Ischaemic strokes in patients with pulmonary arteriovenous malformations and hereditary hemorrhagic telangiectasia: associations with iron deficiency and platelets.

<div><p>Background</p><p>Pulmonary first pass filtration of particles marginally exceeding ∼7 µm (the size of a red blood cell) is used routinely in diagnostics, and allows cellular aggregates forming or entering the circulation in the preceding cardiac cycle to lodge safely in pulmonary capillaries/arterioles. Pulmonary arteriovenous malformations compromise capillary bed filtration, and are commonly associated with ischaemic stroke. Cohorts with CT-scan evident malformations associated with the highest contrast echocardiographic shunt grades are known to be at higher stroke risk. Our goal was to identify within this broad grouping, which patients were at higher risk of stroke.</p><p>Methodology</p><p>497 consecutive patients with CT-proven pulmonary arteriovenous malformations due to hereditary haemorrhagic telangiectasia were studied. Relationships with radiologically-confirmed clinical ischaemic stroke were examined using logistic regression, receiver operating characteristic analyses, and platelet studies.</p><p>Principal Findings</p><p>Sixty-one individuals (12.3%) had acute, non-iatrogenic ischaemic clinical strokes at a median age of 52 (IQR 41–63) years. In crude and age-adjusted logistic regression, stroke risk was associated not with venous thromboemboli or conventional neurovascular risk factors, but with low serum iron (adjusted odds ratio 0.96 [95% confidence intervals 0.92, 1.00]), and more weakly with low oxygen saturations reflecting a larger right-to-left shunt (adjusted OR 0.96 [0.92, 1.01]). For the same pulmonary arteriovenous malformations, the stroke risk would approximately double with serum iron 6 µmol/L compared to mid-normal range (7–27 µmol/L). Platelet studies confirmed overlooked data that iron deficiency is associated with exuberant platelet aggregation to serotonin (5HT), correcting following iron treatment. By MANOVA, adjusting for participant and 5HT, iron or ferritin explained 14% of the variance in log-transformed aggregation-rate (p = 0.039/p = 0.021).</p><p>Significance</p><p>These data suggest that patients with compromised pulmonary capillary filtration due to pulmonary arteriovenous malformations are at increased risk of ischaemic stroke if they are iron deficient, and that mechanisms are likely to include enhanced aggregation of circulating platelets.</p></div

Modulation of macrophage phenotype through controlled release of interleukin-4 from gelatine coatings on titanium surfaces

Pro-inflammatory phenotype (M1) macrophages initiate angiogenesis, while their prolonged activation can induce chronic inflammation. Anti-inflammatory phenotype (M2) macrophages promote vessel maturation and tissue regeneration. Biomaterials which can promote M2 polarisation after appropriate inflammation should enhance angiogenesis and wound healing. Herein, Interleukin-4 (IL-4), an anti-inflammatory cytokine, was adsorbed onto a titanium surface. Then, a genipin cross-linked gelatine hydrogel was coated onto the surface to delay IL-4 release. The cross-linking degree of the hydrogel was modulated by the different amount of genipin to control release of IL-4. When 0.7 wt% (weight %) genipin was used as a cross-linker, the sample (GG07-I) released less IL-4 within the first several days, followed by a sustained release time to 14 d. Meanwhile, the release rate of IL-4 in GG07-I reached a peak between 3 d and 7 d. In culture with macrophages in vitro, GG07-I and GG07 exhibited good cytocompatibility. The phenotypical switch of macrophages stimulated by the samples was determined by FACS, ELISA and PCR. Macrophages cultured with GG07-I, GG07 and PT were firstly activated to the M1 phenotype by interferon-gamma (IFN-γ). Then, due to the release of IL-4 in 5 to 7 d, GG07-I enhanced CD206, increased the secretion and gene expression of M2 marker, such as interleukin-10 (IL-10), arginase-1 (ARG-1) and platelet derived growth factor-BB (PDGF- BB). GG07-I prompted the switch from M1 to M2 phenotype. Those appropriate secretion of cytokines would benefit both vascularisation and osseointegration. Thus, the biomaterial directing inflammatory reaction has good prospects for clinical treatments

Local variation of hashtag spike trains and popularity in Twitter

We draw a parallel between hashtag time series and neuron spike trains. In each case, the process presents complex dynamic patterns including temporal correlations, burstiness, and all other types of nonstationarity. We propose the adoption of the so-called local variation in order to uncover salient dynamics, while properly detrending for the time-dependent features of a signal. The methodology is tested on both real and randomized hashtag spike trains, and identifies that popular hashtags present regular and so less bursty behavior, suggesting its potential use for predicting online popularity in social media.Comment: 7 pages, 7 figure

Metabolic engineering of the iodine content in Arabidopsis

Plants are a poor source of iodine, an essential micronutrient for human health. Several attempts of iodine biofortification of crops have been carried out, but the scarce knowledge on the physiology of iodine in plants makes results often contradictory and not generalizable. In this work, we used a molecular approach to investigate how the ability of a plant to accumulate iodine can be influenced by different mechanisms. In particular, we demonstrated that the iodine content in Arabidopsis thaliana can be increased either by facilitating its uptake with the overexpression of the human sodium-iodide symporter (NIS) or through the reduction of its volatilization by knocking-out HOL-1, a halide methyltransferase. Our experiments show that the iodine content in plants results from a balance between intake and retention. A correct manipulation of this mechanism could improve iodine biofortification of crops and prevent the release of the ozone layer-threatening methyl iodide into the atmosphere

W::Neo: A Novel Dual-Selection Marker for High Efficiency Gene Targeting in Drosophila

We have recently developed a so-called genomic engineering approach that allows for directed, efficient and versatile modifications of Drosophila genome by combining the homologous recombination (HR)-based gene targeting with site-specific DNA integration. In genomic engineering and several similar approaches, a “founder” knock-out line must be generated first through HR-based gene targeting, which can still be a potentially time and resource intensive process. To significantly improve the efficiency and success rate of HR-based gene targeting in Drosophila, we have generated a new dual-selection marker termed W::Neo, which is a direct fusion between proteins of eye color marker White (W) and neomycin resistance (Neo). In HR-based gene targeting experiments, mutants carrying W::Neo as the selection marker can be enriched as much as fifty times by taking advantage of the antibiotic selection in Drosophila larvae. We have successfully carried out three independent gene targeting experiments using the W::Neo to generate genomic engineering founder knock-out lines in Drosophila

Lack of MEF2A Δ7aa mutation in Irish families with early onset ischaemic heart disease, a family based study

BACKGROUND: Ischaemic heart disease (IHD) is a complex disease due to the combination of environmental and genetic factors. Mutations in the MEF2A gene have recently been reported in patients with IHD. In particular, a 21 base pair deletion (Δ7aa) in the MEF2A gene was identified in a family with an autosomal dominant pattern of inheritance of IHD. We investigated this region of the MEF2A gene using an Irish family-based study, where affected individuals had early-onset IHD. METHODS: A total of 1494 individuals from 580 families were included (800 discordant sib-pairs and 64 parent-child trios). The Δ7aa region of the MEF2A gene was investigated based on amplicon size. RESULTS: The Δ7aa mutation was not detected in any individual. Variation in the number of CAG (glutamate) and CCG (proline) residues was detected in a nearby region. However, this was not found to be associated with IHD. CONCLUSION: The Δ7aa mutation was not detected in any individual within the study population and is unlikely to play a significant role in the development of IHD in Ireland. Using family-based tests of association the number of tri-nucleotide repeats in a nearby region of the MEF2A gene was not associated with IHD in our study group

“I would rather be told than not know” - A qualitative study exploring parental views on identifying the future risk of childhood overweight and obesity during infancy

BACKGROUND: Risk assessment tools provide an opportunity to prevent childhood overweight and obesity through early identification and intervention to influence infant feeding practices. Engaging parents of infants is paramount for success however; the literature suggests there is uncertainty surrounding the use of such tools with concerns about stigmatisation, labelling and expressions of parental guilt. This study explores parents' views on identifying future risk of childhood overweight and obesity during infancy and communicating risk to parents. METHODS: Semi-structured qualitative interviews were conducted with 23 parents and inductive, interpretive and thematic analysis performed. RESULTS: Three main themes emerged from the data: 1) Identification of infant overweight and obesity risk. Parents were hesitant about health professionals identifying infant overweight as believed they would recognise this for themselves, in addition parents feared judgement from health professionals. Identification of future obesity risk during infancy was viewed positively however the use of a non-judgemental communication style was viewed as imperative. 2) Consequences of infant overweight. Parents expressed immediate anxieties about the impact of excess weight on infant ability to start walking. Parents were aware of the progressive nature of childhood obesity however, did not view overweight as a significant problem until the infant could walk as viewed this as a point when any excess weight would be lost due to increased energy expenditure. 3) Parental attributions of causality, responsibility, and control. Parents articulated a high level of personal responsibility for preventing and controlling overweight during infancy, which translated into self-blame. Parents attributed infant overweight to overfeeding however articulated a reluctance to modify infant feeding practices prior to weaning. CONCLUSION: This is the first study to explore the use of obesity risk tools in clinical practice, the findings suggest that identification, and communication of future overweight and obesity risk is acceptable to parents of infants. Despite this positive response, findings suggest that parents' acceptance to identification of risk and implementation of behaviour change is time specific. The apparent level of parental responsibility, fear of judgement and self-blame also highlights the importance of health professionals approach to personalised risk communication so feelings of self-blame are negated and stigmatisation avoided

Bioavailability in soils

The consumption of locally-produced vegetables by humans may be an important exposure pathway for soil contaminants in many urban settings and for agricultural land use. Hence, prediction of metal and metalloid uptake by vegetables from contaminated soils is an important part of the Human Health Risk Assessment procedure. The behaviour of metals (cadmium, chromium, cobalt, copper, mercury, molybdenum, nickel, lead and zinc) and metalloids (arsenic, boron and selenium) in contaminated soils depends to a large extent on the intrinsic charge, valence and speciation of the contaminant ion, and soil properties such as pH, redox status and contents of clay and/or organic matter. However, chemistry and behaviour of the contaminant in soil alone cannot predict soil-to-plant transfer. Root uptake, root selectivity, ion interactions, rhizosphere processes, leaf uptake from the atmosphere, and plant partitioning are important processes that ultimately govern the accumulation ofmetals and metalloids in edible vegetable tissues. Mechanistic models to accurately describe all these processes have not yet been developed, let alone validated under field conditions. Hence, to estimate risks by vegetable consumption, empirical models have been used to correlate concentrations of metals and metalloids in contaminated soils, soil physico-chemical characteristics, and concentrations of elements in vegetable tissues. These models should only be used within the bounds of their calibration, and often need to be re-calibrated or validated using local soil and environmental conditions on a regional or site-specific basis.Mike J. McLaughlin, Erik Smolders, Fien Degryse, and Rene Rietr

Semimetallic carbon allotrope with topological nodal line in mixed sp2sp^2-sp3sp^3 bonding networks

Graphene is known as a two-dimensional Dirac semimetal, in which electron states are described by the Dirac equation of relativistic quantum mechanics. Three-dimensional analogues of graphene are characterized by Dirac points or lines in momentum space, which are protected by symmetry. Here, we report a novel 3D carbon allotrope belonging to a class of topological nodal line semimetals, discovered by using an evolutionary structure search method. The new carbon phase in monoclinic $C$2$/m$ space group, termed $m$-$C_8$, consists of five-membered rings with $sp^3$ bonding interconnected by $sp^2$-bonded carbon networks. Enthalpy calculations reveal that $m$-$C_8$ is more favorable over recently reported topological semimetallic carbon allotropes, and the dynamical stability of $m$-$C_8$ is verified by phonon spectra and molecular dynamics simulations. Simulated x-ray diffraction spectra propose that $m$-$C_8$ would be one of the unidentified carbon phases observed in detonation shoot. The analysis of electronic properties indicates that $m$-$C_8$ exhibits the nodal line protected by both inversion and time-reversal symmetries in the absence of spin-orbit coupling and the surface band connecting the projected nodal points. Our results may help design new carbon allotropes with exotic electronic properties.Comment: 18 pages, 5 figure

Atrial Fibrillation Genetic Risk and Ischemic Stroke Mechanisms

$\textit{Background and Purpose:}$ Atrial fibrillation (AF) is a leading cause of cardioembolic stroke, but the relationship between AF and noncardioembolic stroke subtypes are unclear. Because AF may be unrecognized, and because AF has a substantial genetic basis, we assessed for predisposition to AF across ischemic stroke subtypes. $\textit{Methods:}$ We examined associations between AF genetic risk and Trial of Org 10172 in Acute Stroke Treatment stroke subtypes in 2374 ambulatory individuals with ischemic stroke and 5175 without from the Wellcome Trust Case-Control Consortium 2 using logistic regression. We calculated AF genetic risk scores using single-nucleotide polymorphisms associated with AF in a previous independent analysis across a range of preselected significance thresholds. $\textit{Results:}$ There were 460 (19.4%) individuals with cardioembolic stroke, 498 (21.0%) with large vessel, 474 (20.0%) with small vessel, and 814 (32.3%) individuals with strokes of undetermined cause. Most AF genetic risk scores were associated with stroke, with the strongest association ($P$=6×10$^{-4}$) attributed to scores of 944 single-nucleotide polymorphisms (each associated with AF at $P$<1×10$^{-3}$) in a previous analysis). Associations between AF genetic risk and stroke were enriched in the cardioembolic stroke subset (strongest $P$=1.2×10$^{-9}$), 944 single-nucleotide polymorphism score). In contrast, AF genetic risk was not significantly associated with noncardioembolic stroke subtypes. $\textit{Conclusions:}$ Comprehensive AF genetic risk scores were specific for cardioembolic stroke. Incomplete workups and subtype misclassification may have limited the power to detect associations with strokes of undetermined pathogenesis. Future studies are warranted to determine whether AF genetic risk is a useful biomarker to enhance clinical discrimination of stroke pathogeneses.Dr. Lubitz is supported by NIH grants K23HL114724 and a Doris Duke Charitable Foundation Clinical Scientist Development Award 2014105. Dr. Traylor is supported by a British Heart Foundation programme grant (RG/16/4/32218). Dr. Ellinor and Benjamin are supported by 1RO1HL092577, R01HL128914. Dr. Ellinor is supported by grants from the National Institutes of Health K24HL105780 and an Established Investigator Award from the American Heart Association (13EIA14220013) and by the Fondation Leducq (14CVD01). Dr. Dichgans and Dr. Malik were supported by grants from the Deutsche Forschungsgemeinschaft (CRC 1123 [B3] and Munich Cluster for Systems Neurology [SyNergy]), the German Federal Ministry of Education and Research (BMBF, e:Med programme e:AtheroSysMed), the FP7/2007-2103 European Union project CVgenes@target (grant agreement No Health-F2-2013-601456), the European Union Horizon2020 projects SVDs@target (grant agreement No 66688) and CoSTREAM (grant agreement No 667375), the Fondation Leducq (Transatlantic Network of Excellence on the Pathogenesis of Small Vessel Disease of the Brain), the Vascular Dementia Research Foundation, and the Jackstaedt Foundation