 2203. One SJS/TEN case would be avoided for every 556 patients screened. At the cost-effectiveness threshold of USD 8695 per QALY, the probability of current practice being the best choice is 99.9%, in contrast with 0.1 and 0% in HLA-B*58:01 screening and probenecid prescribing, respectively. This is because of the low incidence of allopurinol-induced SJS/TEN in Malaysia and the lower efficacy of probenecid compared with allopurinol in gout control. Conclusion: This analysis showed that HLA-B*58:01 genetic testing before allopurinol initiation is unlikely to be a cost-effective intervention in Malaysia. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Detecting sub-second changes in brain activation patterns during interictal epileptic spike using simultaneous EEG-fMRI

The simultaneous measurement of electroencephalography (EEG) data and functional magnetic resonance imaging (fMRI) has been shown to be effective for the precise identification of the epileptic focus (van Graan et al., 2015; Kobayashi et al., 2006a, 2006b; Moeller et al., 2013). The intense neuronal activity associated with epileptic spikes generates significant changes in blood-oxygenation-level-dependent (BOLD) signal (Ogawa et al., 1990) in brain regions where the spikes originate. These regions can be identified using fMRI by correlating BOLD changes with the occurrence of the discharge, which can be determined from the simultaneously recorded EEG data.

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High Radon Areas and lung cancer prevalence: Evidence from Ireland

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Publication date: February 2018
Source:Journal of Environmental Radioactivity, Volume 182
Author(s): Seraphim Dempsey, Seán Lyons, Anne Nolan
This paper examined the relationship between radon risk and lung cancer prevalence using a novel dataset combining spatially-coded survey data with a radon risk map. A logit model was employed to test for significant associations between a high risk of indoor radon and lung cancer prevalence using data on 5590 people aged 50+ from The Irish Longitudinal Study on Ageing (TILDA) and radon risk data from Ireland's Environmental Protection Agency (EPA). The use of data at the individual level allowed a wide range of potentially confounding factors (such as smoking) to be included. Results indicate that those who lived in an area in which 10%–20% of households were above the national reference level (200 Bq/m3) were 2.9–3.1 times more likely to report a lung cancer diagnosis relative to those who lived in areas in which less than 1% of households were above the national reference level.



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Population sensitivities of animals to chronic ionizing radiation-model predictions from mice to elephant

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Publication date: Available online 20 November 2017
Source:Journal of Environmental Radioactivity
Author(s): Tatiana G. Sazykina
Model predictions of population response to chronic ionizing radiation (endpoint 'morbidity') were made for 11 species of warm-blooded animals, differing in body mass and lifespan – from mice to elephant. Predictions were made also for 3 bird species (duck, pigeon, and house sparrow). Calculations were based on analytical solutions of the mathematical model, simulating a population response to low-LET ionizing radiation in an ecosystem with a limiting resource (Sazykina, Kryshev, 2016). Model parameters for different species were taken from biological and radioecological databases; allometric relationships were employed for estimating some parameter values. As a threshold of decreased health status in exposed populations ('health threshold'), a 10% reduction in self-repairing capacity of organisms was suggested, associated with a decline in ability to sustain environmental stresses. Results of the modeling demonstrate a general increase of population vulnerability to ionizing radiation in animal species of larger size and longevity. Populations of small widespread species (mice, house sparrow; body mass 20–50 g), which are characterized by intensive metabolism and short lifespan, have calculated 'health thresholds' at dose rates about 6.5–7.5 mGy day−1. Widespread animals with body mass 200–500 g (rat, common pigeon) – demonstrate 'health threshold' values at 4–5 mGy day−1. For populations of animals with body mass 2–5 kg (rabbit, fox, raccoon), the indicators of 10% health decrease are in the range 2–3.4 mGy day−1. For animals with body mass 40–100 kg (wolf, sheep, wild boar), thresholds are within 0.5–0.8 mGy day−1; for herbivorous animals with body mass 200–300 kg (deer, horse) – 0.5–0.6 mGy day−1. The lowest health threshold was estimated for elephant (body mass around 5000 kg) - 0.1 mGy day−1. According to the model results, the differences in population sensitivities of warm-blooded animal species to ionizing radiation are generally depended on the metabolic rate and longevity of organisms, also on individual radiosensitivity of biological tissues. The results of 'health threshold' calculations are formulated as a graded scale of wildlife sensitivities to chronic radiation stress, ranging from potentially vulnerable to more resistant species. Further studies are needed to expand the scale of population sensitivities to radiation, including other groups of wildlife - cold-blooded species, invertebrates, and plants.



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Natural radioactivity in soils of the state of Rio de Janeiro (Brazil): Radiological characterization and relationships to geological formation, soil types and soil properties

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Publication date: February 2018
Source:Journal of Environmental Radioactivity, Volume 182
Author(s): F.C.A. Ribeiro, J.I.R. Silva, E.S.A. Lima, N.M.B. do Amaral Sobrinho, D.V. Perez, D.C. Lauria
Located in the south-western part of Brazil, the state of Rio de Janeiro is geotectonically contained within a complex structural province that resulted in the amalgamation of the Western Gondwana Paleocontinent. To undertake an extensive radiological characterization of this complex geological province and investigate the influence of bedrock, soil type and soil chemical-physical characteristics on natural radionuclide levels in soils, 259 surface soil samples were collected that encompassed the main soil types and geological formations throughout the state. Gamma spectrometry analysis of the samples resulted in median values of 114 Bq.kg−1for 40K, 32 Bq.kg−1 for 226Ra and 74 Bq.kg−1 for 228Ra. The median value for 226Ra was similar to the world median value for soils, the 40K value was well below the worldwide value, and that for 228Ra exceeded the world median value. The intense weathering caused by the high rainfall rates and high temperatures may be responsible for the low levels of 40K in the soils, of which the strongly acidic and clayey soils are markedly K-depleted. A soil from a high-grade metamorphic rock (granulite) presented the lowest 226Ra (18 Bq.kg−1) content, whereas the highest levels for 226Ra (92 Bq.kg−1) and 228Ra (139 Bq.kg-1) were observed in a young soil enriched in primary minerals (Leptsol). A lowland soil (Gleysol) showed the highest median of 40K (301 Bq.kg−1). Strongly acidic soils tended to present high amounts of 226Ra, and sandy soils tended to contain low levels of 228Ra. The external radiation dose indicates that the state has a background radiation level within the natural range.



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Inside Front Cover - Editorial Board Page

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Publication date: January 2018
Source:Journal of Environmental Radioactivity, Volume 181





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Predicted cumulative dose to firefighters and the offsite public from natural and anthropogenic radionuclides in smoke from wildland fires at the Savannah River Site, South Carolina USA

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Publication date: February 2018
Source:Journal of Environmental Radioactivity, Volume 182
Author(s): Brian J. Viner, Tim Jannik, Allan Hepworth, Olorunfemi Adetona, Luke Naeher, Teresa Eddy, Eric Doman, John Blake
The contaminated ground surface at Savannah River Site (SRS) is a result of the decades of work that has been performed maintaining the country's nuclear stockpile and performing research and development on nuclear materials. The volatilization of radionuclides during wildfire results in airborne particles that are dispersed within the smoke plume and may result in doses to downwind firefighters and the public. To better understand the risk that these smoke plumes present, we have characterized four regions at SRS in terms of their fuel characteristics and radiological contamination on the ground. Combined with general meteorological conditions describing typical and extreme burn conditions, we have simulated potential fires in these regions and predicted the potential radiological dose that could be received by firefighting personnel and the public surrounding the SRS. In all cases, the predicted cumulative dose was a small percent of the US Department of Energy regulatory limit (0.25 mSv). These predictions were conservative and assumed that firefighters would be exposed for the duration of their shift and the public would be exposed for the entire day over the duration of the burn. Realistically, firefighters routinely rotate off the firefront during their shift and the public would likely remain indoors much of the day. However, we show that even under worst-case conditions the regulatory limits are not exceeded. We can infer that the risks associated with wildfires would not be expected to cause cumulative doses above the level of concern to either responding personnel or the offsite public.



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Topsoil radiological characterisation of L-54M reactor surroundings preliminary to decommissioning operations

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Publication date: Available online 27 November 2017
Source:Journal of Environmental Radioactivity
Author(s): E. Mossini, L. Codispoti, M. Giola, L. Castelli, E. Macerata, A. Porta, F. Campi, M. Mariani
The radiological characterization of the topsoil of the L-54M reactor surroundings carried out in this work aims at obtaining the reference blank point for the forthcoming decommissioning operations and ascertain if unexpected radionuclide release occurred during the operational life of the plant. Standardised methods have been employed in order to collect representative samples and reliable results. Suitable sample pre-treatment procedures were applied. Gamma and beta spectrometric analyses were carried out to measure the activity concentrations of 60Co 137Cs, 152Eu, 241Am and 90Sr. These have been considered as representative radionuclides that could have been originated from reactor operations and that could still be present at four decades post reactor shutdown.



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Analysis of air mass trajectories to explain observed variability of tritium in precipitation at the Southern Sierra Critical Zone Observatory, California, USA

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Publication date: January 2018
Source:Journal of Environmental Radioactivity, Volume 181
Author(s): Ate Visser, Melissa Thaw, Brad Esser
Understanding the behavior of tritium, a radioactive isotope of hydrogen, in the environment is important to evaluate the exposure risk of anthropogenic releases, and for its application as a tracer in hydrology and oceanography. To understand and predict the variability of tritium in precipitation, HYSPLIT air mass trajectories were analyzed for 16 aggregate precipitation samples collected over a 2 year period at irregular intervals at a research site located at 2000 m elevation in the southern Sierra Nevada (California, USA). Attributing the variation in tritium to specific source areas confirms the hypothesis that higher latitude or inland sources bring higher tritium levels in precipitation than precipitation originating in the lower latitude Pacific Ocean. In this case, the source of precipitation accounts for 79% of the variation observed in tritium concentrations. Air mass trajectory analysis is a promising tool to improve the predictions of tritium in precipitation at unmonitored locations and thoroughly understand the processes controlling transport of tritium in the environment.



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Feedback of the third interlaboratory exercise organised on wheat in the framework of the OBT working group

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Publication date: January 2018
Source:Journal of Environmental Radioactivity, Volume 181
Author(s): N. Baglan, C. Cossonnet, E. Roche, S.B. Kim, I. Croudace, P. Warwick
Organically bound tritium (OBT) has become of increasing interest within the last decade, with a focus on its behaviour and also its analysis, which are both important to assess tritium distribution in the environment and dose consequences. After the first OBT International Workshop which was held in France in May 2012, an international working group was created. The expected benefits are the following: remove or reduce uncertainty in OBT analysis results, provide better OBT model validation data and better public dose results, increase the number of potential measuring OBT laboratories, validate all of the stages of the procedures based on a larger population and more statistically significant results, and investigate the feasibility of CRM's and RM's production. In this framework, three OBT exercises were organised; the 1st one on potatoes was conducted in 2013 by the Canadian National Laboratories (former AECL) with about 20 participating labs from around the world, the 2nd one on a sediment was organised in 2014 by GAU Radioanalytical (University of Southampton) on a sediment with again about 20 participating labs and the third one on wheat was organised in 2015 by the Commissariat à l'énergie atomique (CEA) with about 25 participating labs.



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Impact of ventilation systems and energy savings in a building on the mechanisms governing the indoor radon activity concentration

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Publication date: Available online 24 November 2017
Source:Journal of Environmental Radioactivity
Author(s): Bernard Collignan, Emilie Powaga
For a given radon potential in the ground and a given building, the parameters affecting the indoor radon activity concentration (IRnAC) are indoor depressurization of a building and its air change rate. These parameters depend mainly on the building characteristics, such as airtightness, and on the nature and performances of the ventilation system. This study involves a numerical sensitivity assessment of the indoor environmental conditions on the IRnAC in buildings. A numerical ventilation model has been adapted to take into account the effects of variations in the indoor environmental conditions (depressurization and air change rate) on the radon entry rate and on the IRnAC. In the context of the development of a policy to reduce energy consumption in a building, the results obtained showed that IRnAC could be strongly affected by variations in the air permeability of the building associated with the ventilation regime.



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Assessment of uranium release to the environment from a disabled uranium mine in Brazil

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Publication date: Available online 16 November 2017
Source:Journal of Environmental Radioactivity
Author(s): Wagner de Souza Pereira, Alphonse Germaine Albert Charles Kelecom, Ademir Xavier da Silva, Alessander Sá do Carmo, Delcy de Azavedo Py Júnior
The Ore Treatment Unit (in Portuguese Unidade de Tratamento de Minérios - UTM) located in Caldas, MG, Brazil is a disabled uranium mine. Environmental conditions generate acid drainage leaching metals and radionuclides from the waste rock pile. This drainage is treated to remove the heavy metals and radionuclides, before allowing the release of the effluent to the environment. To validate the treatment, samples of the released effluents were collected at the interface of the installation with the environment. Sampling was carried out from 2010 to 2015, and the activity concentration (AC, in Bq·l−1) of uranium in the liquid effluent was analyzed by arzenazo UV-Vis spectrophotometry of the soluble and particulate fractions, and of the sum of both fractions. Descriptive statistics, Z test and Pearson R2 correlation among the fractions were performed. Then, the data were organized by year and both ANOVA and Tukey test were carried out to group the means by magnitude of AC. The annual mean ranged from 0.02 Bq·l−1 in 2015 to 0.11 Bq·l−1 in 2010. The soluble fraction showed a higher AC mean when compared to the mean of the particulate fraction and no correlation of the data could be observed. Concerning the magnitude of the release, the ANOVA associated with the Tukey test, identified three groups of annual means (AC2010> AC2011 = AC2012 = AC2013 = AC2014 > AC2015). The mean values of uranium release at the interface installation-environment checking point (point 014) were within the Authorized Annual Limit (AAL) set by the regulator (0.2 Bq·l−1) indicating compliance of treatment with the licensing established for the unit. Finally, the data showed a decreasing tendency of U release.



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Indoor radon measurements in south west England explained by topsoil and stream sediment geochemistry, airborne gamma-ray spectroscopy and geology

Publication date: January 2018
Source:Journal of Environmental Radioactivity, Volume 181
Author(s): Antonio Ferreira, Zornitza Daraktchieva, David Beamish, Charles Kirkwood, T. Robert Lister, Mark Cave, Joanna Wragg, Kathryn Lee
Predictive mapping of indoor radon potential often requires the use of additional datasets. A range of geological, geochemical and geophysical data may be considered, either individually or in combination.The present work is an evaluation of how much of the indoor radon variation in south west England can be explained by four different datasets: a) the geology (G), b) the airborne gamma-ray spectroscopy (AGR), c) the geochemistry of topsoil (TSG) and d) the geochemistry of stream sediments (SSG). The study area was chosen since it provides a large (197,464) indoor radon dataset in association with the above information.Geology provides information on the distribution of the materials that may contribute to radon release while the latter three items provide more direct observations on the distributions of the radionuclide elements uranium (U), thorium (Th) and potassium (K). In addition, (c) and (d) provide multi-element assessments of geochemistry which are also included in this study.The effectiveness of datasets for predicting the existing indoor radon data is assessed through the level (the higher the better) of explained variation (% of variance or ANOVA) obtained from the tested models. A multiple linear regression using a compositional data (CODA) approach is carried out to obtain the required measure of determination for each analysis.Results show that, amongst the four tested datasets, the soil geochemistry (TSG, i.e. including all the available 41 elements, 10 major – Al, Ca, Fe, K, Mg, Mn, Na, P, Si, Ti - plus 31 trace) provides the highest explained variation of indoor radon (about 40%); more than double the value provided by U alone (ca. 15%), or the sub composition U, Th, K (ca. 16%) from the same TSG data. The remaining three datasets provide values ranging from about 27% to 32.5%. The enhanced prediction of the AGR model relative to the U, Th, K in soils suggests that the AGR signal captures more than just the U, Th and K content in the soil.The best result is obtained by including the soil geochemistry with geology and AGR (TSG + G + AGR, ca. 47%). However, adding G and AGR to the TSG model only slightly improves the prediction (ca. +7%), suggesting that the geochemistry of soils already contain most of the information given by geology and airborne datasets together, at least with regard to the explanation of indoor radon.From the present analysis performed in the SW of England, it may be concluded that each one of the four datasets is likely to be useful for radon mapping purposes, whether alone or in combination with others. The present work also suggest that the complete soil geochemistry dataset (TSG) is more effective for indoor radon modelling than using just the U (+Th, K) concentration in soil.



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Axonal excitability changes and acute symptoms of oxaliplatin treatment: in vivo evidence for slowed sodium channel inactivation

Oxaliplatin is a third-generation platinum analog used for the treatment of solid cancers, in particular as primary and adjuvant treatment of advanced and high-risk colorectal cancer (DCCG, 2015). Neurotoxicity is a frequent and often dose-limiting side effect of oxaliplatin treatment (Gamelin et al., 2002; Argyriou et al., 2013). Oxaliplatin is unique among platinum analogs, as it induces two clinically different types of peripheral neuropathy. One type is a commonly occurring acute neurotoxicity with transient paresthesia, typically triggered by cold exposure, and muscle spasms in the limbs and jaw.

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Novel Inactivating Mutations of the DCAF17 gene in American and Turkish families cause male infertility and female subfertility in the mouse model

ABSTRACT

Loss of function DCAF17 variants cause hypogonadism, partial alopecia, diabetes mellitus, mental retardation, and deafness with variable clinical presentation ranging. DCAF17 pathogenic variants have been largely reported in the Middle Eastern populations, but the incidence in American families is rare and animal models are lacking. Exome sequencing in five women with syndromic hypergonadotropic hypogonadism from two unrelated families revealed novel pathogenic variants in the DCAF17 gene. DCAF17 exon 2 (c.127-1G>C) novel homozygous variants were discovered in four Turkish siblings, while one American was compound heterozygous for one stop gain variant in exon 5 (c.C535T; p.Gln179*) and previously described stop gain variant in exon 9 (c.G906A; p.Trp302*). A mouse model mimicking loss of function in exon 2 of Dcaf17 was generated using CRISPR/Cas9 and showed female subfertility and male infertility. Our results identify two novel variants, and show that Dcaf17 plays a significant role in mammalian gonadal development and infertility.

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Targeted next-generation sequencing and parental genotyping in sporadic Chinese Han deaf patients

Abstract

The interpretation of the targeted next-generation sequencing (NGS) results can be challenging for variants identified in the sporadic deaf patients. In this study, we performed targeted NGS of 143 deafness-associated genes in 44 sporadic deaf patients and use parental genotyping to test whether the candidate pathogenic variants complied with recessive or de novo pattern. Of 29 recessive candidate variants with minor allele frequencies less than 0.005, three pairs of apparent compound heterozygous variants were inherited from the same parental allele, ruling out their pathogenic roles. In addition, non-segregation of an OTOA p.Gln293Arg variant led to the discovery of a genomic microdeletion of OTOA on the opposite allele by copy number variation analysis. Overall 13 pairs of recessive candidate variants were deemed causative in 13 patients. Of the 28 dominant candidate variants with minor allele frequencies less than 0.0005, none occurred de novo, suggesting that they were not disease causing. Our results revealed that targeted NGS in sporadic deaf patients may generate a significant false-positive rate. Parental genotyping is a simple but effective step towards minimizing the false-positive results. Our study also showed that de novo variants in dominant deafness genes may not be a common cause for sporadic deafness.

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Effect of LSR polymorphism on blood lipid levels and age-specific epistatic interaction with the APOE common polymorphism

Abstract

The lipolysis stimulated lipoprotein receptor (LSR) is an apolipoprotein (Apo) B and ApoE receptor that participates in the removal of TG-rich lipoproteins during the postprandial phase. LSR gene is located upstream of APOE, an important risk factor for cardiovascular disease (CVD). Since the APOE common polymorphism significantly affects the variability of lipid metabolism, this study aimed to determine the potential impact of a functional SNP rs916147 in LSR gene on lipid traits in healthy subjects and to investigate potential epistatic interaction between LSR and APOE. Unrelated healthy adults (n = 432) and children (n = 328, <18 years old) from the STANISLAS Family Study were used. Age-specific epistasis was observed between APOE and LSR, reversing the protective effect of APOE ε2 allele on cholesterol, ApoE and low-density lipoprotein levels (beta: 0.114, p: 0.777×10-8, beta: 0.125, p: 0.639×10-3, beta: 0.059, p: 0.531×10-3 respectively). This interaction was verified in an independent adult population (n=1744). These results highlight the importance of the LSR polymorphism and reveal the existence of complex molecular links between LSR and ApoE for the regulation of lipid levels, revealing potential new pathways of interest in type III hyperlipidemia, and its involvement in CVD pathology.

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Pleiotropy of cardiometabolic syndrome with obesity-related anthropometric traits determined using empirically derived kinships from the Busselton Health Study

Abstract

Over two billion adults are overweight or obese and therefore at an increased risk of cardiometabolic syndrome (CMS). Obesity-related anthropometric traits genetically correlated with CMS may provide insight into CMS aetiology. The aim of this study was to utilise an empirically derived genetic relatedness matrix to calculate heritabilities and genetic correlations between CMS and anthropometric traits to determine whether they share genetic risk factors (pleiotropy). We used genome-wide single nucleotide polymorphism (SNP) data on 4671 Busselton Health Study participants. Exploiting both known and unknown relatedness, empirical kinship probabilities were estimated using these SNP data. General linear mixed models implemented in SOLAR were used to estimate narrow-sense heritabilities (h 2) and genetic correlations (r g) between 15 anthropometric and 9 CMS traits. Anthropometric traits were adjusted by body mass index (BMI) to determine whether the observed genetic correlation was independent of obesity. After adjustment for multiple testing, all CMS and anthropometric traits were significantly heritable (h 2 range 0.18–0.57). We identified 50 significant genetic correlations (r g range: − 0.37 to 0.75) between CMS and anthropometric traits. Five genetic correlations remained significant after adjustment for BMI [high density lipoprotein cholesterol (HDL-C) and waist–hip ratio; triglycerides and waist–hip ratio; triglycerides and waist–height ratio; non-HDL-C and waist–height ratio; insulin and iliac skinfold thickness]. This study provides evidence for the presence of potentially pleiotropic genes that affect both anthropometric and CMS traits, independently of obesity.



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Hypoxia-induced intestinal barrier changes in balloon-assisted enteroscopy

Abstract

Balloon-assisted enteroscopy (BAE) is an emerging standard procedure by utilizing distensible balloons to facilitate deep endoscopy. Intestines are known to harbor abundant microflora. Whether balloon distension causes perturbation of blood flow and gut barrier dysfunction, and elicits risk of bacterial translocation remains unknown. Our aims were to 1) conduct a prospective study to gather microbiological and molecular evidence of bacterial translocation by BAE in patients, 2) establish a murine model of colonic balloon distension to investigate tissue hypoxia and intestinal barrier, and 3) assess the effect of short- and long-term hypoxia on epithelial permeability using cell lines. Thirteen patients were enrolled for BAE procedures, and blood samples were obtained before and after BAE for paired comparison. Four of the 13 patients (30.8%) had positive bacterial DNA in blood after BAE. Post-BAE endotoxemia was higher than pre-BAE level. Nevertheless, no clinical symptom of sepsis or fever was reported. To mimic clinical BAE, mice were subjected to colonic balloon distension. Local tissue hypoxia was observed during balloon inflation, and reoxygenation after deflation. A trend of increased gut permeability was seen after long-term distension, whereas a significant reduction of permeability was observed by short-term distention in the proximal colon. Human colonic epithelial Caco-2 cells exposed to hypoxia for 5–20 min exhibited increased tight junctional assembly, while those exposed to longer hypoxia displayed barrier disruption. In conclusion, sporadic cases of bacteremia were found after BAE, without septic symptoms. Short-term hypoxia by balloon distension yielded a protective effect whereas long-term hypoxia caused damage on gut barrier.

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Hyperexcitability of the network contributes to synchronization processes in the human epileptic neocortex

Abstract

Interictal activity is a hallmark in epilepsy diagnostics and is linked to neuronal hypersynchrony. Little is known about perturbations in human epileptic neocortical microcircuits, and their role in generating pathological synchronies. To explore hyperexcitability of the human epileptic network, and its contribution to convulsive activity, we investigated an in vitro model of synchronous burst activity spontaneously occurring in postoperative tissue slices derived from patients with or without preoperative clinical and electrographic manifestations of epileptic activity. Human neocortical slices generated two types of synchronies. Interictal-like discharges (classified as epileptiform events) emerged only in epileptic samples, and were hypersynchronous bursts characterized by considerably elevated levels of excitation. Synchronous population activity was initiated both in epileptic and non-epileptic tissue, with a significantly lower degree of excitability and synchrony, and could not be linked to epilepsy. However, in pharmacoresistant epileptic tissue, higher percentage of slices exhibited population activity, with higher local field potential gradient amplitudes. More intracellularly recorded neurons received depolarizing synaptic potentials, discharging more reliably during the events. Light and electron microscopic examinations showed slightly lower neuron densities, and higher densities of excitatory synapses in the human epileptic neocortex. Our data suggest that human neocortical microcircuits retain their functionality and plasticity in vitro, and can generate two significantly different synchronies. We propose that population bursts might not be pathological events while interictal-like discharges may reflect the epileptogenicity of the human cortex. Our results show that hyperexcitability characterizes the human epileptic neocortical network, and that it is closely related to the emergence of synchronies.

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Rare FMR1 gene mutations causing fragile X syndrome: A review

Fragile X syndrome (FXS) is the most common inherited form of intellectual disability, typically due to CGG-repeat expansions in the FMR1 gene leading to lack of expression. We identified a rare FMR1 gene mutation (c.413G>A), previously reported in a single patient and reviewed the literature for other rare FMR1 mutations. Our patient at 10 years of age presented with the classical findings of FXS including intellectual disability, autism, craniofacial findings, hyperextensibility, fleshy hands, flat feet, unsteady gait, and seizures but without the typical CGG-repeat expansion. He had more features of FXS than the previously reported patient with the same mutation. Twenty individuals reported previously with rare missense or nonsense mutations or other coding disturbances of the FMR1 gene ranged in age from infancy to 50 years; most were verbal with limited speech, had autism and hyperactivity, and all had intellectual disability. Four of the 20 individuals had a mutation within exon 15, three within exon 5, and two within exon 2. The FMR1 missense mutation (c.413G>A) is the same as in a previously reported male where it was shown that there was preservation of the post-synaptic function of the fragile X mental retardation protein (FMRP), the encoded protein of the FMR1 gene was preserved. Both patients with this missense mutation had physical, cognitive, and behavioral features similarly seen in FXS.



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Synthetic biology: Multiplex genome engineering in eukaryotes

Synthetic biology: Multiplex genome engineering in eukaryotes

Synthetic biology: Multiplex genome engineering in eukaryotes, Published online: 27 November 2017; doi:10.1038/nrg.2017.103

Synthetic biology: Multiplex genome engineering in eukaryotes

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