Baseline NT-ProBNP level predicts success of cardioversion of atrial fibrillation with flecainide

BackgroundPatients with acute-onset symptomatic atrial fibrillation (AF) can be treated with flecainide. However, flecainide may induce arrhythmias and/or exaggerate heart failure. Therefore, validated markers to predict the efficacy of flecainide and prevent adverse effects are required. We hypothesised that lower NT-proBNP plasma levels correlate with higher success rates of cardioversion with flecainide in patients with AF.MethodsIn this prospective single-centre study, we included 112 subsequent patients with acute-onset (< 24 h) symptomatic AF. Patients with symptoms of heart failure and ECG signs of ischaemia were excluded. Baseline laboratory measurements, including NT-proBNP, were done. Echocardiograms were performed ~ 2 weeks after restoration of SR.ResultsCardioversion with flecainide was successful in 91 patients (87 %). NT-proBNP was lower in patients with successful cardioversion (P < 0.001). Logistic regression indicated NT-proBNP as an independent predictor of successful cardioversion. A cut-off NT-proBNP value of 1550 pg/ml provided optimal test accuracy to predict successful cardioversion.ConclusionIn patients with < 24 h of symptomatic AF, NT-proBNP levels up to 1550 pg/ml correlate with high success rates (94 %) of cardioversion with flecainide. Conversely, NT-proBNP higher than 1550 pg/ml correlates with poor success rates (36 %). Further research is needed to validate the predictive value of NT-proBNP for successful cardioversion with flecainide.     

The Fowler Syndrome-Associated Protein FLVCR2 Is an Importer of Heme

Mutations in FLVCR2, a cell surface protein related by homology and membrane topology to the heme exporter/retroviral receptor FLVCR1, have recently been associated with Fowler syndrome, a vascular disorder of the brain. We previously identified FLVCR2 to function as a receptor for FY981 feline leukemia virus (FeLV). However, the cellular function of FLVCR2 remains unresolved. Here, we report the cellular function of FLVCR2 as an importer of heme, based on the following observations. First, FLVCR2 binds to hemin-conjugated agarose, and binding is competed by free hemin. Second, mammalian cells and Xenopus laevis oocytes expressing FLVCR2 display enhanced heme uptake. Third, heme import is reduced after the expression of FLVCR2-specific small interfering RNA (siRNA) or after the binding of the FY981 FeLV envelope protein to the FLVCR2 receptor. Finally, cells overexpressing FLVCR2 are more sensitive to heme toxicity, a finding most likely attributable to enhanced heme uptake. Tissue expression analysis indicates that FLVCR2 is expressed in a broad range of human tissues, including liver, placenta, brain, and kidney. The identification of a cellular function for FLVCR2 will have important implications in elucidating the pathogenic mechanisms of Fowler syndrome and of phenotypically associated disorders.Membrane transporters play essential roles in cellular homeostasis by importing substrates critical for cell growth and differentiation or by exporting substrates that cause toxicity. There are five major categories of membrane transporters consisting of over 550 transporter superfamilies (41). The major facilitator superfamily (MFS) is the largest and most diverse superfamily, consisting of over 10,000 members (31, 41). Transporters in this superfamily consist of 12 to 14 transmembrane (TM)-spanning segments and transport substrates as diverse as sugars, polyols, drugs, neurotransmitters, amino acids, organic/inorganic ions, and peptides (31). Recently, a disruption of MFS transporters that is associated with human diseases has been described, further confirming their role in the maintenance of normal cell homeostasis. The DIRC2 MFS transporter (substrate transported unknown) is disrupted in renal cell carcinoma cosegregating with a t(2;3)(q35;q21) chromosomal translocation (4). Mutations in the thiamine transporter THTR1 have been shown to be responsible for Rogers syndrome (14, 21), a thiamine-responsive megaloblastic anemia. We have recently reported that a disruption in the heme exporter FLVCR1 (MFSD7B) plays a role in Diamond Blackfan anemia (DBA) (40), a fatal infant anemia characterized by a block in erythroid progenitor cell development (3, 12, 13). The abrogation of FLVCR1 function in primary human hematopoietic stem cells (40) or in a human erythroid cell line (37) specifically disrupts erythropoiesis, mimicking the hematological features observed for patients with DBA. We have reported previously that FLVCR1 is disrupted not as a consequence of mutations in the FLVCR1 coding region but due to the aberrant splicing of specific FLVCR1 exons that reduces the expression and cell surface localization of the encoded FLVCR1 protein (40). Interestingly, the THTR1 and FLVCR1 proteins were shown previously to function as receptors for entry by feline leukemia retrovirus (FeLV) subgroup A (FeLV-A) (25) and FeLV-C (36, 46), respectively. These viruses disrupt the cellular function of these proteins in infected cats and can induce diseases that correlate with Rogers syndrome (17) and DBA (1, 28).Recently, mutations in the cell surface protein FLVCR2 (MFSD7C), an MFS transporter member, have been shown to be associated with Fowler syndrome (22, 26), a proliferative vascular disorder of the brain (16). A previous study (6) suggested that FLVCR2 functions as a calcium-chelate transporter based on its expression in murine and human tissues involved in calcium homeostasis. We have shown previously that FLVCR2 is highly related to the heme exporter/retroviral receptor FLVCR1 (7), and we have recently shown it to function as a receptor for the subgroup C FeLV variant FY981 (42). Based on its close sequence relationship to the heme exporter/retroviral receptor FLVCR1 and based on previous reports showing that retroviruses often adapt to use closely related cell surface proteins as receptors for infection (27, 30, 44), we investigated the heme transport function of FLVCR2. Here, we show the physiological function of FLVCR2 as an importer of heme.     

Fever-triggered ventricular arrhythmias in Brugada syndrome and type 2 long-QT syndrome

The risk for lethal ventricular arrhythmias is increased in individuals who carry mutations in genes that encode cardiac ion channels. Loss-of-function mutations in SCN5A, the gene encoding the cardiac sodium channel, are linked to Brugada syndrome (BrS). Arrhythmias in BrS are often preceded by coved-type ST-segment elevation in the right-precordial leads V1 and V2. Loss-of-function mutations in KCNH2, the gene encoding the cardiac ion channel that is responsible for the rapidly activating delayed rectifying potassium current, are linked to long-QT syndrome type 2 (LQT-2). LQT-2 is characterised by delayed cardiac repolarisation and rate-corrected QT interval (QTc) prolongation. Here, we report that the risk for ventricular arrhythmias in BrS and LQT-2 is further increased during fever. Moreover, we demonstrate that fever may aggravate coved-type ST-segment elevation in BrS, and cause QTc lengthening in LQT-2. Finally, we describe molecular mechanisms that may underlie the proarrhythmic effects of fever in BrS and LQT-2. (Neth Heart J 2010;18:165-9.)     

Molecular marker assisted broadening of the Central European heterotic groups in rye with Eastern European germplasm

Broadening the genetic base of heterotic pools is a key to ensure continued genetic gains in hybrid breeding and extend hybrid cultivation to new areas. In the present study, two Central European heterotic pools (Carsten and Petkus) and five Eastern European open-pollinated varieties (OPVs, Pop-1 to Pop-5) were studied with the objectives to (1) investigate the genetic diversity in OPVs and the heterotic pools using molecular and field data, (2) evaluate the molecular diversity among OPVs, (3) examine the combining ability for grain yield of the OPVs when crossed with testers in field trials, and (4) develop a strategy for targeted introgression of OPV germplasm into the heterotic pools. In total, 610 S₀ plants, 347 from OPVs and 263 from heterotic pools, were developed. Clones of the S₀ plants of OPVs were crossed with two testers belonging to each heterotic pool, while clones of heterotic pools were crossed with only the opposite tester. Testcrosses were evaluated for grain yield in multi-location trials. In addition, 589 S₀ plants were fingerprinted with 30 SSR markers. The data revealed that the Carsten pool has a narrow genetic base and should be the primary target for broadening the established heterotic pattern. Mean and genetic variance suggested that Pop-2 and Pop-4 are good candidates for introgression in Petkus pool and Pop-5 in Carsten pool. Nevertheless, introgression of Pop-5 in Carsten could reduce the genetic diversity between heterotic pools. Therefore, we suggest that either selected plants of Pop-5 should be introgressed or more Eastern European germplasm should be fingerprinted and field evaluated to identify promising germplasm for broadening the established heterotic pattern.     

Increased expression of costimulatory markers CD134 and CD80 on interleukin-17 producing T cells in patients with systemic lupus erythematosus

Introduction  

There is growing evidence that interleukin 17 (IL-17) producing T cells are involved in the pathogenesis of systemic lupus erythematosus (SLE). Previous studies showed that increased percentages of T-cell subsets expressing the costimulatory molecules CD80 and CD134 are associated with disease activity and renal involvement in SLE. The aim of this study was to investigate the distribution and phenotypical characteristics of IL-17 producing T-cells in SLE, in particular in patients with lupus nephritis, with emphasis on the expression of CD80 and CD134.     

Late assembly steps and dynamics of the cyanobacterial photosystem I

The dynamics of photosystem I assembly in cyanobacteria have been addressed using in vivo pulse-chase labeling of Synechocystis sp. PCC 6803 proteins in combination with blue native polyacrylamide gel electrophoresis. The analyses indicate the existence of three different monomeric photosystem I complexes and also the high stability of photosystem I trimers. We show that in addition to a complete photosystem I monomer, containing all 11 subunits, we detected a PsaK-less monomer and a short-lived PsaL/PsaK-less complex. The latter two monomers were missing in the ycf37 mutant of Synechocystis sp. PCC 6803 that accumulates also less trimers. Pulse-chase experiments suggest that the three monomeric complexes have different functions in the biogenesis of the trimer. Based on these findings we propose a model where PsaK is incorporated in the latest step of photosystem I assembly. The PsaK-less photosystem I monomer may represent an intermediate complex that is important for the exchange of the two PsaK variants during high light acclimation. Implications of the presented data with respect to Ycf37 function are discussed.     

Chromosomal toxin-antitoxin loci can diminish large-scale genome reductions in the absence of selection

Superintegrons (SIs) are chromosomal genetic elements containing assemblies of genes, each flanked by a recombination sequence (attC site) targeted by the integron integrase. SIs may contain hundreds of attC sites and intrinsic instability is anticipated; yet SIs are remarkably stable. This implies that either selective pressure maintains the genes or mechanisms exist which favour their persistence in the absence of selection. Toxin/antitoxin (TA) systems encode a stable toxin and a specific, unstable antitoxin. Once activated, the continued synthesis of the unstable antitoxin is necessary for cell survival. A bioinformatic search of accessible microbial genomes for SIs and TA systems revealed that large SIs harboured TA gene cassettes while smaller SIs did not. We demonstrated the function of TA loci in different genomic contexts where large-scale deletions can occur; in SIs and in a 165 kb dispensable region of the Escherichia coli genome. When devoid of TA loci, large-scale genome loss was evident in both environments. The inclusion of two TA loci, relBE1 and parDE1, which we identified in the Vibrio vulnificus SI rendered these environments refractory to gene loss. Thus, chromosomal TA loci can stabilize massive SI arrays and limit the extensive gene loss that is a hallmark of reductive evolution.     

Genetic predisposition for sudden cardiac death in myocardial ischaemia: the Arrhythmia Genetics in the NEtherlandS study

Sudden cardiac death from ventricular fibrillation during myocardial infarction is a leading cause of total and cardiovascular mortality. This multifactorial, complex condition clusters in families, suggesting a substantial genetic cause. We carried out a genomewide association study (GWAS) for sudden cardiac death, in the AGNES (Arrhythmia Genetics in the Netherlands) population, consisting of patients with (cases) and without (controls) ventricular fibrillation during a first ST-elevation myocardial infarction. The most significant association was found at chromosome 21q21 (rs2824292; odds ratio = 1.78, 95% CI 1.47–2.13, P = 3.3 × 10⁻¹⁰), 98 kb proximal of the CXADR gene, encoding the Coxsackie and adenovirus receptor. This locus has not previously been implicated in arrhythmia susceptibility. Further research on the mechanism of this locus will ultimately provide novel insight into arrhythmia mechanisms in this condition.     

High fat diet-induced changes in mouse muscle mitochondrial phospholipids do not impair mitochondrial respiration despite insulin resistance

Background

Type 2 diabetes mellitus and muscle insulin resistance have been associated with reduced capacity of skeletal muscle mitochondria, possibly as a result of increased intake of dietary fat. Here, we examined the hypothesis that a prolonged high-fat diet consumption (HFD) increases the saturation of muscle mitochondrial membrane phospholipids causing impaired mitochondrial oxidative capacity and possibly insulin resistance.

Methodology

C57BL/6J mice were fed an 8-week or 20-week low fat diet (10 kcal%; LFD) or HFD (45 kcal%). Skeletal muscle mitochondria were isolated and fatty acid (FA) composition of skeletal muscle mitochondrial phospholipids was analyzed by thin-layer chromatography followed by GC. High-resolution respirometry was used to assess oxidation of pyruvate and fatty acids by mitochondria. Insulin sensitivity was estimated by HOMA-IR.

Principal Findings

At 8 weeks, mono-unsaturated FA (16∶1n7, 18∶1n7 and 18∶1n9) were decreased (−4.0%, p<0.001), whereas saturated FA (16∶0) were increased (+3.2%, p<0.001) in phospholipids of HFD vs. LFD mitochondria. Interestingly, 20 weeks of HFD descreased mono-unsaturated FA while n-6 poly-unsaturated FA (18∶2n6, 20∶4n6, 22∶5n6) showed a pronounced increase (+4.0%, p<0.001). Despite increased saturation of muscle mitochondrial phospholipids after the 8-week HFD, mitochondrial oxidation of both pyruvate and fatty acids were similar between LFD and HFD mice. After 20 weeks of HFD, the increase in n-6 poly-unsaturated FA was accompanied by enhanced maximal capacity of the electron transport chain (+49%, p = 0.002) and a tendency for increased ADP-stimulated respiration, but only when fuelled by a lipid-derived substrate. Insulin sensitivity in HFD mice was reduced at both 8 and 20 weeks.

Conclusions/Interpretation

Our findings do not support the concept that prolonged HF feeding leads to increased saturation of skeletal muscle mitochondrial phospholipids resulting in a decrease in mitochondrial fat oxidative capacity and (muscle) insulin resistance.     

H9, H10, and H11 compose a cluster of Hessian fly-resistance genes in the distal gene-rich region of wheat chromosome 1AS

H9, H10, and H11 are major dominant resistance genes in wheat, expressing antibiosis against Hessian fly [(Hf) Mayetiola destructor (Say)] larvae. Previously, H9 and H10 were assigned to chromosome 5A and H11 to 1A. The objectives of this study were to identify simple-sequence-repeat (SSR) markers for fine mapping of these genes and for marker-assisted selection in wheat breeding. Contrary to previous results, H9 and H10 did not show linkage with SSR markers on chromosome 5A. Instead, H9, H10, and H11 are linked with SSR markers on the short arm of chromosome 1A. Both H9 and H10 are tightly linked to flanking markers Xbarc263 and Xcfa2153 within a genetic distance of 0.3–0.5 cM. H11 is tightly linked to flanking markers Xcfa2153 and Xbarc263 at genetic distances of 0.3 cM and 1.7 cM. Deletion bin mapping assigned these markers and genes to the distal 14% of chromosome arm 1AS, where another Hf-resistance gene, Hdic (derived from emmer wheat), was also mapped previously. Marker polymorphism results indicated that a small terminal segment of chromosome 1AS containing H9 or H10 was transferred from the donor parent to the wheat lines Iris or Joy, and a small intercalary fragment carrying H11 was transferred from the resistant donor to the wheat line Karen. Our results suggest that H9, H10, H11, Hdic, and the previously identified H9- or H11-linked genes (H3, H5, H6, H12, H14, H15, H16, H17, H19, H28, and H29) may compose a cluster (or family) of Hf-resistance genes in the distal gene-rich region of wheat chromosome 1AS; and H10 most likely is the same gene as H9.Mention of commercial or proprietary product does not constitute an endorsement by the USDA.