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Sample records for forms amyloid-like fibrils

  1. Genetic engineering combined with deep UV resonance Raman spectroscopy for structural characterization of amyloid-like fibrils.

    Science.gov (United States)

    Sikirzhytski, Vitali; Topilina, Natalya I; Higashiya, Seiichiro; Welch, John T; Lednev, Igor K

    2008-05-07

    Elucidating the structure of the cross-beta core in large amyloid fibrils is a challenging problem in modern structural biology. For the first time, a set of de novo polypeptides was genetically engineered to form amyloid-like fibrils with similar morphology and yet different strand length. Differential ultraviolet Raman spectroscopy allowed for separation of the spectroscopic signatures of the highly ordered beta-sheet strands and turns of the fibril core. The relationship between Raman frequencies and Ramachandran dihedral angles of the polypeptide backbone indicates the nature of the beta-sheet and turn structural elements.

  2. Mechanical properties of amyloid-like fibrils defined by secondary structures

    Science.gov (United States)

    Bortolini, C.; Jones, N. C.; Hoffmann, S. V.; Wang, C.; Besenbacher, F.; Dong, M.

    2015-04-01

    Amyloid and amyloid-like fibrils represent a generic class of highly ordered nanostructures that are implicated in some of the most fatal neurodegenerative diseases. On the other hand, amyloids, by possessing outstanding mechanical robustness, have also been successfully employed as functional biomaterials. For these reasons, physical and chemical factors driving fibril self-assembly and morphology are extensively studied - among these parameters, the secondary structures and the pH have been revealed to be crucial, since a variation in pH changes the fibril morphology and net chirality during protein aggregation. It is important to quantify the mechanical properties of these fibrils in order to help the design of effective strategies for treating diseases related to the presence of amyloid fibrils. In this work, we show that by changing pH the mechanical properties of amyloid-like fibrils vary as well. In particular, we reveal that these mechanical properties are strongly related to the content of secondary structures. We analysed and estimated the Young's modulus (E) by comparing the persistence length (Lp) - measured from the observation of TEM images by using statistical mechanics arguments - with the mechanical information provided by peak force quantitative nanomechanical property mapping (PF-QNM). The secondary structure content and the chirality are investigated by means of synchrotron radiation circular dichroism (SR-CD). Results arising from this study could be fruitfully used as a protocol to investigate other medical or engineering relevant peptide fibrils.Amyloid and amyloid-like fibrils represent a generic class of highly ordered nanostructures that are implicated in some of the most fatal neurodegenerative diseases. On the other hand, amyloids, by possessing outstanding mechanical robustness, have also been successfully employed as functional biomaterials. For these reasons, physical and chemical factors driving fibril self-assembly and morphology

  3. Amyloid-like fibril formation by polyQ proteins: a critical balance between the polyQ length and the constraints imposed by the host protein.

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    Natacha Scarafone

    Full Text Available Nine neurodegenerative disorders, called polyglutamine (polyQ diseases, are characterized by the formation of intranuclear amyloid-like aggregates by nine proteins containing a polyQ tract above a threshold length. These insoluble aggregates and/or some of their soluble precursors are thought to play a role in the pathogenesis. The mechanism by which polyQ expansions trigger the aggregation of the relevant proteins remains, however, unclear. In this work, polyQ tracts of different lengths were inserted into a solvent-exposed loop of the β-lactamase BlaP and the effects of these insertions on the properties of BlaP were investigated by a range of biophysical techniques. The insertion of up to 79 glutamines does not modify the structure of BlaP; it does, however, significantly destabilize the enzyme. The extent of destabilization is largely independent of the polyQ length, allowing us to study independently the effects intrinsic to the polyQ length and those related to the structural integrity of BlaP on the aggregating properties of the chimeras. Only chimeras with 55Q and 79Q readily form amyloid-like fibrils; therefore, similarly to the proteins associated with diseases, there is a threshold number of glutamines above which the chimeras aggregate into amyloid-like fibrils. Most importantly, the chimera containing 79Q forms amyloid-like fibrils at the same rate whether BlaP is folded or not, whereas the 55Q chimera aggregates into amyloid-like fibrils only if BlaP is unfolded. The threshold value for amyloid-like fibril formation depends, therefore, on the structural integrity of the β-lactamase moiety and thus on the steric and/or conformational constraints applied to the polyQ tract. These constraints have, however, no significant effect on the propensity of the 79Q tract to trigger fibril formation. These results suggest that the influence of the protein context on the aggregating properties of polyQ disease-associated proteins could be

  4. Sucrose modulates insulin amyloid-like fibril formation: effect on the aggregation mechanism and fibril morphology

    DEFF Research Database (Denmark)

    Marasini, Carlotta; Foderà, Vito; Vestergaard, Bente

    2017-01-01

    the protein self-assembly pathways. Using a combination of fluorescence spectroscopy, synchrotron radiation circular dichroism and transmission electron microscopy, we study the kinetics of formation and structural properties of human insulin fibrils in the presence of sucrose. The presence of sucrose results...... in a delay of the onset of fibrillation. Moreover, it leads to a dramatic change in both the morphology and overall amount of fibrils. Our results emphasize that the detailed composition of protein surroundings likely influences not only the fibrillation kinetics but also the balance between different...

  5. Polymorphism of amyloid-like fibrils can be defined by the concentration of seeds

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    Tomas Sneideris

    2015-08-01

    Full Text Available Prions are infectious proteins where the same protein may express distinct strains. The strains are enciphered by different misfolded conformations. Strain-like phenomena have also been reported in a number of other amyloid-forming proteins. One of the features of amyloid strains is the ability to self-propagate, maintaining a constant set of physical properties despite being propagated under conditions different from those that allowed initial formation of the strain. Here we report a cross-seeding experiment using strains formed under different conditions. Using high concentrations of seeds results in rapid elongation and new fibrils preserve the properties of the seeding fibrils. At low seed concentrations, secondary nucleation plays the major role and new fibrils gain properties predicted by the environment rather than the structure of the seeds. Our findings could explain conformational switching between amyloid strains observed in a wide variety of in vivo and in vitro experiments.

  6. Evaluation of protease resistance and toxicity of amyloid-like food fibrils from whey, soy, kidney bean, and egg white.

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    Lassé, Moritz; Ulluwishewa, Dulantha; Healy, Jackie; Thompson, Dion; Miller, Antonia; Roy, Nicole; Chitcholtan, Kenny; Gerrard, Juliet A

    2016-02-01

    The structural properties of amyloid fibrils combined with their highly functional surface chemistry make them an attractive new food ingredient, for example as highly effective gelling agents. However, the toxic role of amyloid fibrils in disease may cause some concern about their food safety because it has not been established unequivocally if consumption of food fibrils poses a health risk to consumers. Here we present a study of amyloid-like fibrils from whey, kidney bean, soy bean, and egg white to partially address this concern. Fibrils showed varied resistance to proteolytic digestion in vitro by either Proteinase K, pepsin or pancreatin. The toxicity of mature fibrils was measured in vitro and compared to native protein, early-stage-fibrillar protein, and sonicated fibrils in two immortalised human cancer cell lines, Caco-2 and Hec-1a. There was no reduction in the viability of either Caco-2 or Hec-1a cells after treatment with a fibril concentration of up to 0.25 mg/mL. Copyright © 2015 Elsevier Ltd. All rights reserved.

  7. MLKL forms disulfide bond-dependent amyloid-like polymers to induce necroptosis.

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    Liu, Shuzhen; Liu, Hua; Johnston, Andrea; Hanna-Addams, Sarah; Reynoso, Eduardo; Xiang, Yougui; Wang, Zhigao

    2017-09-05

    Mixed-lineage kinase domain-like protein (MLKL) is essential for TNF-α-induced necroptosis. How MLKL promotes cell death is still under debate. Here we report that MLKL forms SDS-resistant, disulfide bond-dependent polymers during necroptosis in both human and mouse cells. MLKL polymers are independent of receptor-interacting protein kinase 1 and 3 (RIPK1/RIPK3) fibers. Large MLKL polymers are more than 2 million Da and are resistant to proteinase K digestion. MLKL polymers are fibers 5 nm in diameter under electron microscopy. Furthermore, the recombinant N-terminal domain of MLKL forms amyloid-like fibers and binds Congo red dye. MLKL mutants that cannot form polymers also fail to induce necroptosis efficiently. Finally, the compound necrosulfonamide conjugates cysteine 86 of human MLKL and blocks MLKL polymer formation and subsequent cell death. These results demonstrate that disulfide bond-dependent, amyloid-like MLKL polymers are necessary and sufficient to induce necroptosis.

  8. Direct Correlation Between Ligand-Induced α-Synuclein Oligomers and Amyloid-like Fibril Growth

    DEFF Research Database (Denmark)

    Pedersen, Martin Nors; Foderà, Vito; Horvath, Istvan

    2015-01-01

    link to disease related degenerative activity. Fibrils formed in the presence and absence of FN075 are indistinguishable on microscopic and macroscopic levels. Using small angle X-ray scattering, we reveal that FN075 induced oligomers are similar, but not identical, to oligomers previously observed......Aggregation of proteins into amyloid deposits is the hallmark of several neurodegenerative diseases such as Alzheimer's and Parkinson's disease. The suggestion that intermediate oligomeric species may be cytotoxic has led to intensified investigations of pre-fibrillar oligomers, which...

  9. Glucagon Amyloid-like Fibril Morphology Is Selected via Morphology-Dependent Growth Inhibition

    DEFF Research Database (Denmark)

    Andersen, C.B.; Otzen, D.; Christiansen, Gunna

    2007-01-01

    Protein Structure and Biophysics, Novo Nordisk A/S, Novo Nordisk Park, DK-2760 Malov, Denmark, Centre for Insoluble Protein Structures (inSPIN), Department of Life Sciences, Aalborg University, Sohngaardsholmsvej 49, DK-9000 Aalborg, Denmark, and Institute of Medical Microbiology and Immunology...... twisted fibril seeds cannot grow at high concentrations. We conclude that there exists a morphology-dependent mechanism for inhibition of glucagon fibril growth. Light scattering experiments indicate that glucagon is mainly monomeric below 1 mg/mL and increasingly trimeric above this concentration. We...

  10. The architecture of amyloid-like peptide fibrils revealed by X-ray scattering, diffraction and electron microscopy

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    Langkilde, Annette E., E-mail: annette.langkilde@sund.ku.dk [University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen (Denmark); Morris, Kyle L.; Serpell, Louise C. [University of Sussex, Falmer, Brighton (United Kingdom); Svergun, Dmitri I. [European Molecular Biology Laboratory, Hamburg Outstation, 22607 Hamburg (Germany); Vestergaard, Bente [University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen (Denmark)

    2015-04-01

    The aggregation process and the fibril state of an amyloidogenic peptide suggest monomer addition to be the prevailing mechanism of elongation and a model of the peptide packing in the fibrils has been obtained. Structural analysis of protein fibrillation is inherently challenging. Given the crucial role of fibrils in amyloid diseases, method advancement is urgently needed. A hybrid modelling approach is presented enabling detailed analysis of a highly ordered and hierarchically organized fibril of the GNNQQNY peptide fragment of a yeast prion protein. Data from small-angle X-ray solution scattering, fibre diffraction and electron microscopy are combined with existing high-resolution X-ray crystallographic structures to investigate the fibrillation process and the hierarchical fibril structure of the peptide fragment. The elongation of these fibrils proceeds without the accumulation of any detectable amount of intermediate oligomeric species, as is otherwise reported for, for example, glucagon, insulin and α-synuclein. Ribbons constituted of linearly arranged protofilaments are formed. An additional hierarchical layer is generated via the pairing of ribbons during fibril maturation. Based on the complementary data, a quasi-atomic resolution model of the protofilament peptide arrangement is suggested. The peptide structure appears in a β-sheet arrangement reminiscent of the β-zipper structures evident from high-resolution crystal structures, with specific differences in the relative peptide orientation. The complexity of protein fibrillation and structure emphasizes the need to use multiple complementary methods.

  11. The architecture of amyloid-like peptide fibrils revealed by X-ray scattering, diffraction and electron microscopy

    DEFF Research Database (Denmark)

    Langkilde, Annette Eva; Morris, Kyle L; Serpell, Louise C

    2015-01-01

    Structural analysis of protein fibrillation is inherently challenging. Given the crucial role of fibrils in amyloid diseases, method advancement is urgently needed. A hybrid modelling approach is presented enabling detailed analysis of a highly ordered and hierarchically organized fibril of the G......Structural analysis of protein fibrillation is inherently challenging. Given the crucial role of fibrils in amyloid diseases, method advancement is urgently needed. A hybrid modelling approach is presented enabling detailed analysis of a highly ordered and hierarchically organized fibril...

  12. Hsp40 interacts directly with the native state of the yeast prion protein Ure2 and inhibits formation of amyloid-like fibrils.

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    Lian, Hui-Yong; Zhang, Hong; Zhang, Zai-Rong; Loovers, Harriët M; Jones, Gary W; Rowling, Pamela J E; Itzhaki, Laura S; Zhou, Jun-Mei; Perrett, Sarah

    2007-04-20

    Ure2 is the protein determinant of the [URE3] prion phenotype in Saccharomyces cerevisiae and consists of a flexible N-terminal prion-determining domain and a globular C-terminal glutathione transferase-like domain. Overexpression of the type I Hsp40 member Ydj1 in yeast cells has been found to result in the loss of [URE3]. However, the mechanism of prion curing by Ydj1 remains unclear. Here we tested the effect of overexpression of Hsp40 members Ydj1, Sis1, and Apj1 and also Hsp70 co-chaperones Cpr7, Cns1, Sti1, and Fes1 in vivo and found that only Ydj1 showed a strong curing effect on [URE3]. We also investigated the interaction of Ydj1 with Ure2 in vitro. We found that Ydj1 was able to suppress formation of amyloid-like fibrils of Ure2 by delaying the process of fibril formation, as monitored by thioflavin T binding and atomic force microscopy imaging. Controls using bovine serum albumin, Sis1, or the human Hsp40 homologues Hdj1 or Hdj2 showed no significant inhibitory effect. Ydj1 was only effective when added during the lag phase of fibril formation, suggesting that it interacts with Ure2 at an early stage in fibril formation and delays the nucleation process. Using surface plasmon resonance and size exclusion chromatography, we demonstrated a direct interaction between Ydj1 and both wild type and N-terminally truncated Ure2. In contrast, Hdj2, which did not suppress fibril formation, did not show this interaction. The results suggest that Ydj1 inhibits Ure2 fibril formation by binding to the native state of Ure2, thus delaying the onset of oligomerization.

  13. Amyloid-like protein inclusions in tobacco transgenic plants.

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    Anna Villar-Piqué

    Full Text Available The formation of insoluble protein deposits in human tissues is linked to the onset of more than 40 different disorders, ranging from dementia to diabetes. In these diseases, the proteins usually self-assemble into ordered β-sheet enriched aggregates known as amyloid fibrils. Here we study the structure of the inclusions formed by maize transglutaminase (TGZ in the chloroplasts of tobacco transplastomic plants and demonstrate that they have an amyloid-like nature. Together with the evidence of amyloid structures in bacteria and fungi our data argue that amyloid formation is likely a ubiquitous process occurring across the different kingdoms of life. The discovery of amyloid conformations inside inclusions of genetically modified plants might have implications regarding their use for human applications.

  14. Trifluoroethanol modulates α-synuclein amyloid-like aggregate formation, stability and dissolution

    DEFF Research Database (Denmark)

    Di Carlo, Maria Giovanna; Vetri, Valeria; Buscarino, Gianpiero

    2016-01-01

    The conversion of proteins into amyloid fibrils and other amyloid-like aggregates is closely connected to the onset of a series of age-related pathologies. Upon changes in environmental conditions, amyloid-like aggregates may also undergo disassembly into oligomeric aggregates, the latter being r...

  15. Loss of metal ions, disulfide reduction and mutations related to familial ALS promote formation of amyloid-like aggregates from superoxide dismutase.

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    Zeynep A Oztug Durer

    Full Text Available Mutations in the gene encoding Cu-Zn superoxide dismutase (SOD1 are one of the causes of familial amyotrophic lateral sclerosis (FALS. Fibrillar inclusions containing SOD1 and SOD1 inclusions that bind the amyloid-specific dye thioflavin S have been found in neurons of transgenic mice expressing mutant SOD1. Therefore, the formation of amyloid fibrils from human SOD1 was investigated. When agitated at acidic pH in the presence of low concentrations of guanidine or acetonitrile, metalated SOD1 formed fibrillar material which bound both thioflavin T and Congo red and had circular dichroism and infrared spectra characteristic of amyloid. While metalated SOD1 did not form amyloid-like aggregates at neutral pH, either removing metals from SOD1 with its intramolecular disulfide bond intact or reducing the intramolecular disulfide bond of metalated SOD1 was sufficient to promote formation of these aggregates. SOD1 formed amyloid-like aggregates both with and without intermolecular disulfide bonds, depending on the incubation conditions, and a mutant SOD1 lacking free sulfhydryl groups (AS-SOD1 formed amyloid-like aggregates at neutral pH under reducing conditions. ALS mutations enhanced the ability of disulfide-reduced SOD1 to form amyloid-like aggregates, and apo-AS-SOD1 formed amyloid-like aggregates at pH 7 only when an ALS mutation was also present. These results indicate that some mutations related to ALS promote formation of amyloid-like aggregates by facilitating the loss of metals and/or by making the intramolecular disulfide bond more susceptible to reduction, thus allowing the conversion of SOD1 to a form that aggregates to form resembling amyloid. Furthermore, the occurrence of amyloid-like aggregates per se does not depend on forming intermolecular disulfide bonds, and multiple forms of such aggregates can be produced from SOD1.

  16. Unwinding fibril formation of medin, the peptide of the most common form of human amyloid

    International Nuclear Information System (INIS)

    Larsson, Annika; Soederberg, Linda; Westermark, Gunilla T.; Sletten, Knut; Engstroem, Ulla; Tjernberg, Lars O.; Naeslund, Jan; Westermark, Per

    2007-01-01

    Medin amyloid affects the medial layer of the thoracic aorta of most people above 50 years of age. The consequences of this amyloid are not completely known but the deposits may contribute to diseases such as thoracic aortic aneurysm and dissection or to the general diminished elasticity of blood vessels seen in elderly people. We show that the 50-amino acid residue peptide medin forms amyloid-like fibrils in vitro. With the use of Congo red staining, Thioflavin T fluorescence, electron microscopy, and a solid-phase binding assay on different synthetic peptides, we identified the last 18-19 amino acid residues to constitute the amyloid-promoting region of medin. We also demonstrate that the two C-terminal phenylalanines, previously suggested to be of importance for amyloid formation, are not required for medin amyloid formation

  17. The Filament-specific Rep1-1 Repellent of the Phytopathogen Ustilago maydis Forms Functional Surface-active Amyloid-like Fibrils

    NARCIS (Netherlands)

    Teertstra, Wieke R.; van der Velden, Gisela J.; de Jong, Jan F.; Kruijtzer, John A. W.; Liskamp, Rob M. J.; Kroon-Batenburg, Loes M. J.; Muller, Wally H.; Gebbink, Martijn F. B. G.; Wosten, Han A. B.

    2009-01-01

    Repellents of the maize pathogen Ustilago maydis are involved in formation of hydrophobic aerial hyphae and in cellular attachment. These peptides, called Rep1-1 to Rep1-11, are encoded by the rep1 gene and result from cleavage of the precursor protein Rep1 during passage of the secretion pathway.

  18. Insights into amyloid-like aggregation of H2 region of the C-terminal domain of nucleophosmin.

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    Russo, Anna; Diaferia, Carlo; La Manna, Sara; Giannini, Cinzia; Sibillano, Teresa; Accardo, Antonella; Morelli, Giancarlo; Novellino, Ettore; Marasco, Daniela

    2017-02-01

    Nucleophosmin (NPM1) is a multifunctional protein involved in a variety of biological processes including the pathogenesis of several human malignancies and is the most frequently mutated gene in Acute Myeloid Leukemia (AML). To deepen the role of protein regions in its biological activities, lately we reported on the structural behavior of dissected C-terminal domain (CTD) helical fragments. Unexpectedly the H2 (residues 264-277) and H3 AML-mutated regions showed a remarkable tendency to form amyloid-like assemblies with fibrillar morphology and β-sheet structure that resulted as toxic when exposed to human neuroblastoma cells. More recently NPM1 was found to be highly expressed and toxic in neurons of mouse models of Huntington's disease (HD). Here we investigate the role of each residue in the β-strand aggregation process of H2 region of NPM1 by performing a systematic alanine scan of its sequence and structural and kinetic analyses of aggregation of derived peptides by means of Circular Dichorism (CD) and Thioflavin T (Th-T) assay. These solution state investigations pointed out the crucial role exerted by the basic amyloidogenic stretch of H2 (264-271) and to shed light on the initial and main interactions involved in fibril formation we performed studies on fibrils deriving from the related Ala peptides through the analysis of fibrils with birefringence of polarized optical microscopy and wide-angle X-ray scattering (WAXS). This analysis suggested that the presence of branched Ile 269 conferred preferential packing patterns that, instead, appeared geometrically hampered by the aromatic side-chain of Phe 268 . Present investigations could be useful to deepen the knowledge of AML molecular mechanisms and the role of cytoplasmatic aggregates of NPM1c+. Copyright © 2016 Elsevier B.V. All rights reserved.

  19. Cooperative structural transitions in amyloid-like aggregation

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    Steckmann, Timothy; Bhandari, Yuba R.; Chapagain, Prem P.; Gerstman, Bernard S.

    2017-04-01

    Amyloid fibril aggregation is associated with several horrific diseases such as Alzheimer's, Creutzfeld-Jacob, diabetes, Parkinson's, and others. Although proteins that undergo aggregation vary widely in their primary structure, they all produce a cross-β motif with the proteins in β-strand conformations perpendicular to the fibril axis. The process of amyloid aggregation involves forming myriad different metastable intermediate aggregates. To better understand the molecular basis of the protein structural transitions and aggregation, we report on molecular dynamics (MD) computational studies on the formation of amyloid protofibrillar structures in the small model protein ccβ, which undergoes many of the structural transitions of the larger, naturally occurring amyloid forming proteins. Two different structural transition processes involving hydrogen bonds are observed for aggregation into fibrils: the breaking of intrachain hydrogen bonds to allow β-hairpin proteins to straighten, and the subsequent formation of interchain H-bonds during aggregation into amyloid fibrils. For our MD simulations, we found that the temperature dependence of these two different structural transition processes results in the existence of a temperature window that the ccβ protein experiences during the process of forming protofibrillar structures. This temperature dependence allows us to investigate the dynamics on a molecular level. We report on the thermodynamics and cooperativity of the transformations. The structural transitions that occurred in a specific temperature window for ccβ in our investigations may also occur in other amyloid forming proteins but with biochemical parameters controlling the dynamics rather than temperature.

  20. Tuning calcium carbonate growth through physical confinement and templating with amyloid-like polypeptide aggregates

    Science.gov (United States)

    Colaco, Martin Francis

    that this methodology does not extend to three-dimensional confined systems, as the water has no method of escape. Through the addition of an insoluble hydroscopic polymer to our microreactors, amorphous calcium carbonate of controllable sizes can be grown. However, crystalline calcium carbonate cannot be grown without some type of templating. Studies of calcium carbonate templating have predominantly been performed on SAMs or in poorly characterized gels or protein films. The use of ordered protein or polypeptide aggregates for templating permits both geometry and charge surface density to be varied. We have studied the kinetics and final morphology of ordered aggregates of poly-L-glutamic acid and a copolymer of glutamic acid and alanine through experiments and simulations. Electrostatics, not structure, of the monomer appeared to be the dominating factor in the aggregation, as pH and salt concentration changes led to dramatic changes in the kinetics. Examining our experimental with existing models provided inconsistent results, so we developed a new model that yielded physically realistic rate constants, while generating better fits with longer lag phases and faster growths. However, despite the similarity of aggregation conditions, the two polypeptides yielded vastly different morphologies, with the PEA forming typical amyloid-like fibrils and PE forming larger, twisted lamellar aggregates. Templating with these aggregates also yielded dramatically different patterns. Polycrystalline rhombohedral calcite with smooth faces and edges grew on PEA fibrils, with minimal templating in evidence. However, on PE, numerous calcite crystals with triangular projections tracked the surface of the aggregate. The PE lamellae are characterized by extensive beta-sheet structure. In this conformation, the glutamic acid spacings on the surface of the aggregates can mimic the spacings of the carboxylates in the calcite lattice. In addition, the high negative charge density on the

  1. Glycosaminoglycans enhance the fibrillation propensity of the ß2-microglobulin cleavage variant--¿K58-ß2m

    DEFF Research Database (Denmark)

    Corlin, Dorthe B; Johnsen, Christina K; Nissen, Mogens H

    2010-01-01

    when heparan sulfate is present have increased length and diameter, and possess enhanced stability and seeding properties. However, when copper ions are present the fibrils are short, thin and less stable, and form at a slower rate. We suggest that heparan sulfate stabilizes the cleaved monomers...... in the early aggregates, hereby promoting the assembly of these into fibrils, whereas the copper ions appear to have a destabilizing effect on the monomers. This keeps them in a structure forming amorphous aggregates for a longer period of time, leading to the formation of spherical bodies followed...... by the assembly of fibrils. Hence, the in vivo formation of amyloid fibrils in DRA could be initiated by the generation of ¿K58-ß2m which spontaneously aggregate and form fibrils. The fibrillogenesis is enhanced by the involvement of GAGs and/or metal ions, and results in amyloid-like fibrils able to promote...

  2. Observation of the efficacy of radiofrequency catheter ablation on patients with different forms of atrial fibrillation.

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    Zhao, R-C; Han, W; Han, J; Yu, J; Guo, J; Fu, J-L; Li, Z; Zhao, R-Z

    2016-10-01

    To study the efficacy and safety of radiofrequency catheter ablation (RFCA) in patients with different forms of atrial fibrillation. By retrospective analysis, we summarize 720 cases, where patients diagnosed with atrial fibrillation in our hospital were treated with RFCA from February 2010 to October 2014. Among the cases, 425 were diagnosed with paroxysmal atrial fibrillation and 295 with non-paroxysmal atrial fibrillation (including persistent atrial fibrillation and permanent atrial fibrillation). All patients were followed up until June 2015 to compare and analyze the differences in operation success rates, complications and recurrence rates. 395 cases (92.9%) of paroxysmal atrial fibrillation and 253 cases (85.8%) with non-paroxysmal atrial fibrillation were subject to surgery and followed up. The age of onset, disease course, underlying diseases, left atrial diameter and combined anti-arrhythmics of patients with paroxysmal atrial fibrillation were lower than those of patients with non-paroxysmal atrial fibrillation, and the differences were statistically significant (p success rate of the first ablation was higher than that of non-paroxysmal atrial fibrillation. Procedure time, procedure method, complications and recurrence rate of patients with paroxysmal atrial fibrillation were lower than those of non-paroxysmal atrial fibrillation group, and the differences were statistically significant (p failure caused by atrial fibrillation in the two groups, the difference was not statistically significant (Apoplexy: p = 0.186; Heart failure: p = 0.170). The individual ablation success rate was higher for paroxysmal atrial fibrillation, and long-term follow-up showed that the occurrence of apoplexy and heart failure was not different from the non-paroxysmal atrial fibrillation group.

  3. Structural and functional characteristics of myocard in patients with different forms of atrial fibrillation

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    L. I. Vasilyeva

    2015-02-01

    Full Text Available Aim. To study structural and functional characteristics of myocard in patients with different forms of atrial fibrillation. Atrial fibrillation is the most prevalent arrhythmia in clinical practice. Atrial fibrillation is a progressive disease: the duration of paroxysms increases over time and paroxysmal atrial fibrillation transforms to persistent, the last one becomes refractory to pharmacological and electrical cardioversion in time and transforms to permanent. So assessment of myocardial remodeling in patients with persistent and permanent atrial fibrillation is very actual. Methods and results. According to the aim of the study 133 patients with persistent atrial fibrillation and 100 patients with permanent atrial fibrillation were included into the study. Echocardiographic parameters of left and right atria function were studied. Conclusion. It was found that patients with persistent and permanent atrial fibrillation are characterized with both left and right atrias remodeling. Remodeling of the atrias is less pronounced in patients with permanent atrial fibrillation in comparison with persistent atrial fibrillation patients and arrhythmia recurrence.

  4. Lysosomal enzyme cathepsin B enhances the aggregate forming activity of exogenous α-synuclein fibrils.

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    Tsujimura, Atsushi; Taguchi, Katsutoshi; Watanabe, Yoshihisa; Tatebe, Harutsugu; Tokuda, Takahiko; Mizuno, Toshiki; Tanaka, Masaki

    2015-01-01

    The formation of intracellular aggregates containing α-synuclein (α-Syn) is one of the key steps in the progression of Parkinson's disease and dementia with Lewy bodies. Recently, it was reported that pathological α-Syn fibrils can undergo cell-to-cell transmission and form Lewy body-like aggregates. However, little is known about how they form α-Syn aggregates from fibril seeds. Here, we developed an assay to study the process of aggregate formation using fluorescent protein-tagged α-Syn-expressing cells and examined the aggregate forming activity of exogenous α-Syn fibrils. α-Syn fibril-induced formation of intracellular aggregates was suppressed by a cathepsin B specific inhibitor, but not by a cathepsin D inhibitor. α-Syn fibrils pretreated with cathepsin B in vitro enhanced seeding activity in cells. Knockdown of cathepsin B also reduced fibril-induced aggregate formation. Moreover, using LAMP-1 immunocytochemistry and live-cell imaging, we observed that these aggregates initially occurred in the lysosome. They then rapidly grew larger and moved outside the boundary of the lysosome within one day. These results suggest that the lysosomal protease cathepsin B is involved in triggering intracellular aggregate formation by α-Syn fibrils. Copyright © 2015. Published by Elsevier Inc.

  5. Fibrils from designed non-amyloid-related synthetic peptides induce AA-amyloidosis during inflammation in an animal model.

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    Per Westermark

    Full Text Available BACKGROUND: Mouse AA-amyloidosis is a transmissible disease by a prion-like mechanism where amyloid fibrils act by seeding. Synthetic peptides with no amyloid relationship can assemble into amyloid-like fibrils and these may have seeding capacity for amyloid proteins. PRINCIPAL FINDINGS: Several synthetic peptides, designed for nanotechnology, have been examined for their ability to produce fibrils with Congo red affinity and concomitant green birefringence, affinity for thioflavin S and to accelerate AA-amyloidosis in mice. It is shown that some amphiphilic fibril-forming peptides not only produced Congo red birefringence and showed affinity for thioflavin S, but they also shortened the lag phase for systemic AA-amyloidosis in mice when they were given intravenously at the time of inflammatory induction with silver nitride. Peptides, not forming amyloid-like fibrils, did not have such properties. CONCLUSIONS: These observations should caution researchers and those who work with synthetic peptides and their derivatives to be aware of the potential health concerns.

  6. Albumin fibrillization induces apoptosis via integrin/FAK/Akt pathway

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    Liang Chi-Ming

    2009-01-01

    Full Text Available Abstract Background Numerous proteins can be converted to amyloid-like fibrils to increase cytotoxicity and induce apoptosis, but the methods generally require a high concentration of protein, vigorous shaking, or fibril seed. As well, the detailed mechanism of the cytotoxic effects is not well characterized. In this study, we have developed a novel process to convert native proteins into the fibrillar form. We used globular bovine serum albumin (BSA as a model protein to verify the properties of the fibrillar protein, investigated its cellular effects and studied the signaling cascade induced by the fibrillar protein. Results We induced BSA, a non-cytotoxic globular protein, to become fibril by a novel process involving Superdex-200 column chromatography in the presence of anionic or zwittergenic detergent(s. The column pore size was more important than column matrix composite in fibril formation. The fibrillar BSA induced apoptosis in BHK-21 cell as well as breast cancer cell line T47D. Pre-treating cells with anti-integrin antibodies blocked the apoptotic effect. Fibrillar BSA, but not globular BSA, bound to integrin, dephosphorylated focal adhesion kinase (FAK, Akt and glycogen synthase kinase-3β (GSK-3β. Conclusion We report on a novel process for converting globular proteins into fibrillar form to cause apoptosis by modulating the integrin/FAK/Akt/GSK-3β/caspase-3 signaling pathway. Our findings may be useful for understanding the pathogenesis of amyloid-like fibrils and applicable for the development of better therapeutic agents that target the underlying mechanism(s of the etiologic agents.

  7. Formation of DNA-copolymer fibrils through an amyloid-like nucleation polymerization mechanism

    Czech Academy of Sciences Publication Activity Database

    Kedracki, D.; Filippov, Sergey K.; Gour, N.; Schlaad, H.; Nardin, C.

    2015-01-01

    Roč. 36, č. 8 (2015), s. 768-773 ISSN 1022-1336 R&D Projects: GA ČR GAP108/12/0640 Institutional support: RVO:61389013 Keywords : DNA copolymers * fibers * hydrogen bonding Subject RIV: CD - Macromolecular Chemistry Impact factor: 4.638, year: 2015

  8. Amyloid-like interactions within nucleoporin FG hydrogels

    NARCIS (Netherlands)

    Ader, C.; Frey, S.; Maas, W.; Schmidt, H. B.; Görlich, D.; Baldus, M.

    2010-01-01

    The 62 kDa FG repeat domain of the nucleoporin Nsp1p forms a hydrogel-based, sieve-like permeability barrier that excludes inert macromolecules but allows rapid entry of nuclear transport receptors (NTRs). We found that the N-terminal part of this domain, which is characterized by Asn-rich inter-FG

  9. Electrostatics promotes molecular crowding and selects the aggregation pathway in fibril-forming protein solutions

    International Nuclear Information System (INIS)

    Raccosta, S.; Martorana, V.; Manno, M.; Blanco, M.; Roberts, C.J.

    2016-01-01

    The role of intermolecular interaction in fibril-forming protein solutions and its relation with molecular conformation are crucial aspects for the control and inhibition of amyloid structures. Here, we study the fibril formation and the protein-protein interactions for two proteins at acidic ph, lysozyme and α-chymotrypsinogen. By using light scattering experiments and the Kirkwood-Buff integral approach, we show how concentration fluctuations are damped even at moderate protein concentrations by the dominant long-ranged electrostatic repulsion, which determines an effective crowded environment. In denaturing conditions, electrostatic repulsion keeps the monomeric solution in a thermodynamically metastable state, which is escaped through kinetically populated conformational sub-states. This explains how electrostatics acts as a gatekeeper in selecting a specific aggregation pathway.

  10. Oxidized epigallocatechin gallate inhibited lysozyme fibrillation more strongly than the native form

    Directory of Open Access Journals (Sweden)

    Ting-Ting An

    2017-04-01

    Full Text Available Epigallocatechin gallate (EGCG, the most abundant flavanoid in green tea, is currently being evaluated in the clinic due to its benefits in the treatment of amyloid disorders. Its anti-amyloidogenic effect has been attributed to direct interaction of the intact molecule with misfolded polypeptides. In addition, antioxidant activity is also involved in the anti-amyloidogenic role. The detailed molecular mechanism is still unclear and requires further investigation. In the present study, the kinetics of EGCG oxidation and the anti-amyloidogenic effect of the resultant oxidation substances have been examined. The results indicate that EGCG degrades in a medium at pH 8.0 with a half-life less than 2 h. By utilizing lysozyme as an in vitro model, the oxidized EGCG demonstrates a more potent anti-amyloidogenic capacity than the intact molecule, as shown by ThT and ANS fluorescence, TEM determination, and hemolytic assay. The oxidized EGCG also has a stronger disruptive effect on preformed fibrils than the native form. Ascorbic acid eliminates the disruptive role of native EGCG on the fibrils, suggesting that oxidation is a prerequisite in fibril disruption. The results of this work demonstrate that oxidized EGCG plays a more important role than the intact molecule in anti-amyloidogenic activity. These insights into the action of EGCG may provide a novel route to understand the anti-amyloidogenic activity of natural polyphenols.

  11. A NORMAL BRADYSYSTOLIC FORM OF ATRIAL FIBRILLATION (FREDERICQ’S SYNDROME: LATE DIAGNOSIS AND TREATMENT

    Directory of Open Access Journals (Sweden)

    N. Ye. Trekina

    2014-11-01

    Full Text Available It is presented a case of delayed diagnosis brad systole against permanent atrial fibrillation (syndrome Frederick which became to syncope patient and to the later implanting of pacemaker.

  12. Polymorphism of amyloid fibrils formed by a peptide from the yeast prion protein Sup35: AFM and Tip-Enhanced Raman Scattering studies

    Energy Technology Data Exchange (ETDEWEB)

    Krasnoslobodtsev, Alexey V., E-mail: akrasnos@unomaha.edu [Department of Pharmaceutical Sciences, University of Nebraska Medical Center, 986025 Nebraska Medical Center, Omaha, NE 68198 (United States); Department of Physics, University of Nebraska Omaha, Omaha, NE 68182 (United States); Deckert-Gaudig, Tanja [IPHT-Leibniz Institute of Photonic Technology, Albert-Einstein-Str. 9, D-07745 Jena (Germany); Zhang, Yuliang [Department of Pharmaceutical Sciences, University of Nebraska Medical Center, 986025 Nebraska Medical Center, Omaha, NE 68198 (United States); Deckert, Volker [IPHT-Leibniz Institute of Photonic Technology, Albert-Einstein-Str. 9, D-07745 Jena (Germany); Institute for Physical Chemistry and Abbe Center of Photonics, University of Jena, Helmholtzweg 4, D-07743 Jena (Germany); Lyubchenko, Yuri L., E-mail: ylyubchenko@unmc.edu [Department of Pharmaceutical Sciences, University of Nebraska Medical Center, 986025 Nebraska Medical Center, Omaha, NE 68198 (United States)

    2016-06-15

    Aggregation of prion proteins is the cause of various prion related diseases. The infectious form of prions, amyloid aggregates, exist as multiple strains. The strains are thought to represent structurally different prion protein molecules packed into amyloid aggregates, but the knowledge on the structure of different types of aggregates is limited. Here we report on the use of AFM (Atomic Force Microscopy) and TERS (Tip-Enhanced Raman Scattering) to study morphological heterogeneity and access underlying conformational features of individual amyloid aggregates. Using AFM we identified the morphology of amyloid fibrils formed by the peptide (CGNNQQNY) from the yeast prion protein Sup35 that is critically involved in the aggregation of the full protein. TERS results demonstrate that morphologically different amyloid fibrils are composed of a distinct set of conformations. Fibrils formed at pH 5.6 are composed of a mixture of peptide conformations (β-sheets, random coil and α-helix) while fibrils formed in pH~2 solution primarily have β-sheets. Additionally, peak positions in the amide III region of the TERS spectra suggested that peptides have parallel arrangement of β-sheets for pH~2 fibrils and antiparallel arrangement for fibrils formed at pH 5.6. We also developed a methodology for detailed analysis of the peptide secondary structure by correlating intensity changes of Raman bands in different regions of TERS spectra. Such correlation established that structural composition of peptides is highly localized with large contribution of unordered secondary structures on a fibrillar surface. - Highlights: • Amyloid polymorphs were characterized by AFM and TERS. • A mixture of peptide secondary structures in fibrils were identified using TERS. • TERS recognizes packing arrangement (parallel versus antiparallel) of peptides. • TERS is a powerful tool for high resolution structural analysis of fibrils.

  13. Enhanced thermal and mechanical properties of PVA composites formed with filamentous nanocellulose fibrils.

    Science.gov (United States)

    Li, Wei; Wu, Qiong; Zhao, Xin; Huang, Zhanhua; Cao, Jun; Li, Jian; Liu, Shouxin

    2014-11-26

    Long filamentous nanocellulose fibrils (NCFs) were prepared from chemical-thermomechanical pulps (CTMP) using ultrasonication. Their contribution to enhancements in thermal stability and mechanical properties of poly(vinyl alcohol) films were investigated. The unique chemical pretreatment and mechanical effects of CTMP loosen and unfold fibers during the pulping process, which enables further chemical purification and subsequent ultrasound treatment for formation of NCFs. The NCFs exhibited higher crystallinity (72.9%) compared with that of CTMP (61.5%), and had diameters ranging from 50 to 120 nm. A NCF content of 6 wt% was found to yield the best thermal stability, light transmittance, and mechanical properties in the PVA/NCF composites. The composites also exhibited a visible light transmittance of 73.7%, and the tensile strength and Young's modulus were significantly improved, with values 2.8 and 2.4 times larger, respectively, than that of neat PVA. Copyright © 2014 Elsevier Ltd. All rights reserved.

  14. [Atrial fibrillation].

    Science.gov (United States)

    Spinar, J; Vítovec, J

    2003-09-01

    Atrial fibrilation is the most frequent arrhythmia, the occurrence increasing with age and associated diseases. The incidence at the age below 60 years is markedly lower than one per cent, whereas in persons above 80 years of age it exceeds six per cent. The occurrence in patients with heart failure is from 10% (NYHA II) up to 50% (NYHA IV). Atrial fibrillation is classified into that observed for the first time and permanent, respectively, while transient forms include paroxyzmal and persistent atrial fibrillation. The diagnosis is based on ECG recording, while echocardiography is most significant. The therapy includes two basic questions--anticoagulant or anti-aggregation treatment and the control of rhythm or frequency. The anticoagulant therapy should be introduced in all patients, where contraindications are not present, being necessary before every cardioversion, provided atrial fibrillation lasts more than two days. In patients without any heart disease and with a physiological echocardiogram it is possible to administer only anti-aggregation treatment. Cardioversion (the control of rhythm) is recommended to all symptomatic patients, in other cases and especially in older persons the control of frequency is safer and of more advantage. Electrical cardioversion is more effective that a pharmacological treatment, the sinus rhythm is preferably controlled by dofetilid, ibutilid, propafenon and amiodaron. For the control of heart rate beta-blockers, diltiazem, verapamil and digitalis are recommended.

  15. Chirality and chiroptical properties of amyloid fibrils.

    Science.gov (United States)

    Dzwolak, Wojciech

    2014-09-01

    Chirality of amyloid fibrils-linear beta-sheet-rich aggregates of misfolded protein chains-often manifests in morphological traits such as helical twist visible in atomic force microscopy and in chiroptical properties accessible to vibrational circular dichroism (VCD). According to recent studies the relationship between molecular chirality of polypeptide building blocks and superstructural chirality of amyloid fibrils may be more intricate and less deterministic than previously assumed. Several puzzling experimental findings have put into question earlier intuitive ideas on: 1) the bottom-up chirality transfer upon amyloidogenic self-assembly, and 2) the structural origins of chiroptical properties of protein aggregates. For example, removal of a single amino acid residue from an amyloidogenic all-L peptide was shown to reverse handedness of fibrils. On the other hand, certain types of amyloid aggregates revealed surprisingly strong VCD spectra with the sign and shape dependent on the conditions of fibrillation. Hence, microscopic and chiroptical studies have highlighted chirality as one more aspect of polymorphism of amyloid fibrils. This brief review is intended to outline the current state of research on amyloid-like fibrils from the perspective of their structural and superstructural chirality and chiroptical properties. © 2014 Wiley Periodicals, Inc.

  16. PrP aggregation can be seeded by pre-formed recombinant PrP amyloid fibrils without the replication of infectious prions.

    Science.gov (United States)

    Barron, Rona M; King, Declan; Jeffrey, Martin; McGovern, Gillian; Agarwal, Sonya; Gill, Andrew C; Piccardo, Pedro

    2016-10-01

    Mammalian prions are unusual infectious agents, as they are thought to consist solely of aggregates of misfolded prion protein (PrP). Generation of synthetic prions, composed of recombinant PrP (recPrP) refolded into fibrils, has been utilised to address whether PrP aggregates are, indeed, infectious prions. In several reports, neurological disease similar to transmissible spongiform encephalopathy (TSE) has been described following inoculation and passage of various forms of fibrils in transgenic mice and hamsters. However, in studies described here, we show that inoculation of recPrP fibrils does not cause TSE disease, but, instead, seeds the formation of PrP amyloid plaques in PrP-P101L knock-in transgenic mice (101LL). Importantly, both WT-recPrP fibrils and 101L-recPrP fibrils can seed plaque formation, indicating that the fibrillar conformation, and not the primary sequence of PrP in the inoculum, is important in initiating seeding. No replication of infectious prions or TSE disease was observed following both primary inoculation and subsequent subpassage. These data, therefore, argue against recPrP fibrils being infectious prions and, instead, indicate that these pre-formed seeds are acting to accelerate the formation of PrP amyloid plaques in 101LL Tg mice. In addition, these data reproduce a phenotype which was previously observed in 101LL mice following inoculation with brain extract containing in vivo-generated PrP amyloid fibrils, which has not been shown for other synthetic prion models. These data are reminiscent of the "prion-like" spread of aggregated forms of the beta-amyloid peptide (Aβ), α-synuclein and tau observed following inoculation of transgenic mice with pre-formed seeds of each misfolded protein. Hence, even when the protein is PrP, misfolding and aggregation do not reproduce the full clinicopathological phenotype of disease. The initiation and spread of protein aggregation in transgenic mouse lines following inoculation with pre-formed

  17. An NMR-based quenched hydrogen exchange investigation of model amyloid fibrils formed by cold shock protein A.

    Science.gov (United States)

    Alexandrescu, A T

    2001-01-01

    Acid-denatured cold shock protein A (CspA) self-assembles into polymers with properties typical of amyloid fibrils. In the present work, a quenched hydrogen exchange experiment was used to probe the interactions of CspA fibrils with solvent. Exchange was initiated by incubating suspensions of fibrils in D2O, and quenched by flash freezing. Following lyophilization, exchange-quenched samples were dissolved in 90% DMSO/10% D2O, giving DMSO-denatured monomers. Intrinsic exchange rates for denatured CspA in 90% DMSO/10% D2O (pH* 4.5) were sufficiently slow (approximately 1 x 10(-3) min-1) to enable quantification of NMR signal intensity decays due to H/D exchange in the fibrils. Hydrogen exchange rate constants for CspA fibrils were found to vary less than 3-fold from a mean value of 5 x 10(-5) min-1. The uniformity of rate constants suggests that exchange is in the EX1 limit, and that the mechanism of exchange involves a cooperative dissociation of CspA monomers from fibrils, concomitant with unfolding. Previous studies indicated that the highest protection factors in native CspA are approximately 10(3), and that protection factors for the acid-denatured monomer precursors of CspA fibrils are close to unity. Because exchange in is in the EX1 regime, it is only possible to place a lower limit of at least 10(5) on protection factors in CspA fibrils. The observation that all amide protons are protected from exchange indicates that the entire CspA polypeptide chain is structured in the fibrils.

  18. Ex vivo mammalian prions are formed of paired double helical prion protein fibrils.

    Science.gov (United States)

    Terry, Cassandra; Wenborn, Adam; Gros, Nathalie; Sells, Jessica; Joiner, Susan; Hosszu, Laszlo L P; Tattum, M Howard; Panico, Silvia; Clare, Daniel K; Collinge, John; Saibil, Helen R; Wadsworth, Jonathan D F

    2016-05-01

    Mammalian prions are hypothesized to be fibrillar or amyloid forms of prion protein (PrP), but structures observed to date have not been definitively correlated with infectivity and the three-dimensional structure of infectious prions has remained obscure. Recently, we developed novel methods to obtain exceptionally pure preparations of prions from mouse brain and showed that pathogenic PrP in these high-titre preparations is assembled into rod-like assemblies. Here, we have used precise cell culture-based prion infectivity assays to define the physical relationship between the PrP rods and prion infectivity and have used electron tomography to define their architecture. We show that infectious PrP rods isolated from multiple prion strains have a common hierarchical assembly comprising twisted pairs of short fibres with repeating substructure. The architecture of the PrP rods provides a new structural basis for understanding prion infectivity and can explain the inability to systematically generate high-titre synthetic prions from recombinant PrP. © 2016 The Authors.

  19. Molecular Insight into Human Lysozyme and Its Ability to Form Amyloid Fibrils in High Concentrations of Sodium Dodecyl Sulfate: A View from Molecular Dynamics Simulations.

    Directory of Open Access Journals (Sweden)

    Majid Jafari

    Full Text Available Changes in the tertiary structure of proteins and the resultant fibrillary aggregation could result in fatal heredity diseases, such as lysozyme systemic amyloidosis. Human lysozyme is a globular protein with antimicrobial properties with tendencies to fibrillate and hence is known as a fibril-forming protein. Therefore, its behavior under different ambient conditions is of great importance. In this study, we conducted two 500000 ps molecular dynamics (MD simulations of human lysozyme in sodium dodecyl sulfate (SDS at two ambient temperatures. To achieve comparative results, we also performed two 500000 ps human lysozyme MD simulations in pure water as controls. The aim of this study was to provide further molecular insight into all interactions in the lysozyme-SDS complexes and to provide a perspective on the ability of human lysozyme to form amyloid fibrils in the presence of SDS surfactant molecules. SDS, which is an anionic detergent, contains a hydrophobic tail with 12 carbon atoms and a negatively charged head group. The SDS surfactant is known to be a stabilizer for helical structures above the critical micelle concentration (CMC [1]. During the 500000 ps MD simulations, the helical structures were maintained by the SDS surfactant above its CMC at 300 K, while at 370 K, human lysozyme lost most of its helices and gained β-sheets. Therefore, we suggest that future studies investigate the β-amyloid formation of human lysozyme at SDS concentrations above the CMC and at high temperatures.

  20. In situ analysis of Bacillus licheniformis biofilms: amyloid-like polymers and eDNA are involved in the adherence and aggregation of the extracellular matrix.

    Science.gov (United States)

    Randrianjatovo-Gbalou, I; Rouquette, P; Lefebvre, D; Girbal-Neuhauser, E; Marcato-Romain, C-E

    2017-05-01

    This study attempts to determine which of the exopolymeric substances are involved in the adherence and aggregation of a Bacillus licheniformis biofilm. The involvement of extracellular proteins and eDNA were particularly investigated using DNase and proteinase K treatment. The permeability of the biofilms increased fivefold after DNase I treatment. The quantification of the matrix components showed that, irrespective to the enzyme tested, eDNA and amyloid-like polymers were removed simultaneously. Size-exclusion chromatography analyses supported these observations and revealed the presence of associated nucleic acid and protein complexes in the biofilm lysates. These data suggest that some extracellular DNA and amyloid-like proteins were closely interlaced within the matrix. Finally, confocal laser scanning microscopy imaging gave supplementary clues about the 3D organization of the biofilms, confirming that eDNA and exoproteins were essentially layered under and around the bacterial cells, whereas the amyloid-like fractions were homogeneously distributed within the matrix. These results confirm that some DNA-amyloid complexes play a key role in the modulation of the mechanical resistance of B. licheniformis biofilms. The study highlights the need to consider the whole structure of biofilms and to target the interactions between matrix components. A better understanding of B. licheniformis biofilm physiology and the structural organization of the matrix will strengthen strategies of biofilm control. © 2017 The Society for Applied Microbiology.

  1. Toward understanding insulin fibrillation.

    Science.gov (United States)

    Brange, J; Andersen, L; Laursen, E D; Meyn, G; Rasmussen, E

    1997-05-01

    Formation of insulin fibrils is a physical process by which partially unfolded insulin molecules interact with each other to form linear aggregates. Shielding of hydrophobic domains is the main driving force for this process, but formation of intermolecular beta-sheet may further stabilize the fibrillar structure. Conformational displacement of the B-chain C-terminal with exposure of nonpolar, aliphatic core residues, including A2, A3, B11, and B15, plays a crucial role in the fibrillation process. Recent crystal analyses and molecular modeling studies have suggested that when insulin fibrillates this exposed domain interacts with a hydrophobic surface domain formed by the aliphatic residues A13, B6, B14, B17, and B18, normally buried when three insulin dimers form a hexamer. In rabbit immunization experiments, insulin fibrils did not elicit an increased immune response with respect to formation of IgG insulin antibodies when compared with native insulin. In contrast, the IgE response increased with increasing content of insulin in fibrillar form. Strategies and practical approaches to prevent insulin from forming fibrils are reviewed. Stabilization of the insulin hexameric structure and blockage of hydrophobic interfaces by addition of surfactants are the most effective means of counteracting insulin fibrillation.

  2. Back to the oligomeric state pH-induced dissolution of concanavalin A amyloid-like fibrils into non-native oligomers

    DEFF Research Database (Denmark)

    Santangelo, M. G.; Foderà, V.; Militello, V.

    2016-01-01

    The subtle interplay between long range electrostatic forces, hydrophobic interactions and short range protein-protein interactions regulates the onset/evolution of protein aggregation processes as well as the stability of protein supramolecular structures. Using a combination of FTIR spectroscop...

  3. Structural evaluation of an amyloid fibril model using small-angle x-ray scattering

    Science.gov (United States)

    Dahal, Eshan; Choi, Mina; Alam, Nadia; Bhirde, Ashwinkumar A.; Beaucage, Serge L.; Badano, Aldo

    2017-08-01

    Amyloid fibrils are highly structured protein aggregates associated with a wide range of diseases including Alzheimer’s and Parkinson’s. We report a structural investigation of an amyloid fibril model prepared from a commonly used plasma protein (bovine serum albumin (BSA)) using small-angle x-ray scattering (SAXS) technique. As a reference, the size estimates from SAXS are compared to dynamic light scattering (DLS) data and the presence of amyloid-like fibrils is confirmed using Congo red absorbance assay. Our SAXS results consistently show the structural transformation of BSA from spheroid to rod-like elongated structures during the fibril formation process. We observe the elongation of fibrils over two months with fibril length growing from 35.9  ±  3.0 nm to 51.5  ±  2.1 nm. Structurally metastable fibrils with distinct SAXS profiles have been identified. As proof of concept, we demonstrate the use of such distinct SAXS profiles to detect fibrils in the mixture solutions of two species by estimating their volume fractions. This easily detectable and well-characterized amyloid fibril model from BSA can be readily used as a control or standard reference to further investigate SAXS applications in the detection of structurally diverse amyloid fibrils associated with protein aggregation diseases.

  4. The core of Ure2p prion fibrils is formed by the N-terminal segment in a parallel cross-β structure: evidence from solid-state NMR.

    Science.gov (United States)

    Kryndushkin, Dmitry S; Wickner, Reed B; Tycko, Robert

    2011-06-03

    Intracellular fibril formation by Ure2p produces the non-Mendelian genetic element [URE3] in Saccharomyces cerevisiae, making Ure2p a prion protein. We show that solid-state NMR spectra of full-length Ure2p fibrils, seeded with infectious prions from a specific [URE3] strain and labeled with uniformly (15)N-(13)C-enriched Ile, include strong, sharp signals from Ile residues in the globular C-terminal domain (CTD) with both helical and nonhelical (13)C chemical shifts. Treatment with proteinase K eliminates these CTD signals, leaving only nonhelical signals from the Gln-rich and Asn-rich N-terminal segment, which are also observed in the solid-state NMR spectra of Ile-labeled fibrils formed by residues 1-89 of Ure2p. Thus, the N-terminal segment, or "prion domain" (PD), forms the fibril core, while CTD units are located outside the core. We additionally show that, after proteinase K treatment, Ile-labeled Ure2p fibrils formed without prion seeding exhibit a broader set of solid-state NMR signals than do prion-seeded fibrils, consistent with the idea that structural variations within the PD core account for prion strains. Measurements of (13)C-(13)C magnetic dipole-dipole couplings among (13)C-labeled Ile carbonyl sites in full-length Ure2p fibrils support an in-register parallel β-sheet structure for the PD core of Ure2p fibrils. Finally, we show that a model in which CTD units are attached rigidly to the parallel β-sheet core is consistent with steric constraints. Published by Elsevier Ltd.

  5. Atrial fibrillation

    African Journals Online (AJOL)

    ABEOLUGBENGAS

    Mean blood pressures were 126.03± ... optimal. Keywords: Atrial fibrillation, thrombosis, CHADS2 Score, stroke risk, hypertensive heart disease, ... general population and the average age group ... Appendix 1) to stratify the stroke risk and we.

  6. Atrial Fibrillation: Diagnosis

    Science.gov (United States)

    ... of this page please turn JavaScript on. Feature: Atrial Fibrillation Atrial Fibrillation: Diagnosis Past Issues / Winter 2015 Table of Contents ... of your body's cells and organs. Read More "Atrial Fibrillation" Articles Atrial Fibrillation / Who Is at Risk for ...

  7. The Japanese Mutant Aβ (ΔE22-Aβ1–39) Forms Fibrils Instantaneously, with Low-Thioflavin T Fluorescence: Seeding of Wild-Type Aβ1-40 into Atypical Fibrils by ΔE22-Aβ1-39

    Science.gov (United States)

    Cloe, Adam L.; Orgel, Joseph P.R.O.; Sachleben, Joseph R.; Tycko, Robert; Meredith, Stephen C.

    2012-01-01

    The ΔE693 (Japanese) mutation of the β-amyloid precursor protein leads to production of ΔE22-Aβ peptides such as ΔE22-Aβ1–39. Despite reports that these peptides do not form fibrils, here we show that, on the contrary, the peptide forms fibrils essentially instantaneously. The fibrils are typical amyloid fibrils in all respects except that they cause only low levels of thioflavin T (ThT) fluorescence, which, however, develops with no lag phase. The fibrils bind ThT, but with a lower affinity and a smaller number of binding sites than wild-type (WT) Aβ1–40. Fluorescence depolarization confirms extremely rapid aggregation of ΔE22-Aβ1–39. Size exclusion chromatography (SEC) indicates very low concentrations of soluble monomer and oligomer, but only in the presence of some organic solvent, e.g., 2% (v/v) DMSO. The critical concentration is approximately 1 order of magnitude lower for ΔE22-Aβ1–39 than for WTAβ1–40. Several lines of evidence point to an altered structure for ΔE22-Aβ1–39 compared to that of WT Aβ1–40 fibrils. In addition to differences in ThT binding and fluorescence, PITHIRDS-CT solid-state nuclear magnetic resonance (NMR) measurements of ΔE22-Aβ1–39 are not compatible with the parallel in-register β-sheet generally observed for WT Aβ1–40 fibrils. X-ray fibril diffraction showed different D spacings: 4.7 and 10.4 Å for WT Aβ1–40 and 4.7 and 9.6 Å for ΔE22-Aβ1–39. Equimolar mixtures of ΔE22-Aβ1–39 and WT Aβ1–40 also produced fibrils extremely rapidly, and by the criteria of ThT fluorescence and electron microscopic appearance, they were the same as fibrils made from pure ΔE22-Aβ1–39. X-ray diffraction of fibrils formed from 1:1 molar mixtures of ΔE22-Aβ1–39 and WT Aβ1–40 showed the same D spacings as fibrils of the pure mutant peptide, not the wild-type peptide. These findings are consistent with extremely rapid nucleation by ΔE22-Aβ1–39, followed by fibril extension by WT Aβ1–40, and

  8. Screening for Atrial Fibrillation

    DEFF Research Database (Denmark)

    Freedman, Ben; Camm, John; Calkins, Hugh

    2017-01-01

    Approximately 10% of ischemic strokes are associated with atrial fibrillation (AF) first diagnosed at the time of stroke. Detecting asymptomatic AF would provide an opportunity to prevent these strokes by instituting appropriate anticoagulation. The AF-SCREEN international collaboration was formed...

  9. Atrial fibrillation

    DEFF Research Database (Denmark)

    Olesen, Morten S; Nielsen, Morten W; Haunsø, Stig

    2014-01-01

    Atrial fibrillation (AF) is the most common cardiac arrhythmia affecting 1-2% of the general population. A number of studies have demonstrated that AF, and in particular lone AF, has a substantial genetic component. Monogenic mutations in lone and familial AF, although rare, have been recognized...

  10. Nanomechanical properties of single amyloid fibrils

    International Nuclear Information System (INIS)

    Sweers, K K M; Bennink, M L; Subramaniam, V

    2012-01-01

    Amyloid fibrils are traditionally associated with neurodegenerative diseases like Alzheimer’s disease, Parkinson’s disease or Creutzfeldt-Jakob disease. However, the ability to form amyloid fibrils appears to be a more generic property of proteins. While disease-related, or pathological, amyloid fibrils are relevant for understanding the pathology and course of the disease, functional amyloids are involved, for example, in the exceptionally strong adhesive properties of natural adhesives. Amyloid fibrils are thus becoming increasingly interesting as versatile nanobiomaterials for applications in biotechnology. In the last decade a number of studies have reported on the intriguing mechanical characteristics of amyloid fibrils. In most of these studies atomic force microscopy (AFM) and atomic force spectroscopy play a central role. AFM techniques make it possible to probe, at nanometer length scales, and with exquisite control over the applied forces, biological samples in different environmental conditions. In this review we describe the different AFM techniques used for probing mechanical properties of single amyloid fibrils on the nanoscale. An overview is given of the existing mechanical studies on amyloid. We discuss the difficulties encountered with respect to the small fibril sizes and polymorphic behavior of amyloid fibrils. In particular, the different conformational packing of monomers within the fibrils leads to a heterogeneity in mechanical properties. We conclude with a brief outlook on how our knowledge of these mechanical properties of the amyloid fibrils can be exploited in the construction of nanomaterials from amyloid fibrils. (topical review)

  11. Covalent defects restrict supramolecular self-assembly of homopolypeptides: case study of β2-fibrils of poly-L-glutamic acid.

    Directory of Open Access Journals (Sweden)

    Aleksandra Fulara

    Full Text Available Poly-L-glutamic acid (PLGA often serves as a model in studies on amyloid fibrils and conformational transitions in proteins, and as a precursor for synthetic biomaterials. Aggregation of PLGA chains and formation of amyloid-like fibrils was shown to continue on higher levels of superstructural self-assembly coinciding with the appearance of so-called β2-sheet conformation manifesting in dramatic redshift of infrared amide I' band below 1600 cm(-1. This spectral hallmark has been attributed to network of bifurcated hydrogen bonds coupling C = O and N-D (N-H groups of the main chains to glutamate side chains. However, other authors reported that, under essentially identical conditions, PLGA forms the conventional in terms of infrared characteristics β1-sheet structure (exciton-split amide I' band with peaks at ca. 1616 and 1683 cm(-1. Here we attempt to shed light on this discrepancy by studying the effect of increasing concentration of intentionally induced defects in PLGA on the tendency to form β1/β2-type aggregates using infrared spectroscopy. We have employed carbodiimide-mediated covalent modification of Glu side chains with n-butylamine (NBA, as well as electrostatics-driven inclusion of polylysine chains, as two different ways to trigger structural defects in PLGA. Our study depicts a clear correlation between concentration of defects in PLGA and increasing tendency to depart from the β2-structure toward the one less demanding in terms of chemical uniformity of side chains: β1-structure. The varying predisposition to form β1- or β2-type aggregates assessed by infrared absorption was compared with the degree of morphological order observed in electron microscopy images. Our results are discussed in the context of latent covalent defects in homopolypeptides (especially with side chains capable of hydrogen-bonding that could obscure their actual propensities to adopt different conformations, and limit applications in the field of

  12. Covalent Defects Restrict Supramolecular Self-Assembly of Homopolypeptides: Case Study of β2-Fibrils of Poly-L-Glutamic Acid

    Science.gov (United States)

    Fulara, Aleksandra; Hernik, Agnieszka; Nieznańska, Hanna; Dzwolak, Wojciech

    2014-01-01

    Poly-L-glutamic acid (PLGA) often serves as a model in studies on amyloid fibrils and conformational transitions in proteins, and as a precursor for synthetic biomaterials. Aggregation of PLGA chains and formation of amyloid-like fibrils was shown to continue on higher levels of superstructural self-assembly coinciding with the appearance of so-called β2-sheet conformation manifesting in dramatic redshift of infrared amide I′ band below 1600 cm−1. This spectral hallmark has been attributed to network of bifurcated hydrogen bonds coupling C = O and N-D (N-H) groups of the main chains to glutamate side chains. However, other authors reported that, under essentially identical conditions, PLGA forms the conventional in terms of infrared characteristics β1-sheet structure (exciton-split amide I′ band with peaks at ca. 1616 and 1683 cm−1). Here we attempt to shed light on this discrepancy by studying the effect of increasing concentration of intentionally induced defects in PLGA on the tendency to form β1/β2-type aggregates using infrared spectroscopy. We have employed carbodiimide-mediated covalent modification of Glu side chains with n-butylamine (NBA), as well as electrostatics-driven inclusion of polylysine chains, as two different ways to trigger structural defects in PLGA. Our study depicts a clear correlation between concentration of defects in PLGA and increasing tendency to depart from the β2-structure toward the one less demanding in terms of chemical uniformity of side chains: β1-structure. The varying predisposition to form β1- or β2-type aggregates assessed by infrared absorption was compared with the degree of morphological order observed in electron microscopy images. Our results are discussed in the context of latent covalent defects in homopolypeptides (especially with side chains capable of hydrogen-bonding) that could obscure their actual propensities to adopt different conformations, and limit applications in the field of synthetic

  13. Atrial Fibrillation: Treatment

    Science.gov (United States)

    ... of this page please turn JavaScript on. Feature: Atrial Fibrillation Atrial Fibrillation: Treatment Past Issues / Winter 2015 Table of Contents Treatment for atrial fibrillation depends on how often you have symptoms, how ...

  14. Dock 'n roll: folding of a silk-inspired polypeptide into an amyloid-like beta solenoid.

    Science.gov (United States)

    Zhao, Binwu; Cohen Stuart, Martien A; Hall, Carol K

    2016-04-20

    Polypeptides containing the motif ((GA)mGX)n occur in silk and have a strong tendency to self-assemble. For example, polypeptides containing (GAGAGAGX)n, where X = G or H have been observed to form filaments; similar sequences but with X = Q have been used in the design of coat proteins (capsids) for artificial viruses. The structure of the (GAGAGAGX)m filaments has been proposed to be a stack of peptides in a β roll structure with the hydrophobic side chains pointing outwards (hydrophobic shell). Another possible configuration, a β roll or β solenoid structure which has its hydrophobic side chains buried inside (hydrophobic core) was, however, overlooked. We perform ground state analysis as well as atomic-level molecular dynamics simulations, both on single molecules and on two-molecule stacks of the silk-inspired sequence (GAGAGAGQ)10, to decide whether the hydrophobic core or the hydrophobic shell configuration is the most stable one. We find that a stack of two hydrophobic core molecules is energetically more favorable than a stack of two hydrophobic shell molecules. A shell molecule initially placed in a perfect β roll structure tends to rotate its strands, breaking in-plane hydrogen bonds and forming out-of-plane hydrogen bonds, while a core molecule stays in the β roll structure. The hydrophobic shell structure has type II' β turns whereas the core configuration has type II β turns; only the latter secondary structure agrees well with solid-state NMR experiments on a similar sequence (GA)15. We also observe that the core stack has a higher number of intra-molecular hydrogen bonds and a higher number of hydrogen bonds between stack and water than the shell stack. Hence, we conclude that the hydrophobic core configuration is the most likely structure. In the stacked state, each peptide has more intra-molecular hydrogen bonds than a single folded molecule, which suggests that stacking provides the extra stability needed for molecules to reach the folded

  15. Dock ’n Roll: Folding of a Silk-Inspired Polypeptide into an Amyloid-like Beta Solenoid

    Science.gov (United States)

    Zhao, Binwu; Cohen Stuart, Martien A.; Hall, Carol K.

    2016-01-01

    Polypeptides containing the motif ((GA)mGX)n occur in silk (we refer to them as ‘silk-like’) and have a strong tendency to self-assemble. For example, polypeptides containing (GAGAGAGX)n, where X = G or H have been observed to form filaments; similar sequences but with X = Q have been used in the design of coat proteins (capsids) for artificial viruses. The structure of the (GAGAGAGX)m filaments has been proposed to be a stack of peptides in a β roll structure with the hydrophobic side chains pointing outwards (hydrophobic shell). Another possible configuration, a β roll or β solenoid structure which has its hydrophobic side chains buried inside (hydrophobic core) was, however, overlooked. We perform ground state analysis as well as atomic-level molecular dynamics simulations, both on single molecules and on two-molecule stacks of the silk-inspired sequence (GAGAGAGQ)10, to decide whether the hydrophobic core or the hydrophobic shell configuration is the most stable one. We find that a stack of two hydrophobic core molecules is energetically more favorable than a stack of two shell molecules. A shell molecule initially placed in a perfect β roll structure tends to rotate its strands, breaking in-plane hydrogen bonds and forming out-of-plane hydrogen bonds, while a core molecule stays in the β roll structure. The hydrophobic shell structure has type II’ β turns whereas the core configuration has type II β turns; only the latter secondary structure agrees well with solid-state NMR experiments on a similar sequence (GA)15. We also observe that the core stack has a higher number of intra-molecular hydrogen bonds and a higher number of hydrogen bonds between stack and water than the shell stack. Hence, we conclude that the hydrophobic core configuration is the most likely structure. In the stacked state, each peptide has more intra-molecular hydrogen bonds than a single folded molecule, which suggests that stacking provides the extra stability needed for

  16. Imaging and quantification of amyloid fibrillation in the cell nucleus.

    Science.gov (United States)

    Arnhold, Florian; Scharf, Andrea; von Mikecz, Anna

    2015-01-01

    Xenobiotics, as well as intrinsic processes such as cellular aging, contribute to an environment that constantly challenges nuclear organization and function. While it becomes increasingly clear that proteasome-dependent proteolysis is a major player, the topology and molecular mechanisms of nuclear protein homeostasis remain largely unknown. We have shown previously that (1) proteasome-dependent protein degradation is organized in focal microenvironments throughout the nucleoplasm and (2) heavy metals as well as nanoparticles induce nuclear protein fibrillation with amyloid characteristics. Here, we describe methods to characterize the landscape of intranuclear amyloid on the global and local level in different systems such as cultures of mammalian cells and the soil nematode Caenorhabditis elegans. Application of discrete mathematics to imaging data is introduced as a tool to develop pattern recognition of intracellular protein fibrillation. Since stepwise fibrillation of otherwise soluble proteins to insoluble amyloid-like protein aggregates is a hallmark of neurodegenerative protein-misfolding disorders including Alzheimer's disease, CAG repeat diseases, and the prion encephalopathies, investigation of intracellular amyloid may likewise aid to a better understanding of the pathomechanisms involved. We consider aggregate profiling as an important experimental approach to determine if nuclear amyloid has toxic or protective roles in various disease processes.

  17. Chondroitin Sulfate Perlecan Enhances Collagen Fibril Formation

    DEFF Research Database (Denmark)

    Kvist, A. J.; Johnson, A. E.; Mörgelin, M.

    2006-01-01

    in collagen type II fibril assembly by perlecan-null chondrocytes. Cartilage perlecan is a heparin sulfate or a mixed heparan sulfate/chondroitin sulfate proteoglycan. The latter form binds collagen and accelerates fibril formation in vitro, with more defined fibril morphology and increased fibril diameters...... produced in the presence of perlecan. Interestingly, the enhancement of collagen fibril formation is independent on the core protein and is mimicked by chondroitin sulfate E but neither by chondroitin sulfate D nor dextran sulfate. Furthermore, perlecan chondroitin sulfate contains the 4,6-disulfated...... disaccharides typical for chondroitin sulfate E. Indeed, purified glycosaminoglycans from perlecan-enriched fractions of cartilage extracts contain elevated levels of 4,6-disulfated chondroitin sulfate disaccharides and enhance collagen fibril formation. The effect on collagen assembly is proportional...

  18. Atrial Fibrillation

    DEFF Research Database (Denmark)

    Staerk, Laila; Sherer, Jason A; Ko, Darae

    2017-01-01

    The past 3 decades have been characterized by an exponential growth in knowledge and advances in the clinical treatment of atrial fibrillation (AF). It is now known that AF genesis requires a vulnerable atrial substrate and that the formation and composition of this substrate may vary depending...... on comorbid conditions, genetics, sex, and other factors. Population-based studies have identified numerous factors that modify the atrial substrate and increase AF susceptibility. To date, genetic studies have reported 17 independent signals for AF at 14 genomic regions. Studies have established...

  19. EXAMINATION OF ELECTROPHYSIOLOGICAL PARAMETERS OF THE ATRIUMS IN PATIENTS WITH LONG-TERM PERSISTENT FORM OF ATRIAL FIBRILLATION AND VALVULAR HEART DISEASE

    Directory of Open Access Journals (Sweden)

    A. A. Kulikov

    2017-01-01

    Full Text Available The study objective is to examine electrophysiological parameters of atrial myocardium, characteristics of atrioventricular conduction, and potential factors affecting recurrent atrial fibrillation (AF in patients with persistent and long-term persistent forms of AF prior to the Labirynth IIIB surgery with single-step correction of valvular heart disease.Materials and methods. The study included 100 adults (48 men, 52 women with persistent and long-term persistent forms of AF and different valvular heart diseases. Mean patient age was 59 years. Mean AF duration was 4 years. All patients were prescribed antiarrhythmic therapy but it proved ineffective. In 15 % of patients, restoration of the sinus rhythm was attempted through electrical cardioversion but long-term control of the sinus rhythm wasn’t achieved. All patients were diagnosed with organic pathology of the mitral valve. Also, in 80 % of patients, relative insufficiency of the tricuspid valve was detected. Chronic heart failure functional class per NYHA was III. Size of the left atrium was 5 cm, mean left ventricular ejection fraction was 61 %. All patients underwent electrical cardioversion. After successful restoration of the sinus rhythm, endocardial electrophysiology study (EES of the heart was performed. Then, correction of valvular pathologies and the Labyrinth IIIB surgery were performed. Results. Examination of refractoriness of different parts of the atriums has shown that effective refractory period (ERP of the atrioventricular node was minimal compared to other parts of the atriums. Maximal ERP duration was observed in the upper part of the right atrium. Therefore, in patients with long history of AF, heterogeneity of atrial myocardium ERP duration is observed. In 17 % of patients, atrial vulnerability was detected. The area of atrial vulnerability was always associated with ERP. Its duration in patients with atrial vulnerability was significantly higher.Conclusion. Long

  20. Curcumin Protects β-Lactoglobulin Fibril Formation and Fibril-Induced Neurotoxicity in PC12 Cells.

    Directory of Open Access Journals (Sweden)

    Mansooreh Mazaheri

    Full Text Available In this study the β-lactoglobulin fibrillation, in the presence or absence of lead ions, aflatoxin M1 and curcumin, was evaluated using ThT fluorescence, Circular dichroism spectroscopy and atomic force microscopy. To investigate the toxicity of the different form of β-Lg fibrils, in the presence or absence of above toxins and curcumin, we monitored changes in the level of reactive oxygen species and morphology of the differentiated neuron-like PC12 cells. The cell viability, cell body area, average neurite length, neurite width, number of primary neurites, percent of bipolar cells and node/primary neurite ratios were used to assess the growth and complexity of PC12 cells exposed to different form of β-Lg fibrils. Incubation of β-Lg with curcumin resulted in a significant decrease in ROS levels even in the presence of lead ions and aflatoxin M1. The β-Lg fibrils formed in the presence of lead ions and aflatoxin M1 attenuated the growth and complexity of PC12 cells compared with other form of β-Lg fibrils. However, the adverse effects of these toxins and protein fibrils were negated in the presence of curcumin. Furthermore, the antioxidant and inhibitory effects of curcumin protected PC12 cells against fibril neurotoxicity and enhanced their survival. Thus, curcumin may provide a protective effect toward β-Lg, and perhaps other protein, fibrils mediated neurotoxicity.

  1. Atrial fibrillation or flutter

    Science.gov (United States)

    ... this page: //medlineplus.gov/ency/article/000184.htm Atrial fibrillation or flutter To use the sharing features on this page, please enable JavaScript. Atrial fibrillation or flutter is a common type of abnormal ...

  2. Atrial fibrillation - discharge

    Science.gov (United States)

    ... this page: //medlineplus.gov/ency/patientinstructions/000237.htm Atrial fibrillation - discharge To use the sharing features on this ... have been in the hospital because you have atrial fibrillation . This condition occurs when your heart beats faster ...

  3. Atrial Fibrillation - Multiple Languages

    Science.gov (United States)

    ... Are Here: Home → Multiple Languages → All Health Topics → Atrial Fibrillation URL of this page: https://medlineplus.gov/languages/ ... V W XYZ List of All Topics All Atrial Fibrillation - Multiple Languages To use the sharing features on ...

  4. Atrial Fibrillation: Complications

    Science.gov (United States)

    ... of this page please turn JavaScript on. Feature: Atrial Fibrillation Atrial Fibrillation: Complications Past Issues / Winter 2015 Table of Contents ... has two major complications—stroke and heart failure. Atrial Fibrillation and Stroke Click to enlarge image This illustration ...

  5. Metastable Amyloid Phases and their Conversion to Mature Fibrils

    Science.gov (United States)

    Muschol, Martin; Miti, Tatiana; Mulaj, Mentor; Schmit, Jeremy

    Self-assembly of proteins into amyloid fibrils plays a key role in both functional biological responses and pathogenic disorders which include Alzheimer's disease and type II diabetes. Amyloid fibril assembly frequently generates compact oligomeric and curvilinear polymeric intermediates which are implicated to be toxic to cells. Yet, the relation between these early-stage oligomeric aggregates and late-stage rigid fibrils, which are the hallmark structure of amyloid plaques, has remained unclear. Our measurements indicate that lysozyme amyloid oligomers and their curvilinear fibrils only form after crossing a salt and protein concentration dependent threshold. These oligomeric aggregates are structurally distinct from rigid fibrils and are metastable against nucleation and growth of rigid fibrils. Our experimental transition boundaries match well with colloidal model predictions accounting for salt-modulated charge repulsion. We also report our preliminary findings on the mechanism by which these metastable oligomeric phases are converted into stable amyloid fibrils.

  6. Atrial fibrillation.

    Science.gov (United States)

    Bang, Casper N

    2013-10-01

    Atrial fibrillation (AF) is a common complication after myocardial infarction (MI) and new-onset AF has been demonstrated to be associated with adverse outcome and a large excess risk of death in both MI and aortic stenosis (AS) patients. Prevention of new-onset AF is therefore a potential therapeutic target in AS and MI patients. Lipid-lowering drugs, particularly statins, have anti-inflammatory and antioxidant properties that may prevent AF. Accordingly, statins are recommended as a class IIa recommendation for prevention of new-onset AF after coronary artery bypass grafting (CABG). However, this preventive effect has not been investigated on new-onset AF in asymptomatic patients with AS or a large scale first-time MI patient sample and data in patients not undergoing invasive cardiac interventions are limited. This PhD thesis was conducted at the Heart Centre, Rigshospitalet, Denmark, with the aim to investigate the three aforementioned questions and to add to the existing evidence of AF prevention with statins. This was done using three different settings: 1) a randomized patients sample of 1,873 from the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study, 2) a register patient sample of 97,499 with first-time MI, and 3) all published studies until beginning of June 2011 examining statin treatment on new-onset and recurrent AF in patients not undergoing cardiac surgery. This thesis revealed that statins did not lower the incidence or the time to new-onset AF in patients with asymptomatic AS. However, statin treatment showed an independently preventive effect on new-onset AF, including type-dependent effect and a trend to dosage-dependent effect. In addition, this thesis showed that good compliance to statin treatment was important to prevent new-onset AF. Finally, the meta-analysis in this PhD thesis showed a preventive effect in the observational studies although this effect was absent in the randomized controlled trials. Based on this PhD thesis

  7. Preparation of Amyloid Fibrils Seeded from Brain and Meninges.

    Science.gov (United States)

    Scherpelz, Kathryn P; Lu, Jun-Xia; Tycko, Robert; Meredith, Stephen C

    2016-01-01

    Seeding of amyloid fibrils into fresh solutions of the same peptide or protein in disaggregated form leads to the formation of replicate fibrils, with close structural similarity or identity to the original fibrillar seeds. Here we describe procedures for isolating fibrils composed mainly of β-amyloid (Aβ) from human brain and from leptomeninges, a source of cerebral blood vessels, for investigating Alzheimer's disease and cerebral amyloid angiopathy. We also describe methods for seeding isotopically labeled, disaggregated Aβ peptide solutions for study using solid-state NMR and other techniques. These methods should be applicable to other types of amyloid fibrils, to Aβ fibrils from mice or other species, tissues other than brain, and to some non-fibrillar aggregates. These procedures allow for the examination of authentic amyloid fibrils and other protein aggregates from biological tissues without the need for labeling the tissue.

  8. How Glycosaminoglycans Promote Fibrillation of Salmon Calcitonin*

    Science.gov (United States)

    Malmos, Kirsten Gade; Bjerring, Morten; Jessen, Christian Moestrup; Nielsen, Erik Holm Toustrup; Poulsen, Ebbe T.; Christiansen, Gunna; Vosegaard, Thomas; Skrydstrup, Troels; Enghild, Jan J.; Pedersen, Jan Skov; Otzen, Daniel E.

    2016-01-01

    Glycosaminoglycans (GAGs) bind all known amyloid plaques and help store protein hormones in (acidic) granular vesicles, but the molecular mechanisms underlying these important effects are unclear. Here we investigate GAG interactions with the peptide hormone salmon calcitonin (sCT). GAGs induce fast sCT fibrillation at acidic pH and only bind monomeric sCT at acidic pH, inducing sCT helicity. Increasing GAG sulfation expands the pH range for binding. Heparin, the most highly sulfated GAG, binds sCT in the pH interval 3–7. Small angle x-ray scattering indicates that sCT monomers densely decorate and pack single heparin chains, possibly via hydrophobic patches on helical sCT. sCT fibrillates without GAGs, but heparin binding accelerates the process by decreasing the otherwise long fibrillation lag times at low pH and accelerates fibril growth rates at neutral pH. sCT·heparin complexes form β-sheet-rich heparin-covered fibrils. Solid-state NMR reveals that heparin does not alter the sCT fibrillary core around Lys11 but makes changes to Val8 on the exterior side of the β-strand, possibly through contacts to Lys18. Thus GAGs significantly modulate sCT fibrillation in a pH-dependent manner by interacting with both monomeric and aggregated sCT. PMID:27281819

  9. Modeling generic aspects of ideal fibril formation

    Energy Technology Data Exchange (ETDEWEB)

    Michel, D., E-mail: denis.michel@live.fr [Universite de Rennes1-IRSET, Campus de Beaulieu Bat. 13, 35042 Rennes (France)

    2016-01-21

    Many different proteins self-aggregate into insoluble fibrils growing apically by reversible addition of elementary building blocks. But beyond this common principle, the modalities of fibril formation are very disparate, with various intermediate forms which can be reshuffled by minor modifications of physico-chemical conditions or amino-acid sequences. To bypass this complexity, the multifaceted phenomenon of fibril formation is reduced here to its most elementary principles defined for a linear prototype of fibril. Selected generic features, including nucleation, elongation, and conformational recruitment, are modeled using minimalist hypotheses and tools, by separating equilibrium from kinetic aspects and in vitro from in vivo conditions. These reductionist approaches allow to bring out known and new rudiments, including the kinetic and equilibrium effects of nucleation, the dual influence of elongation on nucleation, the kinetic limitations on nucleation and fibril numbers, and the accumulation of complexes in vivo by rescue from degradation. Overlooked aspects of these processes are also pointed: the exponential distribution of fibril lengths can be recovered using various models because it is attributable to randomness only. It is also suggested that the same term “critical concentration” is used for different things, involved in either nucleation or elongation.

  10. The contrasting effect of macromolecular crowding on amyloid fibril formation.

    Directory of Open Access Journals (Sweden)

    Qian Ma

    Full Text Available Amyloid fibrils associated with neurodegenerative diseases can be considered biologically relevant failures of cellular quality control mechanisms. It is known that in vivo human Tau protein, human prion protein, and human copper, zinc superoxide dismutase (SOD1 have the tendency to form fibril deposits in a variety of tissues and they are associated with different neurodegenerative diseases, while rabbit prion protein and hen egg white lysozyme do not readily form fibrils and are unlikely to cause neurodegenerative diseases. In this study, we have investigated the contrasting effect of macromolecular crowding on fibril formation of different proteins.As revealed by assays based on thioflavin T binding and turbidity, human Tau fragments, when phosphorylated by glycogen synthase kinase-3β, do not form filaments in the absence of a crowding agent but do form fibrils in the presence of a crowding agent, and the presence of a strong crowding agent dramatically promotes amyloid fibril formation of human prion protein and its two pathogenic mutants E196K and D178N. Such an enhancing effect of macromolecular crowding on fibril formation is also observed for a pathological human SOD1 mutant A4V. On the other hand, rabbit prion protein and hen lysozyme do not form amyloid fibrils when a crowding agent at 300 g/l is used but do form fibrils in the absence of a crowding agent. Furthermore, aggregation of these two proteins is remarkably inhibited by Ficoll 70 and dextran 70 at 200 g/l.We suggest that proteins associated with neurodegenerative diseases are more likely to form amyloid fibrils under crowded conditions than in dilute solutions. By contrast, some of the proteins that are not neurodegenerative disease-associated are unlikely to misfold in crowded physiological environments. A possible explanation for the contrasting effect of macromolecular crowding on these two sets of proteins (amyloidogenic proteins and non-amyloidogenic proteins has been

  11. Effect of Stirring and Seeding on Whey Protein Fibril Formation

    NARCIS (Netherlands)

    Bolder, S.G.; Sagis, L.M.C.; Venema, P.; Linden, van der E.

    2007-01-01

    The effect of stirring and seeding on the formation of fibrils in whey protein isolate (WPI) solutions was studied. More fibrils of a similar length are formed when WPI is stirred during heating at pH 2 and 80 C compared to samples that were heated at rest. Addition of seeds did not show an

  12. Aggregation properties of a short peptide that mediates amyloid fibril ...

    Indian Academy of Sciences (India)

    Short peptides have been identified from amyloidogenic proteins that form amyloid fibrils in isolation. The ... proteins. These peptide fibrils have the conformational features of β-structure that .... water and immediately deposited on freshly cleaved surface of mica .... with the peptide via electrostatic interactions. NaCl would.

  13. Solid-state NMR detection of 14N-13C dipolar couplings between amino acid side groups provides constraints on amyloid fibril architecture.

    Science.gov (United States)

    Middleton, David A

    2011-02-01

    Solid-state nuclear magnetic resonance (SSNMR) is a powerful technique for the structural analysis of amyloid fibrils. With suitable isotope labelling patterns, SSNMR can provide constraints on the secondary structure, alignment and registration of β-strands within amyloid fibrils and identify the tertiary and quaternary contacts defining the packing of the β-sheet layers. Detection of (14)N-(13)C dipolar couplings may provide potentially useful additional structural constraints on β-sheet packing within amyloid fibrils but has not until now been exploited for this purpose. Here a frequency-selective, transfer of population in double resonance SSNMR experiment is used to detect a weak (14)N-(13)C dipolar coupling in amyloid-like fibrils of the peptide H(2)N-SNNFGAILSS-COOH, which was uniformly (13)C and (15)N labelled across the four C-terminal amino acids. The (14)N-(13)C interatomic distance between leucine and asparagine side groups is constrained between 2.4 and 3.8 Å, which allows current structural models of the β-spine arrangement within the fibrils to be refined. This procedure could be useful for the general structural analysis of other proteins in condensed phases and environments, such as biological membranes. Copyright © 2011 John Wiley & Sons, Ltd.

  14. What Is Atrial Fibrillation?

    Science.gov (United States)

    ANSWERS by heart Cardiovascular Conditions What Is Atrial Fibrillation? Your heart has a natural pacemaker, called the “sinus node,” that makes electrical signals. These signals cause the heart to contract and pump ...

  15. SAS-Based Studies of Protein Fibrillation

    DEFF Research Database (Denmark)

    Marasini, Carlotta; Vestergaard, Bente

    2017-01-01

    Protein fibrillation is associated with a number of fatal amyloid diseases (e.g. Alzheimer's and Parkinson's diseases). From a structural point of view, the aggregation process starts from an ensemble of native states that convert into transiently formed oligomers, higher order assemblies and pro...... and highlight existing reports, exemplifying the wealth of information that can be derived from the method....

  16. Evidence for a central role of PrP helix 2 in the nucleation of amyloid fibrils.

    Science.gov (United States)

    Honda, Ryo; Kuwata, Kazuo

    2018-02-01

    Amyloid fibrils are filamentous protein aggregates associated with the pathogenesis of a wide variety of human diseases. The formation of such aggregates typically follows nucleation-dependent kinetics, wherein the assembly and structural conversion of amyloidogenic proteins into oligomeric aggregates (nuclei) is the rate-limiting step of the overall reaction. In this study, we sought to gain structural insights into the oligomeric nuclei of the human prion protein (PrP) by preparing a series of deletion mutants lacking 14-44 of the C-terminal 107 residues of PrP and examined the kinetics and thermodynamics of these mutants in amyloid formation. An analysis of the experimental data using the concepts of the Φ-value analysis indicated that the helix 2 region (residues 168-196) acquires an amyloid-like β-sheet during nucleation, whereas the other regions preserves a relatively disordered structure in the nuclei. This finding suggests that the helix 2 region serves as the nucleation site for the assembly of amyloid fibrils.-Honda, R., Kuwata, K. Evidence for a central role of PrP helix 2 in the nucleation of amyloid fibrils.

  17. A single amino acid difference between the intracellular domains of amyloid precursor protein and amyloid-like precursor protein 2 enables induction of synaptic depression and block of long-term potentiation.

    Science.gov (United States)

    Trillaud-Doppia, Emilie; Paradis-Isler, Nicolas; Boehm, Jannic

    2016-07-01

    Alzheimer disease (AD) is initially characterized as a disease of the synapse that affects synaptic transmission and synaptic plasticity. While amyloid-beta and tau have been traditionally implicated in causing AD, recent studies suggest that other factors, such as the intracellular domain of the amyloid-precursor protein (APP-ICD), can also play a role in the development of AD. Here, we show that the expression of APP-ICD induces synaptic depression, while the intracellular domain of its homolog amyloid-like precursor protein 2 (APLP2-ICD) does not. We are able to show that this effect by APP-ICD is due to a single alanine vs. proline difference between APP-ICD and APLP2-ICD. The alanine in APP-ICD and the proline in APLP2-ICD lie directly behind a conserved caspase cleavage site. Inhibition of caspase cleavage of APP-ICD prevents the induction of synaptic depression. Finally, we show that the expression of APP-ICD increases and facilitates long-term depression and blocks induction of long-term potentiation. The block in long-term potentiation can be overcome by mutating the aforementioned alanine in APP-ICD to the proline of APLP2. Based on our results, we propose the emergence of a new APP critical domain for the regulation of synaptic plasticity and in consequence for the development of AD. Copyright © 2016 Elsevier Inc. All rights reserved.

  18. Light Chain Amyloid Fibrils Cause Metabolic Dysfunction in Human Cardiomyocytes.

    Directory of Open Access Journals (Sweden)

    Helen P McWilliams-Koeppen

    Full Text Available Light chain (AL amyloidosis is the most common form of systemic amyloid disease, and cardiomyopathy is a dire consequence, resulting in an extremely poor prognosis. AL is characterized by the production of monoclonal free light chains that deposit as amyloid fibrils principally in the heart, liver, and kidneys causing organ dysfunction. We have studied the effects of amyloid fibrils, produced from recombinant λ6 light chain variable domains, on metabolic activity of human cardiomyocytes. The data indicate that fibrils at 0.1 μM, but not monomer, significantly decrease the enzymatic activity of cellular NAD(PH-dependent oxidoreductase, without causing significant cell death. The presence of amyloid fibrils did not affect ATP levels; however, oxygen consumption was increased and reactive oxygen species were detected. Confocal fluorescence microscopy showed that fibrils bound to and remained at the cell surface with little fibril internalization. These data indicate that AL amyloid fibrils severely impair cardiomyocyte metabolism in a dose dependent manner. These data suggest that effective therapeutic intervention for these patients should include methods for removing potentially toxic amyloid fibrils.

  19. Surgery for atrial fibrillation.

    Science.gov (United States)

    Viganò, M; Graffigna, A; Ressia, L; Minzioni, G; Pagani, F; Aiello, M; Gazzoli, F

    1996-01-01

    The mechanisms of atrial fibrillation arc multiple reentry circuits spinning around the atrial surface, and these baffle any attempt to direct surgical interruption. The purpose of this article is to report the surgical experience in the treatment of isolated and concomitant atrial fibrillation at the Cardiac Surgical Institute of the University of Pavia. In cases of atrial fibrillation secondary to mitral/valve disease, surgical isolation of the left atrium at the time of mitral valve surgery can prevent atrial fibrillation from involving the right atrium, which can exert its diastolic pump function on the right ventricle. Left atrial isolation was performed on 205 patients at the time of mitral valve surgery. Atrial partitioning ("maze operation") creates straight and blind atrial alleys so that non-recentry circuits can take place. Five patients underwent this procedure. In eight-cases of atrial fibrillation secondary to atrial septal defect, the adult patients with atrial septal defect and chronic or paroxysmal atrial fibrillation underwent surgical isolation of the right atrium associated which surgical correction of the defect, in order to let sinus rhythm govern the left atrium and the ventricles. "Lone" atrial fibrillation occurs in hearts with no detectable organic disease. Bi-atrial isolation with creation of an atrial septal internodal "corridor" was performed on 14 patients. In cases of atrial fibrillation secondary to mitral valve disease, left atrial isolation was performed on 205 patients at the time of mitral valve surgery with an overall sinus rhythm recovery of 44%. In the same period, sinus rhythm was recovered and persisted in only 19% of 252 patients who underwent mitral valve replacement along (P < 0.001). Sinus rhythm was less likely to recover in patients with right atriomegaly requiring tricuspid valve annuloplasty: 59% vs 84% (P < 0.001). Restoration of the right atrial function raised the cardiac index from 2.25 +/- 0.55 1/min per m2

  20. Nearly reversible conformational change of amyloid fibrils as revealed by pH-jump experiments.

    Science.gov (United States)

    Yamaguchi, Kei-ichi; Kamatari, Yuji O; Fukuoka, Mayuko; Miyaji, Reiji; Kuwata, Kazuo

    2013-10-01

    pH-jump induced conformational transitions between substates of preformed amyloid fibrils made by a fragmented peptide of helix 2 (H2 peptide) of MoPrP were detected, and their kinetics were analyzed using a novel pH-jump apparatus specially designed for observing amyloids. Previously, we reported that H2 peptide formed ordered fibrils with a minimum at 207 nm on CD spectra at pH 2.9 (named pH 2.9 fibrils), but formed aggregate-like fibrils with a minimum at 220 nm at pH 7.5 (named pH 7.5 fibrils). When pH-jump from 2.9 to 7.5 was performed, the CD spectrum changed instantly, but the finally observed ellipticities were clearly distinct from those of pH 7.5 fibrils. Thus, the finally observed state is termed 'pH 7.5-like fibrils'. However, pH 7.5-like fibrils reverted to the conformation very similar to that of the pH 2.9 fibrils when the pH of the solution was restored to 2.9. Then, we examined the kinetics of the nearly reversible conformational changes between pH 2.9 fibrils and pH 7.5-like fibrils using ANS fluorescence stopped-flow, and we observed relatively fast phases (0.7-18 s(-1)). In contrast, the conversion between pH 7.5-like fibrils and pH 7.5 fibrils never occurred (<0.2 day(-1)). Thus, H2 fibrils can be switched readily between distinct conformations separated by a low energy barrier, while a large energy barrier clearly separated the different conformations. These conformational varieties of amyloid fibrils may explain the physical basis of the diversity in prion.

  1. Atrial Fibrillation and Hyperthyroidism

    Directory of Open Access Journals (Sweden)

    Jayaprasad N

    2005-10-01

    Full Text Available Atrial fibrillation occurs in 10 – 15% of patients with hyperthyroidism. Low serum thyrotropin concentration is an independent risk factor for atrial fibrillation. Thyroid hormone contributes to arrythmogenic activity by altering the electrophysiological characteristics of atrial myocytes by shortening the action potential duration, enhancing automaticity and triggered activity in the pulmonary vein cardio myocytes. Hyperthyroidism results in excess mortality from increased incidence of circulatory diseases and dysrhythmias. Incidence of cerebral embolism is more in hyperthyroid patients with atrial fibrillation, especially in the elderly and anti-coagulation is indicated in them. Treatment of hyperthyroidism results in conversion to sinus rhythm in up to two-third of patients. Beta-blockers reduce left ventricular hypertrophy and atrial and ventricular arrhythmias in patients with hyperthyroidism. Treatment of sub clinical hyperthyroidism is controversial. Optimizing dose of thyroxine treatment in those with replacement therapy and beta-blockers is useful in exogenous subclinical hyperthyroidism.

  2. Thyrotoxic atrial fibrillation.

    Science.gov (United States)

    Parmar, Malvinder S

    2005-01-04

    Atrial fibrillation is the most common cardiac complication of hyperthyroidism and occurs in 15% of patients with hyperthyroidism. It is associated with a higher risk of thromboembolism that often involves the central nervous system. Oral anticoagulation is important in the majority of these patients to prevent thromboembolic complications. These patients require adjustment in the dose of various rate-controlling agents because of increased clearance associated with hyperthyroidism and a decrease in warfarin dosage because of increased clearance of vitamin K-dependent clotting factors. The management of thyrotoxic atrial fibrillation is summarized in this clinical review.

  3. Proinsulin C-peptide interferes with insulin fibril formation

    International Nuclear Information System (INIS)

    Landreh, Michael; Stukenborg, Jan-Bernd; Willander, Hanna; Söder, Olle; Johansson, Jan; Jörnvall, Hans

    2012-01-01

    Highlights: ► Insulin and C-peptide can interact under insulin fibril forming conditions. ► C-peptide is incorporated into insulin aggregates and alters aggregation lag time. ► C-peptide changes insulin fibril morphology and affects backbone accessibility. ► C-peptide may be a regulator of fibril formation by β-cell granule proteins. -- Abstract: Insulin aggregation can prevent rapid insulin uptake and cause localized amyloidosis in the treatment of type-1 diabetes. In this study, we investigated the effect of C-peptide, the 31-residue peptide cleaved from proinsulin, on insulin fibrillation at optimal conditions for fibrillation. This is at low pH and high concentration, when the fibrils formed are regular and extended. We report that C-peptide then modulates the insulin aggregation lag time and profoundly changes the fibril appearance, to rounded clumps of short fibrils, which, however, still are Thioflavine T-positive. Electrospray ionization mass spectrometry also indicates that C-peptide interacts with aggregating insulin and is incorporated into the aggregates. Hydrogen/deuterium exchange mass spectrometry further reveals reduced backbone accessibility in insulin aggregates formed in the presence of C-peptide. Combined, these effects are similar to those of C-peptide on islet amyloid polypeptide fibrillation and suggest that C-peptide has a general ability to interact with amyloidogenic proteins from pancreatic β-cell granules. Considering the concentrations, these peptide interactions should be relevant also during physiological secretion, and even so at special sites post-secretory or under insulin treatment conditions in vivo.

  4. Proinsulin C-peptide interferes with insulin fibril formation

    Energy Technology Data Exchange (ETDEWEB)

    Landreh, Michael [Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 77 Stockholm (Sweden); Stukenborg, Jan-Bernd [Department of Women' s and Children' s Health, Astrid Lindgren Children' s Hospital, Pediatric Endocrinology Unit, Karolinska Institutet and University Hospital, S-17176 Stockholm (Sweden); Willander, Hanna [KI-Alzheimer' s Disease Research Center, NVS Department, Karolinska Institutet, S-141 86 Stockholm (Sweden); Soeder, Olle [Department of Women' s and Children' s Health, Astrid Lindgren Children' s Hospital, Pediatric Endocrinology Unit, Karolinska Institutet and University Hospital, S-17176 Stockholm (Sweden); Johansson, Jan [KI-Alzheimer' s Disease Research Center, NVS Department, Karolinska Institutet, S-141 86 Stockholm (Sweden); Department of Anatomy, Physiology and Biochemistry, Swedish University of Agricultural Sciences, S-751 23 Uppsala (Sweden); Joernvall, Hans, E-mail: Hans.Jornvall@ki.se [Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 77 Stockholm (Sweden)

    2012-02-17

    Highlights: Black-Right-Pointing-Pointer Insulin and C-peptide can interact under insulin fibril forming conditions. Black-Right-Pointing-Pointer C-peptide is incorporated into insulin aggregates and alters aggregation lag time. Black-Right-Pointing-Pointer C-peptide changes insulin fibril morphology and affects backbone accessibility. Black-Right-Pointing-Pointer C-peptide may be a regulator of fibril formation by {beta}-cell granule proteins. -- Abstract: Insulin aggregation can prevent rapid insulin uptake and cause localized amyloidosis in the treatment of type-1 diabetes. In this study, we investigated the effect of C-peptide, the 31-residue peptide cleaved from proinsulin, on insulin fibrillation at optimal conditions for fibrillation. This is at low pH and high concentration, when the fibrils formed are regular and extended. We report that C-peptide then modulates the insulin aggregation lag time and profoundly changes the fibril appearance, to rounded clumps of short fibrils, which, however, still are Thioflavine T-positive. Electrospray ionization mass spectrometry also indicates that C-peptide interacts with aggregating insulin and is incorporated into the aggregates. Hydrogen/deuterium exchange mass spectrometry further reveals reduced backbone accessibility in insulin aggregates formed in the presence of C-peptide. Combined, these effects are similar to those of C-peptide on islet amyloid polypeptide fibrillation and suggest that C-peptide has a general ability to interact with amyloidogenic proteins from pancreatic {beta}-cell granules. Considering the concentrations, these peptide interactions should be relevant also during physiological secretion, and even so at special sites post-secretory or under insulin treatment conditions in vivo.

  5. Sequence dependent aggregation of peptides and fibril formation

    Science.gov (United States)

    Hung, Nguyen Ba; Le, Duy-Manh; Hoang, Trinh X.

    2017-09-01

    Deciphering the links between amino acid sequence and amyloid fibril formation is key for understanding protein misfolding diseases. Here we use Monte Carlo simulations to study the aggregation of short peptides in a coarse-grained model with hydrophobic-polar (HP) amino acid sequences and correlated side chain orientations for hydrophobic contacts. A significant heterogeneity is observed in the aggregate structures and in the thermodynamics of aggregation for systems of different HP sequences and different numbers of peptides. Fibril-like ordered aggregates are found for several sequences that contain the common HPH pattern, while other sequences may form helix bundles or disordered aggregates. A wide variation of the aggregation transition temperatures among sequences, even among those of the same hydrophobic fraction, indicates that not all sequences undergo aggregation at a presumable physiological temperature. The transition is found to be the most cooperative for sequences forming fibril-like structures. For a fibril-prone sequence, it is shown that fibril formation follows the nucleation and growth mechanism. Interestingly, a binary mixture of peptides of an aggregation-prone and a non-aggregation-prone sequence shows the association and conversion of the latter to the fibrillar structure. Our study highlights the role of a sequence in selecting fibril-like aggregates and also the impact of a structural template on fibril formation by peptides of unrelated sequences.

  6. Replica Exchange Simulations of the Thermodynamics of Aβ Fibril Growth

    Science.gov (United States)

    Takeda, Takako; Klimov, Dmitri K.

    2009-01-01

    Abstract Replica exchange molecular dynamics and an all-atom implicit solvent model are used to probe the thermodynamics of deposition of Alzheimer's Aβ monomers on preformed amyloid fibrils. Consistent with the experiments, two deposition stages have been identified. The docking stage occurs over a wide temperature range, starting with the formation of the first peptide-fibril interactions at 500 K. Docking is completed when a peptide fully adsorbs on the fibril edge at the temperature of 380 K. The docking transition appears to be continuous, and occurs without free energy barriers or intermediates. During docking, incoming Aβ monomer adopts a disordered structure on the fibril edge. The locking stage occurs at the temperature of ≈360 K and is characterized by the rugged free energy landscape. Locking takes place when incoming Aβ peptide forms a parallel β-sheet structure on the fibril edge. Because the β-sheets formed by locked Aβ peptides are typically off-registry, the structure of the locked phase differs from the structure of the fibril interior. The study also reports that binding affinities of two distinct fibril edges with respect to incoming Aβ peptides are different. The peptides bound to the concave edge have significantly lower free energy compared to those bound on the convex edge. Comparison with the available experimental data is discussed. PMID:19167295

  7. Atrial fibrillation after cardiac surgery

    Directory of Open Access Journals (Sweden)

    Nair Suresh

    2010-01-01

    Full Text Available Once considered as nothing more than a nuisance after cardiac surgery, the importance of postoperative atrial fibrillation (POAF has been realized in the last decade, primarily because of the morbidity associated with the condition. Numerous causative factors have been described without any single factor being singled out as the cause of this complication. POAF has been associated with stroke, renal failure and congestive heart failure, although it is difficult to state whether POAF is directly responsible for these complications. Guidelines have been formulated for prevention of POAF. However, very few cardiothoracic centers follow any form of protocol to prevent POAF. Routine use of prophylaxis would subject all patients to the side effects of anti-arrhythmic drugs, while only a minority of the patients do actually develop this problem postoperatively. Withdrawal of beta blockers in the postoperative period has been implicated as one of the major causes of POAF. Amiodarone, calcium channel blockers and a variety of other pharmacological agents have been used for the prevention of POAF. Atrial pacing is a non-pharmacological measure which has gained popularity in the prevention of POAF. There is considerable controversy regarding whether rate control is superior to rhythm control in the treatment of established atrial fibrillation (AF. Amiodarone plays a central role in both rate control and rhythm control in postoperative AF. Newer drugs like dronedarone and ranazoline are likely to come into the market in the coming years.

  8. Modulation of atrial fibrillation

    NARCIS (Netherlands)

    Geuzebroek, G.S.C.

    2013-01-01

    In this thesis we investigate the results of various surgical procedures for atrial fibrillation which have been performed in the last 2 decades in the Sint Antonius Hospital, Nieuwegein, The Netherlands. In the 1990s the classical Maze III procedure was the main surgical technique for

  9. Ultrafast Hydrogen-Bonding Dynamics in Amyloid Fibrils.

    Science.gov (United States)

    Pazos, Ileana M; Ma, Jianqiang; Mukherjee, Debopreeti; Gai, Feng

    2018-06-08

    While there are many studies on the subject of hydrogen bonding dynamics in biological systems, few, if any, have investigated this fundamental process in amyloid fibrils. Herein, we seek to add insight into this topic by assessing the dynamics of a hydrogen bond buried in the dry interface of amyloid fibrils. To prepare a suitable model peptide system for this purpose, we introduce two mutations into the amyloid-forming Aβ(16-22) peptide. The first one is a lysine analog at position 19, which is used to help form structurally homogeneous fibrils, and the second one is an aspartic acid derivative (DM) at position 17, which is intended (1) to be used as a site-specific infrared probe and (2) to serve as a hydrogen-bond acceptor to lysine so that an inter-β-sheet hydrogen bond can be formed in the fibrils. Using both infrared spectroscopy and atomic force microscopy, we show that (1) this mutant peptide indeed forms well defined fibrils, (2) when bulk solvent is removed, there is no detectable water present in the fibrils, (3) infrared results obtained with the DM probe are consistent with a protofibril structure that is composed of two antiparallel β-sheets stacked in a parallel fashion, leading to formation of the expected hydrogen bond. Using two-dimensional infrared spectroscopy, we further show that the dynamics of this hydrogen bond occur on a timescale of ~2.3 ps, which is attributed to the rapid rotation of the -NH3+ group of lysine around its Cε-Nζ bond. Taken together, these results suggest that (1) DM is a useful infrared marker in facilitating structure determination of amyloid fibrils and (2) even in the tightly packed core of amyloid fibrils certain amino acid sidechains can undergo ultrafast motions, hence contributing to the thermodynamic stability of the system.

  10. Fibril formation from pea protein and subsequent gel formation.

    Science.gov (United States)

    Munialo, Claire Darizu; Martin, Anneke H; van der Linden, Erik; de Jongh, Harmen H J

    2014-03-19

    The objective of this study was to characterize fibrillar aggregates made using pea proteins, to assemble formed fibrils into protein-based gels, and to study the rheological behavior of these gels. Micrometer-long fibrillar aggregates were observed after pea protein solutions had been heated for 20 h at pH 2.0. Following heating of pea proteins, it was observed that all of the proteins were hydrolyzed into peptides and that 50% of these peptides were assembled into fibrils. Changes on a structural level in pea proteins were studied using circular dichroism, transmission electron microscopy, and particle size analysis. During the fibril assembly process, an increase in aggregate size was observed, which coincided with an increase in thioflavin T binding, indicating the presence of β-sheet aggregates. Fibrils made using pea proteins were more branched and curly. Gel formation of preformed fibrils was induced by slow acidification from pH 7.0 to a final pH of around pH 5.0. The ability of pea protein-based fibrillar gels to fracture during an amplitude sweep was comparable to those of soy protein and whey protein-based fibrillar gels, although gels prepared from fibrils made using pea protein and soy protein were weaker than those of whey protein. The findings show that fibrils can be prepared from pea protein, which can be incorporated into protein-based fibrillar gels.

  11. Phosphate and HEPES buffers potently affect the fibrillation and oligomerization mechanism of Alzheimer's Aβ peptide

    International Nuclear Information System (INIS)

    Garvey, Megan; Tepper, Katharina; Haupt, Caroline; Knuepfer, Uwe; Klement, Karolin; Meinhardt, Jessica; Horn, Uwe; Balbach, Jochen; Faendrich, Marcus

    2011-01-01

    Highlights: → Sodium phosphate buffer accelerated Aβ(1-40) nucleation relative to HEPES. → Aβ(1-40) fibrils formed in the two buffers show only minor structural differences. → NMR revealed that Aβ(1-40) histidine residues mediate buffer dependent changes. -- Abstract: The oligomerization of Aβ peptide into amyloid fibrils is a hallmark of Alzheimer's disease. Due to its biological relevance, phosphate is the most commonly used buffer system for studying the formation of Aβ and other amyloid fibrils. Investigation into the characteristics and formation of amyloid fibrils frequently relies upon material formed in vitro, predominantly in phosphate buffers. Herein, we examine the effects on the fibrillation and oligomerization mechanism of Aβ peptide that occur due solely to the influence of phosphate buffer. We reveal that significant differences in amyloid fibrillation are observed due to fibrillation being initiated in phosphate or HEPES buffer (at physiological pH and temperature). Except for the differing buffer ions, all experimental parameters were kept constant. Fibril formation was assessed using fluorescently monitored kinetic studies, microscopy, X-ray fiber diffraction and infrared and nuclear magnetic resonance spectroscopies. Based on this set up, we herein reveal profound effects on the mechanism and speed of Aβ fibrillation. The three histidine residues at positions 6, 13 and 14 of Aβ(1-40) are instrumental in these mechanistic changes. We conclude that buffer plays a more significant role in fibril formation than has been generally acknowledged.

  12. The changing face of glucagon fibrillation: Structural polymorphism and conformational imprinting

    DEFF Research Database (Denmark)

    Pedersen, J.S.; Dikov, D.; Flink, J.L.

    2006-01-01

    concentration) appear less thermostable than those formed under more challenging conditions (high temperatures, low glucagon or low salt concentrations). Properties of preformed fibrils used for seeding are inherited in a prion-like manner. Thus, we conclude that the structure of fibrils formed by glucagon...

  13. HYPERTHYROIDISM AND ATRIAL FIBRILLATION

    Directory of Open Access Journals (Sweden)

    I. M. Marusenko

    2017-01-01

    Full Text Available Review on a problem of the development of atrial fibrillation in patients with thyrotoxicosis is presented. Thyrotoxicosis is one of the most frequent endocrine diseases, conceding only to a diabetes mellitus. The most frequent reasons of hyperthyroidism are Graves’ disease and functional thyroid autonomy. The authors give an analysis of data on the cardiac effects of thyrotoxicosis, features of heart remodeling under the influence of thyroid hyperfunction, prevalence of atrial fibrillation in thyrotoxicosis, depending on age, as well as the possibility of restoring sinus rhythm in the combination of these diseases. Particular attention is paid to the effect on the heart of subclinical thyrotoxicosis, which is defined as a dysfunction of the thyroid gland, characterized by low serum concentration of thyrotropin, normal values of free thyroxine and free triiodothyronine. Subclinical hyperthyroidism is also capable of causing heart remodeling and diastolic dysfunction.Prevalence of thyrotoxicosis in elderly people is higher in areas of iodine deficiency; it is relevant for our country due to the large territory of iodine deficiency. In elderly patients, the cardiac effects of thyrotoxicosis prevail in the clinical picture, that makes it difficult to diagnose endocrine disorders, and correction of thyrotoxicosis is critically important for the successful control of the heart rhythm. The article also discusses the problem of thyrotoxic cardiomyopathy, caused by the toxic effect of excess thyroid hormones: features of this heart disorder, factors affecting its formation, clinical significance and contribution to the development of rhythm disturbances. The greatest significance is the development of atrial fibrillation as a result of thyrotox-icosis in older patients who already have various cardiovascular diseases.Atrial fibrillation is the most frequent heart rhythm disorder in thyrotoxicosis. The main cause of arrhythmia in hyperthyroidism is the

  14. Psychosomatic correlations in atrial fibrillations

    Directory of Open Access Journals (Sweden)

    Vladimir Ernstovich Medvedev

    2011-01-01

    Full Text Available Patients with atrial fibrillations (AF and comorbid mental disorders were examined. Two patient groups differing in the structure of psychosomatic ratios were identified. Group 1 comprised patients with AF and signs of reactivity lability that manifested itself as psychopathological reactions to the primary manifestations of AF; Group 2 included those who had developed mental disorders mainly in end-stage cardiovascular disease (predominantly a permanent form of AF in the presence of such events as chronic heart failure (CHF. The results of the study suggest that the patients with AF have frequently anxiety and hypochondriacal disorders, which agrees with the data available in the literature. In addition, end-stage AF is marked by depressive syndromes caused by the severe course of cardiovascular diseases resulting in CHF.

  15. Genetics Home Reference: familial atrial fibrillation

    Science.gov (United States)

    ... Twitter Home Health Conditions Familial atrial fibrillation Familial atrial fibrillation Printable PDF Open All Close All Enable Javascript to view the expand/collapse boxes. Description Familial atrial fibrillation is an inherited abnormality of the heart's normal ...

  16. Human Islet Amyloid Polypeptide Fibril Binding to Catalase: A Transmission Electron Microscopy and Microplate Study

    Directory of Open Access Journals (Sweden)

    Nathaniel G. N. Milton

    2010-01-01

    Full Text Available The diabetes-associated human islet amyloid polypeptide (IAPP is a 37-amino-acid peptide that forms fibrils in vitro and in vivo. Human IAPP fibrils are toxic in a similar manner to Alzheimer's amyloid-β (Aβ and prion protein (PrP fibrils. Previous studies have shown that catalase binds to Aβ fibrils and appears to recognize a region containing the Gly-Ala-Ile-Ile sequence that is similar to the Gly-Ala-Ile-Leu sequence found in human IAPP residues 24-27. This study presents a transmission electron microscopy (TEM—based analysis of fibril formation and the binding of human erythrocyte catalase to IAPP fibrils. The results show that human IAPP 1-37, 8-37, and 20-29 peptides form fibrils with diverse and polymorphic structures. All three forms of IAPP bound catalase, and complexes of IAPP 1-37 or 8-37 with catalase were identified by immunoassay. The binding of biotinylated IAPP to catalase was high affinity with a KD of 0.77nM, and could be inhibited by either human or rat IAPP 1-37 and 8-37 forms. Fibrils formed by the PrP 118-135 peptide with a Gly-Ala-Val-Val sequence also bound catalase. These results suggest that catalase recognizes a Gly-Ala-Ile-Leu—like sequence in amyloid fibril-forming peptides. For IAPP 1-37 and 8-37, the catalase binding was primarily directed towards fibrillar rather than ribbon-like structures, suggesting differences in the accessibility of the human IAPP 24-27 Gly-Ala-Ile-Leu region. This suggests that catalase may be able to discriminate between different structural forms of IAPP fibrils. The ability of catalase to bind IAPP, Aβ, and PrP fibrils demonstrates the presence of similar accessible structural motifs that may be targets for antiamyloid therapeutic development.

  17. How curcumin affords effective protection against amyloid fibrillation in insulin?

    DEFF Research Database (Denmark)

    Rabiee, Atefeh; Ebrahim Habibi, Azadeh; Ghasemi, Atiyeh Ghasemi

    2013-01-01

    Since the formation of amyloid structures from proteins was recognized in numerous diseases, many efforts have been devoted to the task of finding effective anti-amyloidogenic compounds. In a number of these investigations, the existence of “generic” compounds is implicitly acknowledged. Curcumin...... been shown effectively influenced by micro molar concentrations of curcumin. Under amyloidogenic conditions (pH 2.5 and 37°C), the compound was observed to inhibit fibril formation of insulin in a dose-dependent manner. Moreover, addition of curcumin to the protein incubated in such conditions...... at different time points resulted in reduced amounts of final fibrils. Disaggregation of pre-formed fibrils was also observed upon addition of curcumin, as well as reduction in final fibril amounts after seeding. Overall, this compound appears to be able to interact with native, intermediate and fibrillar...

  18. Insulin fibrillation: The influence and coordination of Zn2+

    DEFF Research Database (Denmark)

    Frankær, Christian Grundahl; Sønderby, Pernille; Bang, Maria Blanner

    2017-01-01

    fibrils has been debated for some years. We have therefore investigated the influence and binding geometry of zinc in fibrillated insulin using extended X-ray absorption fine-structure and X-ray absorption near-edge structure spectroscopy. The results were validated with fibre diffraction, Transmission...... Electron Microscopy and Thioflavin T fluorescence measurements. It is well-known that Zn2+ ions coordinate and stabilize the hexameric forms of insulin. However, this study is the first to show that zinc indeed binds to the insulin fibrils. Furthermore, zinc influences the kinetics and the morphology...... of the fibrils. It also shows that zinc coordinates to histidine residues in an environment, which is similar to the coordination seen in the insulin R6 hexamers, where three histidine residues and a chloride ion is coordinating the zinc....

  19. Fibrillization kinetics of insulin solution in an interfacial shearing flow

    Science.gov (United States)

    Balaraj, Vignesh; McBride, Samantha; Hirsa, Amir; Lopez, Juan

    2015-11-01

    Although the association of fibril plaques with neurodegenerative diseases like Alzheimer's and Parkinson's is well established, in-depth understanding of the roles played by various physical factors in seeding and growth of fibrils is far from well known. Of the numerous factors affecting this complex phenomenon, the effect of fluid flow and shear at interfaces is paramount as it is ubiquitous and the most varying factor in vivo. Many amyloidogenic proteins have been found to denature upon contact at hydrophobic interfaces due to the self-assembling nature of protein in its monomeric state. Here, fibrillization kinetics of insulin solution is studied in an interfacial shearing flow. The transient surface rheological response of the insulin solution to the flow and its effect on the bulk fibrillization process has been quantified. Minute differences in hydrophobic characteristics between two variants of insulin- Human recombinant and Bovine insulin are found to result in very different responses. Results presented will be in the form of fibrillization assays, images of fibril plaques formed, and changes in surface rheological properties of the insulin solution. The interfacial velocity field, measured from images (via Brewster Angle Microscopy), is compared with computations. Supported by NNX13AQ22G, National Aeronautics and Space Administration.

  20. Is Supramolecular Filament Chirality the Underlying Cause of Major Morphology Differences in Amyloid Fibrils?

    Science.gov (United States)

    2015-01-01

    The unique enhanced sensitivity of vibrational circular dichroism (VCD) to the formation and development of amyloid fibrils in solution is extended to four additional fibril-forming proteins or peptides where it is shown that the sign of the fibril VCD pattern correlates with the sense of supramolecular filament chirality and, without exception, to the dominant fibril morphology as observed in AFM or SEM images. Previously for insulin, it has been demonstrated that the sign of the VCD band pattern from filament chirality can be controlled by adjusting the pH of the incubating solution, above pH 2 for “normal” left-hand-helical filaments and below pH 2 for “reversed” right-hand-helical filaments. From AFM or SEM images, left-helical filaments form multifilament braids of left-twisted fibrils while the right-helical filaments form parallel filament rows of fibrils with a flat tape-like morphology, the two major classes of fibril morphology that from deep UV resonance Raman scattering exhibit the same cross-β-core secondary structure. Here we investigate whether fibril supramolecular chirality is the underlying cause of the major morphology differences in all amyloid fibrils by showing that the morphology (twisted versus flat) of fibrils of lysozyme, apo-α-lactalbumin, HET-s (218–289) prion, and a short polypeptide fragment of transthyretin, TTR (105–115), directly correlates to their supramolecular chirality as revealed by VCD. The result is strong evidence that the chiral supramolecular organization of filaments is the principal underlying cause of the morphological heterogeneity of amyloid fibrils. Because fibril morphology is linked to cell toxicity, the chirality of amyloid aggregates should be explored in the widely used in vitro models of amyloid-associated diseases. PMID:24484302

  1. Is supramolecular filament chirality the underlying cause of major morphology differences in amyloid fibrils?

    Science.gov (United States)

    Kurouski, Dmitry; Lu, Xuefang; Popova, Ludmila; Wan, William; Shanmugasundaram, Maruda; Stubbs, Gerald; Dukor, Rina K; Lednev, Igor K; Nafie, Laurence A

    2014-02-12

    The unique enhanced sensitivity of vibrational circular dichroism (VCD) to the formation and development of amyloid fibrils in solution is extended to four additional fibril-forming proteins or peptides where it is shown that the sign of the fibril VCD pattern correlates with the sense of supramolecular filament chirality and, without exception, to the dominant fibril morphology as observed in AFM or SEM images. Previously for insulin, it has been demonstrated that the sign of the VCD band pattern from filament chirality can be controlled by adjusting the pH of the incubating solution, above pH 2 for "normal" left-hand-helical filaments and below pH 2 for "reversed" right-hand-helical filaments. From AFM or SEM images, left-helical filaments form multifilament braids of left-twisted fibrils while the right-helical filaments form parallel filament rows of fibrils with a flat tape-like morphology, the two major classes of fibril morphology that from deep UV resonance Raman scattering exhibit the same cross-β-core secondary structure. Here we investigate whether fibril supramolecular chirality is the underlying cause of the major morphology differences in all amyloid fibrils by showing that the morphology (twisted versus flat) of fibrils of lysozyme, apo-α-lactalbumin, HET-s (218-289) prion, and a short polypeptide fragment of transthyretin, TTR (105-115), directly correlates to their supramolecular chirality as revealed by VCD. The result is strong evidence that the chiral supramolecular organization of filaments is the principal underlying cause of the morphological heterogeneity of amyloid fibrils. Because fibril morphology is linked to cell toxicity, the chirality of amyloid aggregates should be explored in the widely used in vitro models of amyloid-associated diseases.

  2. Morphology and mechanical properties of multi-stranded amyloid fibrils probed by atomistic and coarse-grained simulations

    International Nuclear Information System (INIS)

    Yoon, Gwonchan; Lee, Myeongsang; Kim, Kyungwoo; In Kim, Jae; Joon Chang, Hyun; Baek, Inchul; Na, Sungsoo; Eom, Kilho

    2015-01-01

    Amyloid fibrils are responsible for pathogenesis of various diseases and exhibit the structural feature of an ordered, hierarchical structure such as multi-stranded helical structure. As the multi-strandedness of amyloid fibrils has recently been found to be highly correlated with their toxicity and infectivity, it is necessary to study how the hierarchical (i.e. multi-stranded) structure of amyloid fibril is formed. Moreover, although it has recently been reported that the nanomechanics of amyloid proteins plays a key role on the amyloid-induced pathogenesis, a critical role that the multi-stranded helical structure of the fibrils plays in their nanomechanical properties has not fully characterized. In this work, we characterize the morphology and mechanical properties of multi-stranded amyloid fibrils by using equilibrium molecular dynamics simulation and elastic network model. It is shown that the helical pitch of multi-stranded amyloid fibril is linearly proportional to the number of filaments comprising the amyloid fibril, and that multi-strandedness gives rise to improving the bending rigidity of the fibril. Moreover, we have also studied the morphology and mechanical properties of a single protofilament (filament) in order to understand the effect of cross-β structure and mutation on the structures and mechanical properties of amyloid fibrils. Our study sheds light on the underlying design principles showing how the multi-stranded amyloid fibril is formed and how the structure of amyloid fibrils governs their nanomechanical properties. (paper)

  3. Stabilization and anomalous hydration of collagen fibril under heating.

    Directory of Open Access Journals (Sweden)

    Sasun G Gevorkian

    Full Text Available BACKGROUND: Type I collagen is the most common protein among higher vertebrates. It forms the basis of fibrous connective tissues (tendon, chord, skin, bones and ensures mechanical stability and strength of these tissues. It is known, however, that separate triple-helical collagen macromolecules are unstable at physiological temperatures. We want to understand the mechanism of collagen stability at the intermolecular level. To this end, we study the collagen fibril, an intermediate level in the collagen hierarchy between triple-helical macromolecule and tendon. METHODOLOGY/PRINCIPAL FINDING: When heating a native fibril sample, its Young's modulus decreases in temperature range 20-58°C due to partial denaturation of triple-helices, but it is approximately constant at 58-75°C, because of stabilization by inter-molecular interactions. The stabilization temperature range 58-75°C has two further important features: here the fibril absorbs water under heating and the internal friction displays a peak. We relate these experimental findings to restructuring of collagen triple-helices in fibril. A theoretical description of the experimental results is provided via a generalization of the standard Zimm-Bragg model for the helix-coil transition. It takes into account intermolecular interactions of collagen triple-helices in fibril and describes water adsorption via the Langmuir mechanism. CONCLUSION/SIGNIFICANCE: We uncovered an inter-molecular mechanism that stabilizes the fibril made of unstable collagen macromolecules. This mechanism can be relevant for explaining stability of collagen.

  4. [Atrial fibrillation in elderly].

    Science.gov (United States)

    Arquizan, Caroline

    2012-11-01

    Atrial fibrilation (AF) is frequent and a strong risk factor for ischemic stroke in elderly. Ischemic stroke in patients with AF are more severe. Vitamine K antagonist therapy is highly effective for stroke prevention but is associated with hemorrhagic risk. The new oral anticoagulants (direct thrombin inhibitor [dabigatran], and direct factor Xa inhibitors [rivaroxaban and apixaban]) have all shown non inferiority or superiority, with better safety, considering the risk of intracranial haemorrhage. On this basis, it is justified to give them in priority in the vast majority of patients with AF, the choice of the drug and the dose is individual.

  5. Dynamic behavior of small heat shock protein inhibition on amyloid fibrillization of a small peptide (SSTSAA) from RNase A

    International Nuclear Information System (INIS)

    Xi, Dong; Dong, Xiao; Deng, Wei; Lai, Luhua

    2011-01-01

    Highlights: ► Mechanism of small heat shock protein inhibition on fibril formation was studied. ► Peptide SSTSAA with modified ends was used for amyloid fibril formation. ► FRET signal was followed during the fibril formation. ► Mj HSP16.5 inhibits fibril formation when introduced in the lag phase. ► Mj HSP16.5 slows down fibril formation when introduced after the lag phase. -- Abstract: Small heat shock proteins, a class of molecular chaperones, are reported to inhibit amyloid fibril formation in vitro, while the mechanism of inhibition remains unknown. In the present study, we investigated the mechanism by which Mj HSP16.5 inhibits amyloid fibril formation of a small peptide (SSTSAA) from RNase A. A model peptide (dansyl-SSTSAA-W) was designed by introducing a pair of fluorescence resonance energy transfer (FRET) probes into the peptide, allowing for the monitoring of fibril formation by this experimental model. Mj HSP16.5 completely inhibited fibril formation of the model peptide at a molar ratio of 1:120. The dynamic process of fibril formation, revealed by FRET, circular dichroism, and electron microscopy, showed a lag phase of about 2 h followed by a fast growth period. The effect of Mj HSP16.5 on amyloid fibril formation was investigated by adding it into the incubation solution during different growth phases. Adding Mj HSP16.5 to the incubating peptide before or during the lag phase completely inhibited fibril formation. However, introducing Mj HSP16.5 after the lag phase only slowed down the fibril formation process by adhering to the already formed fibrils. These findings provide insight into the inhibitory roles of small heat shock proteins on amyloid fibril formation at the molecular level.

  6. Dynamic behavior of small heat shock protein inhibition on amyloid fibrillization of a small peptide (SSTSAA) from RNase A

    Energy Technology Data Exchange (ETDEWEB)

    Xi, Dong [BNLMS, State Key Laboratory of Structural Chemistry for Unstable and Stable Species, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871 (China); Center for Theoretical Biology, Peking University, Beijing 100871 (China); Dong, Xiao; Deng, Wei [BNLMS, State Key Laboratory of Structural Chemistry for Unstable and Stable Species, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871 (China); Lai, Luhua, E-mail: lhlai@pku.edu.cn [BNLMS, State Key Laboratory of Structural Chemistry for Unstable and Stable Species, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871 (China); Center for Theoretical Biology, Peking University, Beijing 100871 (China)

    2011-12-09

    Highlights: Black-Right-Pointing-Pointer Mechanism of small heat shock protein inhibition on fibril formation was studied. Black-Right-Pointing-Pointer Peptide SSTSAA with modified ends was used for amyloid fibril formation. Black-Right-Pointing-Pointer FRET signal was followed during the fibril formation. Black-Right-Pointing-Pointer Mj HSP16.5 inhibits fibril formation when introduced in the lag phase. Black-Right-Pointing-Pointer Mj HSP16.5 slows down fibril formation when introduced after the lag phase. -- Abstract: Small heat shock proteins, a class of molecular chaperones, are reported to inhibit amyloid fibril formation in vitro, while the mechanism of inhibition remains unknown. In the present study, we investigated the mechanism by which Mj HSP16.5 inhibits amyloid fibril formation of a small peptide (SSTSAA) from RNase A. A model peptide (dansyl-SSTSAA-W) was designed by introducing a pair of fluorescence resonance energy transfer (FRET) probes into the peptide, allowing for the monitoring of fibril formation by this experimental model. Mj HSP16.5 completely inhibited fibril formation of the model peptide at a molar ratio of 1:120. The dynamic process of fibril formation, revealed by FRET, circular dichroism, and electron microscopy, showed a lag phase of about 2 h followed by a fast growth period. The effect of Mj HSP16.5 on amyloid fibril formation was investigated by adding it into the incubation solution during different growth phases. Adding Mj HSP16.5 to the incubating peptide before or during the lag phase completely inhibited fibril formation. However, introducing Mj HSP16.5 after the lag phase only slowed down the fibril formation process by adhering to the already formed fibrils. These findings provide insight into the inhibitory roles of small heat shock proteins on amyloid fibril formation at the molecular level.

  7. SDS-Induced Fibrillation of α-Synuclein

    DEFF Research Database (Denmark)

    Giehm, L.; Oliveira, Cristiano Luis Pinto De; Pedersen, J.S.

    2010-01-01

    . In this fibrillogenic complex, 4 αSN molecules initially associate with 40-50 SDS molecules to form a shared micelle that gradually grows in size. The complex initially exhibits a mixture of random coil and α-helix, but incubation results in a structural conversion into β-sheet structure and concomitant formation......-stabilized micelles. Thus, fibrillation in this case occurs by a process of continuous accretion rather than by the rate-limiting accumulation of a distinct nucleus. The morphology of the SDS-induced fibrils does not exhibit the classical rod-like structures formed by αSN when aggregated by agitation in the absence...

  8. Double-stranded DNA Stimulates the Fibrillation of alpha-Synuclein in vitro and is Associated with the Mature Fibrils: An Electron Microscopy Study

    NARCIS (Netherlands)

    Cherny, Dmitry; Hoyer, Wolfgang; Subramaniam, Vinod; Jovin, Thomas M.

    2004-01-01

    Filamentous aggregates formed by α-synuclein are a prominent and presumably key etiological factor in Parkinson's and other neurodegenerative diseases characterized by motor disorders. Numerous studies have demonstrated that various environmental and intracellular factors affect the fibrillation

  9. Atrial fibrillation in the elderly

    Science.gov (United States)

    Franken, Roberto A.; Rosa, Ronaldo F.; Santos, Silvio CM

    2012-01-01

    This review discusses atrial fibrillation according to the guidelines of Brazilian Society of Cardiac Arrhythmias and the Brazilian Cardiogeriatrics Guidelines. We stress the thromboembolic burden of atrial fibrillation and discuss how to prevent it as well as the best way to conduct cases of atrial fibrillatios in the elderly, reverting the arrhythmia to sinus rhythm, or the option of heart rate control. The new methods to treat atrial fibrillation, such as radiofrequency ablation, new oral direct thrombin inhibitors and Xa factor inhibitors, as well as new antiarrhythmic drugs, are depicted. PMID:22916053

  10. Role of sequence and structural polymorphism on the mechanical properties of amyloid fibrils.

    Directory of Open Access Journals (Sweden)

    Gwonchan Yoon

    Full Text Available Amyloid fibrils playing a critical role in disease expression, have recently been found to exhibit the excellent mechanical properties such as elastic modulus in the order of 10 GPa, which is comparable to that of other mechanical proteins such as microtubule, actin filament, and spider silk. These remarkable mechanical properties of amyloid fibrils are correlated with their functional role in disease expression. This suggests the importance in understanding how these excellent mechanical properties are originated through self-assembly process that may depend on the amino acid sequence. However, the sequence-structure-property relationship of amyloid fibrils has not been fully understood yet. In this work, we characterize the mechanical properties of human islet amyloid polypeptide (hIAPP fibrils with respect to their molecular structures as well as their amino acid sequence by using all-atom explicit water molecular dynamics (MD simulation. The simulation result suggests that the remarkable bending rigidity of amyloid fibrils can be achieved through a specific self-aggregation pattern such as antiparallel stacking of β strands (peptide chain. Moreover, we have shown that a single point mutation of hIAPP chain constituting a hIAPP fibril significantly affects the thermodynamic stability of hIAPP fibril formed by parallel stacking of peptide chain, and that a single point mutation results in a significant change in the bending rigidity of hIAPP fibrils formed by antiparallel stacking of β strands. This clearly elucidates the role of amino acid sequence on not only the equilibrium conformations of amyloid fibrils but also their mechanical properties. Our study sheds light on sequence-structure-property relationships of amyloid fibrils, which suggests that the mechanical properties of amyloid fibrils are encoded in their sequence-dependent molecular architecture.

  11. Studies of the structure of insulin fibrils by Fourier transform infrared (FTIR) spectroscopy and electron microscopy.

    Science.gov (United States)

    Nielsen, L; Frokjaer, S; Carpenter, J F; Brange, J

    2001-01-01

    Fibril formation (aggregation) of insulin was investigated in acid media by visual inspection, transmission electron microscopy (TEM), and Fourier transform infrared (FTIR) spectroscopy. Insulin fibrillated faster in hydrochloric acid than in acetic acid at elevated temperatures, whereas the fibrillation tendencies were reversed at ambient temperatures. Electron micrographs showed that bovine insulin fibrils consisted of long fibers with a diameter of 5 to 10 nm and lengths of several microns. The fibrils appeared either as helical filaments (in hydrochloric acid) or arranged laterally in bundles (in acetic acid, NaCl). Freeze-thawing cycles broke the fibrils into shorter segments. FTIR spectroscopy showed that the native secondary structure of insulin was identical in hydrochloric acid and acetic acid, whereas the secondary structure of fibrils formed in hydrochloric acid was different from that formed in acetic acid. Fibrils of bovine insulin prepared by heating or agitating an acid solution of insulin showed an increased content of beta-sheet (mostly intermolecular) and a decrease in the intensity of the alpha-helix band. In hydrochloric acid, the frequencies of the beta-sheet bands depended on whether the fibrillation was induced by heating or agitation. This difference was not seen in acetic acid. Freeze-thawing cycles of the fibrils in hydrochloric acid caused an increase in the intensity of the band at 1635 cm(-1) concomitant with reduction of the band at 1622 cm(-1). The results showed that the structure of insulin fibrils is highly dependent on the composition of the acid media and on the treatment. Copyright 2001 Wiley-Liss Inc. and the American Pharmaceutical Association J Pharm Sci 90: 29-37, 2001

  12. Core sequence of PAPf39 amyloid fibrils and mechanism of pH-dependent fibril formation: the role of monomer conformation.

    Science.gov (United States)

    French, Kinsley C; Makhatadze, George I

    2012-12-21

    PAPf39, a 39-residue peptide fragment from human prostatic acidic phosphatase, has been shown to form amyloid fibrils in semen (SEVI), which increase HIV infectivity by up to 5 orders of magnitude. The sequence of the PAPf39 fibrillar core was identified using hydrogen-deuterium exchange (HDX) mass spectrometry and protease protection assays. The central and C-terminal regions are highly protected from HDX and proteolytic cleavage and, thus, are part of the fibrillar core. Conversely, the N-terminal region is unprotected from HDX and proteolytic cleavage, suggesting that it is exposed and not part of the fibrillar core. This finding was tested using two N-terminal truncated variants, PAPf39Δ1-8 and PAPf39Δ1-13. Both variants formed amyloid fibrils at neutral pH. However, these variants showed a markedly different pH dependence of fibril formation versus that of PAPf39. PAPf39 fibrils can form at pH 7.7, but not at pH 5.5 or 2.5, while both N-terminally truncated variants can form fibrils at these pH values. Thus, the N-terminal region is not necessary for fibril formation but modulates the pH dependence of PAPf39 fibril formation. PAPf39Δ1-8 and PAPf39Δ1-13 are capable of seeding PAPf39 fibril formation at neutral pH, suggesting that these variants are structurally compatible with PAPf39, yet no mixed fibril formation occurs between the truncated variants and PAPf39 at low pH. This suggests that pH affects the PAPf39 monomer conformational ensemble, which is supported by far-UV circular dichroism spectroscopy. A conceptual model describing the pH dependence of PAPf39 aggregation is proposed and provides potential biological implications.

  13. Pharmacological Treatment for Atrial Fibrillation

    Directory of Open Access Journals (Sweden)

    Kaoru Sugi, MD PhD

    2005-01-01

    Full Text Available Pharmacological treatment for atrial fibrillation has a variety of purposes, such as pharmacological defibrillation, maintenance of sinus rhythm, heart rate control to prevent congestive heart failure and prevention of both cerebral infarction and atrial remodeling. Sodium channel blockers are superior to potassium channel blockers for atrial defibrillation, while both sodium and potassium channel blockers are effective in the maintenance of sinus rhythm. In general, digitalis or Ca antagonists are used to control heart rate during atrial fibrillation to prevent congestive heart failure, while amiodarone or bepridil also reduce heart rates during atrial fibrillation. Anticoagulant therapy with warfarin is recommended to prevent cerebral infarction and angiotensin converting enzyme antagonists or angiotensin II receptor blockers are also used to prevent atrial remodeling. One should select appropriate drugs for treatment of atrial fibrillation according to the patient's condition.

  14. Fracture mechanics of collagen fibrils

    DEFF Research Database (Denmark)

    Svensson, Rene B; Mulder, Hindrik; Kovanen, Vuokko

    2013-01-01

    Tendons are important load-bearing structures, which are frequently injured in both sports and work. Type I collagen fibrils are the primary components of tendons and carry most of the mechanical loads experienced by the tissue, however, knowledge of how load is transmitted between and within...... fibrils is limited. The presence of covalent enzymatic cross-links between collagen molecules is an important factor that has been shown to influence mechanical behavior of the tendons. To improve our understanding of how molecular bonds translate into tendon mechanics, we used an atomic force microscopy...... technique to measure the mechanical behavior of individual collagen fibrils loaded to failure. Fibrils from human patellar tendons, rat-tail tendons (RTTs), NaBH₄ reduced RTTs, and tail tendons of Zucker diabetic fat rats were tested. We found a characteristic three-phase stress-strain behavior in the human...

  15. The inhalation toxicology of p-aramid fibrils.

    Science.gov (United States)

    Donaldson, Ken

    2009-01-01

    The pandemic of lung disease caused by asbestos has cast suspicion on any industrial fibrous material that can become airborne in respirable form in workplaces, such that the respirable fibres might be inhaled. Fibre toxicology arose as a sub-specialty of particle toxicology to address the specialised nature of fibre effects and has evolved substantially in the last 25 years. It has yielded valuable information on the dosimetry, structure-activity relationships, and mechanism involved in toxicological effects of a range of fibrous materials, including asbestos, other naturally occurring fibrous materials, and synthetic vitreous fibres. A robust structure/activity paradigm has emerged from this research that highlights fibre length, thinness, and biopersistence as major factors in determining the pathogenicity of a fibre. p-Aramid is a manufactured fibre composed of synthetic polyamide (poly paraphenylene terephthalamide) manufactured on a commercial scale since 1970 by polymerisation and spinning steps. It is used as an advanced composite and in fabrics, body armour, friction materials, etc. Respirable fibrils of p-aramid can be released from the fibres during working and can become airborne. A considerable body of research has been carried out into the hazard posed by inhaled p-aramid fibrils, and this review considers this body of literature and summarises the state-of-the-science in the toxicology of p-aramid fibrils in the light of the existing overarching fibre toxicology paradigm. The peer-reviewed studies demonstrate that p-aramid fibrils can be long and thin but that the fibrils are not biopersistent. Residence in the milieu of the lungs leads to fibre shortening, allowing efficient and complete phagocytosis and effective clearance. Subsequently the p-aramid hazard is low, and this is confirmed in animal studies. The mechanism of shortening of p-aramid fibrils is not well-understood, but may involve the action of macrophages on the fibrils following

  16. Assembly of α-synuclein fibrils in nanoscale studied by peptide truncation and AFM

    International Nuclear Information System (INIS)

    Zhang Feng; Lin Xiaojing; Ji Lina; Du Haining; Tang Lin; He Jianhua; Hu Jun; Hu Hongyu

    2008-01-01

    α-Synuclein (α-Syn) fibrils are the major component of Lewy bodies that are closely associated with the pathogenesis of Parkinson's disease, but the mechanism for the fibril assembly remains poorly understood. Here we report using a combination of peptide truncation and atomic force microscopy (AFM) to elucidate the self-assembly and morphology of the α-Syn fibrils. The results show that protease K significantly slims the fibrils from the mean height of ∼6.6 to ∼4.7 nm, whereas chaotropic denaturant urea completely breaks down the fibrils into small particles. The in situ enzymatic digestion also results in thinning of the fibrils, giving rise to some nicks on the fibrils. Moreover, N- or C-terminally truncated α-Syn fragments assemble into thinner filaments with the heights depending on the peptide lengths. A nine-residue peptide corresponding to the homologous GAV-motif sequence can form very thin (∼2.2 nm) but long (>1 μm) filaments. Thus, the central sequence of α-Syn forms a fibrillar core by cross-β-structure that is flanked by two flexible termini, and the orientation of the fibril growth is perpendicular to the β-sheet structures

  17. Atrial fibrillation and hyperthyroidism: A literature review.

    Science.gov (United States)

    Reddy, Vivek; Taha, Wael; Kundumadam, Shanker; Khan, Mazhar

    Atrial fibrillation is the most common arrhythmia worldwide with increasing frequency noted with age. Hyperthyroidism is a well-known cause of atrial fibrillation with a 16%-60% prevalence of atrial fibrillation in patients with known hyperthyroidism Ross et al. (2016). While hyperthyroidism as a causative factor of atrial fibrillation is well established, this literature review aims to answer several questions on this topic including: 1. The relationship of atrial fibrillation to hyperthyroidism 2. Atrial fibrillation as a predictor of hyperthyroidism 3. The pathophysiology of thyrotoxic atrial fibrillation 4. Subclinical hyperthyroidism and the relationship with atrial fibrillation 5. Cardioversion and Catheter ablation of hyperthyroid patients with atrial fibrillation 6. Thrombotic risk of hyperthyroid patients with atrial fibrillation 7. Management of Thyrotoxic Atrial fibrillation 8. Pharmacological rhythm control in patients with hyperthyroidism and atrial fibrillation 9. Treatment of Hyperthyroidism to prevent atrial fibrillation 10. Clinical Implications of Hyperthyroidism and Atrial Fibrillation. Copyright © 2017 Cardiological Society of India. Published by Elsevier B.V. All rights reserved.

  18. How does domain replacement affect fibril formation of the rabbit/human prion proteins.

    Directory of Open Access Journals (Sweden)

    Xu Yan

    Full Text Available It is known that in vivo human prion protein (PrP have the tendency to form fibril deposits and are associated with infectious fatal prion diseases, while the rabbit PrP does not readily form fibrils and is unlikely to cause prion diseases. Although we have previously demonstrated that amyloid fibrils formed by the rabbit PrP and the human PrP have different secondary structures and macromolecular crowding has different effects on fibril formation of the rabbit/human PrPs, we do not know which domains of PrPs cause such differences. In this study, we have constructed two PrP chimeras, rabbit chimera and human chimera, and investigated how domain replacement affects fibril formation of the rabbit/human PrPs.As revealed by thioflavin T binding assays and Sarkosyl-soluble SDS-PAGE, the presence of a strong crowding agent dramatically promotes fibril formation of both chimeras. As evidenced by circular dichroism, Fourier transform infrared spectroscopy, and proteinase K digestion assays, amyloid fibrils formed by human chimera have secondary structures and proteinase K-resistant features similar to those formed by the human PrP. However, amyloid fibrils formed by rabbit chimera have proteinase K-resistant features and secondary structures in crowded physiological environments different from those formed by the rabbit PrP, and secondary structures in dilute solutions similar to the rabbit PrP. The results from transmission electron microscopy show that macromolecular crowding caused human chimera but not rabbit chimera to form short fibrils and non-fibrillar particles.We demonstrate for the first time that the domains beyond PrP-H2H3 (β-strand 1, α-helix 1, and β-strand 2 have a remarkable effect on fibrillization of the rabbit PrP but almost no effect on the human PrP. Our findings can help to explain why amyloid fibrils formed by the rabbit PrP and the human PrP have different secondary structures and why macromolecular crowding has different

  19. Heart failure and atrial fibrillation: current concepts and controversies.

    Science.gov (United States)

    Van den Berg, M. P.; Tuinenburg, A. E.; Crijns, H. J.; Van Gelder, I. C.; Gosselink, A. T.; Lie, K. I.

    1997-01-01

    Heart failure and atrial fibrillation are very common, particularly in the elderly. Owing to common risk factors both disorders are often present in the same patient. In addition, there is increasing evidence of a complex, reciprocal relation between heart failure and atrial fibrillation. Thus heart failure may cause atrial fibrillation, with electromechanical feedback and neurohumoral activation playing an important mediating role. In addition, atrial fibrillation may promote heart failure; in particular, when there is an uncontrolled ventricular rate, tachycardiomyopathy may develop and thereby heart failure. Eventually, a vicious circle between heart failure and atrial fibrillation may form, in which neurohumoral activation and subtle derangement of rate control are involved. Treatment should aim at unloading of the heart, adequate control of ventricular rate, and correction of neurohumoral activation. Angiotensin converting enzyme inhibitors may help to achieve these goals. Treatment should also include an attempt to restore sinus rhythm through electrical cardioversion, though appropriate timing of cardioversion is difficult. His bundle ablation may be used to achieve adequate rate control in drug refractory cases. PMID:9155607

  20. New fluorescent probes for detection and characterization of amyloid fibrils

    Science.gov (United States)

    Gorbenko, Galyna; Trusova, Valeriya; Kirilova, Elena; Kirilov, Georgiy; Kalnina, Inta; Vasilev, Aleksey; Kaloyanova, Stefka; Deligeorgiev, Todor

    2010-08-01

    The applicability of the novel fluorescent probes, aminoderivative of benzanthrone ABM, squaraine dye SQ-1 and polymethine dye V2 to identification and structural analysis of amyloid fibrils has been evaluated using the lysozyme model system in which fibrillar aggregates have been formed in concentrated ethanol solution. The association constant, binding stoichiometry and molar fluorescence of the bound dye have been determined. ABM was found to surpass classical amyloid marker ThT in the sensitivity to the presence of fibrillar aggregates. Resonance energy transfer measurements involving ABM-SQ-1 and SQ-1-V2 donor-acceptor pairs yielded the limits for fractal-like dimension of lysozyme fibrils.

  1. Fibril Formation from Pea Protein and Sesequent Gel Formation

    NARCIS (Netherlands)

    Munialo, C.D.; Martin, A.H.; Linden, van der E.; Jongh, de H.H.J.

    2014-01-01

    The objective of this study was to characterize fibrillar aggregates made using pea proteins, to assemble formed fibrils into protein-based gels, and to study the rheological behavior of these gels. Micrometer-long fibrillar aggregates were observed after pea protein solutions had been heated for 20

  2. Fibril Formation from Pea Protein and Subsequent Gel Formation

    NARCIS (Netherlands)

    Munialo, XC.D.; Martin, A.H.; Linden, E. van der; Jongh, H.H.J de

    2014-01-01

    The objective of this study was to characterize fibrillar aggregates made using pea proteins, to assemble formed fibrils into protein-based gels, and to study the rheological behavior of these gels. Micrometer-long fibrillar aggregates were observed after pea protein solutions had been heated for 20

  3. Effect of Mechanical Stretching of the Skin on Collagen Fibril ...

    African Journals Online (AJOL)

    Dell

    MATERIALS AND METHODS. In vitro Skin Incubation. Samples of tissue were .... experimentally obtained melting curves. Calculation of the entropy of denaturation was ... Temperature (TD), enthalpy (ΔH) and entropy (ΔS) of denaturation of fibrils formed from type I collagen synthesized in the skin in the absence of tensile ...

  4. Evalutating Inward Rectifier Current Inhibiton for Treatment of Atrial Fibrillation

    NARCIS (Netherlands)

    Ji, Yuan

    2017-01-01

    Atrial Fibrillation (AF) is one of the most common forms of cardiac arrhythmia and affects a large percentage of the human population, especially in the elderly. Currently, more than 6 million Europeans suffer from AF, and due to ageing this number will at least double in the next 50 years.

  5. Direct visualization of HIV-enhancing endogenous amyloid fibrils in human semen

    Science.gov (United States)

    Usmani, Shariq M.; Zirafi, Onofrio; Müller, Janis; Sandi-Monroy, Nathallie; Yadav, Jay K.; Meier, Christoph; Weil, Tanja; Roan, Nadia R.; Greene, Warner C.; Walther, Paul; Nilsson, K. Peter R.; Hammarström, Per; Wetzel, Ronald; Pilcher, Christopher D.; Gagsteiger, Friedrich; Fändrich, Marcus; Kirchhoff, Frank; Münch, Jan

    2014-01-01

    Naturally occurring fragments of the abundant semen proteins prostatic acid phosphatase (PAP) and semenogelins form amyloid fibrils in vitro. These fibrils boost HIV infection and may play a key role in the spread of the AIDS pandemic. However, the presence of amyloid fibrils in semen remained to be demonstrated. Here, we use state of the art confocal and electron microscopy techniques for direct imaging of amyloid fibrils in human ejaculates. We detect amyloid aggregates in all semen samples and find that they partially consist of PAP fragments, interact with HIV particles and increase viral infectivity. Our results establish semen as a body fluid that naturally contains amyloid fibrils that are exploited by HIV to promote its sexual transmission. PMID:24691351

  6. Simultaneous measurement of amyloid fibril formation by dynamic light scattering and fluorescence reveals complex aggregation kinetics.

    Directory of Open Access Journals (Sweden)

    Aaron M Streets

    Full Text Available An apparatus that combines dynamic light scattering and Thioflavin T fluorescence detection is used to simultaneously probe fibril formation in polyglutamine peptides, the aggregating subunit associated with Huntington's disease, in vitro. Huntington's disease is a neurodegenerative disorder in a class of human pathologies that includes Alzheimer's and Parkinson's disease. These pathologies are all related by the propensity of their associated protein or polypeptide to form insoluble, β-sheet rich, amyloid fibrils. Despite the wide range of amino acid sequence in the aggregation prone polypeptides associated with these diseases, the resulting amyloids display strikingly similar physical structure, an observation which suggests a physical basis for amyloid fibril formation. Thioflavin T fluorescence reports β-sheet fibril content while dynamic light scattering measures particle size distributions. The combined techniques allow elucidation of complex aggregation kinetics and are used to reveal multiple stages of amyloid fibril formation.

  7. Transmission electron microscopy of amyloid fibrils.

    Science.gov (United States)

    Gras, Sally L; Waddington, Lynne J; Goldie, Kenneth N

    2011-01-01

    Transmission Electron Microscopy of negatively stained and cryo-prepared specimens allows amyloid fibrils to be visualised at high resolution in a dried or a hydrated state, and is an essential method for characterising the morphology of fibrils and pre-fibrillar species. We outline the key steps involved in the preparation and observation of samples using negative staining and cryo-electron preservation. We also discuss methods to measure fibril characteristics, such as fibril width, from electron micrographs.

  8. Cryoballoon Ablation for Atrial Fibrillation

    Directory of Open Access Journals (Sweden)

    Jason G. Andrade, MD

    2012-03-01

    Full Text Available Focal point-by-point radiofrequency catheter ablation has shown considerable success in the treatment of paroxysmal atrial fibrillation. However, it is not without limitations. Recent clinical and preclinical studies have demonstrated that cryothermal ablation using a balloon catheter (Artic Front©, Medtronic CryoCath LP provides an effective alternative strategy to treating atrial fibrillation. The objective of this article is to review efficacy and safety data surrounding cryoballoon ablation for paroxysmal and persistent atrial fibrillation. In addition, a practical step-by-step approach to cryoballoon ablation is presented, while highlighting relevant literature regarding: 1 the rationale for adjunctive imaging, 2 selection of an appropriate cryoballoon size, 3 predictors of efficacy, 4 advanced trouble-shooting techniques, and 5 strategies to reduce procedural complications, such as phrenic nerve palsy.

  9. Personalized management of atrial fibrillation

    DEFF Research Database (Denmark)

    Kirchhof, Paulus; Breithardt, Günter; Aliot, Etienne

    2013-01-01

    The management of atrial fibrillation (AF) has seen marked changes in past years, with the introduction of new oral anticoagulants, new antiarrhythmic drugs, and the emergence of catheter ablation as a common intervention for rhythm control. Furthermore, new technologies enhance our ability......, and hospitalizations. During the fourth Atrial Fibrillation competence NETwork/European Heart Rhythm Association (AFNET/EHRA) consensus conference, we identified the following opportunities to personalize management of AF in a better manner with a view to improve outcomes by integrating atrial morphology and damage...

  10. The Effect of Milk Constituents and Crowding Agents on Amyloid Fibril Formation by κ-Casein.

    Science.gov (United States)

    Liu, Jihua; Dehle, Francis C; Liu, Yanqin; Bahraminejad, Elmira; Ecroyd, Heath; Thorn, David C; Carver, John A

    2016-02-17

    When not incorporated into the casein micelle, κ-casein, a major milk protein, rapidly forms amyloid fibrils at physiological pH and temperature. In this study, the effects of milk components (calcium, lactose, lipids, and heparan sulfate) and crowding agents on reduced and carboxymethylated (RCM) κ-casein fibril formation was investigated using far-UV circular dichroism spectroscopy, thioflavin T binding assays, and transmission electron microscopy. Longer-chain phosphatidylcholine lipids, which form the lining of milk ducts and milk fat globules, enhanced RCM κ-casein fibril formation irrespective of whether the lipids were in a monomeric or micellar state, whereas shorter-chain phospholipids and triglycerides had little effect. Heparan sulfate, a component of the milk fat globule membrane and catalyst of amyloid deposition in extracellular tissue, had little effect on the kinetics of RCM κ-casein fibril formation. Major nutritional components such as calcium and lactose also had no significant effect. Macromolecular crowding enhances protein-protein interactions, but in contrast to other fibril-forming species, the extent of RCM κ-casein fibril formation was reduced by the presence of a variety of crowding agents. These data are consistent with a mechanism of κ-casein fibril formation in which the rate-determining step is dissociation from the oligomer to give the highly amyloidogenic monomer. We conclude that the interaction of κ-casein with membrane-associated phospholipids along its secretory pathway may contribute to the development of amyloid deposits in mammary tissue. However, the formation of spherical oligomers such as casein micelles is favored over amyloid fibrils in the crowded environment of milk, within which the occurrence of amyloid fibrils is low.

  11. Atrial fibrillation and delayed gastric emptying.

    Directory of Open Access Journals (Sweden)

    Isadora C Botwinick

    Full Text Available BACKGROUND: Atrial fibrillation and delayed gastric emptying (DGE are common after pancreaticoduodenectomy. Our aim was to investigate a potential relationship between atrial fibrillation and DGE, which we defined as failure to tolerate a regular diet by the 7(th postoperative day. METHODS: We performed a retrospective chart review of 249 patients who underwent pancreaticoduodenectomy at our institution between 2000 and 2009. Data was analyzed with Fisher exact test for categorical variables and Mann-Whitney U or unpaired T-test for continuous variables. RESULTS: Approximately 5% of the 249 patients included in the analysis experienced at least one episode of postoperative atrial fibrillation. Median age of patients with atrial fibrillation was 74 years, compared with 66 years in patients without atrial fibrillation (p = 0.0005. Patients with atrial fibrillation were more likely to have a history of atrial fibrillation (p = 0.03. 92% of the patients with atrial fibrillation suffered from DGE, compared to 46% of patients without atrial fibrillation (p = 0.0007. This association held true when controlling for age. CONCLUSION: Patients with postoperative atrial fibrillation are more likely to experience delayed gastric emptying. Interventions to manage delayed gastric function might be prudent in patients at high risk for postoperative atrial fibrillation.

  12. Stroke prevention in atrial fibrillation

    DEFF Research Database (Denmark)

    Fanaroff, Alexander C; Steffel, Jan; Alexander, John H

    2018-01-01

    of anticoagulation for atrial fibrillation (AF). Observational studies employing RWD are useful for describing how oral anticoagulants are used in clinical practice, but generally cannot be used to make claims regarding comparative treatment effects. Questions regarding treatment effect generally are best answered...

  13. Risk Factors for Atrial Fibrillation

    NARCIS (Netherlands)

    B.P. Krijthe (Bouwe)

    2013-01-01

    textabstractAtrial fibrillation is a common cardiac arrhythmia that is characterized by rapid disorganized atrial electrical activity resulting in absence of atrial contractions. It is diagnosed on the basis of typical findings on an electrocardiogram (ECG). The characteristic ECG findings are

  14. Genetic basis of atrial fibrillation

    Directory of Open Access Journals (Sweden)

    Oscar Campuzano

    2016-12-01

    Full Text Available Atrial fibrillation is the most common sustained arrhythmia and remains as one of main challenges in current clinical practice. The disease may be induced secondary to other diseases such as hypertension, valvular heart disease, and heart failure, conferring an increased risk of stroke and sudden death. Epidemiological studies have provided evidence that genetic factors play an important role and up to 30% of clinically diagnosed patients may have a family history of atrial fibrillation. To date, several rare variants have been identified in a wide range of genes associated with ionic channels, calcium handling protein, fibrosis, conduction and inflammation. Important advances in clinical, genetic and molecular basis have been performed over the last decade, improving diagnosis and treatment. However, the genetics of atrial fibrillation is complex and pathophysiological data remains still unraveling. A better understanding of the genetic basis will induce accurate risk stratification and personalized clinical treatment. In this review, we have focused on current genetics basis of atrial fibrillation.

  15. Signal analysis of ventricular fibrillation

    NARCIS (Netherlands)

    Herbschleb, J.N.; Heethaar, R.M.; Tweel, L.H. van der; Zimmerman, A.N.E.; Meijler, F.L.

    Signal analysis of electro(cardio)grams during ventricular fibrillation (VF) in dogs and human patients indicates more organization and regularity than the official WHO definition suggests. The majority of the signal is characterized by a power spectrum with narrow, equidistant peaks. In a further

  16. Agent-based modeling traction force mediated compaction of cell-populated collagen gels using physically realistic fibril mechanics.

    Science.gov (United States)

    Reinhardt, James W; Gooch, Keith J

    2014-02-01

    Agent-based modeling was used to model collagen fibrils, composed of a string of nodes serially connected by links that act as Hookean springs. Bending mechanics are implemented as torsional springs that act upon each set of three serially connected nodes as a linear function of angular deflection about the central node. These fibrils were evaluated under conditions that simulated axial extension, simple three-point bending and an end-loaded cantilever. The deformation of fibrils under axial loading varied <0.001% from the analytical solution for linearly elastic fibrils. For fibrils between 100 μm and 200 μm in length experiencing small deflections, differences between simulated deflections and their analytical solutions were <1% for fibrils experiencing three-point bending and <7% for fibrils experiencing cantilever bending. When these new rules for fibril mechanics were introduced into a model that allowed for cross-linking of fibrils to form a network and the application of cell traction force, the fibrous network underwent macroscopic compaction and aligned between cells. Further, fibril density increased between cells to a greater extent than that observed macroscopically and appeared similar to matrical tracks that have been observed experimentally in cell-populated collagen gels. This behavior is consistent with observations in previous versions of the model that did not allow for the physically realistic simulation of fibril mechanics. The significance of the torsional spring constant value was then explored to determine its impact on remodeling of the simulated fibrous network. Although a stronger torsional spring constant reduced the degree of quantitative remodeling that occurred, the inclusion of torsional springs in the model was not necessary for the model to reproduce key qualitative aspects of remodeling, indicating that the presence of Hookean springs is essential for this behavior. These results suggest that traction force mediated matrix

  17. Evidence for novel beta-sheet structures in Iowa mutant beta-amyloid fibrils.

    Science.gov (United States)

    Tycko, Robert; Sciarretta, Kimberly L; Orgel, Joseph P R O; Meredith, Stephen C

    2009-07-07

    Asp23-to-Asn mutation within the coding sequence of beta-amyloid, called the Iowa mutation, is associated with early onset, familial Alzheimer's disease and cerebral amyloid angiopathy, in which patients develop neuritic plaques and massive vascular deposition predominantly of the mutant peptide. We examined the mutant peptide, D23N-Abeta40, by electron microscopy, X-ray diffraction, and solid-state NMR spectroscopy. D23N-Abeta40 forms fibrils considerably faster than the wild-type peptide (k = 3.77 x 10(-3) min(-1) and 1.07 x 10(-4) min(-1) for D23N-Abeta40 and the wild-type peptide WT-Abeta40, respectively) and without a lag phase. Electron microscopy shows that D23N-Abeta40 forms fibrils with multiple morphologies. X-ray fiber diffraction shows a cross-beta pattern, with a sharp reflection at 4.7 A and a broad reflection at 9.4 A, which is notably smaller than the value for WT-Abeta40 fibrils (10.4 A). Solid-state NMR measurements indicate molecular level polymorphism of the fibrils, with only a minority of D23N-Abeta40 fibrils containing the in-register, parallel beta-sheet structure commonly found in WT-Abeta40 fibrils and most other amyloid fibrils. Antiparallel beta-sheet structures in the majority of fibrils are indicated by measurements of intermolecular distances through (13)C-(13)C and (15)N-(13)C dipole-dipole couplings. An intriguing possibility exists that there is a relationship between the aberrant structure of D23N-Abeta40 fibrils and the unusual vasculotropic clinical picture in these patients.

  18. End-to-end Structural Restriction of α-Synuclein and Its Influence on Amyloid Fibril Formation

    International Nuclear Information System (INIS)

    Hong, Chul Suk; Park, Jae Hyung; Choe, Young Jun; Paik, Seung R.

    2014-01-01

    Relationship between molecular freedom of amyloidogenic protein and its self-assembly into amyloid fibrils has been evaluated with α-synuclein, an intrinsically unfolded protein related to Parkinson's disease, by restricting its structural plasticity through an end-to-end disulfide bond formation between two newly introduced cysteine residues on the N- and C-termini. Although the resulting circular form of α-synuclein exhibited an impaired fibrillation propensity, the restriction did not completely block the protein's interactive core since co-incubation with wild-type α-synuclein dramatically facilitated the fibrillation by producing distinctive forms of amyloid fibrils. The suppressed fibrillation propensity was instantly restored as the structural restriction was unleashed with β-mercaptoethanol. Conformational flexibility of the accreting amyloidogenic protein to pre-existing seeds has been demonstrated to be critical for fibrillar extension process by exerting structural adjustment to a complementary structure for the assembly

  19. End-to-end Structural Restriction of α-Synuclein and Its Influence on Amyloid Fibril Formation

    Energy Technology Data Exchange (ETDEWEB)

    Hong, Chul Suk; Park, Jae Hyung; Choe, Young Jun; Paik, Seung R. [Seoul National University, Seoul (Korea, Republic of)

    2014-09-15

    Relationship between molecular freedom of amyloidogenic protein and its self-assembly into amyloid fibrils has been evaluated with α-synuclein, an intrinsically unfolded protein related to Parkinson's disease, by restricting its structural plasticity through an end-to-end disulfide bond formation between two newly introduced cysteine residues on the N- and C-termini. Although the resulting circular form of α-synuclein exhibited an impaired fibrillation propensity, the restriction did not completely block the protein's interactive core since co-incubation with wild-type α-synuclein dramatically facilitated the fibrillation by producing distinctive forms of amyloid fibrils. The suppressed fibrillation propensity was instantly restored as the structural restriction was unleashed with β-mercaptoethanol. Conformational flexibility of the accreting amyloidogenic protein to pre-existing seeds has been demonstrated to be critical for fibrillar extension process by exerting structural adjustment to a complementary structure for the assembly.

  20. Benzofuranone derivatives as effective small molecules related to insulin amyloid fibrillation: a structure-function study

    DEFF Research Database (Denmark)

    Rabiee, Atefeh; Ebrahim-Habibi, Azadeh; Navidpour, Latifeh

    2011-01-01

    amyloid fibrils under slightly destabilizing conditions in vitro and may form amyloid structures when subcutaneously injected into patients with diabetes. There is a great deal of interest in developing novel small molecule inhibitors of amyloidogenic processes, as potential therapeutic compounds...... of the five tested compounds was observed to enhance amyloid fibrillation, while the others inhibited the process when used at micromolar concentrations, which could make them interesting potential lead compounds for the design of therapeutic antiamyloidogenic compounds....

  1. In vitro fibrillization of Alzheimer’s amyloid-β peptide (1-42)

    Energy Technology Data Exchange (ETDEWEB)

    Tiiman, Ann [Department of Gene Technology, Tallinn University of Technology, Tallinn 12618 (Estonia); Department of Biochemistry and Biophysics, Arrhenius Laboratories, Stockholm University, Stockholm, 106 91 (Sweden); Krishtal, Jekaterina; Palumaa, Peep; Tõugu, Vello, E-mail: vello.tougu@ttu.ee [Department of Gene Technology, Tallinn University of Technology, Tallinn 12618 (Estonia)

    2015-09-15

    The amyloid deposition in the form of extracellular fibrillar aggregates of amyloid-β (Aβ) peptide is a critical pathological event in Alzheimer’s disease. Here, we report a systematic investigation of the effects of environmental factors on the kinetics of Aβ fibrillization in vitro. The effects of Aβ42 peptide concentration, temperature, pH, added solvents and the ratio of Aβ40 and Aβ42 on the peptide fibrillization under agitated conditions was studied. The analysis show that the rate of fibril growth by monomer addition is not limited by diffusion but by rearrangement in the monomer structure, which is enhanced by low concentrations of fluorinated alcohols and characterized by the activation energy of 12 kcal/mol. Fibrillization rate decreases at pH values below 7.0 where simultaneous protonation of His 13 and 14 inhibits fibril formation. The lag period for Aβ42 was only twofold shorter and the fibril growth rate twofold faster than those of Aβ40. Lag period was shortened and the fibrillization rate was increased only at 90% content of Aβ42.

  2. Amyloid fibril systems reduce, stabilize and deliver bioavailable nanosized iron

    Science.gov (United States)

    Shen, Yi; Posavec, Lidija; Bolisetty, Sreenath; Hilty, Florentine M.; Nyström, Gustav; Kohlbrecher, Joachim; Hilbe, Monika; Rossi, Antonella; Baumgartner, Jeannine; Zimmermann, Michael B.; Mezzenga, Raffaele

    2017-07-01

    Iron-deficiency anaemia (IDA) is a major global public health problem. A sustainable and cost-effective strategy to reduce IDA is iron fortification of foods, but the most bioavailable fortificants cause adverse organoleptic changes in foods. Iron nanoparticles are a promising solution in food matrices, although their tendency to oxidize and rapidly aggregate in solution severely limits their use in fortification. Amyloid fibrils are protein aggregates initially known for their association with neurodegenerative disorders, but recently described in the context of biological functions in living organisms and emerging as unique biomaterial building blocks. Here, we show an original application for these protein fibrils as efficient carriers for iron fortification. We use biodegradable amyloid fibrils from β-lactoglobulin, an inexpensive milk protein with natural reducing effects, as anti-oxidizing nanocarriers and colloidal stabilizers for iron nanoparticles. The resulting hybrid material forms a stable protein-iron colloidal dispersion that undergoes rapid dissolution and releases iron ions during acidic and enzymatic in vitro digestion. Importantly, this hybrid shows high in vivo iron bioavailability, equivalent to ferrous sulfate in haemoglobin-repletion and stable-isotope studies in rats, but with reduced organoleptic changes in foods. Feeding the rats with these hybrid materials did not result in abnormal iron accumulation in any organs, or changes in whole blood glutathione concentrations, inferring their primary safety. Therefore, these iron-amyloid fibril hybrids emerge as novel, highly effective delivery systems for iron in both solid and liquid matrices.

  3. Risk of atrial fibrillation in diabetes mellitus

    DEFF Research Database (Denmark)

    Pallisgaard, Jannik L; Schjerning, Anne-Marie; Lindhardt, Tommi B

    2016-01-01

    AIM: Diabetes has been associated with atrial fibrillation but the current evidence is conflicting. In particular knowledge regarding young diabetes patients and the risk of developing atrial fibrillation is sparse. The aim of our study was to investigate the risk of atrial fibrillation in patients...... with diabetes compared to the background population in Denmark. METHODS AND RESULTS: Through Danish nationwide registries we included persons above 18 years of age and without prior atrial fibrillation and/or diabetes from 1996 to 2012. The study cohort was divided into a background population without diabetes...... and a diabetes group. The absolute risk of developing atrial fibrillation was calculated and Poisson regression models adjusted for sex, age and comorbidities were used to calculate incidence rate ratios of atrial fibrillation. The total study cohort included 5,081,087 persons, 4,827,713 (95%) in the background...

  4. [Panic disorder and atrial fibrillation].

    Science.gov (United States)

    Olazabal Eizaguirre, N; Chavez, R; González-Torres, M A; Gaviria, M

    2013-10-01

    This paper studies the relationship between atrial fibrillation and panic disorder. There are often doubts on the differential diagnosis in emergency services and general medical settings. Panic disorder prevalence rates have been found to be high in patients suffering from atrial fibrillation. Various studies have observed that patients diagnosed with anxiety disorders frequently have higher cardiovascular disease rates compared to the general population. Usually, patients suffering from panic disorder exhibit somatic complaints suggesting coronary disease, such as chest pain or palpitations. The aim is to make the correct diagnosis and treatment for these different illnesses, and to decrease the costs due to misdiagnosis. Copyright © 2012 Sociedad Española de Médicos de Atención Primaria (SEMERGEN). Publicado por Elsevier España. All rights reserved.

  5. Alginate-Collagen Fibril Composite Hydrogel

    Directory of Open Access Journals (Sweden)

    Mahmoud Baniasadi

    2015-02-01

    Full Text Available We report on the synthesis and the mechanical characterization of an alginate-collagen fibril composite hydrogel. Native type I collagen fibrils were used to synthesize the fibrous composite hydrogel. We characterized the mechanical properties of the fabricated fibrous hydrogel using tensile testing; rheometry and atomic force microscope (AFM-based nanoindentation experiments. The results show that addition of type I collagen fibrils improves the rheological and indentation properties of the hydrogel.

  6. Characterization of fibrillation process of α-synuclein at the initial stage

    International Nuclear Information System (INIS)

    Tashiro, Mitsuru; Kojima, Masaki; Kihara, Hiroshi; Kasai, Kouki; Kamiyoshihara, Tomoaki; Ueda, Kenji; Shimotakahara, Sakurako

    2008-01-01

    α-Synuclein is the major component of the filamentous Lewy bodies and Lewy-related neurites, neuropathological hallmarks of Parkinson's disease. Although numerous studies on α-synuclein fibrillation have been reported, the molecular mechanisms of aggregation and fibrillation at the initial stage are still unclear. In the present study, structural properties and propensities to form fibrils of α-synuclein at the initial stage were investigated using 2D 1 H- 15 N NMR spectroscopy, electron microscope, and small angle X-ray scattering (SAXS). Observation of the 2D 1 H- 15 N HSQC spectra indicated significant attenuation of many cross peak intensities in the regions of KTKEGV-type repeats and the non-Aβ component of Alzheimer's disease amyloid (NAC), suggesting that these regions contributed fibril formation. Oligomerization comprising heptamer was successfully monitored at the initial stage using the time-dependent SAXS measurements

  7. AFM-based force spectroscopy measurements of mature amyloid fibrils of the peptide glucagon

    DEFF Research Database (Denmark)

    Dong, M. D.; Hovgaard, M. B.; Mamdouh, W.

    2008-01-01

    We report on the mechanical characterization of individual mature amyloid fibrils by atomic force microscopy (AFM) and AFM-based single-molecule force spectroscopy (SMFS). These self-assembling materials, formed from the 29-residue amphiphatic peptide hormone glucagon, were found to display...... a reversible elastic behaviour. Based on AFM morphology and SMFS studies, we suggest that the observed elasticity is due to a force-induced conformational transition which is reversible due to the beta-helical conformation of protofibrils, allowing a high degree of extension. The elastic properties...... of such mature fibrils contribute to their high stability, suggesting that the internal hydrophobic interactions of amyloid fibrils are likely to be of fundamental importance in the assembly of amyloid fibrils and therefore for the understanding of the progression of their associated pathogenic disorders...

  8. The role of protonation in protein fibrillation

    DEFF Research Database (Denmark)

    Jeppesen, Martin D; Westh, Peter; Otzen, Daniel E

    2010-01-01

    Many proteins fibrillate at low pH despite a high population of charged side chains. Therefore exchange of protons between the fibrillating peptide and its surroundings may play an important role in fibrillation. Here, we use isothermal titration calorimetry to measure exchange of protons between...... buffer and the peptide hormone glucagon during fibrillation. Glucagon absorbs or releases protons to an extent which allows it to attain a net charge of zero in the fibrillar state, both at acidic and basic pH. Similar results are obtained for lysozyme. This suggests that side chain pKa values change...

  9. Nucleation and growth of elastin-like peptide fibril multilayers: an in situ atomic force microscopy study

    International Nuclear Information System (INIS)

    Yang Guocheng; Yip, Christopher M; Wong, Michael K; Lin, Lauren E

    2011-01-01

    Controlling how molecules assemble into complex supramolecular architectures requires careful consideration of the subtle inter- and intra-molecular interactions that control their association. This is particularly crucial in the context of assembly at interfaces, where both surface chemistry and structure can play a role in directing structure formation. We report here the results of a study into the self-assembly of the elastin-like peptide EP I on structurally modified highly ordered pyrolytic graphite, including the role of spatial confinement on fibril nucleation and the growth of oriented fibril multilayers. In situ atomic force microscopy performed in fluid and at elevated temperature provided direct evidence of frustrated fibril nuclei and oriented growth of independent fibril domains. These results portend the application of this in situ strategy for studies of the nucleation and growth mechanisms of other fibril- and amyloid-forming proteins.

  10. Stop-and-go kinetics in amyloid fibrillation

    DEFF Research Database (Denmark)

    Ferkinghoff-Borg, Jesper; Fonslet, Jesper; Andersen, Christian Beyschau

    2010-01-01

    Many human diseases are associated with protein aggregation and fibrillation. We present experiments on in vitro glucagon fibrillation using total internal reflection fluorescence microscopy, providing real-time measurements of single-fibril growth. We find that amyloid fibrils grow in an intermi......Many human diseases are associated with protein aggregation and fibrillation. We present experiments on in vitro glucagon fibrillation using total internal reflection fluorescence microscopy, providing real-time measurements of single-fibril growth. We find that amyloid fibrils grow...

  11. Amyloid fibril formation in vitro from halophilic metal binding protein: Its high solubility and reversibility minimized formation of amorphous protein aggregations

    Science.gov (United States)

    Tokunaga, Yuhei; Matsumoto, Mitsuharu; Tokunaga, Masao; Arakawa, Tsutomu; Sugimoto, Yasushi

    2013-01-01

    Halophilic proteins are characterized by high net negative charges and relatively small fraction of hydrophobic amino acids, rendering them aggregation resistant. These properties are also shared by histidine-rich metal binding protein (HP) from moderate halophile, Chromohalobacter salexigens, used in this study. Here, we examined how halophilic proteins form amyloid fibrils in vitro. His-tagged HP, incubated at pH 2.0 and 58°C, readily formed amyloid fibrils, as observed by thioflavin fluorescence, CD spectra, and transmission or atomic force microscopies. Under these low-pH harsh conditions, however, His-HP was promptly hydrolyzed to smaller peptides most likely responsible for rapid formation of amyloid fibril. Three major acid-hydrolyzed peptides were isolated from fibrils and turned out to readily form fibrils. The synthetic peptides predicted to form fibrils in these peptide sequences by Waltz software also formed fibrils. Amyloid fibril was also readily formed from full-length His-HP when incubated with 10–20% 2,2,2-trifluoroethanol at pH 7.8 and 25°C without peptide bond cleavage. PMID:24038709

  12. Longitudinal study of experimental induction of AA amyloidosis in mice seeded with homologous and heterologous AA fibrils.

    Science.gov (United States)

    Muhammad, Naeem; Murakami, Tomoaki; Inoshima, Yasuo; Ishiguro, Naotaka

    2016-09-01

    To investigate pathogenesis and kinetics of experimentally induced murine AA amyloidosis seeded with homologous (murine) and heterologous (bovine) AA fibrils. Experimental AA amyloidosis was induced by administration of inflammatory stimulus and preformed AA fibrils to a total of 111 female C57/Black mice. In this longitudinal study, heterologous (bovine) as well as homologous (murine) AA fibrils were injected intraperitoneally to mice in various combinations. Re-stimulation was done at 120 or 300 days post first inoculation. To analyze the intensity of amyloid depositions in mice organs, immunohistochemical techniques and image J software were used. Assessment of cytokines level in sera was done using a Mouse Th1/Th2/Th17 Cytokine CBA Kit. Incidence and severity of AA amyloidosis were quite low in mice inoculated with heterologous bovine AA fibrils than homologous murine one. Homologous AA fibrils administration at first and second inoculation caused maximum amount of amyloid depositions and severe systemic form of amyloidosis. Increase in the level of pro-inflammatory cytokine IL-6 was observed after first inoculation, while second inoculation caused a further increase in the level of anti-inflammatory cytokine IL-10. AA amyloidosis can be induced by heterologous as well as homologous AA fibrils. Severity of AA amyloidosis induced with homologous AA fibrils is higher compared to heterologous AA fibrils.

  13. Structural fingerprints and their evolution during oligomeric vs. oligomer-free amyloid fibril growth.

    Science.gov (United States)

    Foley, Joseph; Hill, Shannon E; Miti, Tatiana; Mulaj, Mentor; Ciesla, Marissa; Robeel, Rhonda; Persichilli, Christopher; Raynes, Rachel; Westerheide, Sandy; Muschol, Martin

    2013-09-28

    Deposits of fibrils formed by disease-specific proteins are the molecular hallmark of such diverse human disorders as Alzheimer's disease, type II diabetes, or rheumatoid arthritis. Amyloid fibril formation by structurally and functionally unrelated proteins exhibits many generic characteristics, most prominently the cross β-sheet structure of their mature fibrils. At the same time, amyloid formation tends to proceed along one of two separate assembly pathways yielding either stiff monomeric filaments or globular oligomers and curvilinear protofibrils. Given the focus on oligomers as major toxic species, the very existence of an oligomer-free assembly pathway is significant. Little is known, though, about the structure of the various intermediates emerging along different pathways and whether the pathways converge towards a common or distinct fibril structures. Using infrared spectroscopy we probed the structural evolution of intermediates and late-stage fibrils formed during in vitro lysozyme amyloid assembly along an oligomeric and oligomer-free pathway. Infrared spectroscopy confirmed that both pathways produced amyloid-specific β-sheet peaks, but at pathway-specific wavenumbers. We further found that the amyloid-specific dye thioflavin T responded to all intermediates along either pathway. The relative amplitudes of thioflavin T fluorescence responses displayed pathway-specific differences and could be utilized for monitoring the structural evolution of intermediates. Pathway-specific structural features obtained from infrared spectroscopy and Thioflavin T responses were identical for fibrils grown at highly acidic or at physiological pH values and showed no discernible effects of protein hydrolysis. Our results suggest that late-stage fibrils formed along either pathway are amyloidogenic in nature, but have distinguishable structural fingerprints. These pathway-specific fingerprints emerge during the earliest aggregation events and persist throughout the

  14. Structural fingerprints and their evolution during oligomeric vs. oligomer-free amyloid fibril growth

    Science.gov (United States)

    Foley, Joseph; Hill, Shannon E.; Miti, Tatiana; Mulaj, Mentor; Ciesla, Marissa; Robeel, Rhonda; Persichilli, Christopher; Raynes, Rachel; Westerheide, Sandy; Muschol, Martin

    2013-09-01

    Deposits of fibrils formed by disease-specific proteins are the molecular hallmark of such diverse human disorders as Alzheimer's disease, type II diabetes, or rheumatoid arthritis. Amyloid fibril formation by structurally and functionally unrelated proteins exhibits many generic characteristics, most prominently the cross β-sheet structure of their mature fibrils. At the same time, amyloid formation tends to proceed along one of two separate assembly pathways yielding either stiff monomeric filaments or globular oligomers and curvilinear protofibrils. Given the focus on oligomers as major toxic species, the very existence of an oligomer-free assembly pathway is significant. Little is known, though, about the structure of the various intermediates emerging along different pathways and whether the pathways converge towards a common or distinct fibril structures. Using infrared spectroscopy we probed the structural evolution of intermediates and late-stage fibrils formed during in vitro lysozyme amyloid assembly along an oligomeric and oligomer-free pathway. Infrared spectroscopy confirmed that both pathways produced amyloid-specific β-sheet peaks, but at pathway-specific wavenumbers. We further found that the amyloid-specific dye thioflavin T responded to all intermediates along either pathway. The relative amplitudes of thioflavin T fluorescence responses displayed pathway-specific differences and could be utilized for monitoring the structural evolution of intermediates. Pathway-specific structural features obtained from infrared spectroscopy and Thioflavin T responses were identical for fibrils grown at highly acidic or at physiological pH values and showed no discernible effects of protein hydrolysis. Our results suggest that late-stage fibrils formed along either pathway are amyloidogenic in nature, but have distinguishable structural fingerprints. These pathway-specific fingerprints emerge during the earliest aggregation events and persist throughout the

  15. Systematic examination of polymorphism in amyloid fibrils by molecular-dynamics simulation.

    Science.gov (United States)

    Berryman, Joshua T; Radford, Sheena E; Harris, Sarah A

    2011-05-04

    Amyloid fibrils often exhibit polymorphism. Polymorphs are formed when proteins or peptides with identical sequences self-assemble into fibrils containing substantially different arrangements of the β-strands. We used atomistic molecular-dynamics simulation to examine the thermodynamic stability of a amyloid fibrils in different polymorphic forms by performing a systematic investigation of sequence and symmetry space for a series of peptides with a range of physicochemical properties. We show that the stability of fibrils depends on both sequence and the symmetry because these factors determine the availability of favorable interactions between the peptide strands within a sheet and in intersheet packing. By performing a detailed analysis of these interactions as a function of symmetry, we obtained a series of simple design rules that can be used to determine which polymorphs of a given sequence are most likely to form thermodynamically stable fibrils. These rules can potentially be employed to design peptide sequences that aggregate into a preferred polymorphic form for nanotechnological purposes. Copyright © 2011 Biophysical Society. Published by Elsevier Inc. All rights reserved.

  16. Aspects epidemiologiques et etiologiques de la fibrillation ...

    African Journals Online (AJOL)

    Conclusion : La fibrillation auriculaire est fréquente chez l'adulte noir togolais. Ses étiologies sont dominées par l'hypertension artérielle et les cardiomyopathies dilatées. complications and stoke. Aim: Our aim was to study epidemiologic and etiologic aspects of atrial fibrillation in black togolese in hospital circle. Material ...

  17. Viscoelastic behavior of discrete human collagen fibrils

    DEFF Research Database (Denmark)

    Svensson, Rene; Hassenkam, Tue; P, Hansen

    2010-01-01

    Whole tendon and fibril bundles display viscoelastic behavior, but to the best of our knowledge this property has not been directly measured in single human tendon fibrils. In the present work an atomic force microscopy (AFM) approach was used for tensile testing of two human patellar tendon fibr...

  18. Fibril assembly in whey protein mixtures

    NARCIS (Netherlands)

    Bolder, S.G.

    2007-01-01

    The objective of this thesis was to study fibril assembly in mixtures of whey proteins. The effect of the composition of the protein mixture on the structures and the resulting phase behaviour was investigated. The current work has shown that beta-lactoglobulin is responsible for the fibril assembly

  19. Disintegration of collagen fibrils by Glucono-δ-lactone: An implied lead for disintegration of fibrosis.

    Science.gov (United States)

    Jayamani, Jayaraman; Ravikanth Reddy, R; Madhan, Balaraman; Shanmugam, Ganesh

    2018-02-01

    Excess accumulation of collagen (fibrosis) undergoes self-aggregation, which leads to fibrillar collagen, on the extracellular matrix is the hallmark of a number of diseases such as keloids, hypertrophic scars, and systemic scleroderma. Direct inhibition or disintegration of collagen fibrils by small molecules offer a therapeutic approach to prevent or treat the diseases related to fibrosis. Herein, the anti-fibrotic property of Glucono-δ-lactone (GdL), known as acidifier, on the fibrillation and its disintegration of collagen was investigated. As collagen fibrillation is pH dependent, the pH modulation property of GdL is attractive to inhibit self-association of collagen. Optical density and microscopic data indicate that GdL elicits concentration-dependent fibril inhibition and also disintegrates pre-formed collagen fibrils. The simultaneous pH analysis showed that the modulation(lowering) of pH by GdL is the primary cause for its anti-fibrotic activity. The intact triple helical structure of collagen upon treatment of GdL suggests that collagen fibril disintegration can be achieved without affecting the native structure of collagen which is essential for any anti-fibrotic agents. Saturation transfer difference (STD) NMR result reveals that GdL is in proximity to collagen. The present results thus suggest that GdL provides a lead to design novel anti-fibrotic agents for the pathologies related to collagen deposition. Copyright © 2017 Elsevier B.V. All rights reserved.

  20. Collagen fibril architecture, domain organization, and triple-helical conformation govern its proteolysis.

    Science.gov (United States)

    Perumal, Shiamalee; Antipova, Olga; Orgel, Joseph P R O

    2008-02-26

    We describe the molecular structure of the collagen fibril and how it affects collagen proteolysis or "collagenolysis." The fibril-forming collagens are major components of all mammalian connective tissues, providing the structural and organizational framework for skin, blood vessels, bone, tendon, and other tissues. The triple helix of the collagen molecule is resistant to most proteinases, and the matrix metalloproteinases that do proteolyze collagen are affected by the architecture of collagen fibrils, which are notably more resistant to collagenolysis than lone collagen monomers. Until now, there has been no molecular explanation for this. Full or limited proteolysis of the collagen fibril is known to be a key process in normal growth, development, repair, and cell differentiation, and in cancerous tumor progression and heart disease. Peptide fragments generated by collagenolysis, and the conformation of exposed sites on the fibril as a result of limited proteolysis, regulate these processes and that of cellular attachment, but it is not known how or why. Using computational and molecular visualization methods, we found that the arrangement of collagen monomers in the fibril (its architecture) protects areas vulnerable to collagenolysis and strictly governs the process. This in turn affects the accessibility of a cell interaction site located near the cleavage region. Our observations suggest that the C-terminal telopeptide must be proteolyzed before collagenase can gain access to the cleavage site. Collagenase then binds to the substrate's "interaction domain," which facilitates the triple-helix unwinding/dissociation function of the enzyme before collagenolysis.

  1. Cetirizine-Induced atrial fibrillation

    Directory of Open Access Journals (Sweden)

    Altuğ Osken

    2016-01-01

    Full Text Available Atrial fibrillation (AF is the most common observed arrhythmia in clinical practice. In the literature, AF events associated with drug induction are available. Cetirizine is a second-generation histamine antagonist used in the treatment of allergies, angioedema, and urticaria. We wish to present an atypical case who took cetirizine medication for relieving symptoms of upper tract respiratory system infection, experienced rapid ventricular response AF and treated successfully. To best of our knowledge, this is the first case of cetirizine-induced AF.

  2. Epigallocatechin-3-gallate rapidly remodels PAP85-120, SEM1(45-107, and SEM2(49-107 seminal amyloid fibrils

    Directory of Open Access Journals (Sweden)

    Laura M. Castellano

    2015-09-01

    Full Text Available Semen harbors amyloid fibrils formed by proteolytic fragments of prostatic acid phosphatase (PAP248-286 and PAP85-120 and semenogelins (SEM1 and SEM2 that potently enhance HIV infectivity. Amyloid but not soluble forms of these peptides enhance HIV infection. Thus, agents that remodel these amyloid fibrils could prevent HIV transmission. Here, we confirm that the green tea polyphenol, epigallocatechin-3-gallate (EGCG, slowly remodels fibrils formed by PAP248-286 termed SEVI (semen derived enhancer of viral infection and also exerts a direct anti-viral effect. We elucidate for the first time that EGCG remodels PAP85-120, SEM1(45-107, and SEM2(49-107 fibrils more rapidly than SEVI fibrils. We establish EGCG as the first small molecule that can remodel all four classes of seminal amyloid. The combined anti-amyloid and anti-viral properties of EGCG could have utility in preventing HIV transmission.

  3. Spectroscopic study of Alzheimer's amyloid fibrils using terahertz time domain spectroscopy

    Energy Technology Data Exchange (ETDEWEB)

    Jung, Euna; Kim, Jeonghoi; Han, Younho; Moon, Kiwon; Lim, Meehyun; Han, Haewook; Park, Joonhyuck; Kim, Sungjee [POSTECH, Pohang (Korea, Republic of)

    2008-11-15

    Alzheimer's disease, one of the most common neurodegenerative diseases, is characterized by extensive amyloid deposition. Amyloid deposits contain the abundant fibrils formed by amyloid β protein (Aβ). Because amyloid fibrils are associated with amyloid diseases, including Alzheimer's disease, type 2 diabetes, prion disease, Parkinson's disease, senile systemic amyloidosis and Huntington's disease, there has been considerable interest within the biomedical and biochemical research communities. In transmission electron microscopic (TEM)images, amyloid firils are 0.1∼10μm long and approximately 10nm wide. Amyloid fibrils commonly exhibit self assembled filaments, often described as twisted or parallel assemblies of finer protofilaments. They are formed by the spontaneous aggregation of a wide variety of peptides and proteins. Structural studies of amyloid fibrils have revealed that the common structural motif of virtually all amyloid fibrils consists of cross β sheets in which the peptide strands are arranged perpendicular to the long axis of the fiber. But little was known until recently about the molecular level structures of amyloid fibils. Therefore, spectroscopic investigation of both amyloid fibrils and Aβ at the molecular level can provide the significant evidence for the molecular understanding of amyloidogenesis and for the development of innovative therapeutic and diagnostic approaches. We used terahertz time domain spectroscopy (THz TDS)to investigate both Aβ and amyloid fibril. THz TDS, developed over the last two decades, is a powerful tool to extract the properties of biomaterials and provides unique spectral signatures of biomolecules within 0.1∼10THz, which exists between microwave and infrared frequency range. Current interest in THz radiation arises from its capability of probing the delocalized collective vibrational modes in proteins. Studying the collective modes of proteins in THz frequency range can play an

  4. Spectroscopic study of Alzheimer's amyloid fibrils using terahertz time domain spectroscopy

    International Nuclear Information System (INIS)

    Jung, Euna; Kim, Jeonghoi; Han, Younho; Moon, Kiwon; Lim, Meehyun; Han, Haewook; Park, Joonhyuck; Kim, Sungjee

    2008-01-01

    Alzheimer's disease, one of the most common neurodegenerative diseases, is characterized by extensive amyloid deposition. Amyloid deposits contain the abundant fibrils formed by amyloid β protein (Aβ). Because amyloid fibrils are associated with amyloid diseases, including Alzheimer's disease, type 2 diabetes, prion disease, Parkinson's disease, senile systemic amyloidosis and Huntington's disease, there has been considerable interest within the biomedical and biochemical research communities. In transmission electron microscopic (TEM)images, amyloid firils are 0.1∼10μm long and approximately 10nm wide. Amyloid fibrils commonly exhibit self assembled filaments, often described as twisted or parallel assemblies of finer protofilaments. They are formed by the spontaneous aggregation of a wide variety of peptides and proteins. Structural studies of amyloid fibrils have revealed that the common structural motif of virtually all amyloid fibrils consists of cross β sheets in which the peptide strands are arranged perpendicular to the long axis of the fiber. But little was known until recently about the molecular level structures of amyloid fibils. Therefore, spectroscopic investigation of both amyloid fibrils and Aβ at the molecular level can provide the significant evidence for the molecular understanding of amyloidogenesis and for the development of innovative therapeutic and diagnostic approaches. We used terahertz time domain spectroscopy (THz TDS)to investigate both Aβ and amyloid fibril. THz TDS, developed over the last two decades, is a powerful tool to extract the properties of biomaterials and provides unique spectral signatures of biomolecules within 0.1∼10THz, which exists between microwave and infrared frequency range. Current interest in THz radiation arises from its capability of probing the delocalized collective vibrational modes in proteins. Studying the collective modes of proteins in THz frequency range can play an important role in

  5. Atrial fibrillation and survival in colorectal cancer

    Directory of Open Access Journals (Sweden)

    Justin Timothy A

    2004-11-01

    Full Text Available Abstract Background Survival in colorectal cancer may correlate with the degree of systemic inflammatory response to the tumour. Atrial fibrillation may be regarded as an inflammatory complication. We aimed to determine if atrial fibrillation is a prognostic factor in colorectal cancer. Patients and methods A prospective colorectal cancer patient database was cross-referenced with the hospital clinical-coding database to identify patients who had underwent colorectal cancer surgery and were in atrial fibrillation pre- or postoperatively. Results A total of 175 patients underwent surgery for colorectal cancer over a two-year period. Of these, 13 patients had atrial fibrillation pre- or postoperatively. Atrial fibrillation correlated with worse two-year survival (p = 0.04; log-rank test. However, in a Cox regression analysis, atrial fibrillation was not significantly associated with survival. Conclusion The presence or development of atrial fibrillation in patients undergoing surgery for colorectal cancer is associated with worse overall survival, however it was not found to be an independent factor in multivariate analysis.

  6. The Nucleation of Protein Aggregates - From Crystals to Amyloid Fibrils.

    Science.gov (United States)

    Buell, Alexander K

    2017-01-01

    The condensation and aggregation of individual protein molecules into dense insoluble phases is of relevance in such diverse fields as materials science, medicine, structural biology and pharmacology. A common feature of these condensation phenomena is that they usually are nucleated processes, i.e. the first piece of the condensed phase is energetically costly to create and hence forms slowly compared to its subsequent growth. Here we give a compact overview of the differences and similarities of various protein nucleation phenomena, their theoretical description in the framework of colloid and polymer science and their experimental study. Particular emphasis is put on the nucleation of a specific type of filamentous protein aggregates, amyloid fibrils. The current experimentally derived knowledge on amyloid fibril nucleation is critically assessed, and we argue that it is less advanced than is generally believed. This is due to (I) the lack of emphasis that has been put on the distinction between homogeneous and heterogeneous nucleation in experimental studies (II) the use of oversimplifying and/or inappropriate theoretical frameworks for the analysis of kinetic data of amyloid fibril nucleation. A strategy is outlined and advocated of how our understanding of this important class of processes can be improved in the future. © 2017 Elsevier Inc. All rights reserved.

  7. Potent inhibition of tau fibrillization with a multivalent ligand

    International Nuclear Information System (INIS)

    Honson, Nicolette S.; Jensen, Jordan R.; Darby, Michael V.; Kuret, Jeff

    2007-01-01

    Small-molecule inhibitors of tau fibrillization are under investigation as tools for interrogating the tau aggregation pathway and as potential therapeutic agents for Alzheimer's disease. Established inhibitors include thiacarbocyanine dyes, which can inhibit recombinant tau fibrillization in the presence of anionic surfactant aggregation inducers. In an effort to increase inhibitory potency, a cyclic bis-thiacarbocyanine molecule containing two thiacarbocyanine moieties was synthesized and characterized with respect to tau fibrillization inhibitory activity by electron microscopy and ligand aggregation state by absorbance spectroscopy. Results showed that the inhibitory activity of the bis-thiacarbocyanine was qualitatively similar to a monomeric cyanine dye, but was more potent with 50% inhibition achieved at ∼80 nM concentration. At all concentrations tested in aqueous solution, the bis-thiacarbocyanine collapsed to form a closed clamshell structure. However, the presence of tau protein selectively stabilized the open conformation. These results suggest that the inhibitory activity of bis-thiacarbocyanine results from multivalency, and reveal a route to more potent tau aggregation inhibitors

  8. The effect of mutations on the structure of insulin fibrils studied by Fourier transform infrared (FTIR) spectroscopy and electron microscopy.

    Science.gov (United States)

    Garriques, Liza Nielsen; Frokjaer, Sven; Carpenter, John F; Brange, Jens

    2002-12-01

    Fibril formation (aggregation) of human and bovine insulin and six human insulin mutants in hydrochloric acid were investigated by visual inspection, Thioflavin T fluorescence spectroscopy, transmission electron microscopy (TEM), and Fourier transform infrared (FTIR) spectroscopy. The fibrillation tendencies of the wild-type insulins and the insulin mutants were (in order of decreasing fibrillation tendencies): Glu(B1) + Glu(B27) = bovine < human < des-(B1,B2)-insulin < Ser(B2) + Asp(B10) < Glu(A13) + Glu(B10) = Gln(B17) < Asp(B10). Transmission electron micrographs showed that the protofibrils of the mutants were similar to those of wild-type insulins and had a diameter of 5-10 nm and lengths varying from 50 nm to several microns. The fibrils of human insulin mutants exhibited varying degrees of lateral aggregation. The Asp(B10) mutant and human insulin had greater tendency to form laterally aggregated fibrils arranged in parallel bundles, whereas fibrils of the other mutants and bovine insulin were mainly arranged in helical filaments. FTIR spectroscopy showed that the native secondary structure of the wild-type insulins and the human insulin mutants in hydrochloric acid were identical, whereas the secondary structure of the fibrils formed by heating at 50 degrees C depended on the amino acid substitution. FTIR spectra of fibrils of the human insulin mutants exhibited different beta-sheet bands at 1,620-1,640 cm(-1), indicating that the beta-sheet interactions in the fibrils depended on variations in the primary structure of insulin. Copyright 2002 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 91:2473-2480, 2002

  9. Computational Insight into the Effect of Natural Compounds on the Destabilization of Preformed Amyloid-β(1–40 Fibrils

    Directory of Open Access Journals (Sweden)

    Francesco Tavanti

    2018-05-01

    Full Text Available One of the principal hallmarks of Alzheimer’s disease (AD is related to the aggregation of amyloid-β fibrils in an insoluble form in the brain, also known as amyloidosis. Therefore, a prominent therapeutic strategy against AD consists of either blocking the amyloid aggregation and/or destroying the already formed aggregates. Natural products have shown significant therapeutic potential as amyloid inhibitors from in vitro studies as well as in vivo animal tests. In this study, the interaction of five natural biophenols (curcumin, dopamine, (--epigallocatechin-3-gallate, quercetin, and rosmarinic acid with amyloid-β(1–40 fibrils has been studied through computational simulations. The results allowed the identification and characterization of the different binding modalities of each compounds and their consequences on fibril dynamics and aggregation. It emerges that the lateral aggregation of the fibrils is strongly influenced by the intercalation of the ligands, which modulates the double-layered structure stability.

  10. Chemical Kinetics for Bridging Molecular Mechanisms and Macroscopic Measurements of Amyloid Fibril Formation.

    Science.gov (United States)

    Michaels, Thomas C T; Šarić, Anđela; Habchi, Johnny; Chia, Sean; Meisl, Georg; Vendruscolo, Michele; Dobson, Christopher M; Knowles, Tuomas P J

    2018-04-20

    Understanding how normally soluble peptides and proteins aggregate to form amyloid fibrils is central to many areas of modern biomolecular science, ranging from the development of functional biomaterials to the design of rational therapeutic strategies against increasingly prevalent medical conditions such as Alzheimer's and Parkinson's diseases. As such, there is a great need to develop models to mechanistically describe how amyloid fibrils are formed from precursor peptides and proteins. Here we review and discuss how ideas and concepts from chemical reaction kinetics can help to achieve this objective. In particular, we show how a combination of theory, experiments, and computer simulations, based on chemical kinetics, provides a general formalism for uncovering, at the molecular level, the mechanistic steps that underlie the phenomenon of amyloid fibril formation.

  11. Confinement-induced liquid crystalline transitions in amyloid fibril cholesteric tactoids

    Science.gov (United States)

    Nyström, Gustav; Arcari, Mario; Mezzenga, Raffaele

    2018-04-01

    Chirality is ubiquitous in nature and plays crucial roles in biology, medicine, physics and materials science. Understanding and controlling chirality is therefore an important research challenge with broad implications. Unlike other chiral colloids, such as nanocellulose or filamentous viruses, amyloid fibrils form nematic phases but appear to miss their twisted form, the cholesteric or chiral nematic phases, despite a well-defined chirality at the single fibril level. Here we report the discovery of cholesteric phases in amyloids, using β-lactoglobulin fibrils shortened by shear stresses. The physical behaviour of these new cholesteric materials exhibits unprecedented structural complexity, with confinement-driven ordering transitions between at least three types of nematic and cholesteric tactoids. We use energy functional theory to rationalize these results and observe a chirality inversion from the left-handed amyloids to right-handed cholesteric droplets. These findings deepen our understanding of cholesteric phases, advancing their use in soft nanotechnology, nanomaterial templating and self-assembly.

  12. Chemical Kinetics for Bridging Molecular Mechanisms and Macroscopic Measurements of Amyloid Fibril Formation

    Science.gov (United States)

    Michaels, Thomas C. T.; Šarić, Anđela; Habchi, Johnny; Chia, Sean; Meisl, Georg; Vendruscolo, Michele; Dobson, Christopher M.; Knowles, Tuomas P. J.

    2018-04-01

    Understanding how normally soluble peptides and proteins aggregate to form amyloid fibrils is central to many areas of modern biomolecular science, ranging from the development of functional biomaterials to the design of rational therapeutic strategies against increasingly prevalent medical conditions such as Alzheimer's and Parkinson's diseases. As such, there is a great need to develop models to mechanistically describe how amyloid fibrils are formed from precursor peptides and proteins. Here we review and discuss how ideas and concepts from chemical reaction kinetics can help to achieve this objective. In particular, we show how a combination of theory, experiments, and computer simulations, based on chemical kinetics, provides a general formalism for uncovering, at the molecular level, the mechanistic steps that underlie the phenomenon of amyloid fibril formation.

  13. Amyloid Fibril Polymorphism: Almost Identical on the Atomic Level, Mesoscopically Very Different.

    Science.gov (United States)

    Seuring, Carolin; Verasdonck, Joeri; Ringler, Philippe; Cadalbert, Riccardo; Stahlberg, Henning; Böckmann, Anja; Meier, Beat H; Riek, Roland

    2017-03-02

    Amyloid polymorphism of twisted and straight β-endorphin fibrils was studied by negative-stain transmission electron microscopy, scanning transmission electron microscopy, and solid-state nuclear magnetic resonance spectroscopy. Whereas fibrils assembled in the presence of salt formed flat, striated ribbons, in the absence of salt they formed mainly twisted filaments. To get insights into their structural differences at the atomic level, 3D solid-state NMR spectra of both fibril types were acquired, allowing the detection of the differences in chemical shifts of 13 C and 15 N atoms in both preparations. The spectral fingerprints and therefore the chemical shifts are very similar for both fibril types. This indicates that the monomer structure and the molecular interfaces are almost the same but that these small differences do propagate to produce flat and twisted morphologies at the mesoscopic scale. This finding is in agreement with both experimental and theoretical considerations on the assembly of polymers (including amyloids) under different salt conditions, which attribute the mesoscopic difference of flat versus twisted fibrils to electrostatic intermolecular repulsions.

  14. Amyloid fibril formation from sequences of a natural beta-structured fibrous protein, the adenovirus fiber.

    Science.gov (United States)

    Papanikolopoulou, Katerina; Schoehn, Guy; Forge, Vincent; Forsyth, V Trevor; Riekel, Christian; Hernandez, Jean-François; Ruigrok, Rob W H; Mitraki, Anna

    2005-01-28

    Amyloid fibrils are fibrous beta-structures that derive from abnormal folding and assembly of peptides and proteins. Despite a wealth of structural studies on amyloids, the nature of the amyloid structure remains elusive; possible connections to natural, beta-structured fibrous motifs have been suggested. In this work we focus on understanding amyloid structure and formation from sequences of a natural, beta-structured fibrous protein. We show that short peptides (25 to 6 amino acids) corresponding to repetitive sequences from the adenovirus fiber shaft have an intrinsic capacity to form amyloid fibrils as judged by electron microscopy, Congo Red binding, infrared spectroscopy, and x-ray fiber diffraction. In the presence of the globular C-terminal domain of the protein that acts as a trimerization motif, the shaft sequences adopt a triple-stranded, beta-fibrous motif. We discuss the possible structure and arrangement of these sequences within the amyloid fibril, as compared with the one adopted within the native structure. A 6-amino acid peptide, corresponding to the last beta-strand of the shaft, was found to be sufficient to form amyloid fibrils. Structural analysis of these amyloid fibrils suggests that perpendicular stacking of beta-strand repeat units is an underlying common feature of amyloid formation.

  15. Elastic properties of woven bone: effect of mineral content and collagen fibrils orientation.

    Science.gov (United States)

    García-Rodríguez, J; Martínez-Reina, J

    2017-02-01

    Woven bone is a type of tissue that forms mainly during fracture healing or fetal bone development. Its microstructure can be modeled as a composite with a matrix of mineral (hydroxyapatite) and inclusions of collagen fibrils with a more or less random orientation. In the present study, its elastic properties were estimated as a function of composition (degree of mineralization) and fibril orientation. A self-consistent homogenization scheme considering randomness of inclusions' orientation was used for this purpose. Lacuno-canalicular porosity in the form of periodically distributed void inclusions was also considered. Assuming collagen fibrils to be uniformly oriented in all directions led to an isotropic tissue with a Young's modulus [Formula: see text] GPa, which is of the same order of magnitude as that of woven bone in fracture calluses. By contrast, assuming fibrils to have a preferential orientation resulted in a Young's modulus in the preferential direction of 9-16 GPa depending on the mineral content of the tissue. These results are consistent with experimental evidence for woven bone in foetuses, where collagen fibrils are aligned to a certain extent.

  16. Idiopathic ventricular tachycardia and fibrillation.

    Science.gov (United States)

    Belhassen, B; Viskin, S

    1993-06-01

    Important data have recently been added to our understanding of sustained ventricular tachyarrhythmias occurring in the absence of demonstrable heart disease. Idiopathic ventricular tachycardia (VT) is usually of monomorphic configuration and can be classified according to its site of origin as either right monomorphic (70% of all idiopathic VTs) or left monomorphic VT. Several physiopathological types of monomorphic VT can be presently individualized, according to their mode of presentation, their relationship to adrenergic stress, or their response to various drugs. The long-term prognosis is usually good. Idiopathic polymorphic VT is a much rarer type of arrhythmia with a less favorable prognosis. Idiopathic ventricular fibrillation may represent an underestimated cause of sudden cardiac death in ostensibly healty patients. A high incidence of inducibility of sustained polymorphic VT with programmed ventricular stimulation has been found by our group, but not by others. Long-term prognosis on Class IA antiarrhythmic medications that are highly effective at electrophysiologic study appears excellent.

  17. Atrial Fibrillation During an Exploration Class Mission

    Science.gov (United States)

    Lipsett, Mark; Hamilton, Douglas; Lemery, Jay; Polk, James

    2011-01-01

    This slide presentation reviews a possible scenario of an astronaut having Atrial Fibrillation during a Mars Mission. In the case review the presentation asks several questions about the alternatives for treatment, medications and the ramifications of the decisions.

  18. [Relations between FANS, PPI and atrial fibrillation].

    Science.gov (United States)

    Ricci, Fabrizio; De Caterina, Raffaele

    2013-05-01

    Recent evidence supports the existence of an association between the use of non-steroidal anti-inflammatory drugs and the risk of atrial fibrillation. Anti-inflammatory drugs are widely used for the treatment of systemic inflammatory disorders, and chronic inflammation is a well-known risk factor for the development of myocardial fibrosis. The latter accounts for atrial inhomogeneities of conduction, thus triggering and perpetuating atrial fibrillation. Atrial inflammatory remodeling may therefore be responsible for the higher incidence of atrial fibrillation among patients assuming steroidal and non-steroidal anti-inflammatory drugs because of an underlying inflammatory disorders. Alternative theories contemplate gastroesophageal reflux, which is extremely common during the use of non-steroidal anti-inflammatory drugs and may trigger atrial fibrillation, as mediating the above-mentioned association.

  19. Salbutamol Abuse is Associated with Ventricular Fibrillation

    Directory of Open Access Journals (Sweden)

    Emin UYSAL

    2015-06-01

    Full Text Available SUMMARY: Salbutamol-induced cardiac complications are well-established. Herein, we describe a case of a 24-year female who was admitted to the emergency department because of a suicide attempt with salbutamol (76 mg. Salbutamol abuse induced the development of supraventricular tachycardia and ventricular fibrillation. Regular sinus rhythm was restored with defibrillation. The hypokalemic patient who stayed in the intensive care unit was discharged after 48 hours of hospitalization. Key words: Salbutamol, suicide, ventricular fibrillation

  20. Imaging in percutaneous ablation for atrial fibrillation

    Energy Technology Data Exchange (ETDEWEB)

    Maksimovic, Ruzica [Erasmus Medical Center, Department of Radiology, GD Rotterdam (Netherlands); Institute for Cardiovascular Diseases of the University Medical Center, Belgrade (Czechoslovakia); Dill, Thorsten [Kerckhoff-Heart Center, Department of Cardiology, Bad Nauheim (Germany); Ristic, Arsen D.; Seferovic, Petar M. [Institute for Cardiovascular Diseases of the University Medical Center, Belgrade (Czechoslovakia)

    2006-11-15

    Percutaneous ablation for electrical disconnection of the arrhythmogenic foci using various forms of energy has become a well-established technique for treating atrial fibrillation (AF). Success rate in preventing recurrence of AF episodes is high although associated with a significant incidence of pulmonary vein (PV) stenosis and other rare complications. Clinical workup of AF patients includes imaging before and after ablative treatment using different noninvasive and invasive techniques such as conventional angiography, transoesophageal and intracardiac echocardiography, computed tomography (CT) and magnetic resonance imaging (MRI), which offer different information with variable diagnostic accuracy. Evaluation before percutaneous ablation involves assessment of PVs (PV pattern, branching pattern, orientation and ostial size) to facilitate position and size of catheters and reduce procedure time as well as examining the left atrium (presence of thrombi, dimensions and volumes). Imaging after the percutaneous ablation is important for assessment of overall success of the procedure and revealing potential complications. Therefore, imaging methods enable depiction of PVs and the anatomy of surrounding structures essential for preprocedural management and early detection of PV stenosis and other ablation-related procedures, as well as long-term follow-up of these patients. (orig.)

  1. Imaging in percutaneous ablation for atrial fibrillation

    International Nuclear Information System (INIS)

    Maksimovic, Ruzica; Dill, Thorsten; Ristic, Arsen D.; Seferovic, Petar M.

    2006-01-01

    Percutaneous ablation for electrical disconnection of the arrhythmogenic foci using various forms of energy has become a well-established technique for treating atrial fibrillation (AF). Success rate in preventing recurrence of AF episodes is high although associated with a significant incidence of pulmonary vein (PV) stenosis and other rare complications. Clinical workup of AF patients includes imaging before and after ablative treatment using different noninvasive and invasive techniques such as conventional angiography, transoesophageal and intracardiac echocardiography, computed tomography (CT) and magnetic resonance imaging (MRI), which offer different information with variable diagnostic accuracy. Evaluation before percutaneous ablation involves assessment of PVs (PV pattern, branching pattern, orientation and ostial size) to facilitate position and size of catheters and reduce procedure time as well as examining the left atrium (presence of thrombi, dimensions and volumes). Imaging after the percutaneous ablation is important for assessment of overall success of the procedure and revealing potential complications. Therefore, imaging methods enable depiction of PVs and the anatomy of surrounding structures essential for preprocedural management and early detection of PV stenosis and other ablation-related procedures, as well as long-term follow-up of these patients. (orig.)

  2. Collagen Fibrils: Nature's Highly Tunable Nonlinear Springs.

    Science.gov (United States)

    Andriotis, Orestis G; Desissaire, Sylvia; Thurner, Philipp J

    2018-03-21

    Tissue hydration is well known to influence tissue mechanics and can be tuned via osmotic pressure. Collagen fibrils are nature's nanoscale building blocks to achieve biomechanical function in a broad range of biological tissues and across many species. Intrafibrillar covalent cross-links have long been thought to play a pivotal role in collagen fibril elasticity, but predominantly at large, far from physiological, strains. Performing nanotensile experiments of collagen fibrils at varying hydration levels by adjusting osmotic pressure in situ during atomic force microscopy experiments, we show the power the intrafibrillar noncovalent interactions have for defining collagen fibril tensile elasticity at low fibril strains. Nanomechanical tensile tests reveal that osmotic pressure increases collagen fibril stiffness up to 24-fold in transverse (nanoindentation) and up to 6-fold in the longitudinal direction (tension), compared to physiological saline in a reversible fashion. We attribute the stiffening to the density and strength of weak intermolecular forces tuned by hydration and hence collagen packing density. This reversible mechanism may be employed by cells to alter their mechanical microenvironment in a reversible manner. The mechanism could also be translated to tissue engineering approaches for customizing scaffold mechanics in spatially resolved fashion, and it may help explain local mechanical changes during development of diseases and inflammation.

  3. A carboxylated Zn-phthalocyanine inhibits fibril formation of Alzheimer's amyloid β peptide.

    Science.gov (United States)

    Tabassum, Shatera; Sheikh, Abdullah M; Yano, Shozo; Ikeue, Takafumi; Handa, Makoto; Nagai, Atsushi

    2015-02-01

    Amyloid β (Aβ), a 39-42 amino acid peptide derived from amyloid precursor protein, is deposited as fibrils in Alzheimer's disease brains, and is considered to play a major role in the pathogenesis of the disease. We have investigated the effects of a water-soluble Zn-phthalocyanine, ZnPc(COONa)₈, a macrocyclic compound with near-infrared optical properties, on Aβ fibril formation in vitro. A thioflavin T fluorescence assay showed that ZnPc(COONa)₈ significantly inhibited Aβ fibril formation, increasing the lag time and dose-dependently decreasing the plateau level of fibril formation. Moreover, it destabilized pre-formedfibrils, resulting in an increase in low-molecular-weight species. After fibril formation in the presence of ZnPc(COONa)₈, immunoprecipitation of Aβ₁₋₄₂ using Aβ-specific antibody followed by near-infrared scanning demonstrated binding of ZnPc(COONa)₈ to Aβ₁₋₄₂. A study using the hydrophobic fluorescent probe 8-anilino-1-naphthalenesulfonic acid showed that ZnPc(COONa)8 decreased the hydrophobicity during Aβ₁₋₄₂ fibril formation. CD spectroscopy showed an increase in the α helix structure and a decrease in the β sheet structure of Aβ₁₋₄₀ in fibril-forming buffer containing ZnPc(COONa)₈. SDS/PAGE and a dot-blot immunoassay showed that ZnPc(COONa)₈ delayed the disappearance of low-molecular-weight species and the appearance of higher-molecular-weight oligomeric species of Aβ₁₋₄₂. A cell viability assay showed that ZnPc(COONa)₈ was not toxic to a neuronal cell line (A1), but instead protected A1 cells against Aβ₁₋₄₂-induced toxicity. Overall, our results indicate that ZnPc(COONa)₈ binds to Aβ and decreases the hydrophobicity, and this change is unfavorable for Aβ oligomerization and fibril formation. © 2014 FEBS.

  4. RR-Interval variance of electrocardiogram for atrial fibrillation detection

    Science.gov (United States)

    Nuryani, N.; Solikhah, M.; Nugoho, A. S.; Afdala, A.; Anzihory, E.

    2016-11-01

    Atrial fibrillation is a serious heart problem originated from the upper chamber of the heart. The common indication of atrial fibrillation is irregularity of R peak-to-R-peak time interval, which is shortly called RR interval. The irregularity could be represented using variance or spread of RR interval. This article presents a system to detect atrial fibrillation using variances. Using clinical data of patients with atrial fibrillation attack, it is shown that the variance of electrocardiographic RR interval are higher during atrial fibrillation, compared to the normal one. Utilizing a simple detection technique and variances of RR intervals, we find a good performance of atrial fibrillation detection.

  5. On the role of fibril mechanics in the work of separation of fibrillating interfaces

    NARCIS (Netherlands)

    Vossen, B.G.; Sluis, van der O.; Schreurs, P.J.G.; Geers, M.G.D.; Neggers, J.; Hoefnagels, J.P.M.

    2015-01-01

    High values for the work of separation have been reported in peel tests on fibrillating interfacial systems. The exact origin of these high values is not properly understood, since it remains unclear which dissipative mechanisms related to fibrillation cause a significant increase in the work of

  6. Brazilin inhibits amyloid β-protein fibrillogenesis, remodels amyloid fibrils and reduces amyloid cytotoxicity

    Science.gov (United States)

    Du, Wen-Jie; Guo, Jing-Jing; Gao, Ming-Tao; Hu, Sheng-Quan; Dong, Xiao-Yan; Han, Yi-Fan; Liu, Fu-Feng; Jiang, Shaoyi; Sun, Yan

    2015-01-01

    Soluble amyloid β-protein (Aβ) oligomers, the main neurotoxic species, are predominantly formed from monomers through a fibril-catalyzed secondary nucleation. Herein, we virtually screened an in-house library of natural compounds and discovered brazilin as a dual functional compound in both Aβ42 fibrillogenesis inhibition and mature fibril remodeling, leading to significant reduction in Aβ42 cytotoxicity. The potent inhibitory effect of brazilin was proven by an IC50 of 1.5 +/- 0.3 μM, which was smaller than that of (-)-epigallocatechin gallate in Phase III clinical trials and about one order of magnitude smaller than those of curcumin and resveratrol. Most importantly, it was found that brazilin redirected Aβ42 monomers and its mature fibrils into unstructured Aβ aggregates with some β-sheet structures, which could prevent both the primary nucleation and the fibril-catalyzed secondary nucleation. Molecular simulations demonstrated that brazilin inhibited Aβ42 fibrillogenesis by directly binding to Aβ42 species via hydrophobic interactions and hydrogen bonding and remodeled mature fibrils by disrupting the intermolecular salt bridge Asp23-Lys28 via hydrogen bonding. Both experimental and computational studies revealed a different working mechanism of brazilin from that of known inhibitors. These findings indicate that brazilin is of great potential as a neuroprotective and therapeutic agent for Alzheimer's disease.

  7. [The contribution of inflammatory process in pathogenesis and natural history of atrial fibrillation].

    Science.gov (United States)

    Zyśko, Dorota; Gajek, Jacek; Mazurek, Walentyna

    2005-02-01

    The inflammatory process plays important role in pathogenesis of some cardiovascular diseases. Atrial fibrillation is atrial arrhythmia with rapid, asynchronous activation of atrial myocytes. The inflammatory process can be responsible for atrial electrical and anatomical remodeling and therefore shifts towards arrhythmia persistence. The presence of systemic inflammation may be assessed by means of C-reactive protein (CRP) measurement. Maximal concentration of CRP coincidences with the peak of paroxysmal atrial fibrillation occurrence in patients after cardiac surgery. In patients with sinus rhythm the concentration of CRP is a risk factor for this arrhythmia in long-term follow-up. In patients with atrial fibrillation mean CRP concentration is 2-fold higher comparing to control group. CRP concentration is higher in patients with chronic than paroxysmal form of this arrhythmia. High CRP level predicts worse results of direct current cardioversion and more frequent paroxysms of atrial fibrillation during follow-up. Besides of, the patients with echocardiographic signs of thromboembolic risk have higher CRP levels than control subjects. There is no data about the influence of anti-inflammatory therapy on atrial fibrillation or its recurrences.

  8. Persistent atrial fibrillation vs paroxysmal atrial fibrillation: differences in management.

    Science.gov (United States)

    Margulescu, Andrei D; Mont, Lluis

    2017-08-01

    Atrial fibrillation (AF) is the most common human arrhythmia. AF is a progressive disease, initially being nonsustained and induced by trigger activity, and progressing towards persistent AF through alteration of the atrial myocardial substrate. Treatment of AF aims to decrease the risk of stroke and improve the quality of life, by preventing recurrences (rhythm control) or controlling the heart rate during AF (rate control). In the last 20 years, catheter-based and, less frequently, surgical and hybrid ablation techniques have proven more successful compared with drug therapy in achieving rhythm control in patients with AF. However, the efficiency of ablation techniques varies greatly, being highest in paroxysmal and lowest in long-term persistent AF. Areas covered: In this review, we discuss the fundamental differences between paroxysmal and persistent AF and the potential impact of those differences on patient management, emphasizing the available therapeutic strategies to achieve rhythm control. Expert commentary: Treatment to prevent AF recurrences is suboptimal, particularly in patients with persistent AF. Emerging technologies, such as documentation of atrial fibrosis using magnetic resonance imaging and documentation of electrical substrate using advanced electrocardiographic imaging techniques are likely to provide valuable insights about patient-specific tailoring of treatments.

  9. Differential effects of divalent cations on elk prion protein fibril formation and stability

    Science.gov (United States)

    Misfolding of the normally folded prion protein of mammals (PrPC) into infectious fibrils causes a variety of different diseases, from scrapie in sheep to bovine spongiform encephalopathy in cattle to chronic wasting disease (CWD) in deer and elk. The misfolded form of PrPC, termed PrPSc, or in this...

  10. Effect of age on stroke prevention therapy in patients with atrial fibrillation: the atrial fibrillation investigators

    DEFF Research Database (Denmark)

    van Walraven, Carl; Hart, Robert G; Connolly, Stuart

    2009-01-01

    contains patient level-data from randomized trials of stroke prevention in atrial fibrillation. We used Cox regression models with age as a continuous variable that controlled for sex, year of randomization, and history of cerebrovascular disease, diabetes, hypertension, and congestive heart failure......BACKGROUND AND PURPOSE: Stroke risk increases with age in patients who have nonvalvular atrial fibrillation. It is uncertain whether the efficacy of stroke prevention therapies in atrial fibrillation changes as patients age. The objective of this study was to determine the effect of age...... on the relative efficacy of oral anticoagulants (OAC) and antiplatelet (AP) therapy (including acetylsalicylic acid and triflusal) on ischemic stroke, serious bleeding, and vascular events in patients with atrial fibrillation. METHODS: This is an analysis of the Atrial Fibrillation Investigators database, which...

  11. Engineering scale development of the vapor-liquid-solid (VLS) process for the production of silicon carbide fibrils. Phase 2

    Energy Technology Data Exchange (ETDEWEB)

    Ohnsorg, R.W.; Hollar, W.E. Jr.; Lau, S.K. [Carborundum Co., Niagara Falls, NY (United States). Technology Div.; Ko, F.K.; Schatz, K. [Advanced Product Development, Bristol, PA (United States)

    1995-04-01

    As reinforcements for composites, VLS SiC fibrils have attractive mechanical properties including high-strength, high modulus, and excellent creep resistance. To make use of their excellent mechanical properties in a composite, a significant volume fraction (>10%) of aligned, long fibrils (>2 mm) needs to be consolidated in the ceramic matrix. The fibrils must be processed into an assembly that will allow for composite fabrication while maintaining fibril alignment and length. With Advanced Product Development (APD) as the yam fabrication subcontractor, Carborundum investigated several approaches to achieve this goaL including traditional yam-forming processes such as carding and air-vortex spinning and nontraditional processes such as tape forming and wet casting. Carborundum additionally performed an economic analysis for producing 500 and 10,000 pounds of SiC fibrils annually using both conservative and more aggressive processing parameters. With the aggressive approach, the projected costs for SiC fibril production for 500 and 10,000 pounds per year are $1,340/pound and $340/pound, respectively.

  12. Interaction of magnetic nanoparticles with lysozyme amyloid fibrils

    Energy Technology Data Exchange (ETDEWEB)

    Gdovinová, Veronika [Institute of Experimental Physics SAS, Watsonova 47, 040 01 Košice (Slovakia); Frank Laboratory of Neutron Physics, Joint Institute for Nuclear Research, Joliot-Curie 6, 141980 Dubna, Moscow Region (Russian Federation); Tomašovičová, Natália, E-mail: nhudak@saske.sk [Institute of Experimental Physics SAS, Watsonova 47, 040 01 Košice (Slovakia); Frank Laboratory of Neutron Physics, Joint Institute for Nuclear Research, Joliot-Curie 6, 141980 Dubna, Moscow Region (Russian Federation); Batko, Ivan; Batková, Marianna; Balejčíková, Lucia [Institute of Experimental Physics SAS, Watsonova 47, 040 01 Košice (Slovakia); Garamus, Vasyl M. [Helmholtz-Zentrum Geesthacht: Zentrum fr Material, und Kstenforschung GmbH, Max-Plank-Strae 1, Geesthacht 216502 (Germany); Petrenko, Viktor I. [Frank Laboratory of Neutron Physics, Joint Institute for Nuclear Research, Joliot-Curie 6, 141980 Dubna, Moscow Region (Russian Federation); Physics Department, Taras Shevchenko Kyiv National University, Volodymyrska Street 64, 01601 Kyiv (Ukraine); Avdeev, Mikhail V. [Frank Laboratory of Neutron Physics, Joint Institute for Nuclear Research, Joliot-Curie 6, 141980 Dubna, Moscow Region (Russian Federation); Kopčanský, Peter [Institute of Experimental Physics SAS, Watsonova 47, 040 01 Košice (Slovakia)

    2017-06-01

    This work is devoted to the structural study of complex solutions of magnetic nanoparticles with lysozyme amyloid fibrils due to possible ordering of such system by applying the external magnetic field. The interaction of magnetic nanoparticles with amyloid fibrils has been followed by atomic force microscopy and small-angle X-ray scattering. It has been observed that magnetic nanoparticles (MNPs) adsorb to lysozyme amyloid fibrils. It was found that MNPs alter amyloids structures, namely the diameter of lysozyme amyloid fibrils is increased whereas the length of fibrils is decreased. In the same time MNPs do not change the helical pitch significantly. - Highlights: • Solution of MNPs with lysozyme amyloid fibrils was characterized by AFM and SAXS. • MNPs adsorb to lysozyme amyloid fibrils. • Diameter and size of lysozyme amyloid fibrils change due to doping with MNPs.

  13. Spectral of electrocardiographic RR intervals to indicate atrial fibrillation

    Science.gov (United States)

    Nuryani, Nuryani; Satrio Nugroho, Anto

    2017-11-01

    Atrial fibrillation is a serious heart diseases, which is associated on the risk of death, and thus an early detection of atrial fibrillation is necessary. We have investigated spectral pattern of electrocardiogram in relation to atrial fibrillation. The utilized feature of electrocardiogram is RR interval. RR interval is the time interval between a two-consecutive R peaks. A series of RR intervals in a time segment is converted to a signal with a frequency domain. The frequency components are investigated to find the components which significantly associate to atrial fibrillation. A segment is defined as atrial fibrillation or normal segments by considering a defined number of atrial fibrillation RR in the segment. Using clinical data of 23 patients with atrial fibrillation, we find that the frequency components could be used to indicate atrial fibrillation.

  14. Risk of atrial fibrillation and stroke in rheumatoid arthritis

    DEFF Research Database (Denmark)

    Lindhardsen, Jesper; Ahlehoff, Ole; Gislason, Gunnar Hilmar

    2012-01-01

    To determine if patients with rheumatoid arthritis have increased risk of atrial fibrillation and stroke.......To determine if patients with rheumatoid arthritis have increased risk of atrial fibrillation and stroke....

  15. Treatment Guidelines of Atrial Fibrillation (AFib or AF)

    Science.gov (United States)

    ... Artery Disease Venous Thromboembolism Aortic Aneurysm More Treatment Guidelines of Atrial Fibrillation (AFib or AF) Updated:Jun 28,2017 What are the treatment guidelines for atrial fibrillation? Medical guidelines are written by ...

  16. Management of atrial fibrillation in the setting of heart failure

    NARCIS (Netherlands)

    Crijns, HJGM; VandenBerg, MP; VanGelder, IC; VanVeldhuisen, DJ

    Heart failure is often complicated by atrial fibrillation. Once atrial fibrillation has started it further enhances heart failure due to uncontrolled rate with shortened filling time and provocation of tachycardiomyopathy. Absent atrial kick and irregularity of the ventricular rhythm also

  17. Rising rates of hospital admissions for atrial fibrillation

    DEFF Research Database (Denmark)

    Friberg, Jens; Buch, Nina Pernille Gardshodn; Scharling, Henrik

    2003-01-01

    Atrial fibrillation is a common arrhythmia associated with excess morbidity and mortality. We studied temporal changes in hospital admission rates for atrial fibrillation using data from a prospective population-based cohort study spanning 2 decades (the Copenhagen City Heart Study).......Atrial fibrillation is a common arrhythmia associated with excess morbidity and mortality. We studied temporal changes in hospital admission rates for atrial fibrillation using data from a prospective population-based cohort study spanning 2 decades (the Copenhagen City Heart Study)....

  18. Artificial atrial fibrillation in the dog. An artifact?

    NARCIS (Netherlands)

    Strackee, J.; Hoelen, A.J.; Zimmerman, A.N.E.; Meijler, F.L.

    R-R interval sequences during artificial atrial fibrillation in dogs were studied in the same way as in patients in a previous study and compared with results obtained in dogs with spontaneous atrial fibrillation. Artificial atrial fibrillation was effected by right atrial stimulation in three

  19. Alcohol consumption and risk of atrial fibrillation

    DEFF Research Database (Denmark)

    Tolstrup, Janne Schurmann; Wium-Andersen, Marie Kim; Ørsted, David Dynnes

    2016-01-01

    BACKGROUND: The aim of this study was to test the hypothesis that alcohol consumption, both observational (self-reported) and estimated by genetic instruments, is associated with a risk of atrial fibrillation and to determine whether people with high cardiovascular risk are more sensitive towards...... alcohol than people with low risk. METHODS: We used data for a total of 88,782 men and women from the Copenhagen City Heart Study 1991-1994 and 2001-2003 and the Copenhagen General Population Study 2003-2010. Information on incident cases of atrial fibrillation was obtained from a validated nationwide...... register. As a measure of alcohol exposure, both self-reported consumption and genetic variations in alcohol metabolizing genes (ADH1B/ADH1C) were used as instrumental variables. The endpoint was admission to hospital for atrial fibrillation as recorded in a validated hospital register. RESULTS: A total...

  20. The atrial fibrillation ablation pilot study

    DEFF Research Database (Denmark)

    Arbelo, Elena; Brugada, Josep; Hindricks, Gerhard

    2014-01-01

    AIMS: The Atrial Fibrillation Ablation Pilot Study is a prospective registry designed to describe the clinical epidemiology of patients undergoing an atrial fibrillation (AFib) ablation, and the diagnostic/therapeutic processes applied across Europe. The aims of the 1-year follow-up were to analyse...... was achieved in 40.7% of patients (43.7% in paroxysmal AF; 30.2% in persistent AF; 36.7% in long-lasting persistent AF). A second ablation was required in 18% of the cases and 43.4% were under antiarrhythmic treatment. Thirty-three patients (2.5%) suffered an adverse event, 272 (21%) experienced a left atrial...... tachycardia, and 4 patients died (1 haemorrhagic stroke, 1 ventricular fibrillation in a patient with ischaemic heart disease, 1 cancer, and 1 of unknown cause). CONCLUSION: The AFib Ablation Pilot Study provided crucial information on the epidemiology, management, and outcomes of catheter ablation of AFib...

  1. Antihypertensive treatment and risk of atrial fibrillation

    DEFF Research Database (Denmark)

    Marott, Sarah C W; Nielsen, Sune F; Benn, Marianne

    2014-01-01

    AIMS: To examine the associations between antihypertensive treatment with angiotensin-converting enzyme inhibitors (ACEis) or angiotensin receptor blockers (ARBs), β-blockers, diuretics, or calcium-antagonists, and risk of atrial fibrillation. We examined these associations using the entire Danish...... population from 1995 through 2010. METHODS AND RESULTS: Excluding medication used in atrial fibrillation, we matched individuals on ACEi monotherapy 1:1 with individuals on β-blocker (n = 48 658), diuretic (n = 69 630), calcium-antagonist (n = 57 646), and ARB monotherapy (n = 20 158). Likewise, individuals...... on ARB monotherapy were matched 1:1 with individuals on β-blocker (n = 20 566), diuretic (n = 20 832), calcium-antagonist (n = 20 232), and ACEi monotherapy (n = 20 158). All were free of atrial fibrillation and of predisposing diseases like heart failure, ischaemic heart disease, diabetes mellitus...

  2. Digoxin for atrial fibrillation and atrial flutter

    DEFF Research Database (Denmark)

    Sethi, Naqash J; Nielsen, Emil E; Safi, Sanam

    2018-01-01

    BACKGROUND: During recent years, systematic reviews of observational studies have compared digoxin to no digoxin in patients with atrial fibrillation or atrial flutter, and the results of these reviews suggested that digoxin seems to increase the risk of all-cause mortality regardless...... of concomitant heart failure. Our objective was to assess the benefits and harms of digoxin for atrial fibrillation and atrial flutter based on randomized clinical trials. METHODS: We searched CENTRAL, MEDLINE, Embase, LILACS, SCI-Expanded, BIOSIS for eligible trials comparing digoxin versus placebo......, no intervention, or other medical interventions in patients with atrial fibrillation or atrial flutter in October 2016. Our primary outcomes were all-cause mortality, serious adverse events, and quality of life. Our secondary outcomes were heart failure, stroke, heart rate control, and conversion to sinus rhythm...

  3. Amide proton solvent protection in amylin fibrils probed by quenched hydrogen exchange NMR.

    Directory of Open Access Journals (Sweden)

    Andrei T Alexandrescu

    Full Text Available Amylin is an endocrine hormone that accumulates in amyloid plaques in patients with advanced type 2 diabetes. The amyloid plaques have been implicated in the destruction of pancreatic β-cells, which synthesize amylin and insulin. To better characterize the secondary structure of amylin in amyloid fibrils we assigned the NMR spectrum of the unfolded state in 95% DMSO and used a quenched hydrogen-deuterium exchange technique to look at amide proton solvent protection in the fibrils. In this technique, partially exchanged fibrils are dissolved in 95% DMSO and information about amide proton occupancy in the fibrils is determined from DMSO-denatured monomers. Hydrogen exchange lifetimes at pH 7.6 and 37°C vary between ∼5 h for the unstructured N-terminus to 600 h for amide protons in the two β-strands that form inter-molecular hydrogen bonds between amylin monomers along the length of the fibril. Based on the protection data we conclude that residues A8-H18 and I26-Y37 comprise the two β-strands in amylin fibrils. There is variation in protection within the β-strands, particularly for strand β1 where only residues F15-H18 are strongly protected. Differences in protection appear to be due to restrictions on backbone dynamics imposed by the packing of two-layers of C2-symmetry-related β-hairpins in the protofilament structure, with strand β1 positioned on the surface and β2 in the interior.

  4. High-Pressure-Driven Reversible Dissociation of α-Synuclein Fibrils Reveals Structural Hierarchy.

    Science.gov (United States)

    Piccirilli, Federica; Plotegher, Nicoletta; Ortore, Maria Grazia; Tessari, Isabella; Brucale, Marco; Spinozzi, Francesco; Beltramini, Mariano; Mariani, Paolo; Militello, Valeria; Lupi, Stefano; Perucchi, Andrea; Bubacco, Luigi

    2017-10-17

    The analysis of the α-synuclein (aS) aggregation process, which is involved in Parkinson's disease etiopathogenesis, and of the structural feature of the resulting amyloid fibrils may shed light on the relationship between the structure of aS aggregates and their toxicity. This may be considered a paradigm of the ground work needed to tackle the molecular basis of all the protein-aggregation-related diseases. With this aim, we used chemical and physical dissociation methods to explore the structural organization of wild-type aS fibrils. High pressure (in the kbar range) and alkaline pH were used to disassemble fibrils to collect information on the hierarchic pathway by which distinct β-sheets sequentially unfold using the unique possibility offered by high-pressure Fourier transform infrared spectroscopy. The results point toward the formation of kinetic traps in the energy landscape of aS fibril disassembly and the presence of transient partially folded species during the process. Since we found that the dissociation of wild-type aS fibrils by high pressure is reversible upon pressure release, the disassembled molecules likely retain structural information that favors fibril reformation. To deconstruct the role of the different regions of aS sequence in this process, we measured the high-pressure dissociation of amyloids formed by covalent chimeric dimers of aS (syn-syn) and by the aS deletion mutant that lacks the C-terminus, i.e., aS (1-99). The results allowed us to single out the role of dimerization and that of the C-terminus in the complete maturation of fibrillar aS. Copyright © 2017 Biophysical Society. Published by Elsevier Inc. All rights reserved.

  5. Atrial natriuretic peptide in patients with heart failure and chronic atrial fibrillation : Role of duration of at atrial fibrillation

    NARCIS (Netherlands)

    Van Den Berg, MP; Crijns, HJGM; Van Veldhuisen, DJ; Van Gelder, IC; De Kam, PJ; Lie, KI

    The purpose of this study was to analyze the determinants of atrial natriuretic peptide level in patients with congestive heart failure and atrial fibrillation. In particular, the duration of atrial fibrillation was analyzed because atrial fibrillation per se might have a specific effect on atrial

  6. Uniform spatial distribution of collagen fibril radii within tendon implies local activation of pC-collagen at individual fibrils

    Science.gov (United States)

    Rutenberg, Andrew D.; Brown, Aidan I.; Kreplak, Laurent

    2016-08-01

    Collagen fibril cross-sectional radii show no systematic variation between the interior and the periphery of fibril bundles, indicating an effectively constant rate of collagen incorporation into fibrils throughout the bundle. Such spatially homogeneous incorporation constrains the extracellular diffusion of collagen precursors from sources at the bundle boundary to sinks at the growing fibrils. With a coarse-grained diffusion equation we determine stringent bounds, using parameters extracted from published experimental measurements of tendon development. From the lack of new fibril formation after birth, we further require that the concentration of diffusing precursors stays below the critical concentration for fibril nucleation. We find that the combination of the diffusive bound, which requires larger concentrations to ensure homogeneous fibril radii, and lack of nucleation, which requires lower concentrations, is only marginally consistent with fully processed collagen using conservative bounds. More realistic bounds may leave no consistent concentrations. Therefore, we propose that unprocessed pC-collagen diffuses from the bundle periphery followed by local C-proteinase activity and subsequent collagen incorporation at each fibril. We suggest that C-proteinase is localized within bundles, at fibril surfaces, during radial fibrillar growth. The much greater critical concentration of pC-collagen, as compared to fully processed collagen, then provides broad consistency between homogeneous fibril radii and the lack of fibril nucleation during fibril growth.

  7. Patients with atrial fibrillation and permanent pacemaker

    DEFF Research Database (Denmark)

    Dalgaard, Frederik; Ruwald, Martin H; Lindhardt, Tommi Bo

    2018-01-01

    BACKGROUND: The management of patients with non-valvular atrial fibrillation (NVAF) with rate-lowering or anti-arrhythmic drugs has markedly changed over the last decade, but it is unknown how these changes have affected patients with NVAF with a permanent pacemaker (PPM). METHODS: Through Danish......,261. Thus, the proportional amount of NVAF patients with a PPM decreased from 1.3% to 1.1% (p = 0.015). Overall 45.9% had atrial fibrillation (AF) duration less than one year and the proportion declined from 55.5% to 42.4% (p

  8. Atrial fibrillation and risk of stroke

    DEFF Research Database (Denmark)

    Christiansen, Christine Benn; Gerds, Thomas A.; Olesen, Jonas Bjerring

    2016-01-01

    AIM: Although the relation between stroke risk factors and stroke in patients with atrial fibrillation (AF) has been extensively examined, only few studies have explored the association of AF and the risk of ischaemic stroke/systemic thromboembolism/transient ischaemic attack (stroke.......5-10.6), and 15.4% (14.5-16.4), respectively. CONCLUSIONS: Stroke/TE/TIA risk was particularly increased when prior stroke/TE/TIA was present. Atrial fibrillation is associated with an increase in risk of stroke/TE/TIA in the absence of other risk factors but only a moderate increase in risk when other risk...

  9. Integrating new approaches to atrial fibrillation management

    DEFF Research Database (Denmark)

    Kotecha, Dipak; Breithardt, Günter; Camm, A John

    2018-01-01

    There are major challenges ahead for clinicians treating patients with atrial fibrillation (AF). The population with AF is expected to expand considerably and yet, apart from anticoagulation, therapies used in AF have not been shown to consistently impact on mortality or reduce adverse...... of the Atrial Fibrillation Network (AFNET) and the European Heart Rhythm Association (EHRA), held at the European Society of Cardiology Heart House in Sophia Antipolis, France, 17-19 January 2017. Sixty-two global specialists in AF and 13 industry partners met to develop innovative solutions based on new...

  10. Initiation of anticoagulation in atrial fibrillation

    DEFF Research Database (Denmark)

    Gundlund, A.; Staerk, L.; Fosbøl, E. L.

    2017-01-01

    Background: The use of non-vitamin K antagonist oral anticoagulants (NOACs) for stroke prophylaxis in atrial fibrillation (AF) is increasing rapidly. We compared characteristics of AF patients initiated on NOACs versus vitamin K antagonists (VKAs). Methods: Using Danish nationwide registry data, we...... compared with a VKA [odds ratio (OR) 1.35, 95% confidence interval (CI) 1.28–1.43]. By contrast, patients with a history of myocardial infarction were less likely to be initiated on a NOAC compared with a VKA (OR 0.72, 95% CI 0.67–0.77). Conclusions: Atrial fibrillation patients who were initiated...

  11. Cryoballoon Catheter Ablation in Atrial Fibrillation

    Directory of Open Access Journals (Sweden)

    Cevher Ozcan

    2011-01-01

    Full Text Available Pulmonary vein isolation with catheter ablation is an effective treatment in patients with symptomatic atrial fibrillation refractory or intolerant to antiarrhythmic medications. The cryoballoon catheter was recently approved for this procedure. In this paper, the basics of cryothermal energy ablation are reviewed including its ability of creating homogenous lesion formation, minimal destruction to surrounding vasculature, preserved tissue integrity, and lower risk of thrombus formation. Also summarized here are the publications describing the clinical experience with the cryoballoon catheter ablation in both paroxysmal and persistent atrial fibrillation, its safety and efficacy, and discussions on the technical aspect of the cryoballoon ablation procedure.

  12. Atrial fibrillation and the 4P medicine.

    Science.gov (United States)

    Censi, Federica; Cianfrocca, Cinzia; Purificato, Ivana

    2013-01-01

    Although the paradigm of the 4P medicine - Predictive, Personalized, Preemptive, and Participatory - has been suggested several years ago, its application to atrial fibrillation is still far away. Given the increasing prevalence and incidence of this pathology it is the time to promote preventive strategies, by identifying the risk factors associated to life style and by incentivizing innovative diagnostic technologies. The promotion of the correct life style and of the use of diagnostic devices based on innovative and reliable technologies, represent a first step towards the full realization of the revolution of 4P medicine in atrial fibrillation.

  13. Atrial fibrillation and the 4P medicine

    Directory of Open Access Journals (Sweden)

    Federica Censi

    2013-09-01

    Full Text Available Although the paradigm of the 4P medicine - Predictive, Personalized, Preemptive, and Participatory - has been suggested several years ago, its application to atrial fibrillation is still far away. Given the increasing prevalence and incidence of this pathology it is the time to promote preventive strategies, by identifying the risk factors associated to life style and by incentivizing innovative diagnostic technologies. The promotion of the correct life style and of the use of diagnostic devices based on innovative and reliable technologies, represent a first step towards the full realization of the revolution of 4P medicine in atrial fibrillation.

  14. Viscoelastic behavior of discrete human collagen fibrils

    DEFF Research Database (Denmark)

    Svensson, René; Hassenkam, Tue; Hansen, Philip

    2010-01-01

    Whole tendon and fibril bundles display viscoelastic behavior, but to the best of our knowledge this property has not been directly measured in single human tendon fibrils. In the present work an atomic force microscopy (AFM) approach was used for tensile testing of two human patellar tendon...... saline, cyclic testing was performed in the pre-yield region at different strain rates, and the elastic response was determined by a stepwise stress relaxation test. The elastic stress-strain response corresponded to a second-order polynomial fit, while the viscous response showed a linear dependence...

  15. A Peptide Derived from the HIV-1 gp120 Coreceptor-Binding Region Promotes Formation of PAP248-286 Amyloid Fibrils to Enhance HIV-1 Infection.

    Directory of Open Access Journals (Sweden)

    Jinquan Chen

    Full Text Available Semen is a major vehicle for HIV transmission. Prostatic acid phosphatase (PAP fragments, such as PAP248-286, in human semen can form amyloid fibrils to enhance HIV infection. Other endogenous or exogenous factors present during sexual intercourse have also been reported to promote the formation of seminal amyloid fibrils.Here, we demonstrated that a synthetic 15-residue peptide derived from the HIV-1 gp120 coreceptor-binding region, designated enhancing peptide 2 (EP2, can rapidly self-assemble into nanofibers. These EP2-derivated nanofibers promptly accelerated the formation of semen amyloid fibrils by PAP248-286, as shown by Thioflavin T (ThT and Congo red assays. The amyloid fibrils presented similar morphology, assessed via transmission electron microscopy (TEM, in the presence or absence of EP2. Circular dichroism (CD spectroscopy revealed that EP2 accelerates PAP248-286 amyloid fibril formation by promoting the structural transition of PAP248-286 from a random coil into a cross-β-sheet. Newly formed semen amyloid fibrils effectively enhanced HIV-1 infection in TZM-bl cells and U87 cells by promoting the binding of HIV-1 virions to target cells.Nanofibers composed of EP2 promote the formation of PAP248-286 amyloid fibrils and enhance HIV-1 infection.

  16. Pulmonary vein isolation in the treatment of atrial fibrillation

    Directory of Open Access Journals (Sweden)

    Kumar S

    2016-05-01

    Full Text Available Saurabh Kumar, Gregory F Michaud Cardiac Arrhythmia Service, Cardiovascular Division, Brigham and Women's Hospital, Boston, MA, USA Abstract: Atrial fibrillation (AF is the commonest arrhythmia in humans and is associated with marked reduction in quality of life and an elevated thromboembolic risk. Paroxysmal, persistent, and permanent forms of AF have been recognized. Whilst antiarrhythmic drugs are considered as first-line therapy, the role of catheter ablation is increasing due to its superior efficacy in terms of quality of life and reduction in AF burden. The central paradigm for catheter ablation of AF is that triggers for AF are located near and within the pulmonary veins (PVs, and electrical isolation of the PVs from the left atrium forms the cornerstone of most catheter ablation strategies. Whilst paroxysmal form is generally trigger dependent, persistent and permanent forms are associated with variable interaction between triggers and "substrate" comprised of atrial and PV electrical and structural remodeling. Nevertheless, isolation of the PVs still forms a critical component of catheter ablation strategies, regardless of AF type. Procedural efficacy, however, is limited by PV conduction recovery. This is likely due to deficiencies in ablation tools or limitations of intraprocedural assessment of lesion efficacy. Careful attention to surrogates of tissue heating, such as impedance decrease and electrogram morphology changes, along with advances in catheter technology like contact force catheters may improve rates of durable PV isolation and single-procedural success. This review discusses the mechanism of paroxysmal AF with particular focus on the role of the PVs in AF initiation and PV isolation in the management of AF. Keywords: contact force, lesion transmurality, radiofrequency catheter ablation, paroxysmal atrial fibrillation, electrophysiology, AF

  17. Insights into Insulin Fibril Assembly at Physiological and Acidic pH and Related Amyloid Intrinsic Fluorescence

    Directory of Open Access Journals (Sweden)

    Clara Iannuzzi

    2017-11-01

    Full Text Available Human insulin is a widely used model protein for the study of amyloid formation as both associated to insulin injection amyloidosis in type II diabetes and highly prone to form amyloid fibrils in vitro. In this study, we aim to gain new structural insights into insulin fibril formation under two different aggregating conditions at neutral and acidic pH, using a combination of fluorescence, circular dichroism, Fourier-transform infrared spectroscopy, and transmission electron miscroscopy. We reveal that fibrils formed at neutral pH are morphologically different from those obtained at lower pH. Moreover, differences in FTIR spectra were also detected. In addition, only insulin fibrils formed at neutral pH showed the characteristic blue-green fluorescence generally associated to amyloid fibrils. So far, the molecular origin of this fluorescence phenomenon has not been clarified and different hypotheses have been proposed. In this respect, our data provide experimental evidence that allow identifying the molecular origin of such intrinsic property.

  18. Heterogeneous Seeding of a Prion Structure by a Generic Amyloid Form of the Fungal Prion-forming Domain HET-s(218-289)

    Energy Technology Data Exchange (ETDEWEB)

    Wan, William; Bian, Wen; McDonald, Michele; Kijac, Aleksandra; Wemmer, David E.; Stubbs, Gerald [UCB; (Vanderbilt); (LBNL)

    2013-11-13

    The fungal prion-forming domain HET-s(218–289) forms infectious amyloid fibrils at physiological pH that were shown by solid-state NMR to be assemblies of a two-rung β-solenoid structure. Under acidic conditions, HET-s(218–289) has been shown to form amyloid fibrils that have very low infectivity in vivo, but structural information about these fibrils has been very limited. We show by x-ray fiber diffraction that the HET-s(218–289) fibrils formed under acidic conditions have a stacked β-sheet architecture commonly found in short amyloidogenic peptides and denatured protein aggregates. At physiological pH, stacked β-sheet fibrils nucleate the formation of the infectious β-solenoid prions in a process of heterogeneous seeding, but do so with kinetic profiles distinct from those of spontaneous or homogeneous (seeded with infectious β-solenoid fibrils) fibrillization. Several serial passages of stacked β-sheet-seeded solutions lead to fibrillization kinetics similar to homogeneously seeded solutions. Our results directly show that structural mutation can occur between substantially different amyloid architectures, lending credence to the suggestion that the processes of strain adaptation and crossing species barriers are facilitated by structural mutation.

  19. New risk factors for atrial fibrillation : causes of 'not-so-lone atrial fibrillation'

    NARCIS (Netherlands)

    Schoonderwoerd, Bas A.; Smit, Marcelle D.; Pen, Lucas; Van Gelder, Isabelle C.

    Atrial fibrillation (AF) is a prevalent arrhythmia in patients with cardiovascular disease. The classical risk factors for developing AF include hypertension, valvular disease, (ischaemic) cardiomyopathy, diabetes mellitus, and thyroid disease. In some patients with AF, no underlying

  20. Protein Polymerization into Fibrils from the Viewpoint of Nucleation Theory.

    Science.gov (United States)

    Kashchiev, Dimo

    2015-11-17

    The assembly of various proteins into fibrillar aggregates is an important phenomenon with wide implications ranging from human disease to nanoscience. Using general kinetic results of nucleation theory, we analyze the polymerization of protein into linear or helical fibrils in the framework of the Oosawa-Kasai (OK) model. We show that while within the original OK model of linear polymerization the process does not involve nucleation, within a modified OK model it is nucleation-mediated. Expressions are derived for the size of the fibril nucleus, the work for fibril formation, the nucleation barrier, the equilibrium and stationary fibril size distributions, and the stationary fibril nucleation rate. Under otherwise equal conditions, this rate decreases considerably when the short (subnucleus) fibrils lose monomers much more frequently than the long (supernucleus) fibrils, a feature that should be born in mind when designing a strategy for stymying or stimulating fibril nucleation. The obtained dependence of the nucleation rate on the concentration of monomeric protein is convenient for experimental verification and for use in rate equations accounting for nucleation-mediated fibril formation. The analysis and the results obtained for linear fibrils are fully applicable to helical fibrils whose formation is describable by a simplified OK model. Copyright © 2015 Biophysical Society. Published by Elsevier Inc. All rights reserved.

  1. Embolic Risk in Atrial Fibrillation that Arises from Hyperthyroidism

    Science.gov (United States)

    Traube, Elie; Coplan, Neil L.

    2011-01-01

    Atrial fibrillation, the most common cardiac complication of hyperthyroidism, occurs in an estimated 10% to 25% of overtly hyperthyroid patients. The prevalence of atrial fibrillation increases with age in the general population and in thyrotoxic patients. Other risk factors for atrial fibrillation in thyrotoxic patients include male sex, ischemic or valvular heart disease, and congestive heart failure. The incidence of arterial embolism or stroke in thyrotoxic atrial fibrillation is less clear. There are many reports of arterial thromboembolism associated with hyperthyroidism, including cases of young adults without coexisting risk factors other than thyrotoxic atrial fibrillation. The use of anticoagulative agents to prevent thromboembolic sequelae of thyrotoxic atrial fibrillation is controversial: national organizations provide conflicting recommendations in their practice guidelines. Herein, we review the medical literature and examine the evidence behind the recommendations in order to determine the best approach to thromboembolic prophylaxis in patients who have atrial fibrillation that is associated with hyperthyroidism. PMID:21720457

  2. Neuronal low-density lipoprotein receptor-related protein 1 binds and endocytoses prion fibrils via receptor cluster 4

    DEFF Research Database (Denmark)

    Jen, Angela; Parkyn, Celia J; Mootoosamy, Roy C

    2010-01-01

    For infectious prion protein (designated PrP(Sc)) to act as a template to convert normal cellular protein (PrP(C)) to its distinctive pathogenic conformation, the two forms of prion protein (PrP) must interact closely. The neuronal receptor that rapidly endocytoses PrP(C) is the low......-density lipoprotein receptor-related protein 1 (LRP1). We show here that on sensory neurons LRP1 is also the receptor that binds and rapidly endocytoses smaller oligomeric forms of infectious prion fibrils, and recombinant PrP fibrils. Although LRP1 binds two molecules of most ligands independently to its receptor...... both prion and LRP1 biology....

  3. Spontaneous conversion of first onset atrial fibrillation

    DEFF Research Database (Denmark)

    Lindberg, Søren Østergaard; Hansen, Sidsel; Nielsen, Tonny

    2011-01-01

    Background  We studied all patients admitted to hospital with first onset atrial fibrillation (AF) to determine the probability of spontaneous conversion to sinus rhythm and to identify factors predictive of such a conversion. Methods and Results  We retrospectively reviewed charts of 438...

  4. Genetic aspects of lone atrial fibrillation

    DEFF Research Database (Denmark)

    Andreasen, Laura; Nielsen, Jonas B; Olesen, Morten S

    2015-01-01

    Atrial fibrillation (AF) is the most common cardiac arrhythmia. A subgroup of patients presents with AF without traditional risk factors and is diagnosed before the age of 60 years. Such patients are commonly referred as having "lone AF" and comprise 10-20% of all cases. A number of studies have...

  5. Atrial fibrillation in the Middle East

    DEFF Research Database (Denmark)

    Al-Shamkhani, Warkaa; Ayetey, Harold; Lip, Gregory Y H

    2018-01-01

    INTRODUCTION: Atrial fibrillation (AF) is the commonest persistent cardiac arrhythmia with an estimated incidence rate of between 1.5-2% and an important cause of strokes. Few epidemiological studies and clinical trials on the management of AF have been conducted outside Europe and North America...

  6. An "account" of digitalis and atrial fibrillation

    NARCIS (Netherlands)

    Meijler, F.L.

    This review deals with the mechanisms by which digitalis exerts its "opium-Iike" action on the ventricular rate in patients with atrial fibrillation. To understand the effect of digitalis on ventricular rate and rhythm, it is essential to learn more about the basic electrophysiologic

  7. Aggregation and fibrillation of bovine serum albumin

    DEFF Research Database (Denmark)

    Holm, NK; Jespersen, SK; Thomassen, LV

    2007-01-01

    The all-alpha helix multi-domain protein bovine serum albumin (BSA) aggregates at elevated temperatures. Here we show that these thermal aggregates have amyloid properties. They bind the fibril-specific dyes Thioflavin T and Congo Red, show elongated although somewhat worm-like morphology...

  8. Characterization of dry globular proteins and protein fibrils by synchrotron radiation vacuum UV circular dichroism

    DEFF Research Database (Denmark)

    Nesgaard, Lise W.; Hoffmann, Søren Vrønning; Andersen, Christian Beyschau

    2008-01-01

    Circular dichroism using synchrotron radiation (SRCD) can extend the spectral range down to approximately 130 nm for dry proteins, potentially providing new structural information. Using a selection of dried model proteins, including alpha-helical, beta-sheet, and mixed-structure proteins, we...... with previously published theoretical calculations related to pi-orbital transitions. We also show that drying does not lead to large changes in the secondary structure and does not induce orientational artifacts. In combination with principal component analysis, our SRCD data allow us to distinguish between two...... different types of protein fibrils, highlighting that bona fide fibrils formed by lysozyme are structurally more similar to the nonclassical fibrillar aggregates formed by the SerADan peptide than with the amyloid formed by alpha-synuclein. Thus, despite the lack of direct structural conclusions...

  9. Kinetics and mechanical stability of the fibril state control fibril formation time of polypeptide chains: A computational study

    Science.gov (United States)

    Kouza, Maksim; Co, Nguyen Truong; Li, Mai Suan; Kmiecik, Sebastian; Kolinski, Andrzej; Kloczkowski, Andrzej; Buhimschi, Irina Alexandra

    2018-06-01

    Fibril formation resulting from protein misfolding and aggregation is a hallmark of several neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. Despite much progress in the understanding of the protein aggregation process, the factors governing fibril formation rates and fibril stability have not been fully understood. Using lattice models, we have shown that the fibril formation time is controlled by the kinetic stability of the fibril state but not by its energy. Having performed all-atom explicit solvent molecular dynamics simulations with the GROMOS43a1 force field for full-length amyloid beta peptides Aβ40 and Aβ42 and truncated peptides, we demonstrated that kinetic stability can be accessed via mechanical stability in such a way that the higher the mechanical stability or the kinetic stability, the faster the fibril formation. This result opens up a new way for predicting fibril formation rates based on mechanical stability that may be easily estimated by steered molecular dynamics.

  10. A setup for simultaneous measurement of infrared spectra and light scattering signals: Watching amyloid fibrils grow from intact proteins

    Energy Technology Data Exchange (ETDEWEB)

    Li, Yang; Maurer, Jürgen; Roth, Andreas; Vogel, Vitali; Winter, Ernst; Mäntele, Werner, E-mail: maentele@biophysik.uni-frankfurt.de [Institut für Biophysik, Goethe-Universität Frankfurt am Main, Max-von Laue-Straße 1, D-60438 Frankfurt am Main (Germany)

    2014-08-15

    A setup for the simultaneous measurement of mid-infrared spectra and static light scattering is described that can be used for the analysis of the formation of nanoscale and microscopic aggregates from smaller molecules to biopolymers. It can be easily integrated into sample chambers of infrared spectrometers or combined with laser beams from tunable infrared lasers. Here, its use for the analysis of the formation of amyloid fibrils from intact proteins is demonstrated. The formation of amyloid fibrils or plaques from proteins is a widespread and pathogenetic relevant process, and a number of diseases are caused and correlated with the deposition of amyloid fibrils in cells and tissues. The molecular mechanisms of these transformations, however, are still unclear. We report here the simultaneous measurement of infrared spectra and static light scattering for the analysis of fibril formation from egg-white lysozyme. The transformation of the native form into non-native forms rich in β-sheet structure is measured by analysis of the amide I spectral region in the infrared spectra, which is sensitive for local structures. At the same time, light scattering signals at forward direction as well as the forward/backward ratio, which are sensitive for the number of scattering centers and their approximate sizes, respectively, are collected for the analysis of fibril growth. Thermodynamic and kinetic parameters as well as mechanistic information are deduced from the combination of the two complementary techniques.

  11. A setup for simultaneous measurement of infrared spectra and light scattering signals: Watching amyloid fibrils grow from intact proteins

    Science.gov (United States)

    Li, Yang; Maurer, Jürgen; Roth, Andreas; Vogel, Vitali; Winter, Ernst; Mäntele, Werner

    2014-08-01

    A setup for the simultaneous measurement of mid-infrared spectra and static light scattering is described that can be used for the analysis of the formation of nanoscale and microscopic aggregates from smaller molecules to biopolymers. It can be easily integrated into sample chambers of infrared spectrometers or combined with laser beams from tunable infrared lasers. Here, its use for the analysis of the formation of amyloid fibrils from intact proteins is demonstrated. The formation of amyloid fibrils or plaques from proteins is a widespread and pathogenetic relevant process, and a number of diseases are caused and correlated with the deposition of amyloid fibrils in cells and tissues. The molecular mechanisms of these transformations, however, are still unclear. We report here the simultaneous measurement of infrared spectra and static light scattering for the analysis of fibril formation from egg-white lysozyme. The transformation of the native form into non-native forms rich in β-sheet structure is measured by analysis of the amide I spectral region in the infrared spectra, which is sensitive for local structures. At the same time, light scattering signals at forward direction as well as the forward/backward ratio, which are sensitive for the number of scattering centers and their approximate sizes, respectively, are collected for the analysis of fibril growth. Thermodynamic and kinetic parameters as well as mechanistic information are deduced from the combination of the two complementary techniques.

  12. Role of PAMAM-OH dendrimers against the fibrillation pathway of biomolecules.

    Science.gov (United States)

    Sekar, Gajalakshmi; Florance, Ida; Sivakumar, A; Mukherjee, Amitava; Chandrasekaran, Natarajan

    2016-12-01

    The binding behavior of nanoparticle with proteins determines its biocompatibility. This study reports the interaction of ten different biomolecules (proteins-BSA, HSA, haemoglobin, gamma globulin, transferrin and enzymes-hog and bacillus amylase, lysozyme from chicken and human and laccases from Tramates versicolor) with a surface group hydroxylated Poly AMido AMide dendrimer (PAMAM) of generation 5. The study has utilized various spectroscopic methods like UV-vis spectroscopy, Fluorescence emission, Synchronous, 3-D spectroscopy and Circular Dichroism to detect the binding induced structural changes in biomolecules that occur upon interaction with mounting concentration of the dendrimers. Aggregation of proteins results in the formation of amyloid fibrils causing several human diseases. In this study, fibrillar samples of all ten biomolecules formed in the absence and the presence of dendrimers were investigated with Congo Red absorbance and ThT Assay to detect fibril formation, Trp Emission and 3-D scan to evaluate the effect of fibrillation on aromatic environment of biomolecules, and CD spectroscopy to measure the conformational changes in a quantitative manner. These assays have generated useful information on the role of dendrimers in amyloid fibril formation of biomolecules. The outcomes of the study remain valuable in evaluating the biological safety of PAMAM-OH dendrimers for their biomedical application in vivo. Copyright © 2016 Elsevier B.V. All rights reserved.

  13. Kinetically controlled thermal response of beta2-microglobulin amyloid fibrils.

    Science.gov (United States)

    Sasahara, Kenji; Naiki, Hironobu; Goto, Yuji

    2005-09-23

    Calorimetric measurements were carried out using a differential scanning calorimeter in the temperature range from 10 to 120 degrees C for characterizing the thermal response of beta2-microglobulin amyloid fibrils. The thermograms of amyloid fibril solution showed a remarkably large decrease in heat capacity that was essentially released upon the thermal unfolding of the fibrils, in which the magnitude of negative heat capacity change was not explicable in terms of the current accessible surface area model of protein structural thermodynamics. The heat capacity-temperature curve of amyloid fibrils prior to the fibril unfolding exhibited an unusual dependence on the fibril concentration and the heating rate. Particularly, the heat needed to induce the thermal response was found to be linearly dependent on the heating rate, indicating that its thermal response is under a kinetic control and precluding the interpretation in terms of equilibrium thermodynamics. Furthermore, amyloid fibrils of amyloid beta peptides also exhibited a heating rate-dependent exothermic process before the fibril unfolding, indicating that the kinetically controlled thermal response may be a common phenomenon to amyloid fibrils. We suggest that the heating rate-dependent negative change in heat capacity is coupled to the association of amyloid fibrils with characteristic hydration pattern.

  14. The C-terminus hot spot region helps in the fibril formation of bacteriophage-associated hyaluronate lyase (HylP2).

    Science.gov (United States)

    Shukla, Harish; Singh, Sudhir Kumar; Singh, Amit Kumar; Mitra, Kalyan; Akhtar, Md Sohail

    2015-09-23

    The bacteriophage encoded hyaluronate lyases (HylP and HylP2) degrade hyaluronan and other glycosaminoglycans. HylP2 forms a functional fibril under acidic conditions in which its N-terminus is proposed to form the fibrillar core, leading to nucleation and acceleration of fibril formation. Here we report the presence of a hot spot region (A144GVVVY149) towards the carboxy terminus of HylP2, essential for the acceleration of fibril formation. The 'hot spot' is observed to be inherently mutated for valines (A178AMVMY183) in case of HylP. The N- terminal swapped chimeras between these phage HLs ((N)HylP2(C)HylP and (N)HylP(C)HylP2) or HylP did not form fibrils at acidic pH. However, seeding of prefibrils of HylP2 recompensed nucleation and led to fibrillation in (N)HylP(C)HylP2. The V147A mutation in the 'hot spot' region abolished fibril formation in HylP2. The M179V and M181V double mutations in the 'hot spot' region of HylP led to fibrillation with the seeding of prefibrils. It appears that fibrillation in HylP2 even though is initiated by the N-terminus, is accelerated by the conserved 'hot spot' region in the C-terminus. A collagenous (Gly-X-Y)10 motif in the N-terminus and a mutated 'hot spot' region in the C-terminus of HylP affect fibrillar nucleation and acceleration respectively.

  15. Current practice for diagnosis and management of silent atrial fibrillation

    DEFF Research Database (Denmark)

    Dobreanu, Dan; Svendsen, Jesper Hastrup; Lewalter, Thorsten

    2013-01-01

    for the diagnosis and management of silent AF. This survey is based on an electronic questionnaire sent to the European Heart Rhythm Association Research Network partners. Responses were received from 33 centres in 16 countries. The preferred screening methods for silent AF in patients with rhythm control...... for such patients. Most responders preferred rate control over rhythm control in patients with silent AF, although some favoured pulmonary vein isolation in young patients. However, oral anticoagulant therapy in patients at high thromboembolic risk was considered mandatory by most, provided that at least one......Although it is well known that silent atrial fibrillation (AF) is associated with morbidity and mortality rates similar to those of symptomatic AF, no specific strategy for screening and management of this form of AF has been advocated. The purpose of this survey was to identify current practices...

  16. Are Amyloid Fibrils RNA-Traps? A Molecular Dynamics Perspective

    Directory of Open Access Journals (Sweden)

    Massimiliano Meli

    2018-06-01

    Full Text Available The self-assembly of proteins and peptides into amyloids is a key feature of an increasing number of diseases. Amyloid fibrils display a unique surface reactivity endowing the sequestration of molecules such as MicroRNAs, which can be the active moiety of the toxic action. To test this hypothesis we studied the recognition between a model RNA and two different steric zipper spines using molecular dynamics simulations. We found that the interaction occurs and displays peptide-sequence dependence. Interestingly, interactions with polar zipper surfaces such as the formed by SNQNNF are more stable and favor the formation of β-barrel like complexes resembling the structures of toxic oligomers. These sequence-structure-recognition relationships of the two different assemblies may be exploited for the design of compounds targeting the fibers or competing with RNA-amyloid attachment

  17. Improving antithrombotic management in patients with atrial fibrillation: current status and perspectives

    DEFF Research Database (Denmark)

    Levi, Marcel; Hobbs, F D Richard; Jacobson, Alan K

    2009-01-01

    Despite overwhelming evidence of the benefits of risk-adjusted oral anticoagulation on stroke reduction in patients with atrial fibrillation (AF), there is still considerable undertreatment. A multidisciplinary expert group was formed to discuss issues surrounding anticoagulant treatment of patie......, such as anticoagulation clinics, or by patient self-management may improve the quality of anticoagulation and facilitate the management of these patients and thereby further facilitate optimal antithrombotic management in patients with AF.......Despite overwhelming evidence of the benefits of risk-adjusted oral anticoagulation on stroke reduction in patients with atrial fibrillation (AF), there is still considerable undertreatment. A multidisciplinary expert group was formed to discuss issues surrounding anticoagulant treatment...... important conclusions of the meeting was to enhance guideline adherence by better communication of the data showing that the benefits of stroke reduction outweigh the risk of bleeding associated with treatment with vitamin K antagonists. Management of oral anticoagulation therapy by dedicated centers...

  18. Atrial fibrillation and vascular disease-a bad combination

    DEFF Research Database (Denmark)

    Bjerring Olesen, Jonas; Gislason, Gunnar Hilmar; Torp-Pedersen, Christian

    2012-01-01

    This article provides an overview of (i) the risk of stroke associated with vascular disease (acute coronary syndromes and peripheral artery disease) in patients with atrial fibrillation, (ii) the frequent coexistence of vascular disease in patients with atrial fibrillation and, (iii...... fibrillation. Indeed, patients with atrial fibrillation often had coexisting vascular disease (around 18%), and the combination of the two diseases substantially increases the risk of future cardiovascular events. The increased risk associated with peripheral artery disease in atrial fibrillation is even more...... pronounced. Patients with atrial fibrillation and stable vascular disease should be treated with oral anticoagulation only, although when these patients present with acute coronary syndrome and/or undergo coronary stenting, concomitant treatment with antiplatelet drugs is indicated. To guide antithrombotic...

  19. Evidence of structurally continuous collagen fibrils in tendon

    DEFF Research Database (Denmark)

    Svensson, Rene B; Herchenhan, Andreas; Starborg, Tobias

    2017-01-01

    favor continuity. This study initially set out to trace the full length of individual fibrils in adult human tendons, using serial block face-scanning electron microscopy. But even with this advanced technique the required length could not be covered. Instead a statistical approach was used on a large...... volume of fibrils in shorter image stacks. Only a single end was observed after tracking 67.5 mm of combined fibril lengths, in support of fibril continuity. To shed more light on this observation, the full length of a short tendon (mouse stapedius, 125 μm) was investigated and continuity of individual...... fibrils was confirmed. In light of these results, possible mechanisms that could reconcile the opposing findings on fibril continuity are discussed. STATEMENT OF SIGNIFICANCE: Connective tissues hold all parts of the body together and are mostly constructed from thin threads of the protein collagen...

  20. α-Synuclein fibril-induced paradoxical structural and functional defects in hippocampal neurons.

    Science.gov (United States)

    Froula, Jessica M; Henderson, Benjamin W; Gonzalez, Jose Carlos; Vaden, Jada H; Mclean, John W; Wu, Yumei; Banumurthy, Gokulakrishna; Overstreet-Wadiche, Linda; Herskowitz, Jeremy H; Volpicelli-Daley, Laura A

    2018-05-01

    Neuronal inclusions composed of α-synuclein (α-syn) characterize Parkinson's Disease (PD) and Dementia with Lewy bodies (DLB). Cognitive dysfunction defines DLB, and up to 80% of PD patients develop dementia. α-Syn inclusions are abundant in the hippocampus, yet functional consequences are unclear. To determine if pathologic α-syn causes neuronal defects, we induced endogenous α-syn to form inclusions resembling those found in diseased brains by treating hippocampal neurons with α-syn fibrils. At seven days after adding fibrils, α-syn inclusions are abundant in axons, but there is no cell death at this time point, allowing us to assess for potential alterations in neuronal function that are not caused by neuron death. We found that exposure of neurons to fibrils caused a significant reduction in mushroom spine densities, adding to the growing body of literature showing that altered spine morphology is a major pathologic phenotype in synucleinopathies. The reduction in spine densities occurred only in wild type neurons and not in neurons from α-syn knockout mice, suggesting that the changes in spine morphology result from fibril-induced corruption of endogenously expressed α-syn. Paradoxically, reduced postsynaptic spine density was accompanied by increased frequency of miniature excitatory postsynaptic currents (EPSCs) and presynaptic docked vesicles, suggesting enhanced presynaptic function. Action-potential dependent activity was unchanged, suggesting compensatory mechanisms responding to synaptic defects. Although activity at the level of the synapse was unchanged, neurons exposed to α-syn fibrils, showed reduced frequency and amplitudes of spontaneous Ca 2+ transients. These findings open areas of research to determine the mechanisms that alter neuronal function in brain regions critical for cognition at time points before neuron death.

  1. Protein disulfide isomerase interacts with tau protein and inhibits its fibrillization.

    Directory of Open Access Journals (Sweden)

    Li-Rong Xu

    Full Text Available BACKGROUND: Tau protein is implicated in the pathogenesis of neurodegenerative disorders such as tauopathies including Alzheimer disease, and Tau fibrillization is thought to be related to neuronal toxicity. Physiological inhibitors of Tau fibrillization hold promise for developing new strategies for treatment of Alzheimer disease. Because protein disulfide isomerase (PDI is both an enzyme and a chaperone, and implicated in neuroprotection against Alzheimer disease, we want to know whether PDI can prevent Tau fibrillization. In this study, we have investigated the interaction between PDI and Tau protein and the effect of PDI on Tau fibrillization. METHODOLOGY/PRINCIPAL FINDINGS: As evidenced by co-immunoprecipitation and confocal laser scanning microscopy, human PDI interacts and co-locates with some endogenous human Tau on the endoplasmic reticulum of undifferentiated SH-SY5Y neuroblastoma cells. The results from isothermal titration calorimetry show that one full-length human PDI binds to one full-length human Tau (or human Tau fragment Tau244-372 monomer with moderate, micromolar affinity at physiological pH and near physiological ionic strength. As revealed by thioflavin T binding assays, Sarkosyl-insoluble SDS-PAGE, and transmission electron microscopy, full-length human PDI remarkably inhibits both steps of nucleation and elongation of Tau244-372 fibrillization in a concentration-dependent manner. Furthermore, we find that two molecules of the a-domain of human PDI interact with one Tau244-372 molecule with sub-micromolar affinity, and inhibit both steps of nucleation and elongation of Tau244-372 fibrillization more strongly than full-length human PDI. CONCLUSIONS/SIGNIFICANCE: We demonstrate for the first time that human PDI binds to Tau protein mainly through its thioredoxin-like catalytic domain a, forming a 1∶1 complex and preventing Tau misfolding. Our findings suggest that PDI could act as a physiological inhibitor of Tau

  2. Endurance Sport Practice and Atrial Fibrillation

    OpenAIRE

    Calvo, Naiara; Mont, Lluis

    2010-01-01

    Atrial fibrillation (AF) is the most common cardiac rhythm disorder in clinical practice, with an estimated prevalence of 0.4% to 1% in the general population, increasing with age to 8% in those older than 80 years. The recognized risk factors for developing AF include age, hypertension, structural heart disease, diabetes mellitus, and hyperthyroidism. However, the etiology remains unclear in a significant number of patients younger than age 60 in whom no cardiovascular disease or any other k...

  3. Red Wine, Resveratrol and Atrial Fibrillation

    OpenAIRE

    Stephan, Laura Siga; Almeida, Eduardo Dytz; Markoski, Melissa Medeiros; Garavaglia, Juliano; Marcadenti, Aline

    2017-01-01

    Atrial fibrillation (AF) is a common cardiac arrhythmia that is associated with increased risk for cardiovascular disease and overall mortality. Excessive alcohol intake is a well-known risk factor for AF, but this correlation is less clear with light and moderate drinking. Besides, low doses of red wine may acutely prolong repolarization and slow cardiac conduction. Resveratrol, a bioactive polyphenol found in grapes and red wine, has been linked to antiarrhythmic properties and may act as a...

  4. Acute atrial fibrillation during dengue hemorrhagic fever

    Directory of Open Access Journals (Sweden)

    Henrique Horta Veloso

    Full Text Available Dengue fever is a viral infection transmitted by the mosquito, Aedes aegypti. Cardiac rhythm disorders, such as atrioventricular blocks and ventricular ectopic beats, appear during infection and are attributed to viral myocarditis. However, supraventricular arrhythmias have not been reported. We present a case of acute atrial fibrillation, with a rapid ventricular rate, successfully treated with intravenous amiodarone, in a 62-year-old man with dengue hemorrhagic fever, who had no structural heart disease.

  5. Acute atrial fibrillation during dengue hemorrhagic fever

    Directory of Open Access Journals (Sweden)

    Veloso Henrique Horta

    2003-01-01

    Full Text Available Dengue fever is a viral infection transmitted by the mosquito, Aedes aegypti. Cardiac rhythm disorders, such as atrioventricular blocks and ventricular ectopic beats, appear during infection and are attributed to viral myocarditis. However, supraventricular arrhythmias have not been reported. We present a case of acute atrial fibrillation, with a rapid ventricular rate, successfully treated with intravenous amiodarone, in a 62-year-old man with dengue hemorrhagic fever, who had no structural heart disease.

  6. The effect of integrated cardiac rehabilitation versus treatment as usual for atrial fibrillation patients treated with ablation

    DEFF Research Database (Denmark)

    Risom, Signe Stelling; Zwisler, Ann-Dorth Olsen; Rasmussen, Trine Bernholdt

    2013-01-01

    fibrillation treated with ablation. METHODS AND ANALYSIS DESIGN: The trial is a multicentre parallel arm design with 1:1 randomisation to the intervention and control group with blinded outcome assessment. 210 patients treated for atrial fibrillation with radiofrequency ablation will be included...... measure is exercise capacity measured by the VO(2) peak. The secondary outcome measure is self-rated mental health measured by the Short Form 36 questionnaire. Postintervention, qualitative interviews will be conducted in 10% of the intervention group. ETHICS AND DISSEMINATION: The protocol is approved...

  7. Atrial Fibrillation in Eight New World Camelids.

    Science.gov (United States)

    Bozorgmanesh, R; Magdesian, K G; Estell, K E; Stern, J A; Swain, E A; Griffiths, L G

    2016-01-01

    There is limited information on the incidence of clinical signs, concurrent illness and treatment options for atrial fibrillation (AF) in New World Camelids (NWC). Describe clinical signs and outcome of AF in NWC. Eight New World Camelids admitted with AF. A retrospective observational study of camelids diagnosed with AF based on characteristic findings on electrocardiogram (ECG). All animals had an irregularly irregular heart rhythm detected on physical examination and 4 cases had obtunded mentation on admission. Three camelids were diagnosed with AF secondary to oleander intoxication, 3 animals had underlying cardiovascular disease, 1 was diagnosed with lone AF and 1 had AF diagnosed on examination for a urethral obstruction. Five of eight animals survived to discharge and nonsurvivors consisted of animals which died or were euthanized as a result of cardiovascular disease (2/8) or extra-cardiac disease unrelated to the AF (1/8). Atrial fibrillation occurs in NWC in association with cardiovascular disease, extra-cardiac disease or as lone AF. Amiodarone and transthoracic cardioversion were attempted in one llama with lone AF, but were unsuccessful. Atrial fibrillation was recorded in 0.1% of admissions. Copyright © 2015 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.

  8. Atrial fibrillation pearls and perils of management.

    Science.gov (United States)

    Kudenchuk, P J

    1996-01-01

    Atrial fibrillation, a common arrhythmia, is responsible for considerable cardiovascular morbidity. Its management demands more than antiarrhythmic therapy alone, but must address the causes and consequences of the arrhythmia. Although remediable causes are infrequently found, a thorough search for associated heart disease or its risk factors results in better-informed patient management. Controlling the ventricular response and protecting from thromboembolic complications are important initial goals of therapy and may include the administration of aspirin in younger, low-risk patients. Older patients and those with risk factors for systemic embolism are not adequately protected from stroke complications by aspirin therapy alone. It remains controversial whether all high-risk patients should receive warfarin and at what intensity. Whether and how sinus rhythm should be restored and maintained poses the greatest therapeutic controversy for atrial fibrillation. The mortal risk of antiarrhythmic therapy is substantially greater in patients with evidence of heart failure. In such persons, the risks and benefits of maintaining normal sinus rhythm with antiarrhythmic medications should be weighted carefully. A definitive cure for atrial fibrillation remains elusive, but promising surgical and catheter ablation therapies are being developed. PMID:8686300

  9. Electromechanical vortex filaments during cardiac fibrillation

    Science.gov (United States)

    Christoph, J.; Chebbok, M.; Richter, C.; Schröder-Schetelig, J.; Bittihn, P.; Stein, S.; Uzelac, I.; Fenton, F. H.; Hasenfuß, G.; Gilmour, R. F., Jr.; Luther, S.

    2018-03-01

    The self-organized dynamics of vortex-like rotating waves, which are also known as scroll waves, are the basis of the formation of complex spatiotemporal patterns in many excitable chemical and biological systems. In the heart, filament-like phase singularities that are associated with three-dimensional scroll waves are considered to be the organizing centres of life-threatening cardiac arrhythmias. The mechanisms that underlie the onset, maintenance and control of electromechanical turbulence in the heart are inherently three-dimensional phenomena. However, it has not previously been possible to visualize the three-dimensional spatiotemporal dynamics of scroll waves inside cardiac tissues. Here we show that three-dimensional mechanical scroll waves and filament-like phase singularities can be observed deep inside the contracting heart wall using high-resolution four-dimensional ultrasound-based strain imaging. We found that mechanical phase singularities co-exist with electrical phase singularities during cardiac fibrillation. We investigated the dynamics of electrical and mechanical phase singularities by simultaneously measuring the membrane potential, intracellular calcium concentration and mechanical contractions of the heart. We show that cardiac fibrillation can be characterized using the three-dimensional spatiotemporal dynamics of mechanical phase singularities, which arise inside the fibrillating contracting ventricular wall. We demonstrate that electrical and mechanical phase singularities show complex interactions and we characterize their dynamics in terms of trajectories, topological charge and lifetime. We anticipate that our findings will provide novel perspectives for non-invasive diagnostic imaging and therapeutic applications.

  10. Exercise-based cardiac rehabilitation for adults with atrial fibrillation

    DEFF Research Database (Denmark)

    Risom, Signe Stelling; Zwisler, Ann-Dorthe; Johansen, Pernille Palm

    2017-01-01

    BACKGROUND: Exercise-based cardiac rehabilitation may benefit adults with atrial fibrillation or those who had been treated for atrial fibrillation. Atrial fibrillation is caused by multiple micro re-entry circuits within the atrial tissue, which result in chaotic rapid activity in the atria....... OBJECTIVES: To assess the benefits and harms of exercise-based rehabilitation programmes, alone or with another intervention, compared with no-exercise training controls in adults who currently have AF, or have been treated for AF. SEARCH METHODS: We searched the following electronic databases; CENTRAL...... the benefits and harms of exercise-based cardiac rehabilitation for adults with atrial fibrillation on patient-relevant outcomes....

  11. In vitro tendon tissue development from human fibroblasts demonstrates collagen fibril diameter growth associated with a rise in mechanical strength

    DEFF Research Database (Denmark)

    Herchenhan, Andreas; Bayer, Monika L; Svensson, René B

    2013-01-01

    Collagen-rich tendons and ligaments are important for joint stability and force transmission, but the capacity to form new tendon is poorly understood. In the present study, we investigated mechanical strength, fibril size, and structure during development of tendon-like tissue from adult human...

  12. Site-specific perturbations of alpha-synuclein fibril structure by the Parkinson's disease associated mutations A53T and E46K.

    Directory of Open Access Journals (Sweden)

    Luisel R Lemkau

    Full Text Available Parkinson's disease (PD is pathologically characterized by the presence of Lewy bodies (LBs in dopaminergic neurons of the substantia nigra. These intracellular inclusions are largely composed of misfolded α-synuclein (AS, a neuronal protein that is abundant in the vertebrate brain. Point mutations in AS are associated with rare, early-onset forms of PD, although aggregation of the wild-type (WT protein is observed in the more common sporadic forms of the disease. Here, we employed multidimensional solid-state NMR experiments to assess A53T and E46K mutant fibrils, in comparison to our recent description of WT AS fibrils. We made de novo chemical shift assignments for the mutants, and used these chemical shifts to empirically determine secondary structures. We observe significant perturbations in secondary structure throughout the fibril core for the E46K fibril, while the A53T fibril exhibits more localized perturbations near the mutation site. Overall, these results demonstrate that the secondary structure of A53T has some small differences from the WT and the secondary structure of E46K has significant differences, which may alter the overall structural arrangement of the fibrils.

  13. Evidence for Intramolecular Antiparallel Beta-Sheet Structure in Alpha-Synuclein Fibrils from a Combination of Two-Dimensional Infrared Spectroscopy and Atomic Force Microscopy

    Science.gov (United States)

    Roeters, Steven J.; Iyer, Aditya; Pletikapić, Galja; Kogan, Vladimir; Subramaniam, Vinod; Woutersen, Sander

    2017-01-01

    The aggregation of the intrinsically disordered protein alpha-synuclein (αS) into amyloid fibrils is thought to play a central role in the pathology of Parkinson’s disease. Using a combination of techniques (AFM, UV-CD, XRD, and amide-I 1D- and 2D-IR spectroscopy) we show that the structure of αS fibrils varies as a function of ionic strength: fibrils aggregated in low ionic-strength buffers ([NaCl] ≤ 25 mM) have a significantly different structure than fibrils grown in higher ionic-strength buffers. The observations for fibrils aggregated in low-salt buffers are consistent with an extended conformation of αS molecules, forming hydrogen-bonded intermolecular β-sheets that are loosely packed in a parallel fashion. For fibrils aggregated in high-salt buffers (including those prepared in buffers with a physiological salt concentration) the measurements are consistent with αS molecules in a more tightly-packed, antiparallel intramolecular conformation, and suggest a structure characterized by two twisting stacks of approximately five hydrogen-bonded intermolecular β-sheets each. We find evidence that the high-frequency peak in the amide-I spectrum of αS fibrils involves a normal mode that differs fundamentally from the canonical high-frequency antiparallel β-sheet mode. The high sensitivity of the fibril structure to the ionic strength might form the basis of differences in αS-related pathologies.

  14. Teaching Form as Form

    DEFF Research Database (Denmark)

    Keiding, Tina Bering

    2012-01-01

    understanding of form per se, or, to use an expression from this text, of form as form. This challenge can be reduced to one question: how can design teaching support students in achieving not only the ability to recognize and describe different form-related concepts in existing design (i.e. analytical...

  15. In vitro disintegration of goat brain cystatin fibrils using conventional and gemini surfactants: Putative therapeutic intervention in amyloidoses.

    Science.gov (United States)

    Bhat, Waseem Feeroze; Bhat, Imtiyaz Ahmad; Bhat, Sheraz Ahmad; Bano, Bilqees

    2016-12-01

    Many protein misfolding diseases in mammalian system are characterised by the accumulation of protein aggregates in amyloid fibrillar forms. Several therapeutic approaches include reduction in the production of the amyloidogenic form of proteins, increase in the clearance rate of misfolded or aggregated proteins, and direct inhibition of the self-assembly process have been explained. One of the possible remedial treatments for such disorders may be to identify molecules which are capable of either preventing formation of fibrils or disintegrating the formed fibrils. In this work, we have studied the effect of conventional surfactants; sodium dodecylsulphate (SDS), cetyl trimethylammonium bromide (CTAB) and dicationic gemini (16-4-16) surfactant on the disintegration of the goat brain cystatin (GBC) fibrils above their critical micelle concentrations (CMC) using ThT fluorescence, CD, TEM, Congo red and turbidity approaches. The results obtained are significant and showing the best disintegrating potency on GBC fibrils with gemini surfactant. The outcome from this work will aid in the development and/or design of potential inhibitory agents against amyloid deposits associated with amyloid diseases. Copyright © 2016 Elsevier B.V. All rights reserved.

  16. Does Myocardial Infarction Beget Atrial Fibrillation and Atrial Fibrillation Beget Myocardial Infarction?

    NARCIS (Netherlands)

    Vermond, Rob A.; Van Gelder, Isabelle C.; Crijns, Harry J.; Rienstra, Michiel

    2015-01-01

    Atrial fibrillation (AF) affects millions of people worldwide.(1) It is already known several decades that AF is not a benign condition, and it's associated with a 5-fold increased risk of stroke, 3-fold increased risk of heart failure, and doubling of risk of dementia and death.(2-4) Myocardial

  17. Family history of atrial fibrillation is associated with earlier-onset and more symptomatic atrial fibrillation

    DEFF Research Database (Denmark)

    Gundlund, Anna; Fosbøl, Emil Loldrup; Kim, Sunghee

    2016-01-01

    BACKGROUND: We addressed whether patients with a family history of atrial fibrillation (AF) were diagnosed as having AF earlier in life, were more symptomatic, and had worse outcomes compared with those without a family history of AF. METHODS: Using the ORBIT-AF, we compared symptoms and disease...

  18. From Fibril Formation to Fibril Properties and Rheology of Food Materials

    NARCIS (Netherlands)

    Linden, van der E.; Venema, P.

    2013-01-01

    For control and design of food properties it is important to understand how molecules and their interactions give rise to formation of microstructures and resulting rheological properties. This will be illustrated by discussing the formation and properties of fibrils in aqueous and non-aqueous

  19. High Tensile Strength of Engineered β-Solenoid Fibrils via Sonication and Pulling.

    Science.gov (United States)

    Peng, Zeyu; Parker, Amanda S; Peralta, Maria D R; Ravikumar, Krishnakumar M; Cox, Daniel L; Toney, Michael D

    2017-11-07

    We present estimates of ultimate tensile strength (UTS) for two engineered β-solenoid protein mutant fibril structures (spruce budworm and Rhagium inquisitor antifreeze proteins) derived from sonication-based measurements and from force pulling molecular dynamics simulations, both in water. Sonication experiments generate limiting scissioned fibrils with a well-defined length-to-width correlation for the mutant spruce budworm protein and the resultant UTS estimate is 0.66 ± 0.08 GPa. For fibrils formed from engineered R. inquisitor antifreeze protein, depending upon geometry, we estimate UTSs of 3.5 ± 3.2-5.5 ± 5.1 GPa for proteins with interfacial disulfide bonds, and 1.6 ± 1.5-2.5 ± 2.3 GPa for the reduced form. The large error bars for the R. inquisitor structures are intrinsic to the broad distribution of limiting scission lengths. Simulations provide pulling velocity-dependent UTSs increasing from 0.2 to 1 GPa in the available speed range, and 1.5 GPa extrapolated to the speeds expected in the sonication experiments. Simulations yield low-velocity values for the Young's modulus of 6.0 GPa. Without protein optimization, these mechanical parameters are similar to those of spider silk and Kevlar, but in contrast to spider silk, these proteins have a precisely known sequence-structure relationship. Copyright © 2017 Biophysical Society. Published by Elsevier Inc. All rights reserved.

  20. Islet amyloid polypeptide and high hydrostatic pressure: towards an understanding of the fibrillization process

    Science.gov (United States)

    Lopes, D. H. J.; Smirnovas, V.; Winter, R.

    2008-07-01

    Type II Diabetes Mellitus is a disease which is characterized by peripheral insulin resistance coupled with a progressive loss of insulin secretion that is associated with a decrease in pancreatic islet β-cell mass and the deposition of amyloid in the extracellular matrix of β-cells, which lead to islet cell death. The principal component of the islet amyloid is a pancreatic hormone called islet amyloid polypeptide (IAPP). High-pressure coupled with FT-IR, CD, ThT fluorescence spectroscopic and AFM studies were carried out to reveal information on the aggregation pathway as well as the aggregate structure of IAPP. Our data indicate that IAPP pre-formed fibrils exhibit a strong polymorphism with heterogeneous structures very sensitive to high hydrostatic pressure, indicating a high percentage of ionic and hydrophobic interactions being responsible for the stability the IAPP fibrils.

  1. Line-Broadening in Low-Temperature Solid-State NMR Spectra of Fibrils

    Energy Technology Data Exchange (ETDEWEB)

    Bauer, Thomas; Dotta, Claudio; Balacescu, Livia; Gath, Julia; Hunkeler, Andreas [ETH Zurich, Physical Chemistry (Switzerland); Böckmann, Anja, E-mail: a.bockmann@ibcp.fr [Université de Lyon 1, Institut de Biologie et Chimie des Protéines, UMR 5086 CNRS (France); Meier, Beat H., E-mail: beme@ethz.ch [ETH Zurich, Physical Chemistry (Switzerland)

    2017-01-15

    The temperature-dependent resonance-line broadening of HET-s(218–289) in its amyloid form is investigated in the range between 110 K and 280 K. Significant differences are observed between residues in the structured hydrophobic triangular core, which are broadened the least and can be detected down to 100 K, and in the solvent-exposed parts, which are broadened the most and often disappear from the observed spectrum around 200 K. Below the freezing of the bulk water, around 273 K, the protein fibrils are still surrounded by a layer of mobile water whose thickness decreases with temperature, leading to drying out of the fibrils.

  2. Beneficial characteristics of mechanically functional amyloid fibrils evolutionarily preserved in natural adhesives

    Energy Technology Data Exchange (ETDEWEB)

    Mostaert, Anika S; Jarvis, Suzanne P [Centre for Research on Adaptive Nanostructures and Nanodevices, Trinity College Dublin, Dublin 2 (Ireland)

    2007-01-31

    While biological systems are notorious for their complexity, nature sometimes displays mechanisms that are elegant in their simplicity. We have recently identified such a mechanism at work to enhance the mechanical properties of certain natural adhesives. The mechanism is simple because it utilizes a non-specific protein folding and subsequent aggregation process, now thought to be generic for any polypeptide under appropriate conditions. This non-specific folding forms proteinaceous crossed {beta}-sheet amyloid fibrils, which are usually associated with neurodegenerative diseases. Here we show evidence for the beneficial mechanical characteristics of these fibrils discovered in natural adhesives. We suggest that amyloid protein quaternary structures should be considered as a possible generic mechanism for mechanical strength in a range of natural adhesives and other natural materials due to their many beneficial mechanical features and apparent ease of self-assembly.

  3. Beneficial characteristics of mechanically functional amyloid fibrils evolutionarily preserved in natural adhesives

    International Nuclear Information System (INIS)

    Mostaert, Anika S; Jarvis, Suzanne P

    2007-01-01

    While biological systems are notorious for their complexity, nature sometimes displays mechanisms that are elegant in their simplicity. We have recently identified such a mechanism at work to enhance the mechanical properties of certain natural adhesives. The mechanism is simple because it utilizes a non-specific protein folding and subsequent aggregation process, now thought to be generic for any polypeptide under appropriate conditions. This non-specific folding forms proteinaceous crossed β-sheet amyloid fibrils, which are usually associated with neurodegenerative diseases. Here we show evidence for the beneficial mechanical characteristics of these fibrils discovered in natural adhesives. We suggest that amyloid protein quaternary structures should be considered as a possible generic mechanism for mechanical strength in a range of natural adhesives and other natural materials due to their many beneficial mechanical features and apparent ease of self-assembly

  4. La fibrillation auriculaire chez le noir Africain: Aspects ...

    African Journals Online (AJOL)

    In this retrospective work realized during two years (1st january 2002 to 31 december 2003), relative to 300 cases hospitalized at the Cardiology Institute of Abidjan, the authors have studied the epidemiologic, etiologic and prognosis factors of black african atrial fibrillation in hospital cercle. The atrial fibrillation was the most ...

  5. Dronedarone in high-risk permanent atrial fibrillation

    DEFF Research Database (Denmark)

    Connolly, Stuart J; Camm, A John; Halperin, Jonathan L

    2011-01-01

    Dronedarone restores sinus rhythm and reduces hospitalization or death in intermittent atrial fibrillation. It also lowers heart rate and blood pressure and has antiadrenergic and potential ventricular antiarrhythmic effects. We hypothesized that dronedarone would reduce major vascular events...... in high-risk permanent atrial fibrillation....

  6. Relevance of Electrical Remodeling in Human Atrial Fibrillation Results of the Asymptomatic Atrial Fibrillation and Stroke Evaluation in Pacemaker Patients and the Atrial Fibrillation Reduction Atrial Pacing Trial Mechanisms of Atrial Fibrillation Study

    NARCIS (Netherlands)

    Healey, Jeff S.; Israel, Carsten W.; Connolly, Stuart J.; Hohnloser, Stefan H.; Nair, Girish M.; Divakaramenon, Syamkumar; Capucci, Alessandro; Van Gelder, Isabelle C.; Lau, Chu-Pak; Gold, Michael R.; Carlson, Mark; Themeles, Ellison; Morillo, Carlos A.

    Background-In animal models of atrial fibrillation (AF), changes in atrial electrophysiological properties are associated with the development of AF. Their relevance to human AF is unclear. Methods and Results-The Asymptomatic Atrial Fibrillation and Stroke Evaluation in Pacemaker Patients and the

  7. The safety of flecainide treatment of atrial fibrillation

    DEFF Research Database (Denmark)

    Almroth, H; Andersson, Torben Bech; Fengsrud, E

    2011-01-01

    To assess the safety of long-term treatment with flecainide in patients with atrial fibrillation (AF), particularly with regard to sudden cardiac death (SCD) and proarrhythmic events.......To assess the safety of long-term treatment with flecainide in patients with atrial fibrillation (AF), particularly with regard to sudden cardiac death (SCD) and proarrhythmic events....

  8. Atrial fibrillation and bleeding complication - risk factors and risk marker

    NARCIS (Netherlands)

    Breithardt, G.; Ravens, U.; Kirchhof, P.; van Gelder, I. C.

    2012-01-01

    The development of atrial fibrillation (AF) is closely linked to risk factors like hypertension and heart failure, diabetes mellitus, myocardial infarction and valvular heart disease. These factors partly overlap with those which determine the progression of atrial fibrillation and the incidence of

  9. Polymorphism complexity and handedness inversion in serum albumin amyloid fibrils.

    Science.gov (United States)

    Usov, Ivan; Adamcik, Jozef; Mezzenga, Raffaele

    2013-12-23

    Protein-based amyloid fibrils can show a great variety of polymorphic structures within the same protein precursor, although the origins of these structural homologues remain poorly understood. In this work we investigate the fibrillation of bovine serum albumin--a model globular protein--and we follow the polymorphic evolution by a statistical analysis of high-resolution atomic force microscopy images, complemented, at larger length scales, by concepts based on polymer physics formalism. We identify six distinct classes of coexisting amyloid fibrils, including flexible left-handed twisted ribbons, rigid right-handed helical ribbons and nanotubes. We show that the rigid fibrils originate from flexible fibrils through two diverse polymorphic transitions, first, via a single-fibril transformation when the flexible left-handed twisted ribbons turn into the helical left-handed ribbons, to finally evolve into nanotube-like structures, and second, via a double-fibril transformation when two flexible left-handed twisted ribbons wind together resulting in a right-handed twisted ribbon, followed by a rigid right-handed helical ribbon polymorphic conformation. Hence, the change in handedness occurs with an increase in the level of the fibril's structural organization.

  10. Genetics of Atrial Fibrillation and Possible Implications for Ischemic Stroke

    Directory of Open Access Journals (Sweden)

    Robin Lemmens

    2011-01-01

    Full Text Available Atrial fibrillation is the most common cardiac arrhythmia mainly caused by valvular, ischemic, hypertensive, and myopathic heart disease. Atrial fibrillation can occur in families suggesting a genetic background especially in younger subjects. Additionally recent studies have identified common genetic variants to be associated with atrial fibrillation in the general population. This cardiac arrhythmia has important public health implications because of its main complications: congestive heart failure and ischemic stroke. Since atrial fibrillation can result in ischemic stroke, one might assume that genetic determinants of this cardiac arrhythmia are also implicated in cerebrovascular disease. Ischemic stroke is a multifactorial, complex disease where multiple environmental and genetic factors interact. Whether genetic variants associated with a risk factor for ischemic stroke also increase the risk of a particular vascular endpoint still needs to be confirmed in many cases. Here we review the current knowledge on the genetic background of atrial fibrillation and the consequences for cerebrovascular disease.

  11. Decorin core protein (decoron) shape complements collagen fibril surface structure and mediates its binding.

    Science.gov (United States)

    Orgel, Joseph P R O; Eid, Aya; Antipova, Olga; Bella, Jordi; Scott, John E

    2009-09-15

    Decorin is the archetypal small leucine rich repeat proteoglycan of the vertebrate extracellular matrix (ECM). With its glycosaminoglycuronan chain, it is responsible for stabilizing inter-fibrillar organization. Type I collagen is the predominant member of the fibrillar collagen family, fulfilling both organizational and structural roles in animal ECMs. In this study, interactions between decoron (the decorin core protein) and binding sites in the d and e(1) bands of the type I collagen fibril were investigated through molecular modeling of their respective X-ray diffraction structures. Previously, it was proposed that a model-based, highly curved concave decoron interacts with a single collagen molecule, which would form extensive van der Waals contacts and give rise to strong non-specific binding. However, the large well-ordered aggregate that is the collagen fibril places significant restraints on modes of ligand binding and necessitates multi-collagen molecular contacts. We present here a relatively high-resolution model of the decoron-fibril collagen complex. We find that the respective crystal structures complement each other well, although it is the monomeric form of decoron that shows the most appropriate shape complementarity with the fibril surface and favorable calculated energies of interaction. One molecule of decoron interacts with four to six collagen molecules, and the binding specificity relies on a large number of hydrogen bonds and electrostatic interactions, primarily with the collagen motifs KXGDRGE and AKGDRGE (d and e(1) bands). This work helps us to understand collagen-decorin interactions and the molecular architecture of the fibrillar ECM in health and disease.

  12. Decorin core protein (decoron shape complements collagen fibril surface structure and mediates its binding.

    Directory of Open Access Journals (Sweden)

    Joseph P R O Orgel

    2009-09-01

    Full Text Available Decorin is the archetypal small leucine rich repeat proteoglycan of the vertebrate extracellular matrix (ECM. With its glycosaminoglycuronan chain, it is responsible for stabilizing inter-fibrillar organization. Type I collagen is the predominant member of the fibrillar collagen family, fulfilling both organizational and structural roles in animal ECMs. In this study, interactions between decoron (the decorin core protein and binding sites in the d and e(1 bands of the type I collagen fibril were investigated through molecular modeling of their respective X-ray diffraction structures. Previously, it was proposed that a model-based, highly curved concave decoron interacts with a single collagen molecule, which would form extensive van der Waals contacts and give rise to strong non-specific binding. However, the large well-ordered aggregate that is the collagen fibril places significant restraints on modes of ligand binding and necessitates multi-collagen molecular contacts. We present here a relatively high-resolution model of the decoron-fibril collagen complex. We find that the respective crystal structures complement each other well, although it is the monomeric form of decoron that shows the most appropriate shape complementarity with the fibril surface and favorable calculated energies of interaction. One molecule of decoron interacts with four to six collagen molecules, and the binding specificity relies on a large number of hydrogen bonds and electrostatic interactions, primarily with the collagen motifs KXGDRGE and AKGDRGE (d and e(1 bands. This work helps us to understand collagen-decorin interactions and the molecular architecture of the fibrillar ECM in health and disease.

  13. NASA's First Atrial Fibrillation Case - Deke Slayton

    Science.gov (United States)

    Tarver, William J.

    2010-01-01

    Concerns about heart dysrhythmia have been present since the earliest days of the US manned space program. While information about an astronaut's health is general kept private, one of the original seven American astronaut's health status was played out in a very public forum. Donald "Deke" Slayton was removed from the second manned space flight when it was discovered he had idiopathic atrial fibrillation. Referencing the original medical documents, details of how this was discovered and managed from the medical perspective will be reviewed. This is NASA's first heart dysrhythmia case in an astronaut and it proves quite interesting when placed in historic perspective.

  14. Current approaches in atrial fibrillation treatment

    Directory of Open Access Journals (Sweden)

    Cenk Sarı

    2014-09-01

    Full Text Available Atrial fibrillation (AF is the most common sustained arrhythmia encountered in clinical practice. Its incidence increases with age. AF is classified into subtypes according to the duration and/or able to provide sinus rhytym. İnitially, patients should be evaluated for rhythm or rate control for appropriate treatment. Second stage of strategy aimed to investigate the feasibility of anticoagulation therapy. Recently, due to the progress made in treatment with rhythm control and anticoagulation therapy, either American or European guidelines have been renovated. These developments have taken place in the newly published guide. In this article, the current change in the management of AF is discussed.

  15. Peptide p5 binds both heparinase-sensitive glycosaminoglycans and fibrils in patient-derived AL amyloid extracts

    Energy Technology Data Exchange (ETDEWEB)

    Martin, Emily B.; Williams, Angela [Department of Medicine, University of Tennessee Graduate School of Medicine, 1924 Alcoa Highway, Knoxville, TN 37922 (United States); Heidel, Eric [Department of Surgery, University of Tennessee Graduate School of Medicine, 1924 Alcoa Highway, Knoxville, TN 37922 (United States); Macy, Sallie [Department of Medicine, University of Tennessee Graduate School of Medicine, 1924 Alcoa Highway, Knoxville, TN 37922 (United States); Kennel, Stephen J. [Department of Medicine, University of Tennessee Graduate School of Medicine, 1924 Alcoa Highway, Knoxville, TN 37922 (United States); Department of Radiology, University of Tennessee Graduate School of Medicine, 1924 Alcoa Highway, Knoxville, TN 37922 (United States); Wall, Jonathan S., E-mail: jwall@utmck.edu [Department of Medicine, University of Tennessee Graduate School of Medicine, 1924 Alcoa Highway, Knoxville, TN 37922 (United States); Department of Radiology, University of Tennessee Graduate School of Medicine, 1924 Alcoa Highway, Knoxville, TN 37922 (United States)

    2013-06-21

    Highlights: •Polybasic peptide p5 binds human light chain amyloid extracts. •The binding of p5 with amyloid involves both glycosaminoglycans and fibrils. •Heparinase treatment led to a correlation between p5 binding and fibril content. •p5 binding to AL amyloid requires electrostatic interactions. -- Abstract: In previously published work, we have described heparin-binding synthetic peptides that preferentially recognize amyloid deposits in a mouse model of reactive systemic (AA) amyloidosis and can be imaged by using positron and single photon emission tomographic imaging. We wanted to extend these findings to the most common form of visceral amyloidosis, namely light chain (AL); however, there are no robust experimental animal models of AL amyloidosis. To further define the binding of the lead peptide, p5, to AL amyloid, we characterized the reactivity in vitro of p5 with in situ and patient-derived AL amyloid extracts which contain both hypersulfated heparan sulfate proteoglycans as well as amyloid fibrils. Histochemical staining demonstrated that the peptide specifically localized with tissue-associated AL amyloid deposits. Although we anticipated that p5 would undergo electrostatic interactions with the amyloid-associated glycosaminoglycans expressing heparin-like side chains, no significant correlation between peptide binding and glycosaminoglycan content within amyloid extracts was observed. In contrast, following heparinase I treatment, although overall binding was reduced, a positive correlation between peptide binding and amyloid fibril content became evident. This interaction was further confirmed using synthetic light chain fibrils that contain no carbohydrates. These data suggest that p5 can bind to both the sulfated glycosaminoglycans and protein fibril components of AL amyloid. Understanding these complex electrostatic interactions will aid in the optimization of synthetic peptides for use as amyloid imaging agents and potentially as

  16. Increased amount of atrial fibrosis in patients with atrial fibrillation secondary to mitral valve disease

    NARCIS (Netherlands)

    Geuzebroek, Guillaume S. C.; van Amersfoorth, Shirley C. M.; Hoogendijk, Mark G.; Kelder, Johannes C.; van Hemel, Norbert M.; de Bakker, Jacques M. T.; Coronel, Ruben

    2012-01-01

    Objective: Atrial fibrosis is related to atrial fibrillation but may differ in patients with mitral valve disease or lone atrial fibrillation. Therefore, we studied atrial fibrosis in patients with atrial fibrillation + mitral valve disease or with lone atrial fibrillation and compared it with

  17. Atrial Fibrillation: When the heart is not in rhythm | NIH MedlinePlus the Magazine

    Science.gov (United States)

    ... of this page please turn JavaScript on. Feature: Atrial Fibrillation Atrial Fibrillation: When the heart is not in rhythm Past ... show, Deal With It . Photo: TBS/Deal Understanding Atrial Fibrillation Atrial fibrillation (AFib) is the most common type ...

  18. Organized Atrial Tachycardias after Atrial Fibrillation Ablation

    Science.gov (United States)

    Castrejón-Castrejón, Sergio; Ortega, Marta; Pérez-Silva, Armando; Doiny, David; Estrada, Alejandro; Filgueiras, David; López-Sendón, José L.; Merino, José L.

    2011-01-01

    The efficacy of catheter-based ablation techniques to treat atrial fibrillation is limited not only by recurrences of this arrhythmia but also, and not less importantly, by new-onset organized atrial tachycardias. The incidence of such tachycardias depends on the type and duration of the baseline atrial fibrillation and specially on the ablation technique which was used during the index procedure. It has been repeatedly reported that the more extensive the left atrial surface ablated, the higher the incidence of organized atrial tachycardias. The exact origin of the pathologic substrate of these trachycardias is not fully understood and may result from the interaction between preexistent regions with abnormal electrical properties and the new ones resultant from radiofrequency delivery. From a clinical point of view these atrial tachycardias tend to remit after a variable time but in some cases are responsible for significant symptoms. A precise knowledge of the most frequent types of these arrhythmias, of their mechanisms and components is necessary for a thorough electrophysiologic characterization if a new ablation procedure is required. PMID:21941669

  19. Advanced glycation end products induce differential structural modifications and fibrillation of albumin

    Science.gov (United States)

    Awasthi, Saurabh; Sankaranarayanan, Kamatchi; Saraswathi, N. T.

    2016-06-01

    Glycation induced amyloid fibrillation is fundamental to the development of many neurodegenerative and cardiovascular complications. Excessive non-enzymatic glycation in conditions such as hyperglycaemia results in the increased accumulation of advanced glycation end products (AGEs). AGEs are highly reactive pro-oxidants, which can lead to the activation of inflammatory pathways and development of oxidative stress. Recently, the effect of non-enzymatic glycation on protein structure has been the major research area, but the role of specific AGEs in such structural alteration and induction of fibrillation remains undefined. In this study, we determined the specific AGEs mediated structural modifications in albumin mainly considering carboxymethyllysine (CML), carboxyethyllysine (CEL), and argpyrimidine (Arg-P) which are the major AGEs formed in the body. We studied the secondary structural changes based on circular dichroism (CD) and spectroscopic analysis. The AGEs induced fibrillation was determined by Congo red binding and examination of scanning and transmission electron micrographs. The amyloidogenic regions in the sequence of BSA were determined using FoldAmyloid. It was observed that CEL modification of BSA leads to the development of fibrillar structures, which was evident from both secondary structure changes and TEM analysis.

  20. Conformations of islet amyloid polypeptide monomers in a membrane environment: implications for fibril formation.

    Directory of Open Access Journals (Sweden)

    Mojie Duan

    Full Text Available The amyloid fibrils formed by islet amyloid polypeptide (IAPP are associated with type II diabetes. One of the proposed mechanisms of the toxicity of IAPP is that it causes membrane damage. The fatal mutation of S20G human IAPP was reported to lead to early onset of type II diabetes and high tendency of amyloid formation in vitro. Characterizing the structural features of the S20G mutant in its monomeric state is experimentally difficult because of its unusually fast aggregation rate. Computational work complements experimental studies. We performed a series of molecular dynamics simulations of the monomeric state of human variants in the membrane. Our simulations are validated by extensive comparisons with experimental data. We find that a helical disruption at His18 is common to both human variants. An L-shaped motif of S20G mutant is observed in one of the conformational families. This motif that bends at His18 resembles the overall topology of IAPP fibrils. The conformational preorganization into the fibril-like topology provides a possible explanation for the fast aggregation rate of S20G IAPP.

  1. Identification of Transthyretin Fibril Formation Inhibitors Using Structure-Based Virtual Screening.

    Science.gov (United States)

    Ortore, Gabriella; Martinelli, Adriano

    2017-08-22

    Transthyretin (TTR) is the primary carrier for thyroxine (T 4 ) in cerebrospinal fluid and a secondary carrier in blood. TTR is a stable homotetramer, but certain factors, genetic or environmental, could promote its degradation to form amyloid fibrils. A docking study using crystal structures of wild-type TTR was planned; our aim was to design new ligands that are able to inhibit TTR fibril formation. The computational protocol was thought to overcome the multiple binding modes of the ligands induced by the peculiarity of the TTR binding site and by the pseudosymmetry of the site pockets, which generally weaken such structure-based studies. Two docking steps, one that is very fast and a subsequent step that is more accurate, were used to screen the Aldrich Market Select database. Five compounds were selected, and their activity toward inhibiting TTR fibril formation was assessed. Three compounds were observed to be actives, two of which have the same potency as the positive control, and the other was found to be a promising lead compound. These results validate a computational protocol that is able to archive information on the key interactions between database compounds and TTR, which is valuable for supporting further studies. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  2. Atrial fibrillation and stroke prevention practices in patients with candidacy for anticoagulation therapy

    International Nuclear Information System (INIS)

    Ullah, I.; Ahmad, S.; Hayat, Y.

    2015-01-01

    Background: Stroke secondary to Atrial Fibrillation is usually due to thrombi formed in the left atrium and left atrial appendage embolizing to cause ischemic stroke. Therefore, in patients with Atrial Fibrillation, antithrombotic therapy is recommended to prevent stroke. Vitamin K antagonist therapy is most widely used antithrombotic therapy for patients with valvular and non valvular AF. Aspirin is recommended only in low risk patients. This study was conducted to determine the stroke prevention practices in local patients with atrial fibrillation who were candidates for anticoagulation therapy. Method: This was descriptive cross sectional study conducted at Cardiovascular Department Lady Reading Hospital Peshawar and Cardiology Department Hayatabad Medical Complex Peshawar. Sampling technique was non probability consecutive. Patients visiting OPD of respective hospitals with EKG evidence of AF and having CHADES VASC score 2 or more or having mitral stenosis and AF were included in the study. Patients with additional indications for anticoagulation were excluded from the study. Results: A total of 205 patients with atrial fibrillation were studied. Mean age was 60.7±14.7 years. Male were 55.6 percentage (n=114) while 44.4 percentage (n=91) were female. Of these 149 (72.7 percentage) were candidates for anticoagulation based on CHA2DS2 VASc score of 2 and more or mitral stenosis with AF. Only 27.5 percentage (n=41) patients were adequately treated with anticoagulant therapy using VKA or novel oral anticoagulant drugs. Majority of them were getting dual antiplatelet therapy (DAPT). Conclusion: Most patients with AF and high risk characteristics for thromboembolism are not receiving proper stroke prevention therapies. (author)

  3. Probing the mechanism of insulin fibril formation with insulin mutants.

    Science.gov (United States)

    Nielsen, L; Frokjaer, S; Brange, J; Uversky, V N; Fink, A L

    2001-07-27

    The molecular basis of insulin fibril formation was investigated by studying the structural properties and kinetics of fibril formation of 20 different human insulin mutants at both low pH (conditions favoring monomer/dimer) and at pH 7.4 (conditions favoring tetramer/hexamer). Small-angle X-ray scattering showed insulin to be monomeric in 20% acetic acid, 0.1 M NaCl, pH 2. The secondary structure of the mutants was assessed using far-UV circular dichroism, and the tertiary structure was determined using near-UV circular dichroism, quenching of intrinsic fluorescence by acrylamide and interactions with the hydrophobic probe 1-anilino-8-naphthalene-sulfonic acid (ANS). The kinetics of fibril formation were monitored with the fluorescent dye, Thioflavin T. The results indicate that the monomer is the state from which fibrils arise, thus under some conditions dissociation of hexamers may be rate limiting or partially rate limiting. The insulin mutants were found to retain substantial nativelike secondary and tertiary structure under all conditions studied. The results suggest that fibril formation of the insulin mutants is controlled by specific molecular interactions that are sensitive to variations in the primary structure. The observed effects of several mutations on the rate of fibril formation are inconsistent with a previously suggested model for fibrillation [Brange, J., Whittingham, J., Edwards, D., Youshang, Z., Wollmer, A., Brandenburg, D., Dodson, G., and Finch, J. (1997) Curr. Sci. 72, 470-476]. Two surfaces on the insulin monomer are identified as potential interacting sites in insulin fibrils, one consisting of the residues B10, B16, and B17 and the other consisting of at least the residues A8 and B25. The marked increase in the lag time for fibril formation with mutations to more polar residues, as well as mutations to charged residues, demonstrates the importance of both hydrophobic and electrostatic interactions in the initial stages of fibrillation

  4. Further exploration of the conformational space of α-synuclein fibrils: solid-state NMR assignment of a high-pH polymorph.

    Science.gov (United States)

    Verasdonck, Joeri; Bousset, Luc; Gath, Julia; Melki, Ronald; Böckmann, Anja; Meier, Beat H

    2016-04-01

    Polymorphism is a common and important phenomenon for protein fibrils which has been linked to the appearance of strains in prion and other neurodegenerative diseases. Parkinson disease is a frequently occurring neurodegenerative pathology, tightly associated with the formation of Lewy bodies. These deposits mainly consist of α-synuclein in fibrillar, β-sheet-rich form. α-synuclein is known to form numerous different polymorphs, which show distinct structural features. Here, we describe the chemical shift assignments, and derive the secondary structure, of a polymorph that was fibrillized at higher-than-physiological pH conditions. The fibrillar core contains residues 40-95, with both the C- and N-terminus not showing any ordered, rigid parts. The chemical shifts are similar to those recorded previously for an assigned polymorph that was fibrillized at neutral pH.

  5. Normal and reversed supramolecular chirality of insulin fibrils probed by vibrational circular dichroism at the protofilament level of fibril structure.

    Science.gov (United States)

    Kurouski, Dmitry; Dukor, Rina K; Lu, Xuefang; Nafie, Laurence A; Lednev, Igor K

    2012-08-08

    Fibrils are β-sheet-rich aggregates that are generally composed of several protofibrils and may adopt variable morphologies, such as twisted ribbons or flat-like sheets. This polymorphism is observed for many different amyloid associated proteins and polypeptides. In a previous study we proposed the existence of another level of amyloid polymorphism, namely, that associated with fibril supramolecular chirality. Two chiral polymorphs of insulin, which can be controllably grown by means of small pH variations, exhibit opposite signs of vibrational circular dichroism (VCD) spectra. Herein, using atomic force microscopy (AFM) and scanning electron microscopy (SEM), we demonstrate that indeed VCD supramolecular chirality is correlated not only by the apparent fibril handedness but also by the sense of supramolecular chirality from a deeper level of chiral organization at the protofilament level of fibril structure. Our microscopic examination indicates that normal VCD fibrils have a left-handed twist, whereas reversed VCD fibrils are flat-like aggregates with no obvious helical twist as imaged by atomic force microscopy or scanning electron microscopy. A scheme is proposed consistent with observed data that features a dynamic equilibrium controlled by pH at the protofilament level between left- and right-twist fibril structures with distinctly different aggregation pathways for left- and right-twisted protofilaments. Copyright © 2012 Biophysical Society. Published by Elsevier Inc. All rights reserved.

  6. Yeast prions form infectious amyloid inclusion bodies in bacteria

    Directory of Open Access Journals (Sweden)

    Espargaró Alba

    2012-06-01

    Full Text Available Abstract Background Prions were first identified as infectious proteins associated with fatal brain diseases in mammals. However, fungal prions behave as epigenetic regulators that can alter a range of cellular processes. These proteins propagate as self-perpetuating amyloid aggregates being an example of structural inheritance. The best-characterized examples are the Sup35 and Ure2 yeast proteins, corresponding to [PSI+] and [URE3] phenotypes, respectively. Results Here we show that both the prion domain of Sup35 (Sup35-NM and the Ure2 protein (Ure2p form inclusion bodies (IBs displaying amyloid-like properties when expressed in bacteria. These intracellular aggregates template the conformational change and promote the aggregation of homologous, but not heterologous, soluble prionogenic molecules. Moreover, in the case of Sup35-NM, purified IBs are able to induce different [PSI+] phenotypes in yeast, indicating that at least a fraction of the protein embedded in these deposits adopts an infectious prion fold. Conclusions An important feature of prion inheritance is the existence of strains, which are phenotypic variants encoded by different conformations of the same polypeptide. We show here that the proportion of infected yeast cells displaying strong and weak [PSI+] phenotypes depends on the conditions under which the prionogenic aggregates are formed in E. coli, suggesting that bacterial systems might become useful tools to generate prion strain diversity.

  7. On the function and fate of chloride ions in amyloidogenic self-assembly of insulin in an acidic environment: salt-induced condensation of fibrils.

    Science.gov (United States)

    Babenko, Viktoria; Surmacz-Chwedoruk, Weronika; Dzwolak, Wojciech

    2015-02-24

    Formation of amyloid fibrils is often facilitated in the presence of specific charge-compensating ions. Dissolved sodium chloride is known to accelerate insulin fibrillation at low pH that has been attributed to the shielding of electrostatic repulsion between positively charged insulin molecules by chloride ions. However, the subsequent fate of Cl(-) anions; that is, possible entrapment within elongating fibrils or escape into the bulk solvent, remains unclear. Here, we show that, while the presence of NaCl at the onset of insulin aggregation induces structural variants of amyloid with distinct fingerprint infrared features, a delayed addition of salt to fibrils that have been already formed in its absence and under quiescent conditions triggers a "condensation effect": amyloid superstructures with strong chiroptical properties are formed. Chloride ions appear to stabilize these superstructures in a manner similar to stabilization of DNA condensates by polyvalent cations. The concentration of residual chloride ions trapped within bovine insulin fibrils grown in 0.1 M NaCl, at pD 1.9, and rinsed extensively with water afterward is less than 1 anion per 16 insulin monomers (as estimated using ion chromatography) implying absence of defined solvent-sequestered nesting sites for chloride counterions. Our results have been discussed in the context of mechanisms of insulin aggregation.

  8. Clinical characteristics, management, and control of permanent vs. nonpermanent atrial fibrillation: insights from the RealiseAF survey.

    LENUS (Irish Health Repository)

    Murin, Jan

    2014-01-01

    Atrial fibrillation can be categorized into nonpermanent and permanent atrial fibrillation. There is less information on permanent than on nonpermanent atrial fibrillation patients. This analysis aimed to describe the characteristics and current management, including the proportion of patients with successful atrial fibrillation control, of these atrial fibrillation subsets in a large, geographically diverse contemporary sample.

  9. Synthesis and characterization of fluorinated magnetic core-shell nanoparticles for inhibition of insulin amyloid fibril formation

    International Nuclear Information System (INIS)

    Skaat, Hadas; Margel, Shlomo; Belfort, Georges

    2009-01-01

    Maghemite (γ-Fe 2 O 3 ) magnetic nanoparticles of 15.0 ± 2.1 nm are formed by nucleation followed by controlled growth of maghemite thin films on gelatin-iron oxide nuclei. Uniform magnetic γ-Fe 2 O 3 /poly (2,2,3,3,4,4,4-heptafluorobutyl acrylate) (γ-Fe 2 O 3 /PHFBA) core-shell nanoparticles are prepared by emulsion polymerization of the fluorinated monomer 2,2,3,3,4,4,4-heptafluorobutyl acrylate (HFBA) in the presence of the maghemite nanoparticles. The kinetics of the insulin fibrillation process in the absence and in the presence of the γ-Fe 2 O 3 /PHFBA core-shell nanoparticles are elucidated. A significant direct slow transition from α-helix to β-sheets during insulin fibril formation is observed in the presence of the γ-Fe 2 O 3 /PHFBA nanoparticles. This is in contradiction to our previous manuscript, which illustrated that the γ-Fe 2 O 3 core nanoparticles do not affect the kinetics of the formation of the insulin fibrils, and to other previous publications that describe acceleration of the fibrillation process by using various types of nanoparticles. These core-shell nanoparticles may therefore be also useful for the inhibition of conformational changes of other amyloidogenic proteins that lead to neurodegenerative diseases such as Alzheimer's, Parkinson's, Huntington's, mad cow and prion diseases.

  10. Sequence-Dependent Self-Assembly and Structural Diversity of Islet Amyloid Polypeptide-Derived β-Sheet Fibrils

    International Nuclear Information System (INIS)

    Wang, Shih-Ting; Lin, Yiyang; Spencer, Ryan K.; Thomas, Michael R.; Nguyen, Andy I.

    2017-01-01

    Determining the structural origins of amyloid fibrillation is essential for understanding both the pathology of amyloidosis and the rational design of inhibitors to prevent or reverse amyloid formation. In this work, the decisive roles of peptide structures on amyloid self-assembly and morphological diversity were investigated by the design of eight amyloidogenic peptides derived from islet amyloid polypeptide. Among the segments, two distinct morphologies were highlighted in the form of twisted and planar (untwisted) ribbons with varied diameters, thicknesses, and lengths. In particular, transformation of amyloid fibrils from twisted ribbons into untwisted structures was triggered by substitution of the C-terminal serine with threonine, where the side chain methyl group was responsible for the distinct morphological change. This effect was confirmed following serine substitution with alanine and valine and was ascribed to the restriction of intersheet torsional strain through the increased hydrophobic interactions and hydrogen bonding. We also studied the variation of fibril morphology (i.e., association and helicity) and peptide aggregation propensity by increasing the hydrophobicity of the peptide side group, capping the N-terminus, and extending sequence length. Lastly, we anticipate that our insights into sequence-dependent fibrillation and morphological diversity will shed light on the structural interpretation of amyloidogenesis and development of structure-specific imaging agents and aggregation inhibitors.

  11. A β-solenoid model of the Pmel17 repeat domain: insights to the formation of functional amyloid fibrils

    Science.gov (United States)

    Louros, Nikolaos N.; Baltoumas, Fotis A.; Hamodrakas, Stavros J.; Iconomidou, Vassiliki A.

    2016-02-01

    Pmel17 is a multidomain protein involved in biosynthesis of melanin. This process is facilitated by the formation of Pmel17 amyloid fibrils that serve as a scaffold, important for pigment deposition in melanosomes. A specific luminal domain of human Pmel17, containing 10 tandem imperfect repeats, designated as repeat domain (RPT), forms amyloid fibrils in a pH-controlled mechanism in vitro and has been proposed to be essential for the formation of the fibrillar matrix. Currently, no three-dimensional structure has been resolved for the RPT domain of Pmel17. Here, we examine the structure of the RPT domain by performing sequence threading. The resulting model was subjected to energy minimization and validated through extensive molecular dynamics simulations. Structural analysis indicated that the RPT model exhibits several distinct properties of β-solenoid structures, which have been proposed to be polymerizing components of amyloid fibrils. The derived model is stabilized by an extensive network of hydrogen bonds generated by stacking of highly conserved polar residues of the RPT domain. Furthermore, the key role of invariant glutamate residues is proposed, supporting a pH-dependent mechanism for RPT domain assembly. Conclusively, our work attempts to provide structural insights into the RPT domain structure and to elucidate its contribution to Pmel17 amyloid fibril formation.

  12. Attitudes Towards Catheter Ablation for Atrial Fibrillation

    DEFF Research Database (Denmark)

    Vadmann, Henrik; Pedersen, Susanne S; Nielsen, Jens Cosedis

    2015-01-01

    BACKGROUND: Catheter ablation for atrial fibrillation (AF) is an important but expensive procedure that is the subject of some debate. Physicians´ attitudes towards catheter ablation may influence promotion and patient acceptance. This is the first study to examine the attitudes of Danish...... cardiologists towards catheter ablation for AF, using a nationwide survey. METHODS AND RESULTS: We developed a purpose-designed questionnaire to evaluate attitudes towards catheter ablation for AF that was sent to all Danish cardiologists (n = 401; response n = 272 (67.8%)). There was no association between...... attitudes towards ablation and the experience or age of the cardiologist with respect to patients with recurrent AF episodes with a duration of 7 days and/or need for cardioversion. The majority (69%) expected a recurrence of AF after catheter ablation in more than 30% of the cases...

  13. Pathogenic Mechanisms of Atrial Fibrillation in Obesity

    Directory of Open Access Journals (Sweden)

    O. M. Drapkina

    2016-01-01

    Full Text Available Atrial fibrillation (AF is one of the most common arrhythmias. It reduces quality of life and its duration due to thromboembolic complications. Obesity contributes to the structural and electrical remodeling of atrial myocardium. This leads to occurrence of ectopic foci in the mouths of the pulmonary veins and the disruption of normal electrical conduction in the atria. Systemic inflammation, myocardial fibrosis, cardiomyocyte overload by Na+ and Ca2+ ions, accumulation in the cells of unoxidized metabolic products, imbalance of the autonomic regulation are considered as the main mechanisms of arrhythmogenic substrate formation. Hypertension, insulin resistance, and obstructive sleep apnea, associated with obesity, increase the risk of development and progression of the arrhythmia. Study of pathogenetic mechanisms of AF in obesity is necessary to develop new strategies for its prevention and the creation of more effective methods of treatment of these patients.

  14. Advances in Imaging for Atrial Fibrillation Ablation

    International Nuclear Information System (INIS)

    D'Silva, A.; Wright, M.; Wright, M.

    2011-01-01

    Over the last fifteen years, our understanding of the pathophysiology of atrial fibrillation (AF) has paved the way for ablation to be utilized as an effective treatment option. With the aim of gaining more detailed anatomical representation, advances have been made using various imaging modalities, both before and during the ablation procedure, in planning and execution. Options have flourished from procedural fluoroscopy, electro anatomic mapping systems, pre procedural computed tomography (CT), magnetic resonance imaging (MRI), ultrasound, and combinations of these technologies. Exciting work is underway in an effort to allow the electro physiologist to assess scar formation in real time. One advantage would be to lessen the learning curve for what are very complex procedures. The hope of these developments is to improve the likelihood of a successful ablation procedure and to allow more patients access to this treatment

  15. Alcohol and Atrial Fibrillation: A Sobering Review.

    Science.gov (United States)

    Voskoboinik, Aleksandr; Prabhu, Sandeep; Ling, Liang-Han; Kalman, Jonathan M; Kistler, Peter M

    2016-12-13

    Alcohol is popular in Western culture, supported by a perception that modest intake is cardioprotective. However, excessive drinking has detrimental implications for cardiovascular disease. Atrial fibrillation (AF) following an alcohol binge or the "holiday heart syndrome" is well characterized. However, more modest levels of alcohol intake on a regular basis may also increase the risk of AF. The pathophysiological mechanisms responsible for the relationship between alcohol and AF may include direct toxicity and alcohol's contribution to obesity, sleep-disordered breathing, and hypertension. We aim to provide a comprehensive review of the epidemiology and pathophysiology by which alcohol may be responsible for AF and determine whether alcohol abstinence is required for patients with AF. Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

  16. [Atrial fibrillation concomitant with valvular heart disease].

    Science.gov (United States)

    Ishii, Yosuke

    2013-01-01

    Patients with valvular heart disease frequently have atrial fibrillation(AF) due to elevated pressure and dilatation of the left and right atria and pulmonary veins. Guidelines for valvular heart disease and AF recommend that surgical treatment for the valvular heart disease should be performed concomitantly with AF surgery. The Full-Maze procedure has evolved into the gold standard of treatment for medically refractory AF. In addition to the pulmonary vein isolation, the right and left atrial incisions of the Full-Maze procedure are designed to block potential macroreentrant pathways. According to the mechanisms of AF with valvular heart disease, the Full-Maze procedure is more effective for the patients than the pulmonary vein isolation alone.

  17. Prognosis of ventricular fibrillation in hospital

    DEFF Research Database (Denmark)

    Jensen, G V; Torp-Pedersen, C; Køber, L

    1992-01-01

    In a retrospective study of 520 patients with in-hospital ventricular fibrillation 421 (81%) had acute myocardial infarction (MI), 66 (13%) had ischaemic heart disease (IHD) without MI, 33 (6%) had no signs of IHD. The in-hospital mortality of these three groups was 51%, 52%, and 27%, respectively...... (P = 0.01). Logistic regression analysis demonstrated that heart failure and cardiogenic shock were significant risk factors for in-hospital death among patients with IHD. Among discharged patients 1 and 5 years survival was 78% and 51% for patients with MI, 63% and 25% for patients with IHD, 67...... with known IHD suffering in-hospital VF without AMI have a very poor short- and long-term prognosis. These patients need extensive cardiac examination....

  18. Visualisation of collagen fibrils in joint cartilage using STIM

    International Nuclear Information System (INIS)

    Reinert, T.; Reibetanz, U.; Vogt, J.; Butz, T.; Werner, A.; Gruender, W.

    2001-01-01

    The scanning transmission ion microscopy (STIM) method was used to investigate the collagen network structure of the articular cartilage from a pig's knee in comparison with high resolution nuclear magnetic resonance imaging (microscopic NMR-tomography) and polarised light microscopy (PLM). Single collagen fibrils down to 200 nm in diameter were visualised. It was proved that the cartilage collagen network consists partly of zones of oriented fibrils as suggested by NMR measurements. Radially oriented fibrils were found in the zone near the calcified zone (hypertrophic zone) of both tibia and femur, and in the tibial radial zone. Tangentially oriented fibrils were found in the femoral and tibial superficial zone and in a second zone of the femoral cartilage. Polarisation light microscopy reveals broader zones of orientation than it was found with STIM

  19. Dabigatran use in Danish atrial fibrillation patients in 2011

    DEFF Research Database (Denmark)

    Sørensen, Rikke; Gislason, Gunnar; Torp-Pedersen, Christian Tobias

    2013-01-01

    Objective: Dabigatran was recently approved for anticoagulation in patients with atrial fibrillation (AF); data regarding real-world use, comparative effectiveness and safety are sparse. Design: Pharmacoepidemiological cohort study. Methods/settings: From nationwide registers, we identified...

  20. Analysis of XFEL serial diffraction data from individual crystalline fibrils

    Directory of Open Access Journals (Sweden)

    David H. Wojtas

    2017-11-01

    Full Text Available Serial diffraction data collected at the Linac Coherent Light Source from crystalline amyloid fibrils delivered in a liquid jet show that the fibrils are well oriented in the jet. At low fibril concentrations, diffraction patterns are recorded from single fibrils; these patterns are weak and contain only a few reflections. Methods are developed for determining the orientation of patterns in reciprocal space and merging them in three dimensions. This allows the individual structure amplitudes to be calculated, thus overcoming the limitations of orientation and cylindrical averaging in conventional fibre diffraction analysis. The advantages of this technique should allow structural studies of fibrous systems in biology that are inaccessible using existing techniques.

  1. Women Sex Importance in Stroke Patients with Atrial Fibrillation

    Directory of Open Access Journals (Sweden)

    Cemile Handan Mısırlı

    2014-08-01

    Full Text Available OBJECTIVE: It was shown the differences in age, risk factors and treatment between women and men in stroke patients with atrial fibrillation METHODS: The stroke patients with atrial fibrillation who were hospitalized in our department at the last 2 years were seperated into 2 groups of aged above 75 and below 75, investigated with CHADS2 and CHA2DS2VASc scores and looked at the sex differences of women and men. RESULTS: Stroke ratio according to sex was statistically meaningful especially in women above the age of 75. Risc factors also were founded in elderly women and CHA2DS2VASc scores were higher in women than men so more anticoagulan treatment were begun. No differences were shown between sexes at lone atrial fibrillation and no treatment were begun. CONCLUSION: Women with atrial fibrillation had more risk factors, higher stroke rate and higher anticoagulation treatment.

  2. Atrial fibrillation in the dog: a review of eight cases

    Energy Technology Data Exchange (ETDEWEB)

    Thomas, R. E. [Vet. Hospital, 34 New Dover Rd, Canterbury, Kent (United Kingdom)

    1984-07-01

    Eight cases of canine atrial fibrillation encountered in small animal practice are reported. Details are included of age, sex and breed, history and clinical signs, thoracic radiography, electrocardiography, clinical pathology, treatment and survival periods.

  3. Atrial fibrillation in the dog: a review of eight cases

    International Nuclear Information System (INIS)

    Thomas, R.E.

    1984-01-01

    Eight cases of canine atrial fibrillation encountered in small animal practice are reported. Details are included of age, sex and breed, history and clinical signs, thoracic radiography, electrocardiography, clinical pathology, treatment and survival periods

  4. Inflammation in the genesis and perpetuation of atrial fibrillation

    DEFF Research Database (Denmark)

    Engelmann, Mads D M; Svendsen, Jesper Hastrup

    2005-01-01

    The prevalence and persistence of atrial fibrillation (AF) and the relative inefficacy of the currently available pharmacotherapy requires development of new treatment strategies. Recent findings have suggested a mechanistic link between inflammatory processes and the development of AF...

  5. Ventricular fibrillation after accidental injection of bupivacaine into the pericardium

    NARCIS (Netherlands)

    Even, B. J.; de Jongh, R. F.; de Hert, S. G.

    1992-01-01

    A postoperative cardiac surgical patient developed ventricular fibrillation immediately after accidental pericardial injection of bupivacaine at room temperature. The possible causes, which include systemic toxicity, local vasoconstriction with myocardial ischaemia, local toxic effect of bupivacaine

  6. Long working hours as a risk factor for atrial fibrillation

    DEFF Research Database (Denmark)

    Kivimäki, Mika; Nyberg, Solja T.; Batty, G. David

    2017-01-01

    long hours (≤55 per week) and those working standard 35-40 h/week. Methods and results In this prospective multi-cohort study from the Individual-Participant-Data Meta-Analysis in Working Populations (IPD-Work) Consortium, the study population was 85 494 working men and women (mean age 43.4 years...... of atrial fibrillation (10-year cumulative incidence 12.4 per 1000). After adjustment for age, sex and socioeconomic status, individuals working long hours had a 1.4-fold increased risk of atrial fibrillation compared with those working standard hours (hazard ratio = 1.42, 95% CI= 1.13-1.80, P= 0......Aims Studies suggest that people who work long hours are at increased risk of stroke, but the association of long working hours with atrial fibrillation, the most common cardiac arrhythmia and a risk factor for stroke, is unknown. We examined the risk of atrial fibrillation in individuals working...

  7. Analysis of amyloid fibrils in the cheetah (Acinonyx jubatus).

    Science.gov (United States)

    Bergström, Joakim; Ueda, Mitsuharu; Une, Yumi; Sun, Xuguo; Misumi, Shogo; Shoji, Shozo; Ando, Yukio

    2006-06-01

    Recently, a high prevalence of amyloid A (AA) amyloidosis has been documented among captive cheetahs worldwide. Biochemical analysis of amyloid fibrils extracted from the liver of a Japanese captive cheetah unequivocally showed that protein AA was the main fibril constituent. Further characterization of the AA fibril components by sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) and Western blot analysis revealed three main protein AA bands with approximate molecular weights of 8, 10 and 12 kDa. Mass spectrometry analysis of the 12-kDa component observed in SDS-PAGE and Western blotting confirmed the molecular weight of a 12,381-Da peak. Our finding of a 12-kDa protein AA component provides evidence that the cheetah SAA sequence is longer than the previously reported 90 amino acid residues (approximately 10 kDa), and hence SAA is part of the amyloid fibril.

  8. Dronedarone in high-risk permanent atrial fibrillation

    DEFF Research Database (Denmark)

    Connolly, Stuart J; Camm, A John; Halperin, Jonathan L

    2011-01-01

    Dronedarone restores sinus rhythm and reduces hospitalization or death in intermittent atrial fibrillation. It also lowers heart rate and blood pressure and has antiadrenergic and potential ventricular antiarrhythmic effects. We hypothesized that dronedarone would reduce major vascular events in ...

  9. Graphene-supporting films and low-voltage STEM in SEM toward imaging nanobio materials without staining: Observation of insulin amyloid fibrils.

    Science.gov (United States)

    Ogawa, Takashi; Gang, Geun Won; Thieu, Minh Thu; Kwon, Hyuksang; Ahn, Sang Jung; Ha, Tai Hwan; Cho, Boklae

    2017-05-01

    Utilization of graphene-supporting films and low-voltage scanning transmission electron microscopy (LV-STEM) in scanning electron microscopy (SEM) is shown to be an effective means of observing unstained nanobio materials. Insulin amyloid fibrils, which are implicated as a cause of type II diabetes, are formed in vitro and observed without staining at room temperature. An in-lens cold field-emission SEM, equipped with an additional homemade STEM detector, provides dark field (DF)-STEM images in the low energy range of 5-30keV, together with secondary electron (SE) images. Analysis based on Lenz's theory is used to interpret the experimental results. Graphene films, where the fibrils are deposited, reduce the background level of the STEM images compared with instances when conventional amorphous carbon films are used. Using 30keV, which is lower than that for conventional TEM (100-300keV), together with low detection angles (15-55mrad) enhances the signals from the fibrils. These factors improve image quality, which enables observation of thin fibrils with widths of 7-8nm. STEM imaging clearly reveals a twisted-ribbon structure of a fibril, and SE imaging shows an emphasized striped pattern of the fibril. The LV-STEM in SEM enables acquisition of two types of images of an identical fibril in a single instrument, which is useful for understanding the structure. This study expands the application of SEM to other systems of interest, which is beneficial to a large number of users. The method in this study can be applied to the observation of various nanobio materials and analysis of their native structures, thus contributing to research in materials and life sciences. Copyright © 2017 Elsevier Ltd. All rights reserved.

  10. Stroke and bleeding in atrial fibrillation with chronic kidney disease

    DEFF Research Database (Denmark)

    Olesen, Jonas Bjerring; Lip, Gregory Y.H.; Kamper, Anne-Lise

    2012-01-01

    Both atrial fibrillation and chronic kidney disease increase the risk of stroke and systemic thromboembolism. However, these risks, and the effects of antithrombotic treatment, have not been thoroughly investigated in patients with both conditions.......Both atrial fibrillation and chronic kidney disease increase the risk of stroke and systemic thromboembolism. However, these risks, and the effects of antithrombotic treatment, have not been thoroughly investigated in patients with both conditions....

  11. Nanomechanical mapping of hydrated rat tail tendon collagen I fibrils.

    Science.gov (United States)

    Baldwin, Samuel J; Quigley, Andrew S; Clegg, Charlotte; Kreplak, Laurent

    2014-10-21

    Collagen fibrils play an important role in the human body, providing tensile strength to connective tissues. These fibrils are characterized by a banding pattern with a D-period of 67 nm. The proposed origin of the D-period is the internal staggering of tropocollagen molecules within the fibril, leading to gap and overlap regions and a corresponding periodic density fluctuation. Using an atomic force microscope high-resolution modulus maps of collagen fibril segments, up to 80 μm in length, were acquired at indentation speeds around 10(5) nm/s. The maps revealed a periodic modulation corresponding to the D-period as well as previously undocumented micrometer scale fluctuations. Further analysis revealed a 4/5, gap/overlap, ratio in the measured modulus providing further support for the quarter-staggered model of collagen fibril axial structure. The modulus values obtained at indentation speeds around 10(5) nm/s are significantly larger than those previously reported. Probing the effect of indentation speed over four decades reveals two distinct logarithmic regimes of the measured modulus and point to the existence of a characteristic molecular relaxation time around 0.1 ms. Furthermore, collagen fibrils exposed to temperatures between 50 and 62°C and cooled back to room temperature show a sharp decrease in modulus and a sharp increase in fibril diameter. This is also associated with a disappearance of the D-period and the appearance of twisted subfibrils with a pitch in the micrometer range. Based on all these data and a similar behavior observed for cross-linked polymer networks below the glass transition temperature, we propose that collagen I fibrils may be in a glassy state while hydrated.

  12. Solid-State-NMR-Structure-Based Inhibitor Design to Achieve Selective Inhibition of the Parallel-in-Register β-Sheet versus Antiparallel Iowa Mutant β-Amyloid Fibrils.

    Science.gov (United States)

    Cheng, Qinghui; Qiang, Wei

    2017-06-08

    Solid-state nuclear magnetic resonance (ssNMR) spectroscopy has been widely applied to characterize the high-resolution structures of β-amyloid (Aβ) fibrils. While these structures provide crucial molecular insights on the deposition of amyloid plaques in Alzheimer's diseases (AD), ssNMR structures have been rarely used so far as the basis for designing inhibitors. It remains a challenge because the ssNMR-based Aβ fibril structures were usually obtained with sparsely isotope-labeled peptides with limited experimental constraints, where the structural models, especially the side-chain coordinates, showed restricted precision. However, these structural models often possess a higher accuracy within the hydrophobic core regions with more well-defined experimental data, which provide potential targets for the molecular design. This work presents an ssNMR-based molecular design to achieve selective inhibition of a particular type of Aβ fibrillar structure, which was formed with the Iowa mutant of Aβ with parallel-in-register β-sheet hydrophobic core. The results show that short peptides that mimic the C-terminal β-strands of the fibril may have a preference in binding to the parallel Aβ fibrils rather than the antiparallel fibrils, mainly due to the differences in the high-resolution structures in the fibril elongation interfaces. The Iowa mutant Aβ fibrils are utilized in this work mainly as a model to demonstrate the feasibility of the strategy because it is relatively straightforward to distinguish the parallel and antiparallel fibril structures using ssNMR. Our results suggest that it is potentially feasible to design structure-selective inhibitors and/or diagnostic agents to Aβ fibrils using ssNMR-based structural models.

  13. Post-operative atrial fibrillation: a maze of mechanisms

    Science.gov (United States)

    Maesen, Bart; Nijs, Jan; Maessen, Jos; Allessie, Maurits; Schotten, Ulrich

    2012-01-01

    Post-operative atrial fibrillation (POAF) is one of the most frequent complications of cardiac surgery and an important predictor of patient morbidity as well as of prolonged hospitalization. It significantly increases costs for hospitalization. Insights into the pathophysiological factors causing POAF have been provided by both experimental and clinical investigations and show that POAF is ‘multi-factorial’. Facilitating factors in the mechanism of the arrhythmia can be classified as acute factors caused by the surgical intervention and chronic factors related to structural heart disease and ageing of the heart. Furthermore, some proarrhythmic mechanisms specifically occur in the setting of POAF. For example, inflammation and beta-adrenergic activation have been shown to play a prominent role in POAF, while these mechanisms are less important in non-surgical AF. More recently, it has been shown that atrial fibrosis and the presence of an electrophysiological substrate capable of maintaining AF also promote the arrhythmia, indicating that POAF has some proarrhythmic mechanisms in common with other forms of AF. The clinical setting of POAF offers numerous opportunities to study its mechanisms. During cardiac surgery, biopsies can be taken and detailed electrophysiological measurements can be performed. Furthermore, the specific time course of POAF, with the delayed onset and the transient character of the arrhythmia, also provides important insight into its mechanisms. This review discusses the mechanistic interaction between predisposing factors and the electrophysiological mechanisms resulting in POAF and their therapeutic implications. PMID:21821851

  14. Both hypothyroidism and hyperthyroidism increase atrial fibrillation inducibility in rats.

    Science.gov (United States)

    Zhang, Youhua; Dedkov, Eduard I; Teplitsky, Diana; Weltman, Nathan Y; Pol, Christine J; Rajagopalan, Viswanathan; Lee, Bianca; Gerdes, A Martin

    2013-10-01

    Evidence indicates that cardiac hypothyroidism may contribute to heart failure progression. It is also known that heart failure is associated with an increased risk of atrial fibrillation (AF). Although it is established that hyperthyroidism increases AF incidence, the effect of hypothyroidism on AF is unclear. This study investigated the effects of different thyroid hormone levels, ranging from hypothyroidism to hyperthyroidism on AF inducibility in thyroidectomized rats. Thyroidectomized rats with serum-confirmed hypothyroidism 1 month after surgery were randomized into hypothyroid (N=9), euthyroid (N=9), and hyperthyroid (N=9) groups. Rats received placebo, 3.3-mg l-thyroxine (T4), or 20-mg T4 pellets (60-day release form) for 2 months, respectively. At the end of treatment, hypothyroid, euthyroid, and hyperthyroid status was confirmed. Hypothyroid animals showed cardiac atrophy and reduced cardiac systolic and diastolic functions, whereas hyperthyroid rats exhibited cardiac hypertrophy and increased cardiac function. Hypothyroidism and hyperthyroidism produced opposite electrophysiological changes in heart rates and atrial effective refractory period, but both significantly increased AF susceptibility. AF incidence was 78% in hypothyroid, 67% in hyperthyroid, and the duration of induced AF was also longer, compared with 11% in the euthyroid group (all Phyperthyroidism lead to increased AF vulnerability in a rat thyroidectomy model. Our results stress that normal thyroid hormone levels are required to maintain normal cardiac electrophysiology and to prevent cardiac arrhythmias and AF.

  15. Both Hypothyroidism and Hyperthyroidism Increase Atrial Fibrillation Inducibility in Rats

    Science.gov (United States)

    Zhang, Youhua; Dedkov, Eduard I.; Teplitsky, Diana; Weltman, Nathan Y.; Pol, Christine J.; Rajagopalan, Viswanathan; Lee, Bianca; Gerdes, A. Martin

    2014-01-01

    Background Evidence indicates that cardiac hypothyroidism may contribute to heart failure (HF) progression. It is also known that HF is associated with an increased risk of atrial fibrillation (AF). While it is established that hyperthyroidism increases AF incidence, the effect of hypothyroidism on AF is unclear. This study investigated the effects of different thyroid hormone levels, ranging from hypothyroidism to hyperthyroidism on AF inducibility in thyroidectomized rats. Methods and Results Thyroidectomized rats with serum confirmed hypothyroidism 1 month after surgery were randomized into hypothyroid (n=9), euthyroid (n=9) and hyperthyroid (n=9) groups. Rats received placebo, 3.3mg L-thyroxine (T4), or 20 mg T4 pellets (60 day release form) for 2 months, respectively. At the end of treatment, hypothyroid, euthyroid and hyperthyroid status was confirmed. Hypothyroid animals showed cardiac atrophy and reduced cardiac systolic and diastolic function, while hyperthyroid rats exhibited cardiac hypertrophy and increased cardiac function. Hypothyroidism and hyperthyroidism produced opposite electrophysiological changes in heart rates and atrial effective refractory period, but both significantly increased AF susceptibility. AF incidence was 78% in hypothyroid, 67% in hyperthyroid, and the duration of induced AF was also longer, compared with 11% in the euthyroid group (all phyperthyroidism lead to increased AF vulnerability in a rat thyroidectomy model. Our results stress that normal thyroid hormone levels are required to maintain normal cardiac electrophysiology and prevent cardiac arrhythmias and AF. PMID:24036190

  16. Viologen-Phosphorus Dendrimers Inhibit α-Synuclein Fibrillation.

    Science.gov (United States)

    Milowska, Katarzyna; Grochowina, Justyna; Katir, Nadia; El Kadib, Abdelkrim; Majoral, Jean-Pierre; Bryszewska, Maria; Gabryelak, Teresa

    2013-03-04

    Inhibition of α-synuclein (ASN) fibril formation is a potential therapeutic strategy in Parkinson's disease and other synucleinopathies. The aim of this study was to examine the role of viologen-phosphorus dendrimers in the α-synuclein fibrillation process and to assess the structural changes in α-synuclein under the influence of dendrimers. ASN interactions with phosphonate and pegylated surface-reactive viologen-phosphorus dendrimers were examined by measuring the zeta potential, which allowed determining the number of dendrimer molecules that bind to the ASN molecule. The fibrillation kinetics and the structural changes were examined using ThT fluorescence and CD spectroscopy. Depending on the concentration of the used dendrimer and the nature of the reactive groups located on the surface, ASN fibrillation kinetics can be significantly reduced, and even, in the specific case of phosphonate dendrimers, the fibrillation can be totally inhibited at low concentrations. The presented results indicate that viologen-phosphorus dendrimers are able to inhibit ASN fibril formation and may be used as fibrillar regulating agents in neurodegenerative disorders.

  17. Dermatopontin interacts with fibronectin, promotes fibronectin fibril formation, and enhances cell adhesion.

    Science.gov (United States)

    Kato, Aiko; Okamoto, Osamu; Ishikawa, Kazushi; Sumiyoshi, Hideaki; Matsuo, Noritaka; Yoshioka, Hidekatsu; Nomizu, Motoyoshi; Shimada, Tatsuo; Fujiwara, Sakuhei

    2011-04-29

    We report that dermatopontin (DP), an abundant dermal extracellular matrix protein, is found in the fibrin clot and in the wound fluid, which comprise the provisional matrix at the initial stage of wound healing. DP was also found in the serum but at a lower concentration than that in wound fluid. DP co-localized with both fibrin and fibronectin on fibrin fibers and interacted with both proteins. Both normal fibroblast and HT1080 cell adhesion to the fibrin-fibronectin matrix were dose-dependently enhanced by DP, and the adhesion was mediated by α5β1 integrin. The cytoskeleton was more organized in the cells that adhered to the fibrin-fibronectin-DP complex. When incubated with DP, fibronectin formed an insoluble complex of fibronectin fibrils as visualized by electron microscopy. The interacting sites of fibronectin with DP were the first, thirteenth, and fourteenth type III repeats (III(1), III(13), and III(14)), with III(13) and III(14) assumed to be the major sites. The interaction between III(2-3) and III(12-14) was inhibited by DP, whereas the interaction between I(1-5) and III(12-14) was specifically and strongly enhanced by DP. Because the interaction between III(2-3) and III(12-14) is involved in forming a globular conformation of fibronectin, and that between I(1-5) and III(12-14) is required for forming fibronectin fibrils, DP promotes fibronectin fibril formation probably by changing the fibronectin conformation. These results suggest that DP has an accelerating role in fibroblast cell adhesion to the provisional matrix in the initial stage of wound healing.

  18. Cardiac rehabilitation versus usual care for patients treated with catheter ablation for atrial fibrillation

    DEFF Research Database (Denmark)

    Risom, Signe S; Zwisler, Ann-Dorthe; Rasmussen, Trine Bernholdt

    2016-01-01

    ) versus 20.7mL kg(-1) min(-1), p of main effect=0.003, p of interaction between time and intervention=0.020). No significant difference between groups on Short Form-36 was found (53.8 versus 51.9 points, P=.20). Two serious adverse events (atrial fibrillation in relation to physical exercise and death...... unrelated to rehabilitation) occurred in the cardiac rehabilitation group versus one in the usual care group (death unrelated to intervention) (P=.56). In the cardiac rehabilitation group 16 patients versus 7 in the usual care group reported non-serious adverse events (P=.047). CONCLUSION: Comprehensive...

  19. Role of the N-terminus for the stability of an amyloid-β fibril with three-fold symmetry.

    Directory of Open Access Journals (Sweden)

    Christian A Söldner

    Full Text Available A key player in Alzheimer's disease is the peptide amyloid-beta (Aβ, whose aggregation into small soluble oligomers, protofilaments, and fibrils finally leads to plaque deposits in human brains. The aggregation behavior of Aβ is strongly modulated by the nature and composition of the peptide's environment and by its primary sequence properties. The N-terminal residues of Aβ play an important role, because they are known to change the peptide's aggregation propensity. Since these residues are for the first time completely resolved at the molecular level in a three-fold symmetric fibril structure derived from a patient, we chose that system as template for a systematic investigation of the influence of the N-terminus upon structural stability. Using atomistic molecular dynamics simulations, we examined several fibrillar systems comprising three, six, twelve and an infinite number of layers, both with and without the first eight residues. First, we found that three layers are not sufficient to stabilize the respective Aβ topology. Second, we observed a clear stabilizing effect of the N-terminal residues upon the overall fibril fold: truncated Aβ systems were less stable than their full-length counterparts. The N-terminal residues Arg5, Asp7, and Ser8 were found to form important interfilament contacts stabilizing the overall fibril structure of three-fold symmetry. Finally, similar structural rearrangements of the truncated Aβ species in different simulations prompted us to suggest a potential mechanism involved in the formation of amyloid fibrils with three-fold symmetry.

  20. Shaking alone induces de novo conversion of recombinant prion proteins to β-sheet rich oligomers and fibrils.

    Directory of Open Access Journals (Sweden)

    Carol L Ladner-Keay

    Full Text Available The formation of β-sheet rich prion oligomers and fibrils from native prion protein (PrP is thought to be a key step in the development of prion diseases. Many methods are available to convert recombinant prion protein into β-sheet rich fibrils using various chemical denaturants (urea, SDS, GdnHCl, high temperature, phospholipids, or mildly acidic conditions (pH 4. Many of these methods also require shaking or another form of agitation to complete the conversion process. We have identified that shaking alone causes the conversion of recombinant PrP to β-sheet rich oligomers and fibrils at near physiological pH (pH 5.5 to pH 6.2 and temperature. This conversion does not require any denaturant, detergent, or any other chemical cofactor. Interestingly, this conversion does not occur when the water-air interface is eliminated in the shaken sample. We have analyzed shaking-induced conversion using circular dichroism, resolution enhanced native acidic gel electrophoresis (RENAGE, electron microscopy, Fourier transform infrared spectroscopy, thioflavin T fluorescence and proteinase K resistance. Our results show that shaking causes the formation of β-sheet rich oligomers with a population distribution ranging from octamers to dodecamers and that further shaking causes a transition to β-sheet fibrils. In addition, we show that shaking-induced conversion occurs for a wide range of full-length and truncated constructs of mouse, hamster and cervid prion proteins. We propose that this method of conversion provides a robust, reproducible and easily accessible model for scrapie-like amyloid formation, allowing the generation of milligram quantities of physiologically stable β-sheet rich oligomers and fibrils. These results may also have interesting implications regarding our understanding of prion conversion and propagation both within the brain and via techniques such as protein misfolding cyclic amplification (PMCA and quaking induced conversion (QuIC.

  1. Factors associated with confidence in decision making and satisfaction with risk communication among patients with atrial fibrillation.

    Science.gov (United States)

    Hedberg, Berith; Malm, Dan; Karlsson, Jan-Erik; Årestedt, Kristofer; Broström, Anders

    2018-06-01

    Atrial fibrillation is a prevalent cardiac arrhythmia. Effective communication of risks (e.g. stroke risk) and benefits of treatment (e.g. oral anticoagulants) is crucial for the process of shared decision making. The aim of this study was to explore factors associated with confidence in decision making and satisfaction with risk communication after a follow-up visit among patients who three months earlier had visited an emergency room for atrial fibrillation related symptoms. A cross-sectional design was used and 322 patients (34% women), mean age 66.1 years (SD 10.5 years) with atrial fibrillation were included in the south of Sweden. Clinical examinations were done post an atrial fibrillation episode. Self-rating scales for communication (Combined Outcome Measure for Risk Communication and Treatment Decision Making Effectiveness), uncertainty in illness (Mishel Uncertainty in Illness Scale-Community), mastery of daily life (Mastery Scale), depressive symptoms (Hospital Anxiety and Depression Scale) and vitality, physical health and mental health (36-item Short Form Health Survey) were used to collect data. Decreased vitality and mastery of daily life, as well as increased uncertainty in illness, were independently associated with lower confidence in decision making. Absence of hypertension and increased uncertainty in illness were independently associated with lower satisfaction with risk communication. Clinical atrial fibrillation variables or depressive symptoms were not associated with satisfaction with confidence in decision making or satisfaction with risk communication. The final models explained 29.1% and 29.5% of the variance in confidence in decision making and satisfaction with risk communication. Confidence in decision making is associated with decreased vitality and mastery of daily life, as well as increased uncertainty in illness, while absence of hypertension and increased uncertainty in illness are associated with risk communication satisfaction.

  2. Recurrence of pulmonary vein conduction and atrial fibrillation after pulmonary vein isolation for atrial fibrillation

    DEFF Research Database (Denmark)

    Nilsson, Brian; Chen, Xu; Pehrson, Steen

    2006-01-01

    BACKGROUND: Both segmental ostial and circumferential extraostial pulmonary vein (PV) isolation have been proven effective in the treatment of atrial fibrillation (AF). However, the recurrence of AF and PV conduction after the 2 ablation strategies has never been compared in a randomized study...... isolation. Extraostial PV isolation was performed by encircling the paired left and right PVs, respectively, guided by an electroanatomic mapping system. RESULTS: A total of 84% of the patients had recurrent AF after the first PV isolation procedure, showing 72% with AF and 12% with organized left atrial...

  3. Aggregation and Fibril Morphology of the Arctic Mutation of Alzheimer’s Aβ peptide by CD, TEM, STEM and in situ AFM

    Science.gov (United States)

    Norlin, Nils; Hellberg, Magnus; Filippov, Andrei; Sousa, Alioscka A.; Gröbner, Gerhard; Leapman, Richard D.; Almqvist, Nils; Antzutkin, Oleg N.

    2012-01-01

    Morphology of aggregation intermediates, polymorphism of amyloid fibrils and aggregation kinetics of the “Arctic” mutant of the Alzheimer’s amyloid β-peptide, Aβ(1-40)(E22G), in a physiologically relevant TRIS buffer (pH 7.4) were thoroughly explored in comparison with the human wild type Alzheimer’s amyloid peptide, wt-Aβ(1-40), using both in situ atomic force and electron microscopy, circular dichroism and thioflavin T fluorescence assays. For arc-Aβ(1-40) at the end of the ‘lag’-period of fibrillization an abrupt appearance of ~3 nm size ‘spherical aggregates’ with a homogeneous morphology, was identified. Then, the aggregation proceeds with a rapid growth of amyloid fibrils with a variety of morphologies, while the spherical aggregates eventually disappeared during in situ measurements. Arc-Aβ(1-40) was also shown to form fibrils at much lower concentrations than wt-Aβ(1-40): ≤2.5 μM and 12.5 μM, respectively. Moreover, at the same concentration, 50 μM, the aggregation process proceeds more rapidly for arc-Aβ(1-40): The first amyloid fibrils were observed after ca 72 hours from the onset of incubation as compared to approximately 7 days for wt-Aβ(1-40). Amyloid fibrils of arc-Aβ(1-40) exhibit a large variety of polymorphs, at least five, both coiled and non-coiled distinct fibril structures were recognized by AFM, while at least four types of arc-Aβ(1-40) fibrils were identified by TEM and STEM and their mass-per-length statistics were collected suggesting supramolecular structures with two, four and six β-sheet laminae. Our results suggest a pathway of fibrillogenesis for full-length Alzheimer’s peptides with small and structurally ordered transient spherical aggregates as on-pathway immediate precursors of amyloid fibrils. PMID:22750418

  4. Wool fibril sponges with perspective biomedical applications

    International Nuclear Information System (INIS)

    Patrucco, A.; Cristofaro, F.; Simionati, M.; Zoccola, M.; Bruni, G.; Fassina, L.; Visai, L.; Magenes, G.

    2016-01-01

    Sheep's wool was used as a natural source to prepare keratin microfibril sponges for scaffolding, by disruption of the histological structure of the fibres through mild alkali treatment, followed by ultrasonication, casting and salt-leaching. The wool sponges showed highly interconnected porosity (93%) and contain intrinsic sites of cellular recognition that mimic the extracellular matrix (ECM). They displayed good thermal and water stability due to the conversion of disulphide cystine bonds into shorter monosulphide lanthionine intermolecular bonds, but significantly swelled in water, because of the high hydrophilicity and porosity, with a volume increasing up to 38%. Nevertheless, sponges were stable in water without structural changes, with a neutral pH in aqueous media, and showed excellent resilience to repeated compression stresses. According to in vitro biocompatibility assays, wool fibril sponges showed a good cell adhesion and proliferation as proved by MTT, FDA assays and SEM observations. The unique structure of the cortical cell network made by wool keratin proteins with controlled-size macro-porosity suitable for cell guesting, and nutrient feeding, provides an excellent scaffold for future tissue engineering applications. - Highlights: • Scaffolds were prepared from wool exploiting the fibres' histology structure. • The scaffold showed high interconnected micro- and macro-porosity. • The microscopic structure is very similar to the extracellular bone matrix. • Scaffolds reversibly swell in water with high resilience to repeated compression. • Composites were cytocompatible and supported the growth of SAOS-2 cell line.

  5. Red Wine, Resveratrol and Atrial Fibrillation

    Science.gov (United States)

    Garavaglia, Juliano; Marcadenti, Aline

    2017-01-01

    Atrial fibrillation (AF) is a common cardiac arrhythmia that is associated with increased risk for cardiovascular disease and overall mortality. Excessive alcohol intake is a well-known risk factor for AF, but this correlation is less clear with light and moderate drinking. Besides, low doses of red wine may acutely prolong repolarization and slow cardiac conduction. Resveratrol, a bioactive polyphenol found in grapes and red wine, has been linked to antiarrhythmic properties and may act as an inhibitor of both intracellular calcium release and pathological signaling cascades in AF, eliminating calcium overload and preserving the cardiomyocyte contractile function. However, there are still no clinical trials at all that prove that resveratrol supplementation leads to improved outcomes. Besides, no observational study supports a beneficial effect of light or moderate alcohol intake and a lower risk of AF. The purpose of this review is to briefly describe possible beneficial effects of red wine and resveratrol in AF, and also present studies conducted in humans regarding chronic red wine consumption, resveratrol, and AF. PMID:29084143

  6. Red Wine, Resveratrol and Atrial Fibrillation

    Directory of Open Access Journals (Sweden)

    Laura Siga Stephan

    2017-10-01

    Full Text Available Atrial fibrillation (AF is a common cardiac arrhythmia that is associated with increased risk for cardiovascular disease and overall mortality. Excessive alcohol intake is a well-known risk factor for AF, but this correlation is less clear with light and moderate drinking. Besides, low doses of red wine may acutely prolong repolarization and slow cardiac conduction. Resveratrol, a bioactive polyphenol found in grapes and red wine, has been linked to antiarrhythmic properties and may act as an inhibitor of both intracellular calcium release and pathological signaling cascades in AF, eliminating calcium overload and preserving the cardiomyocyte contractile function. However, there are still no clinical trials at all that prove that resveratrol supplementation leads to improved outcomes. Besides, no observational study supports a beneficial effect of light or moderate alcohol intake and a lower risk of AF. The purpose of this review is to briefly describe possible beneficial effects of red wine and resveratrol in AF, and also present studies conducted in humans regarding chronic red wine consumption, resveratrol, and AF.

  7. Red Wine, Resveratrol and Atrial Fibrillation.

    Science.gov (United States)

    Stephan, Laura Siga; Almeida, Eduardo Dytz; Markoski, Melissa Medeiros; Garavaglia, Juliano; Marcadenti, Aline

    2017-10-30

    Atrial fibrillation (AF) is a common cardiac arrhythmia that is associated with increased risk for cardiovascular disease and overall mortality. Excessive alcohol intake is a well-known risk factor for AF, but this correlation is less clear with light and moderate drinking. Besides, low doses of red wine may acutely prolong repolarization and slow cardiac conduction. Resveratrol, a bioactive polyphenol found in grapes and red wine, has been linked to antiarrhythmic properties and may act as an inhibitor of both intracellular calcium release and pathological signaling cascades in AF, eliminating calcium overload and preserving the cardiomyocyte contractile function. However, there are still no clinical trials at all that prove that resveratrol supplementation leads to improved outcomes. Besides, no observational study supports a beneficial effect of light or moderate alcohol intake and a lower risk of AF. The purpose of this review is to briefly describe possible beneficial effects of red wine and resveratrol in AF, and also present studies conducted in humans regarding chronic red wine consumption, resveratrol, and AF.

  8. Atrial fibrillation: effects beyond the atrium?

    Science.gov (United States)

    Wijesurendra, Rohan S; Casadei, Barbara

    2015-03-01

    Atrial fibrillation (AF) is the most common sustained clinical arrhythmia and is associated with significant morbidity, mostly secondary to heart failure and stroke, and an estimated two-fold increase in premature death. Efforts to increase our understanding of AF and its complications have focused on unravelling the mechanisms of electrical and structural remodelling of the atrial myocardium. Yet, it is increasingly recognized that AF is more than an atrial disease, being associated with systemic inflammation, endothelial dysfunction, and adverse effects on the structure and function of the left ventricular myocardium that may be prognostically important. Here, we review the molecular and in vivo evidence that underpins current knowledge regarding the effects of human or experimental AF on the ventricular myocardium. Potential mechanisms are explored including diffuse ventricular fibrosis, focal myocardial scarring, and impaired myocardial perfusion and perfusion reserve. The complex relationship between AF, systemic inflammation, as well as endothelial/microvascular dysfunction and the effects of AF on ventricular calcium handling and oxidative stress are also addressed. Finally, consideration is given to the clinical implications of these observations and concepts, with particular reference to rate vs. rhythm control. © The Author 2015. Published by Oxford University Press on behalf of the European Society of Cardiology.

  9. Wool fibril sponges with perspective biomedical applications

    Energy Technology Data Exchange (ETDEWEB)

    Patrucco, A., E-mail: a.patrucco@bi.ismac.cnr.it [CNR-ISMAC, Italian National Research Council, Institute for Macromolecular Studies, Corso G. Pella 16, 13900, Biella (Italy); Cristofaro, F., E-mail: francesco.cristofaro01@universitadipavia.it [Department of Molecular Medicine, INSTM UdR of Pavia, University of Pavia, Viale Taramelli 3/B, 27100, Pavia (Italy); Centre for Health Technologies (CHT), University of Pavia, Via Ferrata 1, 27100, Pavia (Italy); Simionati, M., E-mail: m.simionati@bi.ismac.cnr.it [CNR-ISMAC, Italian National Research Council, Institute for Macromolecular Studies, Corso G. Pella 16, 13900, Biella (Italy); Zoccola, M., E-mail: m.zoccola@bi.ismac.cnr.it [CNR-ISMAC, Italian National Research Council, Institute for Macromolecular Studies, Corso G. Pella 16, 13900, Biella (Italy); Bruni, G., E-mail: giovanna.bruni@unipv.it [Department of Chemistry, — Physical-Chemistry Section, University of Pavia, Viale Taramelli 16, 27100, Pavia (Italy); Fassina, L., E-mail: lorenzo.fassina@unipv.it [Centre for Health Technologies (CHT), University of Pavia, Via Ferrata 1, 27100, Pavia (Italy); Department of Electrical, Computer and Biomedical Engineering, University of Pavia, Via Ferrata 1, 27100, Pavia (Italy); Visai, L., E-mail: livia.visai@unipv.it [Department of Molecular Medicine, INSTM UdR of Pavia, University of Pavia, Viale Taramelli 3/B, 27100, Pavia (Italy); Centre for Health Technologies (CHT), University of Pavia, Via Ferrata 1, 27100, Pavia (Italy); Department of Occupational Medicine, Toxicology and Environmental Risks, S. Maugeri Foundation, IRCCS, Via S. Boezio, 28, 27100, Pavia (Italy); Magenes, G., E-mail: giovanni.magenes@unipv.it [Centre for Health Technologies (CHT), University of Pavia, Via Ferrata 1, 27100, Pavia (Italy); Department of Electrical, Computer and Biomedical Engineering, University of Pavia, Via Ferrata 1, 27100, Pavia (Italy); and others

    2016-04-01

    Sheep's wool was used as a natural source to prepare keratin microfibril sponges for scaffolding, by disruption of the histological structure of the fibres through mild alkali treatment, followed by ultrasonication, casting and salt-leaching. The wool sponges showed highly interconnected porosity (93%) and contain intrinsic sites of cellular recognition that mimic the extracellular matrix (ECM). They displayed good thermal and water stability due to the conversion of disulphide cystine bonds into shorter monosulphide lanthionine intermolecular bonds, but significantly swelled in water, because of the high hydrophilicity and porosity, with a volume increasing up to 38%. Nevertheless, sponges were stable in water without structural changes, with a neutral pH in aqueous media, and showed excellent resilience to repeated compression stresses. According to in vitro biocompatibility assays, wool fibril sponges showed a good cell adhesion and proliferation as proved by MTT, FDA assays and SEM observations. The unique structure of the cortical cell network made by wool keratin proteins with controlled-size macro-porosity suitable for cell guesting, and nutrient feeding, provides an excellent scaffold for future tissue engineering applications. - Highlights: • Scaffolds were prepared from wool exploiting the fibres' histology structure. • The scaffold showed high interconnected micro- and macro-porosity. • The microscopic structure is very similar to the extracellular bone matrix. • Scaffolds reversibly swell in water with high resilience to repeated compression. • Composites were cytocompatible and supported the growth of SAOS-2 cell line.

  10. Ventricular fibrillation time constant for swine

    International Nuclear Information System (INIS)

    Wu, Jiun-Yan; Sun, Hongyu; Nimunkar, Amit J; Webster, John G; O'Rourke, Ann; Huebner, Shane; Will, James A

    2008-01-01

    The strength–duration curve for cardiac excitation can be modeled by a parallel resistor–capacitor circuit that has a time constant. Experiments on six pigs were performed by delivering current from the X26 Taser dart at a distance from the heart to cause ventricular fibrillation (VF). The X26 Taser is an electromuscular incapacitation device (EMD), which generates about 50 kV and delivers a pulse train of about 15–19 pulses s −1 with a pulse duration of about 150 µs and peak current about 2 A. Similarly a continuous 60 Hz alternating current of the amplitude required to cause VF was delivered from the same distance. The average current and duration of the current pulse were estimated in both sets of experiments. The strength–duration equation was solved to yield an average time constant of 2.87 ms ± 1.90 (SD). Results obtained may help in the development of safety standards for future electromuscular incapacitation devices (EMDs) without requiring additional animal tests

  11. The mechanisms of atrial fibrillation in hyperthyroidism

    Directory of Open Access Journals (Sweden)

    Bielecka-Dabrowa Agata

    2009-04-01

    Full Text Available Abstract Atrial fibrillation (AF is a complex condition with several possible contributing factors. The rapid and irregular heartbeat produced by AF increases the risk of blood clot formation inside the heart. These clots may eventually become dislodged, causing embolism, stroke and other disorders. AF occurs in up to 15% of patients with hyperthyroidism compared to 4% of people in the general population and is more common in men and in patients with triiodothyronine (T3 toxicosis. The incidence of AF increases with advancing age. Also, subclinical hyperthyroidism is a risk factor associated with a 3-fold increase in development of AF. Thyrotoxicosis exerts marked influences on electrical impulse generation (chronotropic effect and conduction (dromotropic effect. Several potential mechanisms could be invoked for the effect of thyroid hormones on AF risk, including elevation of left atrial pressure secondary to increased left ventricular mass and impaired ventricular relaxation, ischemia resulting from increased resting heart rate, and increased atrial eopic activity. Reentry has been postulated as one of the main mechanisms leading to AF. AF is more likely if effective refractory periods are short and conduction is slow. Hyperthyroidism is associated with shortening of action potential duration which may also contribute to AF.

  12. Atrial Fibrillation Predictors: Importance of the Electrocardiogram.

    Science.gov (United States)

    German, David M; Kabir, Muammar M; Dewland, Thomas A; Henrikson, Charles A; Tereshchenko, Larisa G

    2016-01-01

    Atrial fibrillation (AF) is the most common arrhythmia in adults and is associated with significant morbidity and mortality. Substantial interest has developed in the primary prevention of AF, and thus the identification of individuals at risk for developing AF. The electrocardiogram (ECG) provides a wealth of information, which is of value in predicting incident AF. The PR interval and P wave indices (including P wave duration, P wave terminal force, P wave axis, and other measures of P wave morphology) are discussed with regard to their ability to predict and characterize AF risk in the general population. The predictive value of the QT interval, ECG criteria for left ventricular hypertrophy, and findings of atrial and ventricular ectopy are also discussed. Efforts are underway to develop models that predict AF incidence in the general population; however, at present, little information from the ECG is included in these models. The ECG provides a great deal of information on AF risk and has the potential to contribute substantially to AF risk estimation, but more research is needed. © 2015 Wiley Periodicals, Inc.

  13. Michler’s Hydrol Blue: A Sensitive Probe for Amyloid Fibril Detection

    KAUST Repository

    Kitts, Catherine C.; Beke-Somfai, Tamás; Nordén, Bengt

    2011-01-01

    amyloid probe, can differentiate between insulin and lysozyme fibrils by a more red-shifted excitation spectrum for insulin fibrils. To support the experimental observations, time-dependent density functional theory (TDDFT) calculations were performed

  14. Risk of atrial fibrillation as a function of the electrocardiographic PR interval

    DEFF Research Database (Denmark)

    Nielsen, Jonas Bille; Pietersen, Adrian; Graff, Claus

    2013-01-01

    Prolongation of the PR interval has been associated with an increased risk of incident atrial fibrillation (AF).......Prolongation of the PR interval has been associated with an increased risk of incident atrial fibrillation (AF)....

  15. A randomized study of the effects of exercise training on patients with atrial fibrillation

    DEFF Research Database (Denmark)

    Osbak, Philip Samuel; Mourier, Malene; Kjaer, Andreas

    2011-01-01

    Exercise training is beneficial in ischemic and congestive heart disease. However, the effect on atrial fibrillation (AF) is unknown.......Exercise training is beneficial in ischemic and congestive heart disease. However, the effect on atrial fibrillation (AF) is unknown....

  16. Determination of collagen fibril structure and orientation in connective tissues by X-ray diffraction

    Science.gov (United States)

    Wilkinson, S. J.; Hukins, D. W. L.

    1999-08-01

    Elastic scattering of X-rays can provide the following information on the fibrous protein collagen: its molecular structure, the axial arrangement of rod-like collagen molecules in a fibril, the lateral arrangement of molecules within a fibril, and the orientation of fibrils within a biological tissue. The first part of the paper reviews the principles involved in deducing this information. The second part describes a new computer program for measuring the equatorial intensity distribution, that provides information on the lateral arrangement of molecules within a fibril, and the angular distribution of the equatorial peaks that provides information on the orientation of fibrils. Orientation of fibrils within a tissue is quantified by the orientation distribution function, g( φ), which represents the probability of finding a fibril oriented between φ and φ+ δφ. The application of the program is illustrated by measurement of g( φ) for the collagen fibrils in demineralised cortical bone from cow tibia.

  17. Long-Term Exposure to Traffic-Related Air Pollution and Risk of Incident Atrial Fibrillation

    DEFF Research Database (Denmark)

    Monrad, Maria; Sajadieh, Ahmad; Christensen, Jeppe Schultz

    2017-01-01

    BACKGROUND: Atrial fibrillation is the most common sustained arrhythmia and associated with cardiovascular morbidity and mortality. The few studies conducted on short-term effects of air pollution on episodes of atrial fibrillation indicates a positive association, though not consistently...

  18. Newer Anticoagulants for Non-Valvular Atrial Fibrillation

    Directory of Open Access Journals (Sweden)

    Joseph M. Harburger

    2012-05-01

    Full Text Available Non-valvular atrial fibrillation is a recognized risk factor for stroke and systemic embolism. It has been clearly established that warfarin reduces the risk of stroke and systemic embolism in persons with atrial fibrillation and additional risk factors for stroke. The use of warfarin, however, requires frequent monitoring, and there is great variability in patient response to warfarin. Warfarin interacts with several medications and foods. In addition, warfarin use portends a significant risk of bleeding. For these reasons, warfarin is frequently not prescribed to persons for whom the drug would provide a clear benefit. Over the past decade, attempts have been made to develop drugs that are at least as safe and effective as warfarin for the treatment of atrial fibrillation that do not require monitoring nor have as many interactions. Initial studies of compounds in this regard ultimately failed due to safety concerns, but over the past two years two novel agents have been approved by the United States Food and Drug Association for anticoagulation in non-valvular atrial fibrillation, another drug is under review, and additional compounds are being studied. This article will review the use of warfarin and these new agents in the treatment of non-valvular atrial fibrillation.

  19. Elasticity in Physically Cross-Linked Amyloid Fibril Networks

    Science.gov (United States)

    Cao, Yiping; Bolisetty, Sreenath; Adamcik, Jozef; Mezzenga, Raffaele

    2018-04-01

    We provide a constitutive model of semiflexible and rigid amyloid fibril networks by combining the affine thermal model of network elasticity with the Derjaguin-Landau-Vervey-Overbeek (DLVO) theory of electrostatically charged colloids. When compared to rheological experiments on β -lactoglobulin and lysozyme amyloid networks, this approach provides the correct scaling of elasticity versus both concentration (G ˜c2.2 and G ˜c2.5 for semiflexible and rigid fibrils, respectively) and ionic strength (G ˜I4.4 and G ˜I3.8 for β -lactoglobulin and lysozyme, independent from fibril flexibility). The pivotal role played by the screening salt is to reduce the electrostatic barrier among amyloid fibrils, converting labile physical entanglements into long-lived cross-links. This gives a power-law behavior of G with I having exponents significantly larger than in other semiflexible polymer networks (e.g., actin) and carrying DLVO traits specific to the individual amyloid fibrils.

  20. Synaptic Plasticity in Cardiac Innervation and Its Potential Role in Atrial Fibrillation

    Directory of Open Access Journals (Sweden)

    Jesse L. Ashton

    2018-03-01

    Full Text Available Synaptic plasticity is defined as the ability of synapses to change their strength of transmission. Plasticity of synaptic connections in the brain is a major focus of neuroscience research, as it is the primary mechanism underpinning learning and memory. Beyond the brain however, plasticity in peripheral neurons is less well understood, particularly in the neurons innervating the heart. The atria receive rich innervation from the autonomic branch of the peripheral nervous system. Sympathetic neurons are clustered in stellate and cervical ganglia alongside the spinal cord and extend fibers to the heart directly innervating the myocardium. These neurons are major drivers of hyperactive sympathetic activity observed in heart disease, ventricular arrhythmias, and sudden cardiac death. Both pre- and postsynaptic changes have been observed to occur at synapses formed by sympathetic ganglion neurons, suggesting that plasticity at sympathetic neuro-cardiac synapses is a major contributor to arrhythmias. Less is known about the plasticity in parasympathetic neurons located in clusters on the heart surface. These neuronal clusters, termed ganglionated plexi, or “little brains,” can independently modulate neural control of the heart and stimulation that enhances their excitability can induce arrhythmia such as atrial fibrillation. The ability of these neurons to alter parasympathetic activity suggests that plasticity may indeed occur at the synapses formed on and by ganglionated plexi neurons. Such changes may not only fine-tune autonomic innervation of the heart, but could also be a source of maladaptive plasticity during atrial fibrillation.

  1. Investigation of the structural preference and flexibility of the loop residues in amyloid fibrils of the HET-s prion.

    Science.gov (United States)

    Dolenc, Jožica; Meier, Beat H; Rusu, Victor H; van Gunsteren, Wilfred F

    2016-02-17

    The structural variability of a 16-residue loop (residues 246-261) which is in part disordered and connects two layers of the β-solenoid formed by the prion-form of HET-s and its prion domain HET-s(218-289) is investigated using molecular dynamics computer simulation. A system of three HET-s(218-289) molecules in a β-sheet structure as in the fibril is simulated in aqueous solution. The trajectory structures appear to be consistent with the Cα chemical shift data obtained. In order to delineate the influence of the β-sheet core of the fibril upon the structural variability of the loop, the latter is also simulated without the β-sheet core, but with its N- and C-terminal residues restrained at their positions in the fibril. The analysis of the trajectories shows that the structural variability of the loop is restricted by the β-sheet core, least at its N-terminal end and most in the middle of the trimer.

  2. Modulation of α-synuclein fibrillization by ring-fused 2-pyridones: templation and inhibition involve oligomers with different structure.

    Science.gov (United States)

    Horvath, Istvan; Sellstedt, Magnus; Weise, Christoph; Nordvall, Lina-Maria; Krishna Prasad, G; Olofsson, Anders; Larsson, Göran; Almqvist, Fredrik; Wittung-Stafshede, Pernilla

    2013-04-15

    In a recent study we discovered that a ring-fused 2-pyridone compound triggered fibrillization of a key protein in Parkinson's disease, α-synuclein. To reveal how variations in compound structure affect protein aggregation, we now prepared a number of strategic analogs and tested their effects on α-synuclein amyloid fiber formation in vitro. We find that, in contrast to the earlier templating effect, some analogs inhibit α-synuclein fibrillization. For both templating and inhibiting compounds, the key species formed in the reactions are α-synuclein oligomers that contain compound. Despite similar macroscopic appearance, the templating and inhibiting oligomers are distinctly different in secondary structure content. When the inhibitory oligomers are added in seed amounts, they inhibit fresh α-synuclein aggregation reactions. Our study demonstrates that small chemical changes to the same central fragment can result in opposite effects on protein aggregation. Copyright © 2013 Elsevier Inc. All rights reserved.

  3. Critical residues in the PMEL/Pmel17 N-terminus direct the hierarchical assembly of melanosomal fibrils

    Science.gov (United States)

    Leonhardt, Ralf M.; Vigneron, Nathalie; Hee, Jia Shee; Graham, Morven; Cresswell, Peter

    2013-01-01

    PMEL (also called Pmel17 or gp100) is a melanocyte/melanoma-specific glycoprotein that plays a critical role in melanosome development by forming a fibrillar amyloid matrix in the organelle for melanin deposition. Although ultimately not a component of mature fibrils, the PMEL N-terminal region (NTR) is essential for their formation. By mutational analysis we establish a high-resolution map of this domain in which sequence elements and functionally critical residues are assigned. We show that the NTR functions in cis to drive the aggregation of the downstream polycystic kidney disease (PKD) domain into a melanosomal core matrix. This is essential to promote in trans the stabilization and terminal proteolytic maturation of the repeat (RPT) domain–containing MαC units, precursors of the second fibrillogenic fragment. We conclude that during melanosome biogenesis the NTR controls the hierarchical assembly of melanosomal fibrils. PMID:23389629

  4. Towards revealing the structure of bacterial inclusion bodies.

    Science.gov (United States)

    Wang, Lei

    2009-01-01

    Protein aggregation is a widely observed phenomenon in human diseases, biopharmaceutical production, and biological research. Protein aggregates are generally classified as highly ordered, such as amyloid fibrils, or amorphous, such as bacterial inclusion bodies. Amyloid fibrils are elongated filaments with diameters of 6-12 nm, they are comprised of residue-specific cross-beta structure, and display characteristic properties, such as binding with amyloid-specific dyes. Amyloid fibrils are associated with dozens of human pathological conditions, including Alzheimer disease and prion diseases. Distinguished from amyloid fibrils, bacterial inclusion bodies display apparent amorphous morphology. Inclusion bodies are formed during high-level recombinant protein production, and formation of inclusion bodies is a major concern in biotechnology. Despite of the distinctive morphological difference, bacterial inclusion bodies have been found to have some amyloid-like properties, suggesting that they might contain structures similar to amyloid-like fibrils. Recent structural data further support this hypothesis, and this review summarizes the latest progress towards revealing the structural details of bacterial inclusion bodies.

  5. 77 FR 11121 - Scientific Information Request on Treatment of Atrial Fibrillation

    Science.gov (United States)

    2012-02-24

    ... Information Request on Treatment of Atrial Fibrillation AGENCY: Agency for Healthcare Research and Quality... Review of the Treatment of Atrial Fibrillation, which is currently being conducted by the Evidence-based... the treatment of atrial fibrillation. The EHC Program is dedicated to identifying as many studies as...

  6. 78 FR 11207 - Clinical Study Designs for Surgical Ablation Devices for Treatment of Atrial Fibrillation...

    Science.gov (United States)

    2013-02-15

    ...] Clinical Study Designs for Surgical Ablation Devices for Treatment of Atrial Fibrillation; Guidance for... devices intended for the treatment of atrial fibrillation. DATES: Submit either electronic or written... Study Designs for Surgical Ablation Devices for Treatment of Atrial Fibrillation'' to the Division of...

  7. SAFETY OF AMIODARONE USAGE IN PATIENTS WITH WOLFF-PARKINSON-WHITE SYNDROME AND ATRIAL FIBRILLATION

    Directory of Open Access Journals (Sweden)

    D. A. Kuzhel

    2010-01-01

    Full Text Available Amiodarone is one of the basic antiarrhytmic drugs for atrial fibrillation treatment. However application of amiodarone in patients with atrial fibrillation and Wolff-Parkinson-White syndrome can induce ventricular fibrillation. Amiodarone usage in these patients should be accompanied by readiness for performance of resuscitation. This is confirmed by clinical case presentation.

  8. Meta-analysis identifies six new susceptibility loci for atrial fibrillation

    NARCIS (Netherlands)

    Ellinor, Patrick T; Lunetta, Kathryn L; Albert, Christine M; Glazer, Nicole L; Ritchie, Marylyn D; Smith, Albert V; Arking, Dan E; Müller-Nurasyid, Martina; Krijthe, Bouwe P; Lubitz, Steven A; Bis, Joshua C; Chung, Mina K; Dörr, Marcus; Ozaki, Kouichi; Roberts, Jason D; Smith, J Gustav; Pfeufer, Arne; Sinner, Moritz F; Lohman, Kurt; Ding, Jingzhong; Smith, Nicholas L; Smith, Jonathan D; Rienstra, Michiel; Rice, Kenneth M; Van Wagoner, David R; Magnani, Jared W; Wakili, Reza; Clauss, Sebastian; Rotter, Jerome I; Steinbeck, Gerhard; Launer, Lenore J; Davies, Robert W; Borkovich, Matthew; Harris, Tamara B; Lin, Honghuang; Völker, Uwe; Völzke, Henry; Milan, David J; Hofman, Albert; Boerwinkle, Eric; Chen, Lin Y; Soliman, Elsayed Z; Voight, Benjamin F; Li, Guo; Chakravarti, Aravinda; Kubo, Michiaki; Tedrow, Usha B; Rose, Lynda M; Ridker, Paul M; Conen, David; Tsunoda, Tatsuhiko; Furukawa, Tetsushi; Sotoodehnia, Nona; Xu, Siyan; Kamatani, Naoyuki; Levy, Daniel; Nakamura, Yusuke; Parvez, Babar; Mahida, Saagar; Furie, Karen L; Rosand, Jonathan; Muhammad, Raafia; Psaty, Bruce M; Meitinger, Thomas; Perz, Siegfried; Wichmann, H-Erich; Witteman, Jacqueline C M; Kao, W H Linda; Kathiresan, Sekar; Roden, Dan M; Uitterlinden, Andre G; Rivadeneira, Fernando; McKnight, Barbara; Sjögren, Marketa; Newman, Anne B; Liu, Yongmei; Gollob, Michael H; Melander, Olle; Tanaka, Toshihiro; Stricker, Bruno H Ch; Felix, Stephan B; Alonso, Alvaro; Darbar, Dawood; Barnard, John; Chasman, Daniel I; Heckbert, Susan R; Benjamin, Emelia J; Gudnason, Vilmundur; Kääb, Stefan

    Atrial fibrillation is a highly prevalent arrhythmia and a major risk factor for stroke, heart failure and death. We conducted a genome-wide association study (GWAS) in individuals of European ancestry, including 6,707 with and 52,426 without atrial fibrillation. Six new atrial fibrillation

  9. Optimizing cellulose fibrillation for the production of cellulose nanofibrils by a disk grinder

    Science.gov (United States)

    Chuanshuang Hu; Yu Zhao; Kecheng Li; J.Y. Zhu; Roland Gleisner

    2015-01-01

    The fibrillation of a bleached kraft eucalyptus pulp was investigated by means of a laboratory-scale disk grinder for the production of cellulose nanofibrils (CNF), while the parameters disk rotating speed, solid loading, and fibrillation duration were varied. The cumulative energy consumption was monitored during fibrillation. The degree of polymerization (DP) and...

  10. Formation of soluble amyloid oligomers and amyloid fibrils by the multifunctional protein vitronectin

    Directory of Open Access Journals (Sweden)

    Langen Ralf

    2008-10-01

    Full Text Available Abstract Background The multifunctional protein vitronectin is present within the deposits associated with Alzheimer disease (AD, age-related macular degeneration (AMD, atherosclerosis, systemic amyloidoses, and glomerulonephritis. The extent to which vitronectin contributes to amyloid formation within these plaques, which contain misfolded, amyloidogenic proteins, and the role of vitronectin in the pathophysiology of the aforementioned diseases is currently unknown. The investigation of vitronectin aggregation is significant since the formation of oligomeric and fibrillar structures are common features of amyloid proteins. Results We observed vitronectin immunoreactivity in senile plaques of AD brain, which exhibited overlap with the amyloid fibril-specific OC antibody, suggesting that vitronectin is deposited at sites of amyloid formation. Of particular interest is the growing body of evidence indicating that soluble nonfibrillar oligomers may be responsible for the development and progression of amyloid diseases. In this study we demonstrate that both plasma-purified and recombinant human vitronectin readily form spherical oligomers and typical amyloid fibrils. Vitronectin oligomers are toxic to cultured neuroblastoma and retinal pigment epithelium (RPE cells, possibly via a membrane-dependent mechanism, as they cause leakage of synthetic vesicles. Oligomer toxicity was attenuated in RPE cells by the anti-oligomer A11 antibody. Vitronectin fibrils contain a C-terminal protease-resistant fragment, which may approximate the core region of residues essential to amyloid formation. Conclusion These data reveal the propensity of vitronectin to behave as an amyloid protein and put forth the possibilities that accumulation of misfolded vitronectin may contribute to aggregate formation seen in age-related amyloid diseases.

  11. Aβ(39–42) Modulates Aβ Oligomerization but Not Fibril Formation

    Science.gov (United States)

    Gessel, Megan Murray; Wu, Chun; Li, Huiyuan; Bitan, Gal; Shea, Joan-Emma; Bowers, Michael T.

    2012-01-01

    Recently, certain C-terminal fragments (CTFs) of Aβ42 have been shown to be effective inhibitors of Aβ42 toxicity. Here, we examine the interactions between the shortest CTF in the original series, Aβ(39–42) and full-length Aβ. Mass spectrometry results indicate that Aβ(39–42) binds directly to Aβ monomers and to the n=2,4, and 6 oligomers. The Aβ42:Aβ(39–42) complex is further probed using in molecular dynamics simulations. Although the CTF was expected to bind to the hydrophobic C-terminus of Aβ42, the simulations show that Aβ(39–42) binds at several locations on Aβ42, including the C-terminus, other hydrophobic regions, and preferentially in the N-terminus. Ion mobility-mass spectrometry (IM-MS) and electron microscopy experiments indicate that Aβ(39–42) disrupts the early assembly of full-length Aβ. Specifically, the ion-mobility results show that Aβ(39–42) prevents the formation of large decamer/dodecamer Aβ42 species and, moreover, can remove these structures from solution. At the same time, thioflavin T fluorescence and electron microscopy results show that the CTF does not inhibit fibril formation, lending strong support to the hypothesis that oligomers and not amyloid fibrils are the Aβ form responsible for toxicity. The results emphasize the role of small, soluble assemblies in Aβ-induced toxicity and suggest that Aβ(39–42) inhibits Aβ-induced toxicity by a unique mechanism, modulating early assembly into non-toxic heterooligomers, without preventing fibril formation. PMID:22129303

  12. Disease management: atrial fibrillation and home monitoring.

    Science.gov (United States)

    Ricci, Renato Pietro

    2013-06-01

    Device-detected atrial fibrillation (AF) episodes predict poor clinical outcome regardless of symptoms. Potential benefits of remote monitoring are early arrhythmia detection and patient continuous monitoring. Several studies of device remote monitoring consistently demonstrated that AF represents the most common clinical alert and that detailed information on arrhythmia onset, duration, and burden as well as on the ventricular rate may be early available for clinical evaluation. Reaction time to AF alerts was very short in all series involving either pacemakers or defibrillators and action ability of AF alerts was very high. In the Home Guide Registry, in which 1650 patients were enrolled, AF was detected in 16.3% of patients and represented 36% of all cardiovascular events during the follow-up. Timely anticoagulation introduction in asymptomatic patients may impact on the stroke rate. According to the results of repeated Monte Carlo simulations based on a real population of 166 patients, daily monitoring may reduce the 2-year stroke risk by 9-18% with an absolute reduction of 0.2-0.6%, compared with conventional inter-visit intervals of 6-12 months. In the COMPAS trial, the incidence of hospitalizations for atrial arrhythmias and related stroke was significantly higher in the control group than in the remote monitoring group. Major questions will be addressed by the ongoing IMPACT trial in which a remote monitoring guided anticoagulation strategy based on AF detection will be compared with a physician-directed standard strategy. In patients with heart failure, AF early detection combined with other indexes may help prevent hospitalizations.

  13. Calcium signalling silencing in atrial fibrillation.

    Science.gov (United States)

    Greiser, Maura

    2017-06-15

    Subcellular calcium signalling silencing is a novel and distinct cellular and molecular adaptive response to rapid cardiac activation. Calcium signalling silencing develops during short-term sustained rapid atrial activation as seen clinically during paroxysmal atrial fibrillation (AF). It is the first 'anti-arrhythmic' adaptive response in the setting of AF and appears to counteract the maladaptive changes that lead to intracellular Ca 2+ signalling instability and Ca 2+ -based arrhythmogenicity. Calcium signalling silencing results in a failed propagation of the [Ca 2+ ] i signal to the myocyte centre both in patients with AF and in a rabbit model. This adaptive mechanism leads to a substantial reduction in the expression levels of calcium release channels (ryanodine receptors, RyR2) in the sarcoplasmic reticulum, and the frequency of Ca 2+ sparks and arrhythmogenic Ca 2+ waves remains low. Less Ca 2+ release per [Ca 2+ ] i transient, increased fast Ca 2+ buffering strength, shortened action potentials and reduced L-type Ca 2+ current contribute to a substantial reduction of intracellular [Na + ]. These features of Ca 2+ signalling silencing are distinct and in contrast to the changes attributed to Ca 2+ -based arrhythmogenicity. Some features of Ca 2+ signalling silencing prevail in human AF suggesting that the Ca 2+ signalling 'phenotype' in AF is a sum of Ca 2+ stabilizing (Ca 2+ signalling silencing) and Ca 2+ destabilizing (arrhythmogenic unstable Ca 2+ signalling) factors. Calcium signalling silencing is a part of the mechanisms that contribute to the natural progression of AF and may limit the role of Ca 2+ -based arrhythmogenicity after the onset of AF. © 2017 The Authors. The Journal of Physiology © 2017 The Physiological Society.

  14. Clinical application of low energy intracardiac cardioversion of atrial fibrillation

    International Nuclear Information System (INIS)

    Wu Liqun; Gu Gang; Su Kan; Su Renying; Shen Yongchu; Shen Weifeng

    2002-01-01

    Objective: To evaluate the efficacy and safety of low energy intracardiac cardioversion in persistent atria fibrillation. Methods: Low energy intracardiac cardioversion was performed by delivering R wave-synchronized biphasic shocks in 7 patients (4 men, 3 women) with persistent atrial fibrillation. Prior to the procedure, all patients underwent transesophageal echocardiographic examinations to rule out the presence of intracardiac thrombus and received subcutaneous injection of low molecular weight heparin for 3-5 days. Two custom-made 6 Fr catheters (Rhythm Technologies of Getz, USA) were used for de-fibrillation shock delivery. One catheter was positioned in the lower right atrium so that the majority of the catheter electrodes had firm contact with the right atrial free wall. The second catheter was placed randomly either in coronary sinus through right internal jugular vein or in the left pulmonary artery through femoral vein. In addition, a standard diagnostic 6-F quadrupolar catheter was placed at the right ventricular apex for ventricular synchronization and postshock ventricular pacing. Shocks were delivered by Implant Support Device (Model 4510, Teleceronics). After conversion, all patients were treated with intravenous amiodarone in the first 24 hours followed by oral administration. Results: In all 7 patients cardioversion of atrial fibrillation to sinus rhythm was successfully obtained. A mean of 2 ± 1 shocks per patient has been delivered with a total amount of 13 shocks. The average delivered energy was 7.8 ± 2.2 Joules. No complication occurred. At a mean follow-up of 18 ± 9 months, 4 of the 7 patients treated successfully showed sinus rhythm there after. Atrial fibrillation recurred in 3 patients at the second, fifth day and eighth month after cardioversion. Conclusions: Low energy intracardiac cardioversion is effective and safe, and can be easily performed in patients without general anesthesia. It offers a new option for restoring sinus

  15. Failure of antiarrhythmic drugs to prevent experimental reperfusion ventricular fibrillation.

    Science.gov (United States)

    Naito, M; Michelson, E L; Kmetzo, J J; Kaplinsky, E; Dreifus, L S

    1981-01-01

    Ninety-nine adult mongrel dogs underwent acute ligation of the proximal left anterior descending coronary artery. Thirty minutes later, the occlusion was released to evaluate the effectiveness of five antiarrhythmic protocols in eliminating reperfusion ventricular fibrillation. The five protocols included: protocol 1 --i.v. lidocaine, preligation and prerelease (n = 19); protocol 2 -- i.v. lidocaine, prereperfusion only (n = 22); protocol 3 -- chronic, oral, daily amiodarone for 2 weeks preligation (n = 19); protocol 4 -- i.v. procainamide, preligation and prereperfusion (n = 21); and protocol 5 -- i.v. verapamil, prereperfusion (n = 18). Each regimen was evaluated with respect to the incidence of reperfusion ventricular fibrillation in dogs that survived to reperfusion, and the results were compared to 77 control dogs that underwent identical coronary artery occlusion and release procedures without drug therapy. The incidence of reperfusion ventricular fibrillation was as follows: protocol 1 -- seven of 15 dogs (47%); protocol 2 -- six of 18 (33%); protocol 3 -- 11 of 16 dogs (69%); protocol 4 -- eight of 17 dogs (47%); and protocol 5 -- 10 of 17 dogs (59%), compared with 36 of 60 (60%) in control dogs. Using chi-square analysis, protocol 2 was beneficial (p antecedent coronary artery ligation periods, and predictive risk indexes for the occurrence of reperfusion ventricular fibrillation were developed. the Mantel-Haenszel method of statistical analysis revealed that none of these protocols resulted in a statistically significant reduction in the incidence of reperfusion ventricular fibrillation. Thus, use of these predictive indexes plus appropriate statistical methods has revealed, unexpectedly, limitations in the efficacy of a spectrum of antiarrhythmic agents in preventing reperfusion ventricular fibrillation.

  16. Exploring the early steps of aggregation of amyloid-forming peptide KFFE

    International Nuclear Information System (INIS)

    Wei Guanghong; Mousseau, Normand; Derreumaux, Philippe

    2004-01-01

    It has been shown recently that even a tetrapeptide can form amyloid fibrils sharing all the characteristics of amyloid fibrils built from large proteins. Recent experimental studies also suggest that the toxicity observed in several neurodegenerative diseases, such as Alzheimer's disease and Creutzfeldt-Jakob disease, is not only related to the mature fibrils themselves, but also to the soluble oligomers formed early in the process of fibrillogenesis. This raises the interest in studying the early steps of the aggregation process. Although fibril formation follows the nucleation-condensation process, characterized by the presence of lag phase, the exact pathways remain to be determined. In this study, we used the activation-relaxation technique and a generic energy model to explore the process of self-assembly and the structures of the resulting aggregates of eight KFFE peptides. Our simulations show, starting from different states with a preformed antiparallel dimer, that eight chains can self-assemble to adopt, with various orientations, four possible distant oligomeric well-aligned structures of similar energy. Two of these structures show a double-layer β-sheet organization, in agreement with the structure of amyloid fibrils as observed by x-ray diffraction; another two are mixtures of dimers and trimers. Our results also suggest that octamers are likely to be below the critical size for nucleation of amyloid fibrils for small peptides

  17. Exploring the early steps of aggregation of amyloid-forming peptide KFFE

    Energy Technology Data Exchange (ETDEWEB)

    Wei Guanghong [Departement de Physique and Regroupement Quebecois sur les Materiaux de Pointe, Universite de Montreal, CP 6128, succursale centre-ville, Montreal, QC, H3C 3J7 (Canada); Mousseau, Normand [Departement de Physique and Regroupement Quebecois sur les Materiaux de Pointe, Universite de Montreal, CP 6128, succursale centre-ville, Montreal, QC, H3C 3J7 (Canada); Derreumaux, Philippe [Laboratoire de Biochimie, Theorique, UPR 9080 CNRS, IBPC, Universite Paris 7 Denis-Diderot, 13 rue Pierre et Marie Curie, 75005 Paris (France)

    2004-11-10

    It has been shown recently that even a tetrapeptide can form amyloid fibrils sharing all the characteristics of amyloid fibrils built from large proteins. Recent experimental studies also suggest that the toxicity observed in several neurodegenerative diseases, such as Alzheimer's disease and Creutzfeldt-Jakob disease, is not only related to the mature fibrils themselves, but also to the soluble oligomers formed early in the process of fibrillogenesis. This raises the interest in studying the early steps of the aggregation process. Although fibril formation follows the nucleation-condensation process, characterized by the presence of lag phase, the exact pathways remain to be determined. In this study, we used the activation-relaxation technique and a generic energy model to explore the process of self-assembly and the structures of the resulting aggregates of eight KFFE peptides. Our simulations show, starting from different states with a preformed antiparallel dimer, that eight chains can self-assemble to adopt, with various orientations, four possible distant oligomeric well-aligned structures of similar energy. Two of these structures show a double-layer {beta}-sheet organization, in agreement with the structure of amyloid fibrils as observed by x-ray diffraction; another two are mixtures of dimers and trimers. Our results also suggest that octamers are likely to be below the critical size for nucleation of amyloid fibrils for small peptides.

  18. Exposure-Based Therapy for Symptom Preoccupation in Atrial Fibrillation

    DEFF Research Database (Denmark)

    Särnholm, Josefin; Skúladóttir, Helga; Rück, Christian

    2017-01-01

    Atrial fibrillation (AF) is the most common cardiac arrhythmia. Patients often experience a range of symptoms resulting in a markedly reduced quality of life, and commonly show symptom preoccupation in terms of avoidance and control behaviors. Cognitive behavior therapy (CBT) has been shown...... with symptomatic paroxysmal (intermittent) atrial fibrillation who were assessed pre- and posttreatment and at 6-month follow-up. The CBT lasted 10 weeks and included exposure to physical sensations similar to AF symptoms, exposure to avoided situations or activities, and behavioral activation. We observed large...

  19. Gender Differences in Antithrombotic Treatment for Newly Diagnosed Atrial Fibrillation

    DEFF Research Database (Denmark)

    Mazurek, Michał; Huisman, Menno V; Rothman, Kenneth J

    2018-01-01

    was -0.5% (95% CI, -1.8%, 0.8%). VKAs were prescribed to 32.8% and 31.9% (NOACs 46.8% and 48.3%) of women and men, respectively. No confounder for the association between gender and anticoagulant prescription was identified. Between-gender differences in anticoagulant use (lower use in women compared......AIMS: Data on gender differences in oral anticoagulation for stroke prevention in patients with atrial fibrillation are conflicting, largely limited to regional reports and Vitamin K antagonist (VKA) use. We aimed to analyze gender-specific anticoagulant prescription patterns early following...... atrial fibrillation (difference in prevalence of anticoagulant use...

  20. Circadian variation in dominant atrial fibrillation frequency in persistent atrial fibrillation

    International Nuclear Information System (INIS)

    Sandberg, Frida; Stridh, Martin; Sörnmo, Leif; Bollmann, Andreas; Husser, Daniela

    2010-01-01

    Circadian variation in atrial fibrillation (AF) frequency is explored in this paper by employing recent advances in signal processing. Once the AF frequency has been estimated and tracked by a hidden Markov model approach, the resulting trend is analyzed for the purpose of detecting and characterizing the presence of circadian variation. With cosinor analysis, the results show that the short-term variations in the AF frequency exceed the variation that may be attributed to circadian. Using the autocorrelation method, circadian variation was found in 13 of 18 ambulatory ECG recordings (Holter) acquired from patients with long-standing persistent AF. Using the ensemble correlation method, the highest AF frequency usually occurred during the afternoon, whereas the lowest usually occurred during late night. It is concluded that circadian variation is present in most patients with long-standing persistent AF though the short-term variation in the AF frequency is considerable and should be taken into account

  1. Analysis of brain natriuretic peptide in 30 patients with atrial fibrillation

    International Nuclear Information System (INIS)

    Jin Qiang; Lu Jianghui; Li Weipeng; Yuan Yuan; Sun Weili

    2009-01-01

    To investigate the relationship between atrial fibrillation and brain natriuretic peptide (BNP), plasma levels of BNP in 30 patients with atrial fibrillation and 30 health controls were assayed and compared. The results showed that plasma levels of BNP in patients with atrial fibrillation were significantly higher than those of health controls (P<0.05). When the patients with atrial fibrillation were restored sinus rhythm, the concentration of BNP decreased significantly (P<0.05). BNP was a sensitive marker of cardiac dysfunction, and BNP was positively correlated with atrial fibrillation. (authors)

  2. Clinical Benefit of Ablating Localized Sources for Human Atrial Fibrillation: The Indiana University FIRM Registry.

    Science.gov (United States)

    Miller, John M; Kalra, Vikas; Das, Mithilesh K; Jain, Rahul; Garlie, Jason B; Brewster, Jordan A; Dandamudi, Gopi

    2017-03-14

    Mounting evidence shows that localized sources maintain atrial fibrillation (AF). However, it is unclear in unselected "real-world" patients if sources drive persistent atrial fibrillation (PeAF), long-standing persistent atrial fibrillation (LPeAF), or paroxysmal atrial fibrillation (PAF); if right atrial sites are important; and what the long-term success of source ablation is. The aim of this study was to analyze the role of rotors and focal sources in a large academic registry of consecutive patients undergoing source mapping for AF. One hundred seventy consecutive patients (mean age 59 ± 12 years, 79% men) with PAF (37%), PeAF (31%), or LPeAF (32%). Of these, 73 (43%) had undergone at least 1 prior ablation attempt (mean 1.9 ± 0.8; range: 1 to 4). Focal impulse and rotor modulation (FIRM) with an endocardial basket catheter was used in all cases. FIRM analysis revealed sources in the right atrium in 85% of patients (1.8 ± 1.3) and in the left atrium in 90% of patients (2.0 ± 1.3). FIRM ablation terminated AF to sinus rhythm or atrial flutter or tachycardia in 59% (PAF), 37% (PeAF), and 19% (LPeAF) of patients, with 15 of 67 terminations due to right atrial ablation. On follow-up, freedom from AF after a single FIRM procedure for the entire series was 95% (PAF), 83% (PeAF), and 82% (LPeAF) at 1 year and freedom from all atrial arrhythmias was 77% (PAF), 75% (PeAF), and 57% (LPeAF). In the Indiana University FIRM registry, FIRM-guided ablation produced high single-procedure success, mostly in patients with nonparoxysmal AF. Data from mapping, acute terminations, and outcomes strongly support the mechanistic role of biatrial rotors and focal sources in maintaining AF in diverse populations. Randomized trials of FIRM-guided ablation and mechanistic studies to determine how rotors form, progress, and regress are needed. Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

  3. Amyloid fibril formation of peptides derived from the C-terminus of CETP modulated by lipids

    Energy Technology Data Exchange (ETDEWEB)

    García-González, Victor [Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, 04510 México, DF (Mexico); Mas-Oliva, Jaime, E-mail: jmas@ifc.unam.mx [Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, 04510 México, DF (Mexico); División de Investigación, Facultad de Medicina, Universidad Nacional Autónoma de México, 04510 México, DF (Mexico)

    2013-04-26

    Highlights: •The secondary structure of a C-terminal peptide derived from CETP was studied. •Lipids modulate secondary structure changes of a C-terminal peptide derived from CETP. •Lysophosphatidic acid maintains a functional α-helix and prevents fibril formation. •Transfer of lipids by CETP is related to the presence of an α-helix at its C-end. -- Abstract: Cholesteryl-ester transfer protein (CETP) is a plasmatic protein involved in neutral lipid transfer between lipoproteins. Focusing on the last 12 C-terminus residues we have previously shown that mutation D{sub 470}N promotes a conformational change towards a β-secondary structure. In turn, this modification leads to the formation of oligomers and fibrillar structures, which cause cytotoxic effects similar to the ones provoked by amyloid peptides. In this study, we evaluated the role of specific lipid arrangements on the structure of peptide helix-Z (D{sub 470}N) through the use of thioflavin T fluorescence, peptide bond absorbance, circular dichroism and electron microscopy. The results indicate that the use of micelles formed with lysophosphatidylcholine and lysophosphatidic acid (LPA) under neutral pH induce a conformational transition of peptide helix-Z containing a β-sheet conformation to a native α-helix structure, therefore avoiding the formation of amyloid fibrils. In contrast, incubation with phosphatidic acid does not change the profile for the β-sheet conformation. When the electrostatic charge at the surface of micelles or vesicles is regulated through the use of lipids such as phospholipid and LPA, minimal changes and the presence of β-structures were recorded. Mixtures with a positive net charge diminished the percentage of β-structure and the amount of amyloid fibrils. Our results suggest that the degree of solvation determined by the presence of a free hydroxyl group on lipids such as LPA is a key condition that can modulate the secondary structure and the consequent formation of

  4. Amyloid fibril formation of peptides derived from the C-terminus of CETP modulated by lipids

    International Nuclear Information System (INIS)

    García-González, Victor; Mas-Oliva, Jaime

    2013-01-01

    Highlights: •The secondary structure of a C-terminal peptide derived from CETP was studied. •Lipids modulate secondary structure changes of a C-terminal peptide derived from CETP. •Lysophosphatidic acid maintains a functional α-helix and prevents fibril formation. •Transfer of lipids by CETP is related to the presence of an α-helix at its C-end. -- Abstract: Cholesteryl-ester transfer protein (CETP) is a plasmatic protein involved in neutral lipid transfer between lipoproteins. Focusing on the last 12 C-terminus residues we have previously shown that mutation D 470 N promotes a conformational change towards a β-secondary structure. In turn, this modification leads to the formation of oligomers and fibrillar structures, which cause cytotoxic effects similar to the ones provoked by amyloid peptides. In this study, we evaluated the role of specific lipid arrangements on the structure of peptide helix-Z (D 470 N) through the use of thioflavin T fluorescence, peptide bond absorbance, circular dichroism and electron microscopy. The results indicate that the use of micelles formed with lysophosphatidylcholine and lysophosphatidic acid (LPA) under neutral pH induce a conformational transition of peptide helix-Z containing a β-sheet conformation to a native α-helix structure, therefore avoiding the formation of amyloid fibrils. In contrast, incubation with phosphatidic acid does not change the profile for the β-sheet conformation. When the electrostatic charge at the surface of micelles or vesicles is regulated through the use of lipids such as phospholipid and LPA, minimal changes and the presence of β-structures were recorded. Mixtures with a positive net charge diminished the percentage of β-structure and the amount of amyloid fibrils. Our results suggest that the degree of solvation determined by the presence of a free hydroxyl group on lipids such as LPA is a key condition that can modulate the secondary structure and the consequent formation of amyloid

  5. Ventricular fibrillation development following atrial fibrillation after the ingestion of sildenaphil in a patient with Wolff-Parkinson-White syndrome.

    Science.gov (United States)

    Inci, Sinan; Izgu, Ibrahim; Aktas, Halil; Dogan, Pinar; Dogan, Ali

    2015-08-01

    Complications in the accessory pathway in Wolff-Parkinson-White (WPW) syndrome could cause different clinical conditions by inducing different arrhythmias. Atrial fibrillation (AF) is one of these arrhythmias and is important as it causes life-threatening arrhythmias. It is known that some drugs, underlying cardiac diseases, and the number of accessory pathways, cause a predisposition to this condition. In the current report, we presented a patient with WPW who was admitted to the emergency department with AF, wide QRS and a rapid ventricular response that progressed to ventricular fibrillation.

  6. Fibril morphology and tendon mechanical properties in patellar tendinopathy: effects of heavy slow resistance training

    DEFF Research Database (Denmark)

    Kongsgaard, Mads; Qvortrup, Klaus; Larsen, Jytte Overgaard

    2010-01-01

    BACKGROUND: Patellar tendinopathy is characterized by pathologic abnormalities. Heavy slow resistance training (HSR) is effective in the management of patellar tendinopathy, but the underlying functional mechanisms remain elusive. PURPOSE: To investigate fibril morphology and mechanical properties...... assessed symptoms/function and maximal tendon pain during activity. Tendon biopsy samples were analyzed for fibril density, volume fraction, and mean fibril area. Tendon mechanical properties were assessed using force and ultrasonography samplings. RESULTS: Patients improved in symptoms/function (P = .02...... area decreased (-26% +/- 21%, P = .04) in tendinopathic tendons after HSR. CONCLUSION: Fibril morphology is abnormal in tendinopathy, but tendon mechanical properties are not. Clinical improvements after HSR were associated with changes in fibril morphology toward normal fibril density and mean fibril...

  7. Embolic risk in atrial fibrillation that arises from hyperthyroidism: review of the medical literature.

    Science.gov (United States)

    Traube, Elie; Coplan, Neil L

    2011-01-01

    Atrial fibrillation, the most common cardiac complication of hyperthyroidism, occurs in an estimated 10% to 25% of overtly hyperthyroid patients. The prevalence of atrial fibrillation increases with age in the general population and in thyrotoxic patients. Other risk factors for atrial fibrillation in thyrotoxic patients include male sex, ischemic or valvular heart disease, and congestive heart failure. The incidence of arterial embolism or stroke in thyrotoxic atrial fibrillation is less clear. There are many reports of arterial thromboembolism associated with hyperthyroidism, including cases of young adults without coexisting risk factors other than thyrotoxic atrial fibrillation. The use of anticoagulative agents to prevent thromboembolic sequelae of thyrotoxic atrial fibrillation is controversial: National organizations provide conflicting recommendations in their practice guidelines. Herein, we review the medical literature and examine the evidence behind the recommendations in order to determine the best approach to thromboembolic prophylaxis in patients who have atrial fibrillation that is associated with hyperthyroidism.

  8. [Recurrent right atrial thrombus in a patient with atrial fibrillation and heart failure].

    Science.gov (United States)

    Elikowski, Waldemar; Wróblewski, Dariusz; Małek-Elikowska, Małgorzata; Mazurek, Andrzej; Foremska-Iciek, Joanna; Łazowski, Stanisław

    2015-11-01

    Atrial fibrillation and heart failure are factors predisposing to locally formed intracardiac thrombosis, which is usually localized in left-sided chambers. A case report. The authors present a case of a 50-year-old male with permanent atrial fibrillation and dilated cardiomyopathy in whom recurrent right atrial thrombus was observed. Initially, the lesion was detected in echocardiography while he was hospitalized due to extensive right-sided pneumonia. The thrombus was successfully treated with heparin, followed by warfarin. Even though the patient continued warfarin use properly, there was recurrence of the thrombus two years later during a new episode of heart failure exacerbation. Because the thrombus was resistant to intensified anticoagulation, cardiac surgery was needed. A large (30 x 25 mm) pedunculated thrombus, as well as two smaller ones (each of 10 x 10 mm) attached closely to the atrial wall and previously not detected either by echocardiography or by magnetic resonance imaging, were excited. A partially organized pattern of the thrombi in histological examination can explain lack of anticoagulation effectiveness. © 2015 MEDPRESS.

  9. TFE-induced local unfolding and fibrillation of SOD1: bridging the experiment and simulation studies.

    Science.gov (United States)

    Kumar, Vijay; Prakash, Amresh; Pandey, Preeti; Lynn, Andrew M; Hassan, Md Imtaiyaz

    2018-05-18

    Misfolding and aggregation of Cu, Zn Superoxide dismutase (SOD1) is involved in the neurodegenerative disease, amyotrophic lateral sclerosis. Many studies have shown that metal-depleted, monomeric form of SOD1 displays substantial local unfolding dynamics and is the precursor for aggregation. Here, we have studied the structure and dynamics of different apo monomeric SOD1 variants associated with unfolding and aggregation in aqueous trifluoroethanol (TFE) through experiments and simulation. TFE induces partially unfolded β-sheet-rich extended conformations in these SOD1 variants, which subsequently develops aggregates with fibril-like characteristics. Fibrillation was achieved more easily in disulfide-reduced monomeric SOD1 when compared with wild-type and mutant monomeric SOD1. At higher concentrations of TFE, a native-like structure with the increase in α-helical content was observed. The molecular dynamics simulation results illustrate distinct structural dynamics for different regions of SOD1 variants and show uniform local unfolding of β-strands. The strands protected by the zinc-binding and electrostatic loops were found to unfold first in 20% (v/v) TFE, leading to a partial unfolding of β-strands 4, 5, and 6 which are prone to aggregation. Our results thus shed light on the role of local unfolding and conformational dynamics in SOD1 misfolding and aggregation. © 2018 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

  10. Gender and culture differences in the quality of life among Americans and Koreans with atrial fibrillation.

    Science.gov (United States)

    Kang, Younhee

    2009-09-01

    This study examined the gender and culture differences in relation to the quality of life among Americans and Koreans with atrial fibrillation. It employed secondary data analysis and a descriptive comparative design. The settings were the cardiology outpatient clinics and the outpatient clinic in two urban hospitals in the USA and one university hospital in Korea. The quality of life was measured by the Short-Form Health Survey. The data from 129 subjects were analyzed by two-way ANCOVA and a post-hoc test. In relation to physical function, there was a statistically significant effect shown by gender, but no significant differences were found by the main effect of culture and the interaction effect of gender and culture. The significant interaction effect of gender and culture on mental health was shown. In conclusion, gender differences in the quality of life perceived by patients with atrial fibrillation varied with their cultural background. Thus, patients' cultural background should be considered in nursing practice.

  11. Postoperative atrial fibrillation in patients on statins undergoing ...

    African Journals Online (AJOL)

    Introduction: The efficacy of perioperative statin therapy in decreasing postoperative morbidity in patients undergoing valve replacements and repairs is unknown. The aim of our study was to determine whether or not the literature supports the hypothesis that statins decrease postoperative atrial fibrillation (AF), and hence ...

  12. Atrial Fibrillation in Embolic Stroke: Anticoagulant Therapy at UNTH ...

    African Journals Online (AJOL)

    Objective: The decision to commence anticoagulation in a patient with embolic stroke and atrial fibrillation (AF) is often a difficult one for many clinicians. The result can have significant impact on the patient. This study was therefore undertaken to review the use of anticoagulation in embolic stroke in the setting of atrial ...

  13. Frequency analysis of the ECG before and during ventricular fibrillation

    NARCIS (Netherlands)

    Herbschleb, J.N.; Heethaar, R.M.; Tweel, I. van der; Meijler, F.L.

    1980-01-01

    Frequency analysis of cardiac electrograms of dogs with ventricular fibrillation (VF) during complete cardiopulmonary bypass and coronary perfusion showed a power spectrum with a peak around 12 Hz and its higher harmonics, suggesting more organization than generally assumed. As a next step to see

  14. Occlusion of left atrial appendage in patients with atrial fibrillation

    Directory of Open Access Journals (Sweden)

    О. Н. Ганеева

    2015-10-01

    Full Text Available The article reviews a new method of prophylaxis of thromboembolitic complications, specifically occlusion of left atrial appendage, in patients with atrial fibrillation. Indications and contraindications for the procedure, as well as a step-by-step process of the intervention itself are described. Special emphasis is placed on the up-to-date evidence and the review of clinical trials.

  15. Abnormal atrial activation in young patients with lone atrial fibrillation

    DEFF Research Database (Denmark)

    Holmqvist, Fredrik; Olesen, Morten S; Tveit, Arnljot

    2011-01-01

    Patients with a history of atrial fibrillation (AF) have previously been shown to have altered atrial conduction, as seen non-invasively using signal-averaged P-wave analysis. However, little is known about the P-wave morphology in patients in the early phases of AF with structurally normal hearts....

  16. Cancer antigen-125 and risk of atrial fibrillation

    DEFF Research Database (Denmark)

    Cheung, Angel; Gong, Mengqi; Bellanti, Roberto

    2018-01-01

    Background: Cancer antigen-125 (Ca-125) is traditionally recognised as a tumour marker and its role in cardiovascular diseases has been studied only in recent years. Whether Ca-125 is elevated in patients with atrial fibrillation (AF) and its levels predict the risk of AF remains controversial. T...

  17. P-wave duration and the risk of atrial fibrillation

    DEFF Research Database (Denmark)

    Nielsen, Jonas B; Kühl, Jørgen T; Pietersen, Adrian

    2015-01-01

    BACKGROUND: Results on the association between P-wave duration and the risk of atrial fibrillation (AF) are conflicting. OBJECTIVE: The purpose of this study was to obtain a detailed description of the relationship between P-wave duration and the risk of AF. METHODS: Using computerized analysis o...

  18. Paroxysmal Atrial Fibrillation in a Mission-Assigned Astronaut

    Science.gov (United States)

    Bauer, Peter A.; Polk, J. D.

    2010-01-01

    This presentation will explore the clinical and administrative conundrums faced by the flight surgeon upon discovering asymptomatic paroxysmal atrial fibrillation seven months prior to scheduled long duration spaceflight. The presenter will discuss the decision-making process as well as the clinical and operational outcomes.

  19. Molecular Mechanisms and New Treatment Paradigm for Atrial Fibrillation.

    Science.gov (United States)

    Sirish, Padmini; Li, Ning; Timofeyev, Valeriy; Zhang, Xiao-Dong; Wang, Lianguo; Yang, Jun; Lee, Kin Sing Stephen; Bettaieb, Ahmed; Ma, Sin Mei; Lee, Jeong Han; Su, Demetria; Lau, Victor C; Myers, Richard E; Lieu, Deborah K; López, Javier E; Young, J Nilas; Yamoah, Ebenezer N; Haj, Fawaz; Ripplinger, Crystal M; Hammock, Bruce D; Chiamvimonvat, Nipavan

    2016-05-01

    Atrial fibrillation represents the most common arrhythmia leading to increased morbidity and mortality, yet, current treatment strategies have proven inadequate. Conventional treatment with antiarrhythmic drugs carries a high risk for proarrhythmias. The soluble epoxide hydrolase enzyme catalyzes the hydrolysis of anti-inflammatory epoxy fatty acids, including epoxyeicosatrienoic acids from arachidonic acid to the corresponding proinflammatory diols. Therefore, the goal of the study is to directly test the hypotheses that inhibition of the soluble epoxide hydrolase enzyme can result in an increase in the levels of epoxyeicosatrienoic acids, leading to the attenuation of atrial structural and electric remodeling and the prevention of atrial fibrillation. For the first time, we report findings that inhibition of soluble epoxide hydrolase reduces inflammation, oxidative stress, atrial structural, and electric remodeling. Treatment with soluble epoxide hydrolase inhibitor significantly reduces the activation of key inflammatory signaling molecules, including the transcription factor nuclear factor κ-light-chain-enhancer, mitogen-activated protein kinase, and transforming growth factor-β. This study provides insights into the underlying molecular mechanisms leading to atrial fibrillation by inflammation and represents a paradigm shift from conventional antiarrhythmic drugs, which block downstream events to a novel upstream therapeutic target by counteracting the inflammatory processes in atrial fibrillation. © 2016 American Heart Association, Inc.

  20. Atrial fibrillation: Therapeutic potential of atrial K+ channel blockers.

    Science.gov (United States)

    Ravens, Ursula; Odening, Katja E

    2017-08-01

    Despite the epidemiological scale of atrial fibrillation, current treatment strategies are of limited efficacy and safety. Ideally, novel drugs should specifically correct the pathophysiological mechanisms responsible for atrial fibrillation with no other cardiac or extracardiac actions. Atrial-selective drugs are directed toward cellular targets with sufficiently different characteristics in atria and ventricles to modify only atrial function. Several potassium (K + ) channels with either predominant expression in atria or distinct electrophysiological properties in atria and ventricles can serve as atrial-selective drug targets. These channels include the ultra-rapidly activating, delayed outward-rectifying Kv1.5 channel conducting I Kur , the acetylcholine-activated inward-rectifying Kir3.1/Kir3.4 channel conducting I K,ACh , the Ca 2+ -activated K + channels of small conductance (SK) conducting I SK , and the two pore domain K + (K2P) channels TWIK-1, TASK-1 and TASK-3 that are responsible for voltage-independent background currents I TWIK-1 , I TASK-1 , and I TASK-3 . Here, we briefly review the characteristics of these K + channels and their roles in atrial fibrillation. The antiarrhythmic potential of drugs targeting the described channels is discussed as well as their putative value in treatment of atrial fibrillation. Copyright © 2016 Elsevier Inc. All rights reserved.

  1. Posibilities of cardiac pacemaker use in paroxsysmal atrial fibrilation

    Directory of Open Access Journals (Sweden)

    Borut Kamenik

    2005-12-01

    Full Text Available Background: Prevention of atrial fibrillation is a big therapeutic challenge because of all known negative consequences of this the most frequent cardiac arrhythmia. Numerous of clinical studies showed bad control or ineffectiveness of antiarhythmic drugs. Nonfarmakological therapies like surgical treatment, radiofrequency ablation and atrial pacing are being tested. Effectiveness of atrial pacing in prevention of paroxysmal artial fibrillation has been documented in numerous prospective studies and is effective for a long time interval, but only for patients with bradicardic underlying cardiac rhythm. In Normocardic rhythm or normal AV conduction the effective Atrial fibrillation prevention was not proven. The mechanism of action is based on premature atrial complex suppression, reduction of dispersion of refractoriness after short-long cycles and reduction of interatrial conduction delay. The atrial stimulation site or multi-site atrial pacing could be effective in AF prevention when interatrial conduction delay is present; otherwise the difference is not significant.Conclusions: In bradicardic patient who has frequent paroxysms of atrial fibrillation, regardless if bradycardia is due to ineffective antiarrhythmic drug treathement, implantation of DDDR pacemaker with atrial prevention algorhythm is indicated. If the P-wave duration is >120 milliseconds multi-site atrial pacing or septal atrial pacing should be considered. Pacemaker diagnostic tools could be used for adequate start of anticoagulant therapy and control of effectiveness of anthyarhythmic drug therapy.

  2. Pattern of atrial fibrillation and risk of outcomes

    DEFF Research Database (Denmark)

    Banerjee, Amitava; Taillandier, Sophie; Olesen, Jonas Bjerring

    2012-01-01

    BACKGROUND: Risk of stroke and thromboembolism (TE) in patients with non-valvular atrial fibrillation (NVAF) is categorised in stroke risk stratification scores. The role of pattern of NVAF in risk prediction is unclear in contemporary 'real world' cohorts. METHODS AND RESULTS: Patients with NVAF...

  3. Outcomes Associated With Familial Versus Nonfamilial Atrial Fibrillation

    DEFF Research Database (Denmark)

    Gundlund, Anna; Olesen, Jonas Bjerring; Staerk, Laila

    2016-01-01

    BACKGROUND: We examined all-cause mortality and long-term thromboembolic risk (ischemic stroke, transient ischemic attack, systemic thromboembolism) in patients with and without familial atrial fibrillation (AF). METHODS AND RESULTS: Using Danish nationwide registry data, we identified all patients...

  4. Ebstein's anomaly as a cause of paroxysmal atrial fibrillation

    Directory of Open Access Journals (Sweden)

    Damjanović Miodrag R.

    2008-01-01

    Full Text Available Background. Ebstein's anomaly is characterized by a displacement of the tricuspid valve toward apex, because of anomalous attachment of the tricuspid leaflets. There are type B of Wolff-Parkinson-White (WPW syndrome and paroxysmal arrhythmias in more than a half of all patients. Case report. We presented a female, 32-year old, with frequent paroxysms of atrial fibrillation. After conversion of rhythm an ECG showed WPW syndrome. Echocardiographic examination discovered normal size of the left cardiac chambers with paradoxical ventricular septal motion. The right ventricle was very small because of its atrialization. The origin of the tricuspid valve was 20 mm closer to apex of the right ventricle than the origin of the mitral valve. Electrophysiological examination showed a posterolateral right accesorial pathway. Atrial fibrillation was induced very easily in electrophysiological laboratory and a successful ablation of accessorial pathway was made. There were no WPW syndrome and paroxysms of atrial fibrillation after that. Conclusion. Ebstein's anomaly is one of the reasons of paroxysmal atrial fibrillation, especially in young persons with WPW syndrome.

  5. Apixaban versus warfarin in patients with atrial fibrillation

    NARCIS (Netherlands)

    Granger, C.B.; Alexander, J.H.; McMurray, J.J.; Lopes, R.D.; Hylek, E.M.; Hanna, M.; Al-Khalidi, H.R.; Ansell, J.; Atar, D.; Avezum, A.; Bahit, M.C.; Diaz, R.; Easton, J.D.; Ezekowitz, J.A.; Flaker, G.; Garcia, D.; Geraldes, M.; Gersh, B.J.; Golitsyn, S.; Goto, S.; Hermosillo, A.G.; Hohnloser, S.H.; Horowitz, J.; Mohan, P.; Jansky, P.; Lewis, B.S.; Lopez-Sendon, J.L.; Pais, P.; Parkhomenko, A.; Verheugt, F.W.A.; Zhu, J.; Wallentin, L.

    2011-01-01

    BACKGROUND: Vitamin K antagonists are highly effective in preventing stroke in patients with atrial fibrillation but have several limitations. Apixaban is a novel oral direct factor Xa inhibitor that has been shown to reduce the risk of stroke in a similar population in comparison with aspirin.

  6. Hospitalisation patterns change over time in patients with atrial fibrillation

    DEFF Research Database (Denmark)

    Fristrup Qvist, Janne; Høgh Sørensen, Pernille; Dixen, Ulrik

    2014-01-01

    INTRODUCTION: Atrial fibrillation (AF) is a cardiac epidemic. In this study, we aimed to describe the causes of hospital-isation in an AF population over time and to study how different AF treatment strategies affected hospitalization. MATERIAL AND METHODS: This was an observational study in which...

  7. Ganglion Plexus Ablation in Advanced Atrial Fibrillation: The AFACT Study

    NARCIS (Netherlands)

    Driessen, Antoine H. G.; Berger, Wouter R.; Krul, Sébastien P. J.; van den Berg, Nicoline W. E.; Neefs, Jolien; Piersma, Femke R.; Chan Pin Yin, Dean R. P. P.; de Jong, Jonas S. S. G.; van Boven, WimJan P.; de Groot, Joris R.

    2016-01-01

    Patients with long duration of atrial fibrillation (AF), enlarged atria, or failed catheter ablation have advanced AF and may require more extensive treatment than pulmonary vein isolation. The aim of this study was to investigate the efficacy and safety of additional ganglion plexus (GP) ablation

  8. Dabigatran versus warfarin in patients with atrial fibrillation

    NARCIS (Netherlands)

    Connolly, Stuart J.; Ezekowitz, Michael D.; Yusuf, Salim; Eikelboom, John; Oldgren, Jonas; Parekh, Amit; Pogue, Janice; Reilly, Paul A.; Themeles, Ellison; Varrone, Jeanne; Wang, Susan; Alings, Marco; Xavier, Denis; Zhu, Jun; Diaz, Rafael; Lewis, Basil S.; Darius, Harald; Diener, Hans-Christoph; Joyner, Campbell D.; Wallentin, Lars; Connolly, S. J.; Ezekowitz, M. D.; Yusuf, S.; Eikelboom, J.; Oldgren, J.; Parekh, A.; Reilly, P. A.; Themeles, E.; Varrone, J.; Wang, S.; Palmcrantz-Graf, E.; Haehl, M.; Wallentin, L.; Alings, A. M. W.; Amerena, J. V.; Avezum, A.; Baumgartner, I.; Brugada, J.; Budaj, A.; Caicedo, V.; Ceremuzynski, L.; Chen, J. H.; Commerford, P. J.; Dans, A. L.; Darius, H.; Di Pasquale, G.; Diaz, R.; Erol, C.; Ferreira, J.; Flaker, G. C.; Flather, M. D.; Franzosi, M. G.; Gamboa, R.; Golitsyn, S. P.; Gonzalez Hermosillo, J. A.; Halon, D.; Heidbuchel, H.; Hohnloser, S. H.; Hori, M.; Huber, K.; Jansky, P.; Kamensky, G.; Keltai, M.; Kim, S.; Lau, C. P.; Le Heuzey, J. Y. F.; Lewis, B. S.; Liu, L. S.; Nanas, J.; Razali, O.; Pais, P. S.; Parkhomenko, A. N.; Pedersen, K. E.; Piegas, L. S.; Raev, D.; Simmers, T. A.; Smith, P. J.; Talajic, M.; Tan, R. S.; Tanomsup, S.; Toivonen, L.; Vinereanu, D.; Xavier, D.; Zhu, J.; Diener, H. C.; Joyner, C. D.; Diehl, A.; Ford, G.; Robinson, M.; Silva, J.; Sleight, P.; Wyse, D. G.; Collier, J.; de Mets, D.; Hirsh, J.; Lesaffre, E.; Ryden, L.; Sandercock, P.; Anastasiou-Nana, M. I.; Andersen, G.; Annex, B. H.; Atra, M.; Bornstein, N. M.; Boysen, G.; Brouwers, P. J. A. M.; Buerke, M.; Burrell, L. M.; Chan, Y. K.; Chen, W. H.; Cheung, R. T. F.; Divakaramenon, S.; Donnan, G. A.; Duray, G. Z.; Dvorakova, H.; Fiedler, J.; Gardinale, E.; Gates, P. C.; Goshev, E. G.; Goto, S.; Gross, B.; Guimaraes, H. P.; Gulkevych, O.; Haberl, R. L.; Hankey, G.; Hartikainen, J.; Healey, J.; Iliesiu, A. M.; Irkin, O.; Jaxa-Chamiec, T.; Jolly, S.; Kaste, K. A. M.; Kies, B.; Kostov, K. D.; Kristensen, K. S.; Labovitz, A. J.; Lassila, R. P. T.; Lee, K. L. F.; Lutay, Y. M.; Magloire, P.; Mak, K. H.; Meijer, A.; Mihov, L.; Morillo, C. A.; Morillo, L. E.; Nair, G. M.; Norrving, B.; Ntalianis, A.; Ntsekhe, M.; Olah, L.; Pasco, P. M. D.; Peeters, A.; Perovic, V.; Petrov, I.; Pizzolato, G.; Rafti, F.; Rey, N. R.; Ribas, S.; Rokoss, M.; Sarembock, I. J.; Sheth, T.; Shuaib, A.; Sitkei, E.; Sorokin, E.; Srámek, M.; Strozynska, E.; Tanne, D.; Thijs, V. N. S.; Tomek, A.; Turazza, F.; Vanhooren, G.; Vizel, S. A.; Vos, J.; Wahlgren, N.; Weachter, R.; Zaborska, B.; Zaborski, J.; Zimlichman, R.; Cong, J.; Fendt, K.; Muldoon, S.; Bajkor, S.; Grinvalds, A.; Malvaso, M.; Pogue, J.; Simek, K.; Yang, S.; Alzogaray, M. F.; Bono, J. O.; Caccavo, A.; Cartasegna, L.; Casali, W. P.; Cuello, J. L.; Cuneo, C. A.; Elizari, M. V.; Fernandez, A. A.; Ferrari, A. E.; Gabito, A. J.; Goicoechea, R. F.; Gorosito, V. M.; Hirschson, A.; Hominal, M. A.; Hrabar, A. D.; Liberman, A.; Mackinnon, I. J.; Manzano, R. D.; Muratore, C. A.; Nemi, S. A.; Rodriguez, M. A.; Sanchez, A. S.; Secchi, J.; Vogel, D. R.; Colquhoun, D. M.; Crimmins, D. S.; Dart, A. M.; Davis, S. M.; Hand, P. J.; Kubler, P. A.; Lehman, R. G.; McBain, G.; Morrison, H. C.; New, G.; Singh, B. B.; Spence, C. Z.; Waites, J. H.; Auer, J.; Doweik, L.; Freihoff, F.; Gaul, G.; Gazo, F.; Geiger, H.; Giacomini, G.; Huber, G. W.; Jukic, I.; Lamm, G.; Niessner, H.; Podczeck, A.; Schuh, J.; Siostrzonek, P.; Steger, C.; Vogel, B.; Watzak, R.; Weber, H. S.; Weihs, W.; Blankoff, I.; Boland, J. L.; Brike, C.; Carlier, M.; Cools, F.; de Meester, A.; de Raedt, H. J.; de Wolf, L.; Dhooghe, G. M.; Dilling-Boer, D.; Elshot, S. R.; Fasseaux, S.; Goethals, M.; Goethals, P.; Gurne, O.; Hellemans, S.; Ivan, B.; Jottrand, M.; Kersschot, I.; Lecoq, E.; Marcovitch, O.; Melon, D.; Miljoen, H.; Missault, L.; Pierard, L. A.; Provenier, F.; Rousseau, M. F.; Stockman, D.; Tran-Ngoc, E.; van Mieghem, W.; Vandekerckhove, Y.; Vandervoort, P.; Verrostte, J.; Vijgen, J.; Armaganijan, D.; Braga, C.; Braga, J. C. F.; Cipullo, R.; Cunha, C. L. P.; de Paola, A.; Delmonaco, M. I.; Guimaraes, F. V.; Herek, L.; Kerr Saraiva, J. F.; Maia, L. N.; Lorga, A. M.; Lorga-Filho, A. M.; Marino, R. L.; Melo, C. S.; Mouco, O. M.; Pereira, V. C.; Precoma, D. B.; Rabelo, W.; Rassi, S.; Rossi, P. R.; Rossi Neto, J. M.; Silva, F. M.; Vidotti, M. H.; Zimmermann, S. L.; Anev, E. D.; Balabanov, T. A.; Baldjiev, E. S.; Bogusheva, E. S.; Chaneva, M. A.; Filibev, I. G.; Gotcheva, N. N.; Goudev, A. R.; Gruev, I. T.; Guenova, D. T.; Kamenova, Z. A.; Manov, E. I.; Panov, I. A.; Parvanova, Z. I.; Pehlivanova, M. B.; Penchev, P. T.; Penkov, N. Y.; Radoslavov, A. L.; Ramshev, K. N.; Runev, N. M.; Sindzhielieva, M. N.; Spirova, D. A.; Tsanova, V. M.; Tzekova, M. L.; Yaramov, G. K.; Aggarwal, R.; Bakbak, A. I.; Bayly, K.; Berlingieri, J. C.; Blackburn, K.; Bobbie, C.; Booth, A. W.; Borts, D.; Bose, S.; Boucher, P.; Brown, K.; Burstein, J. M.; Butt, J. C.; Carlson, B. D.; Chetty, R.; Chiasson, J. D.; Constance, C.; Costi, P.; Coutu, B.; Deneufbourg, I.; Dion, D.; Dorian, P.; Douketis, J. D.; Farukh, S.; Filipchuk, N. G.; Fox, B. A.; Fox, H. I.; Gailey, C. B.; Gauthier, M.; Glanz, A.; Green, M. S.; Habot, J.; Hink, H.; Kearon, C.; Kouz, S.; Lai, C.; Lai, K.; Lalani, A. V.; Lam, A. S.; Lapointe, L. A.; Leather, R. A.; Ma, P. T. S.; MacKay, E.; Mangat, I.; Mansour, S.; Melton, E.; Mitchell, L. B.; Morris, A. L.; Nisker, W. A.; O'Donnell, M. J.; O'Hara, G.; Omichinski, L. M.; Pandey, A. S.; Parkash, R.; Pesant, Y.; Pilon, C.; Pistawka, K. J.; Powell, C. N.; Price, J. B.; Prieur, S.; Rebane, T. M.; Ricci, A. J.; Roberge, J.; Roy, M.; Sapp, J. L.; Savard, D.; Schulman, S.; Sehl, M. J.; Sestier, F.; Shandera, R.; Shu, D.; Sterns, L. D.; St-Hilaire, R.; Syan, G. S.; Talbot, P.; Teitelbaum, I.; Tytus, R. H.; Winkler, L.; Zadra, R.; Zidel, B. S.; Bai, X. J.; Gao, W.; Gao, X.; Guan, D. M.; He, Z. S.; Hua, Q.; Li, H.; Li, L.; Li, W. M.; Lu, G. P.; Lv, S.; Meng, K.; Niu, H. Y.; Qi, D. G.; Qi, S. Y.; Qian, F.; Sun, N. L.; Wang, H. Y.; Wang, N. F.; Yang, Y. M.; Zeng, H.; Zhang, F.; Zhang, F. R.; Zhang, L.; Bohorquez, R.; Rosas, J. F.; Saent, L.; Vacca, M.; Velasco, V. M.; Belohlavek, J.; Cernohous, M.; Choura, M.; Dedek, V.; Filipensky, B.; Hemzsky, L.; Karel, I.; Kopeckova, I.; Kovarova, K.; Labrova, R.; Madr, T.; Poklopova, Z.; Rucka, D.; Simon, J.; Skalicka, H.; Smidova, M.; Spinar, J.; Dodt, K. K.; Egstrup, K.; Friberg, J.; Haar, D.; Husted, S.; Jensen, G. V.; Joensen, A. M.; Klarlund, K. K.; Lind Rasmussen, S.; Melchior, T. M.; Olsen, M. E.; Poulsen, M. K.; Ralfkiaer, N.; Rasmussen, L. H.; Skagen, K.; Airaksinen, K. E.; Huikuri, H. V.; Hussi, E. J.; Kettunen, P.; Mänttäri, M.; Melin, J. H.; Mikkelsson, J.; Peuhkurinen, K.; Virtanen, V. K.; Ylitalo, A.; Agraou, B.; Boucher, L.; Bouvier, J. M.; Boye, A.; Boye, B.; Decoulx, E. M.; Defaye, P.; Delay, M.; Desrues, H.; Gacem, K.; Igigabel, P.; Jacon, P.; Leparree, S.; Magnani, C.; Martelet, M.; Movallem, J.; Olive, T.; Poulard, J. E.; Tiam, B.; Appel, K. F.; Appel, S.; Bansemir, L.; Borggrefe, M.; Brachmann, J.; Bulut-Streich, N.; Busch, K.; Dempfle, C. E. H.; Desaga, M.; Desaga, V.; Dormann, A.; Fechner, I.; Genth-Zotz, S.; Haberbosch, W. G.; Harenberg, J.; Haverkamp, W. L.; Henzgen, R.; Heuer, H.; Horacek, T.; Huttner, H. B.; Janssens, U.; Jantke, H. J.; Klauss, V.; Koudonas, D.; Kreuzer, J.; Kuckuck, H.; Maselli, A.; Müegge, A.; Munzel, T. F.; Nitsche, K.; Nledegjen, A.; Parwani, A.; Pluemer-Schmidt, M.; Pollock, B. W.; Salbach, B. I.; Salbach, P. B.; Schaufele, T.; Schoels, W.; Schwab, S.; Siegmund, U.; Veltkamp, R.; Von Hodenberg, E.; Weber, R.; Zechmeister, M.; Anastasopoulous, A. A.; Foulidis, V. O.; Kaldara, E.; Karamitsos, K.; Karantzis, J.; Kirpizidis, H.; Kokkinakis, C.; Krommydas, A.; Lappas, C.; Lappas, G. I.; Manolis, A.; Manolis, A. S.; Orfanidis, Z.; Papamichalis, M.; Peltekis, L.; Savvas, S.; Skoumpourdis, E. A.; Stakos, D. A.; Styliadis, I.; Triposkiadis, F.; Tsounis, D.; Tziakas, D. N.; Zafiridis, T.; Zarifis, J. H.; Chan, G. C. P.; Chan, W. K.; Chan, W. S.; Lau, C. L.; Tse, H. F.; Tsui, P. T.; Yu, C. M.; Yue, C. S.; Fugedi, K.; Garai, B.; Jánosi, A.; Kadar, A.; Karpati, P.; Keltai, K.; Kosa, I.; Kovacs, I.; Laszlo, Z.; Mezei, L.; Rapi, J.; Regos, L. I.; Szakal, I.; Szigyarto, I.; Toth, K.; Zsa'ry, A.; Agarwal, D. K.; Aggarwal, R. K.; Arulvenkatesh, R.; Bharani, A.; Bhuvaneswaran, J. S.; Byrapaneni, R. B.; Chandwani, P.; Chopra, S.; Desai, N.; Deshpande, V.; Golla, N. P.; Gupta, J. B.; Haridas, K. K.; Hiremath, J.; Jain, A. S.; Jain, M.; Jhala, D. A.; Joseph, J.; Kaila, M.; Kannaiyan, A.; Kumar, S.; Kuruvila, P.; Mahorkar, V. K.; Metha, A.; Naik, A. M.; Narayanan, S.; Panwar, R. B.; Reddy, C.; Sawhney, J. P. S.; Shah, S. M.; Sharma, S.; Shetty, G. S.; Sinha, N.; Sontakke, N. N.; Srinivas, A.; Trivedi, M. R.; Vadagenalli, P. S.; Vijayakumar, M.; Ben-Aharon, Y.; Benhorin, J.; Bogomolny, N.; Botwin-Shimko, S.; Bova, I.; Brenner, B.; Burstein, M.; Butnaru, A.; Caspi, A.; Danenberg, H. D.; Dayan, M.; Eldar, M.; Elian, D.; Elias, M.; Elis, A.; Esanu, G.; Genin, I.; Goldstein, L. H.; Grossman, E.; Hamoud, S.; Hayek, T.; Ilani, N.; Ilia, R.; Klainman, E. I.; Leibowitz, A.; Leibowitz, D.; Levin, I.; Lishner, M.; Lotan, C.; Mahagney, A.; Marmor, A.; Motro, M.; Peres, D.; Plaev, T.; Reisen, L. H.; Rogowski, O.; Schwammenthal, E.; Schwammenthal, Y.; Shechter, M.; Shochat, M.; Shotan, A.; Strasberg, B.; Sucher, E.; Telman, G.; Turgeman, Y.; Tzoran, I.; Weiss, A. T.; Weitsman, T.; Weller, B.; Wexler, D. H.; Wolff, R.; Yarnitsky, D.; Zeltser, D.; Argiolas, G.; Arteni, F.; Barbiero, M.; Bazzucco, R.; Bernardi, D.; Bianconi, L.; Bicego, D.; Brandini, R.; Bresciani, B.; Busoni, F.; Carbonieri, E.; Carini, M.; Catalano, A.; Cavallini, C.; D'Angelo, G.; de Caterina, R.; Di Niro, M.; Filigheddu, F.; Fraticelli, A.; Marconi, R.; Mennuni, M.; Moretti, L.; Mos, L.; Pancaldi, L. G.; Pirelli, S.; Renda, G.; Santini, M.; Tavarozzi, I.; Terrosu, P.; Uneddu, F.; Viccione, M.; Zanini, R.; Zingarini, G.; Aoyagi, T.; Eguma, H.; Fujii, K.; Fukuchi, M.; Fukunami, M.; Furukawa, Y.; Furuya, J.; Haneda, K.; Hara, S.; Hiroe, M.; Iesaka, Y.; Iijima, T.; Ishibashi, Y.; Iwade, K.; Kajiya, T.; Kakinoki, S.; Kamakura, S.; Katayama, Y.; Kihara, Y.; Kimura, K.; Kobayashi, S.; Kono, K.; Koretsune, Y.; Marui, N.; Matsuyama, T.; Meno, H.; Miyamoto, N.; Morikawa, S.; Myojin, K.; Nakamura, T.; Nishi, Y.; Ogawa, T.; Onaka, H.; Sakakibara, T.; Sakurai, S.; Sasaki, Y.; Sato, H.; Sugii, M.; Sumii, K.; Suzuki, S.; Takagi, M.; Takenaka, T.; Takeuchi, K.; Tanaka, S.; Tanouchi, J.; Ueda, K.; Ueyama, Y.; Ujihira, T.; Usui, M.; Yagi, M.; Yamada, T.; Yamamoto, H.; Yokochi, M.; Zen, E.; Abd Ghaphar, A. K.; Ang, C. K.; Chee, K. H.; Fong, A. F. Y.; Ismail, O.; Jeyaindran, S.; Kaur, S.; Lee, T. C.; Sandhu, R. S.; Shah, R. P.; Suganthi, S.; Zainal Abidin, S.; Alvarado-Ruiz, R.; Carrillo, J.; Delgado, E.; Fernandez Bonetti, P. A.; Leiva, J. L.; Meaney, A.; Olvera, R.; Peralta-Heredia, R.; Rodriguez, I.; Ruiz Rabasa, C. M.; Solache, G.; Villeda Espinosa, E.; Ahmed, S.; Badings, E.; Bartels, G. L.; Beganovic, M.; Bruning, T. A.; Ciampricotti, R.; Cozijnsen, L.; Crijns, H. J.; Daniels, M. C. G.; de Waard, D. E. P.; den Hartog, F. R.; Dirkali, A.; Groenemeijer, B. E.; Heesen, W. F.; Heijmeriks, J. A.; Hoogslag, P. A.; Huizenga, A.; Idzerda, H. H.; Kragten, J. A.; Krasznai, K.; Lenderink, T.; Liem, A. H.; Linssen, G. C.; Lok, D. J.; Meeder, J. G.; Michels, H. R.; Plomp, J.; Pos, L.; Posma, J. L.; Postema, P. G.; Salomonsz, R.; Stoel, I.; Tans, J. G.; Thijssen, H. J.; Timmermans, A. J. M.; Tteleman, R. G.; van Bergen, P. F. M. M.; van de Klippe, H. A.; van der Zwaan, C.; van Eck, J. W. M.; van Es, A. J. J.; van Gelder, I. C.; van Kempen, L. H.; van Kesteren, H. A.; van Rossum, P.; Veldmeyer, S.; Wilde, A. A. M.; Arnesen, H.; Atar, D.; Breder, O.; Istad, H.; Radunovic, Z.; Rykke, D. E.; Sirnes, P. A.; Tveit, A.; Ulimoen, S. R.; Cabrera, W.; Duenas, R.; Heredia, J. M.; Horna, M. E.; Hurtado, Y.; Salazar, P. M.; Abola, M. T. B.; Anonuevo, J. C.; Arellano, R. S.; Dioquino, C.; Morales, D. D.; Reyes, E. B.; Rogelio, G. G.; Roxas, A. A.; Sulit, D. J. V.; Bacior, B.; Dulak, E.; Gniot, J.; Goncikowski, J.; Grodecki, J.; Kalarus, Z. F.; Kawecka-Jaszcz, K.; Miekus, P.; Monies, F.; Piepiorka, M.; Pilichowska, E.; Plizio, E.; Rekosz, J.; Rybicka-Musialik, A.; Streb, W. A.; Styczkiewicz, M.; Szpajer, M.; Trusz-Gluza, M.; Wasilewska-Piepiorka, A.; Adragao, P.; Branco, V.; Canhão, P.; Cunha, L.; Falcão, F.; Lopes, G.; Machado, C.; Martinez-Marcos, J.; Monteiro, P. F.; Parreira, L.; Pinto, A. N.; Providencia, L. A.; Salgado, A. V.; Santos, J. F.; Timoteo, A. T.; Capalneanu, R.; Cinteza, M. A.; Margulesai, A. D.; Turdeanu, D. S.; Vintila, V. D.; Baranov, V. L.; Berngardt, E. R.; Dzhordzhikiya, T. R.; Gordeev, I. G.; Grigoryev, Y. V.; Isaeva, M. U.; Ivleva, A. Y.; Kokorin, V. A.; Komarov, A. L.; Maximenko, O. K.; Maykov, E. B.; Novikova, N.; Novikova, T. N.; Panchenko, E. P.; Poltavskaya, M. G.; Popova, Y. N.; Pronina, S. A.; Revishvili, A. Sh; Shlyakhto, E. V.; Shustov, S. B.; Sidorenko, B. A.; Sinopalnikov, A. I.; Sulimov, V.; Syrkin, A. L.; Titkov, A. Y.; Titkov, Y. S.; Zateyshchikov, D. A.; Zavaritskaya, O. P.; Chia, P. L.; Foo, D.; Sim, K. L.; Bugan, V.; Buganova, I.; Dúbrava, J.; Kaliska, G.; Masarovicova, M.; Mikes, P.; Mikes, Z.; Murin, J.; Pella, D.; Rybar, R.; Sedlák, J.; Skamla, M.; Spurný, P.; Strbova, J.; Uhliar, R.; Disler, L. J.; Engelbrecht, J. M.; Jankelow, D.; King, J.; Klug, E. Q.; Munnick, M.; Okreglicki, A. M.; Routier, R. J.; Snyders, F. A.; Theron, H. D.; Wittmer, H.; Cha, T. J.; Cho, J. G.; Choi, I. S.; Choi, J. I.; Choi, K. J.; Han, K. R.; Heo, J. H.; Jang, S. W.; Kang, T. S.; Kim, H. S.; Kim, K. S.; Kim, S. J.; Kim, S. S.; Kim, Y. H.; Kim, Y. N.; Lee, M. H.; Lee, M. Y.; Nam, G. B.; Oh, D. J.; Park, H. W.; Park, J. S.; Rho, T. H.; Shin, D. G.; Shin, E. K.; Alonso, J. J.; Cano, L.; Castellano, N. P.; Criado-Millan, A. J.; Curcio, A.; Egea, P.; Escudier, J. M.; Grande, A.; Grande, J. M.; Gusi-Tragant, G.; Lozano, I. F.; Martin, A. M.; Martinez-Rubio, A.; Mont, L.; Perez-Villacastin, J.; Sosa, L.; Ali, M.; Andersson, T.; Bandh, S.; Blomstrom Lundqvist, C. M.; Cherfan, P.; Fengsrud, E.; Fluur, C.; Herlitz, J.; Hijazi, Z.; Hoglund, N.; Hojeberg, B.; Jabro, J.; Juhlin, T.; Kjellman, B.; Lonnberg, I.; Maru, F.; Morlid, L.; Nilsson, O. R.; Ronn, F.; Rosenqvist, M.; Walfridsson, H.; Engelter, S. T.; Gallino, A.; Lyrer, P. A.; Moccetti, T.; Petrova, I.; Chang, Y. J.; Chen, C. H.; Chen, M. Y. C.; Cheng, J. J.; Chiang, T. R.; Chung, W. T.; Hsia, C. H.; Hsu, C. Y.; Hu, H. H.; Jeng, J. S.; Lai, W. T.; Lien, L. M.; Lin, K. H.; Liu, C. H.; Lo, H. S.; Peng, G. S.; Po, H. L.; Ryu, S. J.; Tsai, C. D.; Tsai, L. M.; Tseng, C. D.; Wang, J. H.; Wang, S. F.; Yang, S. P.; Kiatchoosakun, S.; Krittayaphong, R.; Kuanprasert, S.; Ngarmukos, T.; Simtharakaew, T.; Sukanandachai, B.; Sukonthasam, A.; Suwanagool, A.; Tatsanavivat, P.; Atmaca, Y.; Baris, N.; Boyaci, B.; Demir, M.; Guneri, S.; Usal, A.; Yalcin, R.; Amosova, K. M.; Beregova, O. P.; Besaga, Y. E. M.; Ikorkin, M. R.; Karapetyan, K.; Karpenko, O. I.; Kononenko, L.; Kuryata, O.; Martynova, L.; Motylevska, T.; Okhryamkina, O.; Pavlyk, S. S.; Perepelytsya, M. V.; Rudenko, L. V.; Skarzhevsky, O. A.; Tkachenko, L. A.; Tseluyko, V.; Usan, N.; Voronkov, L. G.; Yshchenko, K. V.; Zharinov, O. J.; Bryson, V. G.; Butler, R.; Cargill, R. I.; Chahal, N. S.; Cleland, J. G.; Cohen, A. T.; Cruddas, E. M.; Davey, P.; Davies, J.; Ford, S. L.; Griffith, K.; Haynes, R.; Hill, S.; Javed, M.; Kadr, H. H.; Lip, G. H.; Machin, J.; McEneaney, D. J.; McInnes, G. T.; McNeill, A. J.; Moriarty, A. J.; Muir, S.; O'Callaghan, J.; Purvis, J. A.; Pye, M.; Senior, R.; Sutton, D. A.; Thomas, S. H. 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W.; Meisner, J. S.; Melucci, M. B.; Mercando, A.; Merlino, J. D.; Meymandi, S. K.; Miele, M. B.; Miller, R. H.; Miller, S. H.; Minor, S. T.; Mitchell, M. R.; Modi, M.; Mody, F. V.; Moeller, C. L.; Moloney, J. F.; Moran, J. E.; Morcos, N. C.; Morgan, A.; Mukherjee, S. K.; Mullinax, K.; Murphy, A. L.; Mustin, A. J.; Myers, G. I.; Naccarelli, G. V.; Nadar, V. K.; Nallasivan, M.; Navas, J. P.; Niazi, I. K.; Nsah, E. N.; Nunamaker, J. L.; Ochalek, T. B.; O'dea, D. J.; Ogilvie, P. D.; Olliff, B.; Omalley, A. K.; O'Neill, P. G.; Onufer, J. R.; Orchard, R. C.; Orihuela, L. A.; Ortiz, E. C.; O'Sullivan, M. T.; Padanilam, B. J.; Pandey, P.; Patel, D. V.; Patel, R. J.; Patel, V. B.; Patlola, R. R.; Pennock, G. D.; Perlman, R.; Peters, P. H.; Petrillo, A. V.; Pezzella, S.; Phillips, D.; Pierre-Louis, J. R.; Pilcher, G.; Pillai, C.; Pollock, S. G.; Pond, M. S.; Porterfield, J. K.; Presant, L.; Pressler, J.; Pribble, A. H.; Promisloff, S. D.; Pudi, K. K.; Putnam, D. L.; Quartner, J.; Quinn, J. C.; Quinnell, C. M.; Raad, G. L.; Rasmussen, L. A.; Ray, C.; Reiffel, J. A.; Reynertson, S.; Richardson, J. W.; Riley, C. P.; Rippy, J. S.; Rittelmeyer, J. T.; Roberts, D. M.; Robertson, R.; Robinson, V. J. B.; Rocco, T. A.; Rosenbaum, D.; Roth, E. M.; Rottman, J. N.; Rough, R. R.; Rubenstein, J. J.; Sakkal, A. M.; Saleem, T.; Salerno, D. M.; Samendinger, M. L.; Sandeno, S.; Santilli, T. M.; Santucci, P.; Sattar, P.; Saxman, K. A.; Schaefer, S.; Schmidt, J.; Schneider, R. M.; Schocken, D. D.; Schrader, M. K.; Schramm, B. A.; Schultz, R. W.; Schussheim, A. E.; Schwarz, E. F.; Seamon, M. C.; Sestero, J. D.; Shah, M. P.; Shah, R.; Shalaby, A.; Shanes, J. G.; Sheftel, G. L.; Sheikh, K. H.; Shein, A. B.; Shemonsky, N. K.; Shepler, A.; Sheridan, E.; Shipwash, T. M.; Shopnick, R. I.; Short, W. G.; Shoukfeh, M. F.; Sibia, R. S.; Siler, T. M.; Silva, J. A.; Simons, G. R.; Simpson, A. G.; Simpson, H. R.; Simpson, V. J.; Singh, B. N.; Singh, N.; Singh, V. N.; Sitz, C. J.; Skatrud, L.; Sklar, J.; Slotwiner, D. J.; Smith, P. F.; Smith, P. N.; Smith, R. H.; Smith, J. E.; Sodowick, B. C.; Solomon, A. J.; Soltero, E. A.; Sonel, A. F.; Sperling, R.; Spiller, C.; Spink, B. Z.; Sprinkle, L. W.; Spyropoulos, A. C.; Stamos, T. D.; Steljes, A. D.; Stillabower, M. E.; Stover, T.; Strain, J. E.; Strickland, T. L.; Suresh, D. P.; Takata, T. S.; Taylor, J. S.; Taylor, M.; Teague, S. M.; Teixeia, J. M.; Telfer, E. A.; Terry, P. S.; Terry, R. W.; Thai, H. M.; Thalin, M.; Thomas, V. N.; Thompson, C. A.; Thompson, M. A.; Thornton, J. W.; Tidman, R. E.; Toler, B. S.; Traina, M. I.; Trippi, J. A.; Ujiiye, D. L.; Usedom, J. E.; van de Graaff, E.; van de Wall, L. R.; Vaughn, J. W.; Ver Steeg, D.; Vicari, R. M.; Vijay, N.; Vitale, C. B.; Vlastaris, A. G.; Voda, J.; Vora, K. N.; Voyles, W. F.; Vranian, R. B.; Vrooman, P. S.; Waack, P.; Waldo, A. L.; Walker, J. L.; Wallace, M. A.; Walsh, E. A.; Walsh, R. L.; Walton, A.; Washam, M.; Wehner, P. S.; Wei, J. Y.; Weiner, S.; Weiss, R. J.; Wells, D. M.; Wera-Archakul, W.; Wertheimer, J. H.; West, S. A.; Whitaker, J. H.; White, M. L.; White, R. H.; Whitehill, J. N.; Wiegman, P. J.; Wiesel, J.; Williams, J.; Williams, L. E.; Williams, M. L.; Williamson, V. K.; Wilson, V. E.; Wilson, W. W.; Woodfield, S. L.; Wulff, C. W.; Yates, S. W.; Yousuf, K. A.; Zakhary, B. G.; Zambrano, R.; Zimetbaum, P.; Zoble, R.; Zopo, A. R.; Zwerner, P. L.

    2009-01-01

    BACKGROUND: Warfarin reduces the risk of stroke in patients with atrial fibrillation but increases the risk of hemorrhage and is difficult to use. Dabigatran is a new oral direct thrombin inhibitor. METHODS: In this noninferiority trial, we randomly assigned 18,113 patients who had atrial

  9. Comparative study of atrial fibrillation and AV conduction in mammals

    NARCIS (Netherlands)

    Meijler, F.L.; Tweel, I. van der

    1987-01-01

    Atrial fibrillation is one ofthe most common cardiac arrhythmias in humans. It a1so occurs quite frequent1y in dogs and horses. Comparative study of this arrhythmia may contribute to better understanding of the pathophysiologica1 mechanisms involved. In this study, we present a quantitative

  10. Quinidine-induced ventricular flutter and fibrillation without digitalis therapy

    NARCIS (Netherlands)

    Koster, R. W.; Wellens, H. J.

    1976-01-01

    Three cases are described with documented ventricular flutter and fibrillation during quinidine medication without concomitant digitalis therapy. In all three patients the arrhythmia developed while they were receiving moderate doses of quinidine. Although no changes in QRS width were observed after

  11. Managing atrial fibrillation in the elderly: critical appraisal of dronedarone

    Directory of Open Access Journals (Sweden)

    Trigo P

    2011-12-01

    Full Text Available Paula Trigo, Gregory W FischerDepartment of Anesthesiology, Mount Sinai School of Medicine, New York, NY, USAAbstract: Atrial fibrillation is the most commonly seen arrhythmia in the geriatric population and is associated with increased cardiovascular morbidity and mortality. Treatment of the elderly with atrial fibrillation remains challenging for physicians, because this unique subpopulation is characterized by multiple comorbidities requiring chronic use of numerous medications, which can potentially lead to severe drug interactions. Furthermore, age-related changes in the cardiovascular system as well as other physiological changes result in altered drug pharmacokinetics. Dronedarone is a new drug recently approved for the treatment of arrhythmias, such as atrial fibrillation and/or atrial flutter. Dronedarone is a benzofuran amiodarone analog which lacks the iodine moiety and contains a methane sulfonyl group that decreases its lipophilicity. These differences in chemical structure are responsible for making dronedarone less toxic than amiodarone which, in turn, results in fewer side effects. Adverse events for dronedarone include gastrointestinal side effects and rash. No dosage adjustments are required for patients with renal impairment. However, the use of dronedarone is contraindicated in the presence of severe hepatic dysfunction.Keywords: atrial fibrillation, elderly, antiarrhythmic agents, amiodarone, dronedarone

  12. Antithrombotic therapy in atrial fibrillation associated with valvular heart disease

    DEFF Research Database (Denmark)

    Lip, Gregory Y H; Collet, Jean Philippe; Caterina, Raffaele de

    2017-01-01

    Atrial fibrillation (AF) is a major worldwide public health problem, and AF in association with valvular heart disease (VHD) is also common. However, management strategies for this group of patients have been less informed by randomized trials, which have largely focused on 'non-valvular AF' pati...

  13. Edoxaban versus warfarin in patients with atrial fibrillation

    NARCIS (Netherlands)

    Giugliano, R.P.; Ruff, C.T.; Braunwald, E.; Murphy, S.A.; Wiviott, S.D.; Halperin, J.L.; Waldo, A.L.; Ezekowitz, M.D.; Weitz, J.I.; Spinar, J.; Ruzyllo, W.; Ruda, M.; Koretsune, Y.; Betcher, J.; Shi, M.; Grip, L.T.; Patel, S.P.; Patel, I.; Hanyok, J.J.; Mercuri, M.; Antman, E.M.; Verheugt, F.W.A.; et al.,

    2013-01-01

    BACKGROUND: Edoxaban is a direct oral factor Xa inhibitor with proven antithrombotic effects. The long-term efficacy and safety of edoxaban as compared with warfarin in patients with atrial fibrillation is not known. METHODS: We conducted a randomized, double-blind, double-dummy trial comparing two

  14. Edoxaban versus Warfarin in Patients with Atrial Fibrillation

    NARCIS (Netherlands)

    Giugliano, Robert P.; Ruff, Christian T.; Braunwald, Eugene; Murphy, Sabina A.; Wiviott, Stephen D.; Halperin, Jonathan L.; Waldo, Albert L.; Ezekowitz, Michael D.; Weitz, Jeffrey I.; Špinar, Jindřich; Ruzyllo, Witold; Ruda, Mikhail; Koretsune, Yukihiro; Betcher, Joshua; Shi, Minggao; Grip, Laura T.; Patel, Shirali P.; Patel, Indravadan; Hanyok, James J.; Mercuri, Michele; Antman, Elliott M.; Braunwald, E.; Antman, E. M.; Giugliano, R. P.; Ruff, C. T.; Morin, S. E.; Hoffman, E. B.; Murphy, S. A.; Deenadayalu, N.; Grip, L.; Mercuri, M.; Lanz, H.; Patel, I.; Curt, V.; Duggal, A.; Hanyok, J.; Davé, J.; Morgan, D.; Choi, Y.; Shi, M.; Jin, J.; Xie, J.; Crerand, W.; Kappelhof, J.; Maxwell, W.; Zhang, X.; Zhang, Z.; de Groot, J. [=Joris R.; de Vos, R.; Hoekstra, J.

    2013-01-01

    BackgroundEdoxaban is a direct oral factor Xa inhibitor with proven antithrombotic effects. The long-term efficacy and safety of edoxaban as compared with warfarin in patients with atrial fibrillation is not known. MethodsWe conducted a randomized, double-blind, double-dummy trial comparing two

  15. Atrial fibrillation in patients with sick sinus syndrome

    DEFF Research Database (Denmark)

    Nielsen, Jens Cosedis; Thomsen, Poul Erik B; Højberg, Søren

    2012-01-01

    between minimal-paced programmed AVI = 100 and >100 ms (median value), respectively (P= 0.60).ConclusionsThe present study indicates that a longer baseline PQ-interval is associated with an increased risk of AF in patients with sick sinus syndrome. Atrial fibrillation burden is not associated...

  16. Management and prognosis of atrial fibrillation in diabetic patients

    DEFF Research Database (Denmark)

    Fumagalli, Stefano; Said, Salah A; Laroche, Cecile

    2017-01-01

    Aims: Diabetes mellitus (DM) is one of the most important cardiovascular (CV) risk factors. The aim of this study was to evaluate clinical correlates of DM, including management and outcomes, in the EURObservational Research Programme (EORP) - Atrial Fibrillation (AF) General Pilot (EORP-AF) Regi...

  17. Surgical Ablation of Atrial Fibrillation Using Energy Sources.

    Science.gov (United States)

    Brick, Alexandre Visconti; Braile, Domingo Marcolino

    2015-01-01

    Surgical ablation, concomitant with other operations, is an option for treatment in patients with chronic atrial fibrillation. The aim of this study is to present a literature review on surgical ablation of atrial fibrillation in patients undergoing cardiac surgery, considering energy sources and return to sinus rhythm. A comprehensive survey was performed in the literature on surgical ablation of atrial fibrillation considering energy sources, sample size, study type, outcome (early and late), and return to sinus rhythm. Analyzing studies with immediate results (n=5), the percentage of return to sinus rhythm ranged from 73% to 96%, while those with long-term results (n=20) (from 12 months on) ranged from 62% to 97.7%. In both of them, there was subsequent clinical improvement of patients who underwent ablation, regardless of the energy source used. Surgical ablation of atrial fibrillation is essential for the treatment of this arrhythmia. With current technology, it may be minimally invasive, making it mandatory to perform a procedure in an attempt to revert to sinus rhythm in patients requiring heart surgery.

  18. Atrial fibrillation: To map or not to map?

    NARCIS (Netherlands)

    A. Yaksh (Ameeta); C. Kik (Charles); S.P. Knops (Simon); J.W. Roos-Hesselink (Jolien); A.J.J.C. Bogers (Ad); F. Zijlstra (Felix); M.A. Allessie (Maurits); N.M.S. de Groot (Natasja)

    2014-01-01

    textabstractIsolation of the pulmonary veins may be an effective treatment modality for eliminating atrial fibrillation (AF) episodes but unfortunately not for all patients. When ablative therapy fails, it is assumed that AF has progressed from a trigger-driven to a substrate-mediated arrhythmia.

  19. Role of the Atrioventricular Node in Atrial Fibrillation

    NARCIS (Netherlands)

    Meijler, F.L.; Wittkampf, F.H.M.

    1997-01-01

    Atrial fibrillation (AF) is probably the most cornmon cardiac arrhythmia in humans, particularly in the elderly (1-3). The irregularity and inequality of the he art beat first described by Hering in 1903 were, and continue to be, the landmark of the clinical diagnosis of AF (4,5). Sir Thomas

  20. A roadmap to improve the quality of atrial fibrillation management

    DEFF Research Database (Denmark)

    Kirchhof, Paulus; Breithardt, Günter; Bax, Jeroen

    2016-01-01

    . Hence, there are important unmet clinical and research needs in the evaluation and management of AF patients. The ensuing needs and opportunities for improving the quality of AF care were discussed during the fifth Atrial Fibrillation Network/European Heart Rhythm Association consensus conference...

  1. Effect of environmental factors on the kinetics of insulin fibril formation: elucidation of the molecular mechanism.

    Science.gov (United States)

    Nielsen, L; Khurana, R; Coats, A; Frokjaer, S; Brange, J; Vyas, S; Uversky, V N; Fink, A L

    2001-05-22

    In the search for the molecular mechanism of insulin fibrillation, the kinetics of insulin fibril formation were studied under different conditions using the fluorescent dye thioflavin T (ThT). The effect of insulin concentration, agitation, pH, ionic strength, anions, seeding, and addition of 1-anilinonaphthalene-8-sulfonic acid (ANS), urea, TMAO, sucrose, and ThT on the kinetics of fibrillation was investigated. The kinetics of the fibrillation process could be described by the lag time for formation of stable nuclei (nucleation) and the apparent rate constant for the growth of fibrils (elongation). The addition of seeds eliminated the lag phase. An increase in insulin concentration resulted in shorter lag times and faster growth of fibrils. Shorter lag times and faster growth of fibrils were seen at acidic pH versus neutral pH, whereas an increase in ionic strength resulted in shorter lag times and slower growth of fibrils. There was no clear correlation between the rate of fibril elongation and ionic strength. Agitation during fibril formation attenuated the effects of insulin concentration and ionic strength on both lag times and fibril growth. The addition of ANS increased the lag time and decreased the apparent growth rate for insulin fibril formation. The ANS-induced inhibition appears to reflect the formation of amorphous aggregates. The denaturant, urea, decreased the lag time, whereas the stabilizers, trimethylamine N-oxide dihydrate (TMAO) and sucrose, increased the lag times. The results indicated that both nucleation and fibril growth were controlled by hydrophobic and electrostatic interactions. A kinetic model, involving the association of monomeric partially folded intermediates, whose concentration is stimulated by the air-water interface, leading to formation of the critical nucleus and thence fibrils, is proposed.

  2. The α-helical C-terminal domain of full-length recombinant PrP converts to an in-register parallel β-sheet structure in PrP fibrils: evidence from solid state nuclear magnetic resonance.

    Science.gov (United States)

    Tycko, Robert; Savtchenko, Regina; Ostapchenko, Valeriy G; Makarava, Natallia; Baskakov, Ilia V

    2010-11-09

    We report the results of solid state nuclear magnetic resonance (NMR) measurements on amyloid fibrils formed by the full-length prion protein PrP (residues 23−231, Syrian hamster sequence). Measurements of intermolecular 13C−13C dipole−dipole couplings in selectively carbonyl-labeled samples indicate that β-sheets in these fibrils have an in-register parallel structure, as previously observed in amyloid fibrils associated with Alzheimer’s disease and type 2 diabetes and in yeast prion fibrils. Two-dimensional 13C−13C and 15N−13C solid state NMR spectra of a uniformly 15N- and 13C-labeled sample indicate that a relatively small fraction of the full sequence, localized to the C-terminal end, forms the structurally ordered, immobilized core. Although unique site-specific assignments of the solid state NMR signals cannot be obtained from these spectra, analysis with a Monte Carlo/simulated annealing algorithm suggests that the core is comprised primarily of residues in the 173−224 range. These results are consistent with earlier electron paramagnetic resonance studies of fibrils formed by residues 90−231 of the human PrP sequence, formed under somewhat different conditions [Cobb, N. J., Sonnichsen, F. D., McHaourab, H., and Surewicz, W. K. (2007) Proc. Natl. Acad. Sci. U.S.A. 104, 18946−18951], suggesting that an in-register parallel β-sheet structure formed by the C-terminal end may be a general feature of PrP fibrils prepared in vitro.

  3. Synthesis and characterization of fluorinated magnetic core-shell nanoparticles for inhibition of insulin amyloid fibril formation

    Energy Technology Data Exchange (ETDEWEB)

    Skaat, Hadas; Margel, Shlomo [Department of Chemistry, Bar-Ilan University, Ramat-Gan 52900 (Israel); Belfort, Georges [Howard P Isermann Department of Chemical and Biological Engineering, Rensselaer Polytechnic Institute, Troy, NY 12180 (United States)], E-mail: ch348@mail.biu.ac.il, E-mail: belfog@rpi.edu, E-mail: Shlomo.margel@mail.biu.ac.il

    2009-06-03

    Maghemite ({gamma}-Fe{sub 2}O{sub 3}) magnetic nanoparticles of 15.0 {+-} 2.1 nm are formed by nucleation followed by controlled growth of maghemite thin films on gelatin-iron oxide nuclei. Uniform magnetic {gamma}-Fe{sub 2}O{sub 3}/poly (2,2,3,3,4,4,4-heptafluorobutyl acrylate) ({gamma}-Fe{sub 2}O{sub 3}/PHFBA) core-shell nanoparticles are prepared by emulsion polymerization of the fluorinated monomer 2,2,3,3,4,4,4-heptafluorobutyl acrylate (HFBA) in the presence of the maghemite nanoparticles. The kinetics of the insulin fibrillation process in the absence and in the presence of the {gamma}-Fe{sub 2}O{sub 3}/PHFBA core-shell nanoparticles are elucidated. A significant direct slow transition from {alpha}-helix to {beta}-sheets during insulin fibril formation is observed in the presence of the {gamma}-Fe{sub 2}O{sub 3}/PHFBA nanoparticles. This is in contradiction to our previous manuscript, which illustrated that the {gamma}-Fe{sub 2}O{sub 3} core nanoparticles do not affect the kinetics of the formation of the insulin fibrils, and to other previous publications that describe acceleration of the fibrillation process by using various types of nanoparticles. These core-shell nanoparticles may therefore be also useful for the inhibition of conformational changes of other amyloidogenic proteins that lead to neurodegenerative diseases such as Alzheimer's, Parkinson's, Huntington's, mad cow and prion diseases.

  4. Fibril specific, conformation dependent antibodies recognize a generic epitope common to amyloid fibrils and fibrillar oligomers that is absent in prefibrillar oligomers

    Directory of Open Access Journals (Sweden)

    Rasool Suhail

    2007-09-01

    Full Text Available Abstract Background Amyloid-related degenerative diseases are associated with the accumulation of misfolded proteins as amyloid fibrils in tissue. In Alzheimer disease (AD, amyloid accumulates in several distinct types of insoluble plaque deposits, intracellular Aβ and as soluble oligomers and the relationships between these deposits and their pathological significance remains unclear. Conformation dependent antibodies have been reported that specifically recognize distinct assembly states of amyloids, including prefibrillar oligomers and fibrils. Results We immunized rabbits with a morphologically homogeneous population of Aβ42 fibrils. The resulting immune serum (OC specifically recognizes fibrils, but not random coil monomer or prefibrillar oligomers, indicating fibrils display a distinct conformation dependent epitope that is absent in prefibrillar oligomers. The fibril epitope is also displayed by fibrils of other types of amyloids, indicating that the epitope is a generic feature of the polypeptide backbone. The fibril specific antibody also recognizes 100,000 × G soluble fibrillar oligomers ranging in size from dimer to greater than 250 kDa on western blots. The fibrillar oligomers recognized by OC are immunologically distinct from prefibrillar oligomers recognized by A11, even though their sizes overlap broadly, indicating that size is not a reliable indicator of oligomer conformation. The immune response to prefibrillar oligomers and fibrils is not sequence specific and antisera of the same specificity are produced in response to immunization with islet amyloid polypeptide prefibrillar oligomer mimics and fibrils. The fibril specific antibodies stain all types of amyloid deposits in human AD brain. Diffuse amyloid deposits stain intensely with anti-fibril antibody although they are thioflavin S negative, suggesting that they are indeed fibrillar in conformation. OC also stains islet amyloid deposits in transgenic mouse models of type

  5. Familial clustering of atrial fibrillation and comparative longitudinal outcomes of familial and non-familial atrial fibrillation

    DEFF Research Database (Denmark)

    Gundlund, Anna; Olesen, Jonas B.; Peterson, Eric D.

    2017-01-01

    Several studies have suggested that family history of atrial fibrillation (AF) is an important risk factor for AF, with several specific genetic regions now implicated through Genome Wide Association Studies. In addition, familial AF is associated with earlier age of onset and affects patients...

  6. Cost-effectiveness of a specialized atrial fibrillation clinic vs. usual care in patients with atrial fibrillation

    NARCIS (Netherlands)

    Hendriks, Jeroen; Tomini, Florian; van Asselt, Thea; Crijns, Harry; Vrijhoef, Hubertus

    AIMS: A recent randomized controlled trial demonstrated significant reductions in cardiovascular hospitalizations and deaths with a nurse-led integrated chronic care approach in patients with atrial fibrillation (AF) compared with usual care. The aim of the present study is to assess

  7. Cost-effectiveness of a specialized atrial fibrillation clinic vs. usual care in patients with atrial fibrillation

    NARCIS (Netherlands)

    Hendriks, J.M.L.; Tomini, F.; van Asselt, A.D.I.; Crijns, H.J.G.M.; Vrijhoef, H.J.M.

    2013-01-01

    Aims A recent randomized controlled trial demonstrated significant reductions in cardiovascular hospitalizations and deaths with a nurse-led integrated chronic care approach in patients with atrial fibrillation (AF) compared with usual care. The aim of the present study is to assess

  8. Early recurrences of atrial fibrillation after electrical cardioversion : A result of fibrillation-induced electrical remodeling of the atria?

    NARCIS (Netherlands)

    Tieleman, RG; Van Gelder, IC; Crijns, HJGM; De Kam, PJ; Van den Berg, MP; Haaksma, J; Van der Woude, HJ; Allessie, MA

    Objectives, We sought to investigate whether, in humans, the timing and incidence of a relapse of atrial fibrillation (AF) during the first month after cardioversion indicates the presence of electrical remodeling and whether this could be influenced by prevention of intracellular calcium overload

  9. (EOI) Form

    International Development Research Centre (IDRC) Digital Library (Canada)

    Dorine Odongo

    COLLABORATING TECHNICAL AGENCIES: EXPRESSION OF INTEREST FORM. • Please read the information provided about the initiative and the eligibility requirements in the Prospectus before completing this application form. • Ensure all the sections of the form are accurately completed and saved in PDF format.

  10. Modular forms

    NARCIS (Netherlands)

    Edixhoven, B.; van der Geer, G.; Moonen, B.; Edixhoven, B.; van der Geer, G.; Moonen, B.

    2008-01-01

    Modular forms are functions with an enormous amount of symmetry that play a central role in number theory, connecting it with analysis and geometry. They have played a prominent role in mathematics since the 19th century and their study continues to flourish today. Modular forms formed the

  11. Atrial fibrillation detection by heart rate variability in Poincare plot.

    Science.gov (United States)

    Park, Jinho; Lee, Sangwook; Jeon, Moongu

    2009-12-11

    Atrial fibrillation (AFib) is one of the prominent causes of stroke, and its risk increases with age. We need to detect AFib correctly as early as possible to avoid medical disaster because it is likely to proceed into a more serious form in short time. If we can make a portable AFib monitoring system, it will be helpful to many old people because we cannot predict when a patient will have a spasm of AFib. We analyzed heart beat variability from inter-beat intervals obtained by a wavelet-based detector. We made a Poincare plot using the inter-beat intervals. By analyzing the plot, we extracted three feature measures characterizing AFib and non-AFib: the number of clusters, mean stepping increment of inter-beat intervals, and dispersion of the points around a diagonal line in the plot. We divided distribution of the number of clusters into two and calculated mean value of the lower part by k-means clustering method. We classified data whose number of clusters is more than one and less than this mean value as non-AFib data. In the other case, we tried to discriminate AFib from non-AFib using support vector machine with the other feature measures: the mean stepping increment and dispersion of the points in the Poincare plot. We found that Poincare plot from non-AFib data showed some pattern, while the plot from AFib data showed irregularly irregular shape. In case of non-AFib data, the definite pattern in the plot manifested itself with some limited number of clusters or closely packed one cluster. In case of AFib data, the number of clusters in the plot was one or too many. We evaluated the accuracy using leave-one-out cross-validation. Mean sensitivity and mean specificity were 91.4% and 92.9% respectively. Because pulse beats of ventricles are less likely to be influenced by baseline wandering and noise, we used the inter-beat intervals to diagnose AFib. We visually displayed regularity of the inter-beat intervals by way of Poincare plot. We tried to design an

  12. TYPES OF RADIOFREQUENCY ABLATION AND CLINICAL SYMPTOMS IN PATIENTS WITH ATRIAL FIBRILLATION AND FLUTTER

    Directory of Open Access Journals (Sweden)

    Zolotarova T. V.

    2017-12-01

    Full Text Available The study involved 76 patients with atrial fibrillation and atrial flutter (AF/AFL who were divided into groups depending on conducted surgery (radiofrequency ablation of pulmonary veins (RFA PV, cavo-tricuspid isthmus (CTI, a combined strategy (PV + CTI. We evaluated the sex and age of patients, AF and AFL form, duration of AF/AFL, classification of AF / AFL by the different scales, stage and degree of hypertension (AT; types of coronary heart disease (CHD; diabetes mellitus type 2; acute cerebrovascular accident history; functional class and stage of chronic heart failure (FC CHF. The frequency distribution of basic cardiovascular diseases and their clinical signs are observed equally in patients with AF/AFL, regardless of the type of surgery carried out and they do not influence the choice of the latter. Male patients often held RFA CTI and women – RFA PV. Patients with persistent AF often require alternative treatments, especially catheter ablation of arrhythmic substrate.

  13. IKs Gain- and Loss-of-Function In Early-Onset Lone Atrial Fibrillation

    DEFF Research Database (Denmark)

    Steffensen, Annette Buur; Refsgaard, Lena; Andersen, Martin Nybo

    2015-01-01

    INTRODUCTION: Atrial fibrillation (AF) is the most frequent cardiac arrhythmia. The potassium current IKs is essential for cardiac repolarization. Gain-of-function mutation in KCNQ1, the gene encoding the pore-forming α-subunit of the IKs channel (KV 7.1), was the first ion channel dysfunction...... to be associated with familial AF. We hypothesized that early-onset lone AF is associated with a high prevalence of mutations in KCNQ1. METHODS AND RESULTS: We bidirectionally sequenced the entire coding sequence of KCNQ1 in 209 unrelated patients with early-onset lone AF (...-of-function phenotype. CONCLUSIONS: Mutations in the IKs channel leading to gain-of-function have previously been described in familial AF, yet this is the first time a loss-of-function mutation in KCNQ1 is associated with early-onset lone AF. These findings suggest that both gain-of function and loss...

  14. Changes in plasma atrial natriuretic factor in patients with idiopathic atrial fibrillation

    International Nuclear Information System (INIS)

    Du Tongxin; Xia Xiaojie; Qu Wei; Wang Shukui; Sun Junjiang

    2002-01-01

    To observe the changes in plasma atrial natriuretic factor (AFN) in patients with idiopathic atrial fibrillation and investigate its mechanism, plasma ANF, platelet count and hematocrit were detected in 21 cases with transient idiopathic atrial fibrillation (group A, A1 representing attack, while A2 termination), 28 with persistent idiopathic atrial fibrillation (group B), 27 suffered from rheumatic heart disease with mitral stenosis and persistent atrial fibrillation (group C), 32 with transient supraventricular tachycardia (group D) and 20 normal controls (group E). It was found that the level of ANF was significantly higher in patients with attacking transient idiopathic atrial fibrillation than that in group A2, D and E (P 0.05), while there was significant difference in hematocrit in group A1 compared with group A2, D, E (P < 0.01). It suggested that ANF and hematocrit play an important role in the attack of idiopathic atrial fibrillation

  15. Synergistic Inhibition of Protein Fibrillation by Proline and Sorbitol: Biophysical Investigations.

    Directory of Open Access Journals (Sweden)

    Sinjan Choudhary

    Full Text Available We report here interesting synergistic effects of proline and sorbitol, two well-known chemical chaperones, in the inhibition of fibrillation of two proteins, insulin and lysozyme. A combination of many biophysical techniques has been used to understand the structural morphology and modes of interaction of the chaperones with the proteins during fibrillation. Both the chaperones establish stronger polar interactions in the elongation and saturation stages of fibrillation compared to that in the native stage. However, when presented as a mixture, we also see contribution of hydrophobic interactions. Thus, a co-operative adjustment of polar and hydrophobic interactions between the chaperones and the protein surface seems to drive the synergistic effects in the fibrillation process. In insulin, this synergy is quantitatively similar in all the stages of the fibrillation process. These observations would have significant implications for understanding protein folding concepts, in general, and for designing combination therapies against protein fibrillation, in particular.

  16. Synergistic Inhibition of Protein Fibrillation by Proline and Sorbitol: Biophysical Investigations.

    Science.gov (United States)

    Choudhary, Sinjan; Save, Shreyada N; Kishore, Nand; Hosur, Ramakrishna V

    2016-01-01

    We report here interesting synergistic effects of proline and sorbitol, two well-known chemical chaperones, in the inhibition of fibrillation of two proteins, insulin and lysozyme. A combination of many biophysical techniques has been used to understand the structural morphology and modes of interaction of the chaperones with the proteins during fibrillation. Both the chaperones establish stronger polar interactions in the elongation and saturation stages of fibrillation compared to that in the native stage. However, when presented as a mixture, we also see contribution of hydrophobic interactions. Thus, a co-operative adjustment of polar and hydrophobic interactions between the chaperones and the protein surface seems to drive the synergistic effects in the fibrillation process. In insulin, this synergy is quantitatively similar in all the stages of the fibrillation process. These observations would have significant implications for understanding protein folding concepts, in general, and for designing combination therapies against protein fibrillation, in particular.

  17. Does in-hospital ventricular fibrillation affect prognosis after myocardial infarction?

    DEFF Research Database (Denmark)

    Jensen, G V; Torp-Pedersen, C; Hildebrandt, P

    1997-01-01

    with ventricular fibrillation in time intervals, indicated that the importance of ventricular fibrillation for risk of death was exhausted during the initial 60 days after infarction. CONCLUSION: Ventricular fibrillation is associated with an independent increased risk of death within 0-60 days after infarction......AIM: The aim of this study was to estimate the prognostic information to be gained from ventricular fibrillation in patients with myocardial infarction. METHODS AND RESULTS: We studied 4259 consecutive patients with myocardial infarction admitted to one centre in 1977-1988. Five hundred and twenty......-eight (12.4%) of the patients had ventricular fibrillation in hospital. The following risk factors were included in multivariate models to estimate their importance for 30-day and long-term (median 7 year) prognosis: age, gender, ventricular fibrillation, congestive heart failure, pulmonary oedema...

  18. Decision-making interventions to stop the global atrial fibrillation-related stroke tsunami.

    Science.gov (United States)

    Cerasuolo, Joshua O; Montero-Odasso, Manuel; Ibañez, Agustin; Doocy, Shannon; Lip, Gregory Yh; Sposato, Luciano A

    2017-04-01

    Atrial fibrillation affects 33.5 million people worldwide and its prevalence is expected to double by 2050 because of the aging population. Atrial fibrillation confers a 5-fold higher risk of ischemic stroke compared to sinus rhythm. We present our view of the role of shared medical decision-making to combat global underutilization of oral anticoagulation for stroke prevention in atrial fibrillation patients. Oral anticoagulation underuse is widespread as it is present within atrial fibrillation patients of all risk strata and in countries across all income levels. Reasons for oral anticoagulation underuse include but are probably not limited to poor risk stratification, over-interpretation of contraindications, and discordance between physician prescription preferences and actual administration. By comparing a catastrophic event to the consequences of atrial fibrillation related strokes, it may help physicians and patients understand the negative outcomes associated with oral anticoagulation under-utilization and the magnitude to which oral anticoagulations neutralize atrial fibrillation burden.

  19. Novel squarylium dyes for detection of amyloid fibrils in vitro

    Directory of Open Access Journals (Sweden)

    K. O. Vus

    2015-04-01

    Full Text Available A series of novel symmetrical and asymmetrical squarylium dyes with the different substituents in the donor moieties have been tested for their ability to detect and characterize insulin and lysozyme amyloid fibrils prepared in acidic buffer at elevated temperature. The dye-protein binding parameters were estimated in terms of the one-site Langmuir adsorption model using the data of direct and reverse fluorimetric titrations. By comparing the dye quantum yields, binding affinities, and extents of the fluorescence enhancement in the protein-bound state, G6 and G7 were selected as the most prospective amyloid tracers. Furthermore, these probes provided evidence for the lower polarity of the lysozyme fibrillar grooves compared to insulin aggregates. The novel dyes G6 and G7 were recommended for amyloid fibril detection and characterization in the near-infrared region.

  20. Dynamical mechanism of atrial fibrillation: A topological approach

    Science.gov (United States)

    Marcotte, Christopher D.; Grigoriev, Roman O.

    2017-09-01

    While spiral wave breakup has been implicated in the emergence of atrial fibrillation, its role in maintaining this complex type of cardiac arrhythmia is less clear. We used the Karma model of cardiac excitation to investigate the dynamical mechanisms that sustain atrial fibrillation once it has been established. The results of our numerical study show that spatiotemporally chaotic dynamics in this regime can be described as a dynamical equilibrium between topologically distinct types of transitions that increase or decrease the number of wavelets, in general agreement with the multiple wavelets' hypothesis. Surprisingly, we found that the process of continuous excitation waves breaking up into discontinuous pieces plays no role whatsoever in maintaining spatiotemporal complexity. Instead, this complexity is maintained as a dynamical balance between wave coalescence—a unique, previously unidentified, topological process that increases the number of wavelets—and wave collapse—a different topological process that decreases their number.

  1. Unexpected guest: Atrial fibrillation due to electrical shock

    Directory of Open Access Journals (Sweden)

    Mehmet Zihni Bilik

    2016-03-01

    Full Text Available Cardiac arrhythmias due to electrical injuries are rare among emergency service admittances. A 35 year-old female patient was admitted to emergency service with palpitation after electrical injury as a result of contact with a domestic low-voltage source. Electrocardiography (ECG showed atrial fibrillation with rapid ventricular response. Transthoracic echocardiography findings were normal. Atrial fibrillation spontaneously converted to normal sinus rhythm after rate limiting treatment with beta-blocker. The patient was discharged without any complication on the third day of hospitalization. Although cardiac arrhythmias rarely occur after electrical injury, cardiac monitoring is recommended for all patients with documented rhythm disorder, loss of consciousness, or abnormal ECG at admission.

  2. Atrial fibrillation in fracture patients treated with oral bisphosphonates

    DEFF Research Database (Denmark)

    Abrahamsen, B; Eiken, P; Brixen, K

    2009-01-01

    OBJECTIVES: To determine if patients receiving oral bisphosphonates are at excess risk of atrial fibrillation (AF), stroke and myocardial infarction. DESIGN: Register-based restricted cohort study. SETTING: National Hospital Discharge Register and National Prescriptions Database (1995-2005). SUBJ......OBJECTIVES: To determine if patients receiving oral bisphosphonates are at excess risk of atrial fibrillation (AF), stroke and myocardial infarction. DESIGN: Register-based restricted cohort study. SETTING: National Hospital Discharge Register and National Prescriptions Database (1995...... to adherence. There was no increased risk of ischaemic stroke and an increased risk of myocardial infarction was not significant after adjustment for comorbidity. CONCLUSIONS: The increased occurrence of AF in fracture patients who are users of oral bisphosphonates should be attributed to targeting...

  3. Paroxysmal atrial fibrillation occurs often in cryptogenic ischaemic stroke

    DEFF Research Database (Denmark)

    Christensen, L M; Krieger, D W; Højberg, S

    2014-01-01

    BACKGROUND AND PURPOSE: Atrial fibrillation (AF) increases the risk of stroke fourfold and is associated with a poor clinical outcome. Despite work-up in compliance with guidelines, up to one-third of patients have cryptogenic stroke (CS). The prevalence of asymptomatic paroxysmal atrial fibrilla......BACKGROUND AND PURPOSE: Atrial fibrillation (AF) increases the risk of stroke fourfold and is associated with a poor clinical outcome. Despite work-up in compliance with guidelines, up to one-third of patients have cryptogenic stroke (CS). The prevalence of asymptomatic paroxysmal atrial...... lasting predominantly between 1 and 4 h. Four recurrent strokes were observed, three in patients with PAF; all three patients were on oral anticoagulation (OAC). CONCLUSIONS: One in five patients with CS had PAF, which occurred at low burden and long after stroke. Future studies should determine the role...

  4. [Atrial fibrillation as consequence and cause of structural changes of atria].

    Science.gov (United States)

    Aparina, O P; Chikhireva, L N; Stukalova, O V; Mironova, N A; Kashtanova, S Iu; Ternovoĭ, S K; Golitsyn, S P

    2014-01-01

    Changes of atrial structure and function are the contributors of atrial fibrillation clinical course, complications and treatment effectiveness. Effects of inflammation and mechanical stretch on atrial structural remodeling leading to atrial fibrillation are reviewed in the article. Contemporary invasive and non-invasive methods of evaluation (including late gadolinium enhancement magnetic resonance imaging) of patients with atrial structural remodeling in atrial fibrillation are also described.

  5. Cardiac ion channels and mechanisms for protection against atrial fibrillation

    DEFF Research Database (Denmark)

    Grunnet, Morten; Bentzen, Bo Hjorth; Sørensen, Ulrik S

    2011-01-01

    Atrial fibrillation (AF) is recognised as the most common sustained cardiac arrhythmia in clinical practice. Ongoing drug development is aiming at obtaining atrial specific effects in order to prevent pro-arrhythmic, devastating ventricular effects. In principle, this is possible due to a differe...... to the recent discovery that Ca(2+)-activated small conductance K(+) channels (SK channels) are important for the repolarisation of atrial action potentials. Finally, an overview of current pharmacological treatment of AF is included....

  6. Slow ventricular response atrial fibrillation related to mad honey poisoning

    Science.gov (United States)

    Osken, A.; Yaylacı, S.; Aydın, E.; Kocayigit, İ; Cakar, M.A.; Tamer, A.; Gündüz, H.

    2012-01-01

    Mad honey poisoning which is induced by Grayanotoxin (Andromedotoxin), is also known to have adverse effects in the cardiovascular system leading to different clinical entities. This toxin is produced by a member of the Rhododendron genus of plants of two R. Luteum and R. Panticum. In this article, we presented a case of slow ventricular response atrial fibrillation complaints with nausea, vomiting, dizziness and chest pain about an hour after eating honey produced in the Black Sea Region. PMID:22923947

  7. Slow ventricular response atrial fibrillation related to mad honey poisoning

    OpenAIRE

    Osken, A.; Yaylacı, S.; Aydın, E.; Kocayigit, İ; Cakar, M.A.; Tamer, A.; Gündüz, H.

    2012-01-01

    Mad honey poisoning which is induced by Grayanotoxin (Andromedotoxin), is also known to have adverse effects in the cardiovascular system leading to different clinical entities. This toxin is produced by a member of the Rhododendron genus of plants of two R. Luteum and R. Panticum. In this article, we presented a case of slow ventricular response atrial fibrillation complaints with nausea, vomiting, dizziness and chest pain about an hour after eating honey produced in the Black Sea Region.

  8. Artificial Intelligence Methods Applied to Parameter Detection of Atrial Fibrillation

    Science.gov (United States)

    Arotaritei, D.; Rotariu, C.

    2015-09-01

    In this paper we present a novel method to develop an atrial fibrillation (AF) based on statistical descriptors and hybrid neuro-fuzzy and crisp system. The inference of system produce rules of type if-then-else that care extracted to construct a binary decision system: normal of atrial fibrillation. We use TPR (Turning Point Ratio), SE (Shannon Entropy) and RMSSD (Root Mean Square of Successive Differences) along with a new descriptor, Teager- Kaiser energy, in order to improve the accuracy of detection. The descriptors are calculated over a sliding window that produce very large number of vectors (massive dataset) used by classifier. The length of window is a crisp descriptor meanwhile the rest of descriptors are interval-valued type. The parameters of hybrid system are adapted using Genetic Algorithm (GA) algorithm with fitness single objective target: highest values for sensibility and sensitivity. The rules are extracted and they are part of the decision system. The proposed method was tested using the Physionet MIT-BIH Atrial Fibrillation Database and the experimental results revealed a good accuracy of AF detection in terms of sensitivity and specificity (above 90%).

  9. Artificially modified collagen fibril orientation affects leather tear strength.

    Science.gov (United States)

    Kelly, Susyn J; Wells, Hannah C; Sizeland, Katie H; Kirby, Nigel; Edmonds, Richard L; Ryan, Tim; Hawley, Adrian; Mudie, Stephen; Haverkamp, Richard G

    2018-07-01

    Ovine leather has around half the tear strength of bovine leather and is therefore not suitable for high-value applications such as shoes. Tear strength has been correlated with the natural collagen fibril alignment (orientation index, OI). It is hypothesized that it could be possible to artificially increase the OI of the collagen fibrils and that an artificial increase in OI could increase tear strength. Ovine skins, after pickling and bating, were strained biaxially during chrome tanning. The strain ranged from 2 to 15% of the initial sample length, either uniformly in both directions by 10% or with 3% in one direction and 15% in the other. Once tanned, the leather tear strengths were measured and the collagen fibril orientation was measured using synchrotron-based small-angle X-ray scattering. The OI increased as a result of strain during tanning from 0.48 to 0.79 (P = 0.001) measured edge-on and the thickness-normalized tear strength increased from 27 to 43 N mm -1 (P leather was strained 10% in two orthogonal directions. This is evidence to support a causal relationship between high OI (measured edge-on), highly influenced by thickness, and tear strength. It also provides a method to produce stronger leather. © 2017 Society of Chemical Industry. © 2017 Society of Chemical Industry.

  10. Maze Procedures for Atrial Fibrillation, From History to Practice.

    Science.gov (United States)

    Kik, Charles; Bogers, Ad J J C

    2011-10-01

    Atrial fibrillation may result in significant symptoms, (systemic) thrombo-embolism, as well as tachycardia-induced cardiomyopathy with cardiac failure, and consequently be associated with significant morbidity and mortality. Nowadays symptomatic atrial fibrillation can be treated with catheter-based ablation, surgical ablation or hybrid approaches. In this setting a fairly large number of surgical approaches and procedures are described and being practised. It should be clear that the Cox-maze procedure resulted from building up evidence and experience in different steps, while some of the present surgical approaches and techniques are being based only on technical feasibility with limited experience, rather than on a process of consequent methodology. Some of the issues still under debate are whether or not the maze procedure can be limited to the left atrium or even to isolation of the pulmonary veins or that bi-atrial procedures are indicated, whether or not cardiopulmonary bypass is to be applied and which route of exposure facilitates an optimal result. In addition, maze procedures are not procedures guide by electrophysiological mapping. At least in theory not in all patients all lesions of the maze procedures are necessary. A history and aspects of current practise in surgical treatment of atrial fibrillation is presented.

  11. Managing atrial fibrillation in the elderly: critical appraisal of dronedarone.

    Science.gov (United States)

    Trigo, Paula; Fischer, Gregory W

    2012-01-01

    Atrial fibrillation is the most commonly seen arrhythmia in the geriatric population and is associated with increased cardiovascular morbidity and mortality. Treatment of the elderly with atrial fibrillation remains challenging for physicians, because this unique subpopulation is characterized by multiple comorbidities requiring chronic use of numerous medications, which can potentially lead to severe drug interactions. Furthermore, age-related changes in the cardiovascular system as well as other physiological changes result in altered drug pharmacokinetics. Dronedarone is a new drug recently approved for the treatment of arrhythmias, such as atrial fibrillation and/or atrial flutter. Dronedarone is a benzofuran amiodarone analog which lacks the iodine moiety and contains a methane sulfonyl group that decreases its lipophilicity. These differences in chemical structure are responsible for making dronedarone less toxic than amiodarone which, in turn, results in fewer side effects. Adverse events for dronedarone include gastrointestinal side effects and rash. No dosage adjustments are required for patients with renal impairment. However, the use of dronedarone is contraindicated in the presence of severe hepatic dysfunction.

  12. Cost of illness of atrial fibrillation: a nationwide study of societal impact.

    Science.gov (United States)

    Johnsen, Søren Paaske; Dalby, Lene Worsaae; Täckström, Tomas; Olsen, Jens; Fraschke, Anina

    2017-11-10

    The prevalence of atrial fibrillation is increasing rapidly; however, to date, population-based data are lacking on the attributable cost of illness of atrial fibrillation from a societal perspective, including both direct and indirect costs. The study was an incidence-based cost-of-illness study based on national registries covering the entire population of Denmark. We identified all patients with a first-time hospital diagnosis of atrial fibrillation between 2001 and 2012. For every atrial fibrillation patient, we identified three age- and sex-matched controls from the general population. Both the total and the attributable costs of atrial fibrillation were estimated based on individual level information on hospital care (in- and out-patient contacts), primary sector care, use of prescription drugs and productivity loss. Average 3-year societal costs per patient attributable to atrial fibrillation were estimated to be €20,403-26,544 during the study period. The costs were highest during the first year after diagnosis of atrial fibrillation. Admission costs constituted the largest cost component, whereas primary sector costs and medicine costs only constituted minor components. The attributable costs were more than two-fold higher among patients experiencing a stroke. The total 3-year cost attributable to atrial fibrillation in Denmark was estimated to be €219-295 million. The societal costs attributable to atrial fibrillation are significant. Reducing the need for hospitalizations, in particular from stroke, is a key factor in controlling the costs.

  13. Iowa Mutant Apolipoprotein A-I (ApoA-IIowa) Fibrils Target Lysosomes.

    Science.gov (United States)

    Kameyama, Hirokazu; Nakajima, Hiroyuki; Nishitsuji, Kazuchika; Mikawa, Shiho; Uchimura, Kenji; Kobayashi, Norihiro; Okuhira, Keiichiro; Saito, Hiroyuki; Sakashita, Naomi

    2016-07-28

    The single amino acid mutation G26R in human apolipoprotein A-I (apoA-IIowa) is the first mutation that was associated with familial AApoA1 amyloidosis. The N-terminal fragments (amino acid residues 1-83) of apoA-I containing this mutation deposit as amyloid fibrils in patients' tissues and organs, but the mechanisms of cellular degradation and cytotoxicity have not yet been clarified. In this study, we demonstrated degradation of apoA-IIowa fibrils via the autophagy-lysosomal pathway in human embryonic kidney 293 cells. ApoA-IIowa fibrils induced an increase in lysosomal pH and the cytosolic release of the toxic lysosomal protease cathepsin B. The mitochondrial dysfunction caused by apoA-IIowa fibrils depended on cathepsin B and was ameliorated by increasing the degradation of apoA-IIowa fibrils. Thus, although apoA-IIowa fibril transport to lysosomes and fibril degradation in lysosomes may have occurred, the presence of an excess number of apoA-IIowa fibrils, more than the lysosomes could degrade, may be detrimental to cells. Our results thus provide evidence that the target of apoA-IIowa fibrils is lysosomes, and we thereby gained a novel insight into the mechanism of AApoA1 amyloidosis.

  14. Intraoperative Inducibility of Atrial Fibrillation Does Not Predict Early Postoperative Atrial Fibrillation.

    Science.gov (United States)

    Lanters, Eva A H; Teuwen, Christophe P; Yaksh, Ameeta; Kik, Charles; van der Does, Lisette J M E; Mouws, Elisabeth M J P; Knops, Paul; van Groningen, Nicole J; Hokken, Thijmen; Bogers, Ad J J C; de Groot, Natasja M S

    2018-03-10

    Early postoperative atrial fibrillation (EPoAF) is associated with thromboembolic events, prolonged hospitalization, and development of late PoAF (LPoAF). It is, however, unknown if EPoAF can be predicted by intraoperative AF inducibility. The aims of this study are therefore to explore (1) the value of intraoperative inducibility of AF for development of both EPoAF and LPoAF and (2) the predictive value of de novo EPoAF for recurrence of LPoAF. Patients (N=496, 75% male) undergoing cardiothoracic surgery for coronary and/or valvular heart disease were included. AF induction was attempted by atrial pacing, before extracorporeal circulation. All patients were on continuous rhythm monitoring until discharge to detect EPoAF. During a follow-up period of 2 years, LPoAF was detected by ECGs and Holter recordings. Sustained AF was inducible in 56% of patients. There was no difference in patients with or without AF before surgery ( P =0.159), or between different types of surgery ( P =0.687). In patients without a history of AF, incidence of EPoAF and LPoAF was 37% and 2%, respectively. EPoAF recurred in 58% patients with preoperative AF, 53% developed LPoAF. There were no correlations between intraoperative inducibility and EPoAF or LPoAF ( P >0.05). EPoAF was not correlated with LPoAF in patients without a history of AF ( P =0.116), in contrast to patients with AF before surgery ( P <0.001). Intraoperative AF inducibility does not predict development of either EPoAF or LPoAF. In patients with AF before surgery, EPoAF is correlated with LPoAF recurrences. This correlation is absent in patients without AF before surgery. © 2018 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

  15. Rapid biomimetic mineralization of collagen fibrils and combining with human umbilical cord mesenchymal stem cells for bone defects healing

    Energy Technology Data Exchange (ETDEWEB)

    Ye, Bihua; Luo, Xueshi; Li, Zhiwen [Department of Material Science and Engineering, Engineering Research Center of Artificial Organs and Materials, Jinan University, Guangzhou 510632 (China); Zhuang, Caiping [Department of Anesthesiology, Huizhou Central People' s Hospital, Huizhou 516001 (China); Li, Lihua, E-mail: tlihuali@jnu.edu.cn [Department of Material Science and Engineering, Engineering Research Center of Artificial Organs and Materials, Jinan University, Guangzhou 510632 (China); Lu, Lu; Ding, Shan; Tian, Jinhuan [Department of Material Science and Engineering, Engineering Research Center of Artificial Organs and Materials, Jinan University, Guangzhou 510632 (China); Zhou, Changren, E-mail: tcrz9@jnu.edu.cn [Department of Material Science and Engineering, Engineering Research Center of Artificial Organs and Materials, Jinan University, Guangzhou 510632 (China)

    2016-11-01

    Collagen biomineralization is regulated by complicated interactions between the collagen matrix and non-collagenous extracellular proteins. Here, the use of sodium tripolyphosphate to simulate the templating functional motif of the C-terminal fragment of non-collagenous proteins is reported, and a low molecular weight polyacrylic acid served as a sequestration agent to stabilize amorphous calcium phosphate into nanoprecursors. Self-assembled collagen fibrils served as a fixed template for achieving rapid biomimetic mineralization in vitro. Results demonstrated that, during the mineralization process, intrafibrillar and extrafibrillar hydroxyapatite mineral with collagen fibrils formed and did so via bottom-up nanoparticle assembly based on the non-classical crystallization approach in the presence of these dual biomimetic functional analogues. In vitro human umbilical cord mesenchymal stem cell (hUCMSC) culture found that the mineralized scaffolds have a better cytocompatibility in terms of cell viability, adhesion, proliferation, and differentiation into osteoblasts. A rabbit femoral condyle defect model was established to confirm the ability of the n-HA/collagen scaffolds to facilitate bone regeneration and repair. The images of gross anatomy, MRI, CT and histomorphology taken 6 and 12 weeks after surgery showed that the biomimetic mineralized collagen scaffolds with hUCMSCs can promote the healing speed of bone defects in vivo, and both of the scaffolds groups performing better than the bone defect control group. As new bone tissue formed, the scaffolds degraded and were gradually absorbed. All these results demonstrated that both of the scaffolds and cells have better histocompatibility. - Highlights: • A rapid and facile biomimetic mineralization approach is proposed. • Intrafibrillar and extrafibrillar mineralization of collagen fibrils was achieved. • HA/COL scaffolds promote hUCMSCs adhesion, proliferation, and differentiation. • Feasibility of h

  16. Rapid biomimetic mineralization of collagen fibrils and combining with human umbilical cord mesenchymal stem cells for bone defects healing

    International Nuclear Information System (INIS)

    Ye, Bihua; Luo, Xueshi; Li, Zhiwen; Zhuang, Caiping; Li, Lihua; Lu, Lu; Ding, Shan; Tian, Jinhuan; Zhou, Changren

    2016-01-01

    Collagen biomineralization is regulated by complicated interactions between the collagen matrix and non-collagenous extracellular proteins. Here, the use of sodium tripolyphosphate to simulate the templating functional motif of the C-terminal fragment of non-collagenous proteins is reported, and a low molecular weight polyacrylic acid served as a sequestration agent to stabilize amorphous calcium phosphate into nanoprecursors. Self-assembled collagen fibrils served as a fixed template for achieving rapid biomimetic mineralization in vitro. Results demonstrated that, during the mineralization process, intrafibrillar and extrafibrillar hydroxyapatite mineral with collagen fibrils formed and did so via bottom-up nanoparticle assembly based on the non-classical crystallization approach in the presence of these dual biomimetic functional analogues. In vitro human umbilical cord mesenchymal stem cell (hUCMSC) culture found that the mineralized scaffolds have a better cytocompatibility in terms of cell viability, adhesion, proliferation, and differentiation into osteoblasts. A rabbit femoral condyle defect model was established to confirm the ability of the n-HA/collagen scaffolds to facilitate bone regeneration and repair. The images of gross anatomy, MRI, CT and histomorphology taken 6 and 12 weeks after surgery showed that the biomimetic mineralized collagen scaffolds with hUCMSCs can promote the healing speed of bone defects in vivo, and both of the scaffolds groups performing better than the bone defect control group. As new bone tissue formed, the scaffolds degraded and were gradually absorbed. All these results demonstrated that both of the scaffolds and cells have better histocompatibility. - Highlights: • A rapid and facile biomimetic mineralization approach is proposed. • Intrafibrillar and extrafibrillar mineralization of collagen fibrils was achieved. • HA/COL scaffolds promote hUCMSCs adhesion, proliferation, and differentiation. • Feasibility of h

  17. Imaging β-amyloid fibrils in Alzheimer's disease: a critical analysis through simulation of amyloid fibril polymerization

    International Nuclear Information System (INIS)

    Shoghi-Jadid, Kooresh; Barrio, Jorge R.; Kepe, Vladimir; Wu, H.-M.; Small, Gary W.; Phelps, Michael E.; Huang, S.-C.

    2005-01-01

    The polymerization of β-amyloid (Aβ) peptides into fibrillary plaques is implicated, in part, in the pathogenesis of Alzheimer's disease. Aβ molecular imaging probes (Aβ-MIPs) have been introduced in an effort to quantify amyloid burden or load, in subjects afflicted with AD by invoking the classic PET receptor model for the quantitation of neuronal receptor density. In this communication, we explore conceptual differences between imaging the density of amyloid fibril polymers and neuronal receptors. We formulate a mathematical model for the polymerization of Aβ with parameters that are mapped to biological modulators of fibrillogenesis and introduce a universal measure for amyloid load to accommodate various interactions of Aβ-MIPs with fibrils. Subsequently, we hypothesize four Aβ-MIPs and utilize the fibrillogenesis model to simulate PET tissue time activity curves (TACs). Given the unique nature of polymer growth and resulting PET TAC, the four probes report differing amyloid burdens for a given brain pathology, thus complicating the interpretation of PET images. In addition, we introduce the notion of an MIP's resolution, apparent maximal binding site concentration, optimal kinetic topology and its resolving power in characterizing the pathological progression of AD and the effectiveness of drug therapy. The concepts introduced in this work call for a new paradigm that goes beyond the classic parameters B max and K D to include binding characteristics to polymeric peptide aggregates such as amyloid fibrils, neurofibrillary tangles and prions

  18. Clinical Differences between Subtypes of Atrial Fibrillation and Flutter: Cross-Sectional Registry of 407 Patients

    Directory of Open Access Journals (Sweden)

    Eduardo Dytz Almeida

    2015-01-01

    Full Text Available Introduction: Atrial fibrillation and atrial flutter account for one third of hospitalizations due to arrhythmias, determining great social and economic impacts. In Brazil, data on hospital care of these patients is scarce. Objective: To investigate the arrhythmia subtype of atrial fibrillation and flutter patients in the emergency setting and compare the clinical profile, thromboembolic risk and anticoagulants use. Methods: Cross-sectional retrospective study, with data collection from medical records of every patient treated for atrial fibrillation and flutter in the emergency department of Instituto de Cardiologia do Rio Grande do Sul during the first trimester of 2012. Results: We included 407 patients (356 had atrial fibrillation and 51 had flutter. Patients with paroxysmal atrial fibrillation were in average 5 years younger than those with persistent atrial fibrillation. Compared to paroxysmal atrial fibrillation patients, those with persistent atrial fibrillation and flutter had larger atrial diameter (48.6 ± 7.2 vs. 47.2 ± 6.2 vs. 42.3 ± 6.4; p < 0.01 and lower left ventricular ejection fraction (66.8 ± 11 vs. 53.9 ± 17 vs. 57.4 ± 16; p < 0.01. The prevalence of stroke and heart failure was higher in persistent atrial fibrillation and flutter patients. Those with paroxysmal atrial fibrillation and flutter had higher prevalence of CHADS2 score of zero when compared to those with persistent atrial fibrillation (27.8% vs. 18% vs. 4.9%; p < 0.01. The prevalence of anticoagulation in patients with CHA2DS2-Vasc ≤ 2 was 40%. Conclusions: The population in our registry was similar in its comorbidities and demographic profile to those of North American and European registries. Despite the high thromboembolic risk, the use of anticoagulants was low, revealing difficulties for incorporating guideline recommendations. Public health strategies should be adopted in order to improve these rates.

  19. Chemical modification of lysine residues in lysozyme may dramatically influence its amyloid fibrillation.

    Science.gov (United States)

    Morshedi, Dina; Ebrahim-Habibi, Azadeh; Moosavi-Movahedi, Ali Akbar; Nemat-Gorgani, Mohsen

    2010-04-01

    Studies on the aggregation of mutant proteins have provided new insights into the genetics of amyloid diseases and the role of the net charge of the protein on the rate, extent, and type of aggregate formation. In the present work, hen egg white lysozyme (HEWL) was employed as the model protein. Acetylation and (separately) citraconylation were employed to neutralize the charge on lysine residues. Acetylation of the lysine residues promoted amyloid formation, resulting in more pronounced fibrils and a dramatic decline in the nucleation time. In contrast, citraconylation produced the opposite effect. In both cases, native secondary and tertiary structures appeared to be retained. Studies on the effect of pH on aggregation suggested greater possibilities for amorphous aggregate formation rather than fibrillation at pH values closer to neutrality, in which the protein is known to take up a conformation more similar to its native form. This is in accord with reports in the literature suggesting that formation of amorphous aggregates is more favored under relatively more native conditions. pH 5 provided a critical environment in which a mixture of amorphous and fibrillar structures were observed. Use of Tango and Aggrescan software which describe aggregation tendencies of different parts of a protein structure suggested critical importance of some of the lysine residues in the aggregation process. Results are discussed in terms of the importance of the net charge in control of protein-protein interactions leading to aggregate formation and possible specific roles of lysine residues 96 and 97. Copyright 2009 Elsevier B.V. All rights reserved.

  20. Mid-Term Results of Surgical Treatment of Atrial Fibrillation in Valvular Heart Disease Assesed by Speckle Tracking Echocardiography.

    Science.gov (United States)

    Lorenzo, Natalia; Mendez, Irene; Taibo, Mikel; Martinis, Gianfranco; Badia, Sara; Reyes, Guillermo; Aguilar, Rio

    2018-03-19

    Atrial fibrillation frequently affects patients with valvular heart disease. Ablation of atrial fibrillation during valvular surgery is an alternative for restoring sinus rhythm. This study aimed to evaluate mid-term results of successful atrial fibrillation surgical ablation during valvular heart disease surgery, to explore left atrium post-ablation mechanics and to identify predictors of recurrence. Fifty-three consecutive candidates were included. Eligibility criteria for ablation included persistent atrial fibrillation valvular heart disease surgery.

  1. Axonal transport and secretion of fibrillar forms of α-synuclein, Aβ42 peptide and HTTExon 1.

    Science.gov (United States)

    Brahic, Michel; Bousset, Luc; Bieri, Gregor; Melki, Ronald; Gitler, Aaron D

    2016-04-01

    Accruing evidence suggests that prion-like behavior of fibrillar forms of α-synuclein, β-amyloid peptide and mutant huntingtin are responsible for the spread of the lesions that characterize Parkinson disease, Alzheimer disease and Huntington disease, respectively. It is unknown whether these distinct protein assemblies are transported within and between neurons by similar or distinct mechanisms. It is also unclear if neuronal death or injury is required for neuron-to-neuron transfer. To address these questions, we used mouse primary cortical neurons grown in microfluidic devices to measure the amounts of α-synuclein, Aβ42 and HTTExon1 fibrils transported by axons in both directions (anterograde and retrograde), as well as to examine the mechanism of their release from axons after anterograde transport. We observed that the three fibrils were transported in both anterograde and retrograde directions but with strikingly different efficiencies. The amount of Aβ42 fibrils transported was ten times higher than that of the other two fibrils. HTTExon1 was efficiently transported in the retrograde direction but only marginally in the anterograde direction. Finally, using neurons from two distinct mutant mouse strains whose axons are highly resistant to neurodegeneration (Wld(S) and Sarm1(-/-)), we found that the three different fibrils were secreted by axons after anterograde transport, in the absence of axonal lysis, indicating that trans-neuronal spread can occur in intact healthy neurons. In summary, fibrils of α-synuclein, Aβ42 and HTTExon1 are all transported in axons but in directions and amounts that are specific of each fibril. After anterograde transport, the three fibrils were secreted in the medium in the absence of axon lysis. Continuous secretion could play an important role in the spread of pathology between neurons but may be amenable to pharmacological intervention.

  2. Contemporary management of patients undergoing atrial fibrillation ablation: in-hospital and 1-year follow-up findings from the ESC-EHRA atrial fibrillation ablation long-term registry.

    Science.gov (United States)

    Arbelo, Elena; Brugada, Josep; Blomström-Lundqvist, Carina; Laroche, Cécile; Kautzner, Josef; Pokushalov, Evgeny; Raatikainen, Pekka; Efremidis, Michael; Hindricks, Gerhard; Barrera, Alberto; Maggioni, Aldo; Tavazzi, Luigi; Dagres, Nikolaos

    2017-05-01

    The ESC-EHRA Atrial Fibrillation Ablation Long-Term registry is a prospective, multinational study that aims at providing an accurate picture of contemporary real-world ablation for atrial fibrillation (AFib) and its outcome. A total of 104 centres in 27 European countries participated and were asked to enrol 20-50 consecutive patients scheduled for first and re-do AFib ablation. Pre-procedural, procedural and 1-year follow-up data were captured on a web-based electronic case record form. Overall, 3630 patients were included, of which 3593 underwent an AFib ablation (98.9%). Median age was 59 years and 32.4% patients had lone atrial fibrillation. Pulmonary vein isolation was attempted in 98.8% of patients and achieved in 95-97%. AFib-related symptoms were present in 97%. In-hospital complications occurred in 7.8% and one patient died due to an atrioesophageal fistula. One-year follow-up was performed in 3180 (88.6%) at a median of 12.4 months (11.9-13.4) after ablation: 52.8% by clinical visit, 44.2% by telephone contact and 3.0% by contact with the general practitioner. At 12-months, the success rate with or without antiarrhythmic drugs (AADs) was 73.6%. A significant portion (46%) was still on AADs. Late complications included 14 additional deaths (4 cardiac, 4 vascular, 6 other causes) and 333 (10.7%) other complications. AFib ablation in clinical practice is mostly performed in symptomatic, relatively young and otherwise healthy patients. Overall success rate is satisfactory, but complication rate remains considerable and a significant portion of patients remain on AADs. Monitoring after ablation shows wide variations. Antithrombotic treatment after ablation shows insufficient guideline-adherence. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For Permissions, please email: journals.permissions@oup.com.

  3. Percutaneous Occlusion of the Left Atrial Appendage with the Watchman Device in an Active Duty Sailor with Atrial Fibrillation and Recurrent Thromboembolism Despite Appropriate Use of Oral Anticoagulation.

    Science.gov (United States)

    Cox, Justin M; Choi, Anthony J; Oakley, Luke S; Francisco, Gregory M; Nayak, Keshav R

    2018-05-23

    Atrial fibrillation is the most common significant cardiac arrhythmia and is associated with a five-fold increased risk of stroke from thromboembolism. Over 94% of these emboli arise from the left atrial appendage. Systemic embolic phenomena are rare, accounting for less than 1 out of 10 of all embolic events, but have a similar prevention strategy. Anticoagulation significantly reduces the risk of these events, and thus forms the cornerstone of therapy for most patients with atrial fibrillation. Left atrial appendage occlusion with the Watchman device is a recently approved alternative for stroke prevention in selected patients. We present a case of an active duty U.S. Navy sailor at low risk for thromboembolism who nonetheless suffered recurrent thromboembolic events despite appropriate anticoagulation, and thus underwent Watchman implantation. The therapy in this case will ideally provide a lifetime of protection from recurrent systemic embolization while allowing the patient to continue his active duty military career without restriction due to oral anticoagulation.

  4. Use of Vitamins K antagonists in non-valvular atrial fibrillation ...

    African Journals Online (AJOL)

    Introduction: atrial fibrillation is the commonest cardiac rythm disorder. Thromboembolic accidents are common complications that should be prevented by anticoagulant treatment. The aim of our study is to assess the use of vitamins K antagonists in the prevention of thromboembolic risk in atrial fibrillation. Methods: it was a ...

  5. Mechanistic study of the inhibitory activity of Geum urbanum extract against α-Synuclein fibrillation

    DEFF Research Database (Denmark)

    Lobbens, Eva Stephanie; Breydo, Leonid; Pedersen, Thomas Skamris

    2016-01-01

    microscopy. Since the extract is a complex mixture, structure-function relationships could not be determined. Under the experimental conditions investigated, Geum urbanum was found to inhibit α-Synuclein fibrillation in a concentration dependent way, and to partly disintegrate preformed α-Synuclein fibrils...

  6. Mouse senile amyloid fibrils deposited in skeletal muscle exhibit amyloidosis-enhancing activity.

    Directory of Open Access Journals (Sweden)

    Jinze Qian

    2010-05-01

    Full Text Available Amyloidosis describes a group of protein folding diseases in which amyloid proteins are abnormally deposited in organs and/or tissues as fine fibrils. Mouse senile amyloidosis is a disorder in which apolipoprotein A-II (apoA-II deposits as amyloid fibrils (AApoAII and can be transmitted from one animal to another both by the feces and milk excreted by mice with amyloidosis. Thus, mouse AApoAII amyloidosis has been demonstrated to be a "transmissible disease". In this study, to further characterize the transmissibility of amyloidosis, AApoAII amyloid fibrils were injected into transgenic Apoa2(cTg(+/- and normal R1.P1-Apoa2(c mice to induce AApoAII systemic amyloidosis. Two months later, AApoAII amyloid deposits were found in the skeletal muscles of amyloid-affected mice, primarily in the blood vessels and in the interstitial tissues surrounding muscle fibers. When amyloid fibrils extracted from the skeletal muscles were subjected to Western blot analysis, apoA-II was detected. Amyloid fibril fractions isolated from the muscles not only demonstrated the structure of amyloid fibrils but could also induce amyloidosis in young mice depending on its fibril conformation. These findings present a possible pathogenesis of amyloidosis: transmission of amyloid fibril conformation through muscle, and shed new light on the etiology involved in amyloid disorders.

  7. Alcohol consumption and risk of atrial fibrillation in men and women: the Copenhagen City Heart Study

    DEFF Research Database (Denmark)

    Mukamal, Kenneth J; Tolstrup, Janne S; Friberg, Jens

    2005-01-01

    and incident atrial fibrillation among 16,415 women and men enrolled in the Copenhagen City Heart Study. We ascertained use of beer, wine, and spirits individually at up to 3 study visits with a structured questionnaire. We identified cases of atrial fibrillation by routine study ECGs and a validated...

  8. Identification of a Common Binding Mode for Imaging Agents to Amyloid Fibrils from Molecular Dynamics Simulations

    DEFF Research Database (Denmark)

    Skeby, Katrine Kirkeby; Sørensen, Jesper; Schiøtt, Birgit

    2013-01-01

    experimentally due to the insoluble nature of amyloid fibrils. This study uses molecular dynamics simulations to investigate the interactions between 13 aromatic amyloid imaging agents, entailing 4 different organic scaffolds, and a model of an amyloid fibril. Clustering analysis combined with free energy...

  9. Prednisone prevents atrial fibrillation promotion by atrial tachycardia remodeling in dogs

    NARCIS (Netherlands)

    Shiroshita-Takeshita, A; Brundel, BJJM; Lavoie, J; Nattel, S

    2006-01-01

    Background: There is evidence suggesting involvement of oxidative stress, inflammation, and calcineurin/nuclear factor of activated T cell pathways in atrial fibrillation. This study evaluated the efficacy of anti-inflammatory and calcineurin-inhibitory drugs on promotion of atrial fibrillation by

  10. Amyloid Fibril-Induced Structural and Spectral Modifications in the Thioflavin-T Optical Probe

    DEFF Research Database (Denmark)

    Murugan, N. Arul; Olsen, Jógvan Magnus Haugaard; Kongsted, Jacob

    2013-01-01

    Motivated by future possibilities to design target molecules for fibrils with diagnostic or therapeutic capability related to amyloidosis diseases, we investigate in this work the dielectric nature of amyloid fibril microenvironments in different binding sites using an optical probe, thioflavin-T...

  11. Influence of Aluminium and EGCG on Fibrillation and Aggregation of Human Islet Amyloid Polypeptide

    Directory of Open Access Journals (Sweden)

    Zhi-Xue Xu

    2016-01-01

    Full Text Available The abnormal fibrillation of human islet amyloid polypeptide (hIAPP has been implicated in the development of type II diabetes. Aluminum is known to trigger the structural transformation of many amyloid proteins and induce the formation of toxic aggregate species. The (−-epigallocatechin gallate (EGCG is considered capable of binding both metal ions and amyloid proteins with inhibitory effect on the fibrillation of amyloid proteins. However, the effect of Al(III/EGCG complex on hIAPP fibrillation is unclear. In the present work, we sought to view insight into the structures and properties of Al(III and EGCG complex by using spectroscopic experiments and quantum chemical calculations and also investigated the influence of Al(III and EGCG on hIAPP fibrillation and aggregation as well as their combined interference on this process. Our studies demonstrated that Al(III could promote fibrillation and aggregation of hIAPP, while EGCG could inhibit the fibrillation of hIAPP and lead to the formation of hIAPP amorphous aggregates instead of the ordered fibrils. Furthermore, we proved that the Al(III/EGCG complex in molar ratio of 1 : 1 as Al(EGCG(H2O2 could inhibit the hIAPP fibrillation more effectively than EGCG alone. The results provide the invaluable reference for the new drug development to treat type II diabetes.

  12. Risk of atrial fibrillation among bisphosphonate users: a multicenter, population-based, Italian study

    NARCIS (Netherlands)

    L. Herrera (Lizbeth); I. Leal (Ingrid); F. Lapi (Francesco); M.J. Schuemie (Martijn); V. Arcoraci (Vincenzo); F. Cipriani (Francesco); E. Sessa (E.); A. Vaccheri (Alberto); C. Piccinni (C.); T. Staniscia (Tommaso); A. Vestri (Annarita); M. Di Bari (M.); G. Corrao (Giovanni); A. Zambon (A.); D Gregori (Dario); F. Carle (F.); M.C.J.M. Sturkenboom (Miriam); G. Mazzaglia (Giampiero); G. Trifirò (Gianluca)

    2015-01-01

    textabstractSummary: Bisphosphonate treatment is used to prevent bone fractures. A controversial association of bisphosphonate use and risk of atrial fibrillation has been reported. In our study, current alendronate users were associated with a higher risk of atrial fibrillation as compared with

  13. Apixaban in patients at risk of stroke undergoing atrial fibrillation ablation

    DEFF Research Database (Denmark)

    Kirchhof, Paulus; Haeusler, Karl Georg; Blank, Benjamin

    2018-01-01

    Aims: It is recommended to perform atrial fibrillation ablation with continuous anticoagulation. Continuous apixaban has not been tested. Methods and results: We compared continuous apixaban (5 mg b.i.d.) to vitamin K antagonists (VKA, international normalized ratio 2-3) in atrial fibrillation pa...

  14. Time to implement fitness and reduction of fatness in atrial fibrillation therapy

    NARCIS (Netherlands)

    Van Gelder, Isabelle C.; Hobbelt, Anne H.; Brugemann, Johan; Rienstra, Michiel

    This editorial refers to ‘Self-reported physical activity and major adverse events in patients with atrial fibrillation: a report from the EURObservational Research Programme Pilot Survey on Atrial Fibrillation (EORP-AF) General Registry’ by M. Proietti et al. , doi:10.1093/europace/euw150. Atrial

  15. Warfarin for the prevention of systemic embolism in patients with non-valvular atrial fibrillation

    DEFF Research Database (Denmark)

    Andersen, L V; Vestergaard, P; Deichgraeber, P

    2008-01-01

    Warfarin for stroke prevention in patients with atrial fibrillation (AF) is well documented. However, it has not been examined in the prevention of systemic embolism.......Warfarin for stroke prevention in patients with atrial fibrillation (AF) is well documented. However, it has not been examined in the prevention of systemic embolism....

  16. Heat-induced whey protein isolate fibrils: Conversion, hydrolysis, and disulphide bond formation

    NARCIS (Netherlands)

    Bolder, S.G.; Vasbinder, A.; Sagis, L.M.C.; Linden, van der E.

    2007-01-01

    Fibril formation of individual pure whey proteins and whey protein isolate (WPI) was studied. The heat-induced conversion of WPI monomers into fibrils at pH 2 and low ionic strength increased with heating time and protein concentration. Previous studies, using a precipitation method, size-exclusion

  17. J-shaped association between QTc interval duration and the risk of atrial fibrillation

    DEFF Research Database (Denmark)

    Nielsen, Jonas Bille; Graff, Claus; Pietersen, Adrian

    2013-01-01

    The aim of this study was to investigate whether the heart rate-corrected QT (QTc) interval on the electrocardiogram (ECG) is associated with the onset of atrial fibrillation (AF).......The aim of this study was to investigate whether the heart rate-corrected QT (QTc) interval on the electrocardiogram (ECG) is associated with the onset of atrial fibrillation (AF)....

  18. Lessons from comparative studies of atrial fibrillation in dog, man and horse

    NARCIS (Netherlands)

    Meijler, F.L.; Tweel, I. van der; Herbschleb, J.N.; Heethaar, R.M.; Borst, C.

    1985-01-01

    Since its first description in 1903 by Hering, the irregularity of the heart beat has been the most striking characteristic of atrial fibrillation and has been subject of many studies. To quote Selzer, "Atrial fibrillation is the grandfather of cardiac arrhythmias." It is an arrhythmia that 1)

  19. Systolic and Diastolic Function by Tissue Doppler Imaging Predicts Mortality in Patients with Atrial Fibrillation

    DEFF Research Database (Denmark)

    Dons, Maria; BieringSørensen, Tor; Jensen, Jan Skov

    2015-01-01

    AIM: Tissue Doppler Imaging (TDI) detects early signs of left ventricular dysfunction. The prognostic potential of TDI in patients with atrial fibrillation (AF) has, however, not yet been clarified. This study evaluates the prognostic value of TDI in patients with atrial fibrillation. METHODS...

  20. Cardiovascular exercise and burden of arrhythmia in patients with atrial fibrillation

    DEFF Research Database (Denmark)

    Skielboe, Ane Katrine; Bandholm, Thomas Quaade; Hakmann, Stine

    2017-01-01

    BACKGROUND: Physical activity at moderate-high intensity is recommended to prevent lifestyle diseases. Patients with atrial fibrillation are at risk of a sedentary lifestyle due to fear of exercise-induced episodes of atrial fibrillation. The burden of arrhythmia can be reduced by physical exercise...

  1. The spectrum of thyroid disease and risk of new onset atrial fibrillation

    DEFF Research Database (Denmark)

    Selmer, Christian; Olesen, Jonas Bjerring; Hansen, Morten Lock

    2012-01-01

    To examine the risk of atrial fibrillation in relation to the whole spectrum of thyroid function in a large cohort of patients.......To examine the risk of atrial fibrillation in relation to the whole spectrum of thyroid function in a large cohort of patients....

  2. Essential Oils May Lead α-Synuclein towards Toxic Fibrils Formation

    Directory of Open Access Journals (Sweden)

    Dina Morshedi

    2016-01-01

    Full Text Available α-Synuclein (α-Syn fibrillation links with Parkinson’s disease (PD and several related syndromes. It is believed that exposure to the factors which promote fibrillation may induce and progress such neurodegenerative diseases (NDs. Herein, the effects of some wildly used essential oils including Myrtus communis (M. communis on α-Syn fibrillation were examined. M. communis particularly increased α-Syn fibrillation in a concentration dependent manner. Given that applications of M. communis are very extensive in Asian societies, especially Zoroastrians, this study was extended towards its role on α-Syn fibrillation/cytotoxicity. By using a unilamellar vesicle, it was shown that the aggregated species with tendency to perturb membrane were increased in the presence of M. communis. In this regard, the cytotoxicity of α-Syn on SH-SH5Y cells was also increased significantly. Inappropriately, the effects of fibrillation inhibitors, baicalein and cuminaldehyde, were modulated in the presence of M. communis. However, major components of M. communis did not induce fibrillation and also the effect of M. communis was limited on other fibrinogenic proteins. Assuming that essential oils have the ability to pass through the blood brain barrier (BBB along with the popular attention on aromatherapy for the incurable ND, these findings suggest an implementation of fibrillation tests for essential oils.

  3. Insulin fibrillation: The influence and coordination of Zn2+

    DEFF Research Database (Denmark)

    Frankær, Christian Grundahl; Sønderby, Pernille; Bang, Maria Blanner

    2017-01-01

    fibrils has been debated for some years. We have therefore investigated the influence and binding geometry of zinc in fibrillated insulin using extended X-ray absorption fine-structure and X-ray absorption near-edge structure spectroscopy. The results were validated with fibre diffraction, Transmission...

  4. A new LMS algorithm for analysis of atrial fibrillation signals.

    Science.gov (United States)

    Ciaccio, Edward J; Biviano, Angelo B; Whang, William; Garan, Hasan

    2012-03-26

    A biomedical signal can be defined by its extrinsic features (x-axis and y-axis shift and scale) and intrinsic features (shape after normalization of extrinsic features). In this study, an LMS algorithm utilizing the method of differential steepest descent is developed, and is tested by normalization of extrinsic features in complex fractionated atrial electrograms (CFAE). Equations for normalization of x-axis and y-axis shift and scale are first derived. The algorithm is implemented for real-time analysis of CFAE acquired during atrial fibrillation (AF). Data was acquired at a 977 Hz sampling rate from 10 paroxysmal and 10 persistent AF patients undergoing clinical electrophysiologic study and catheter ablation therapy. Over 24 trials, normalization characteristics using the new algorithm with four weights were compared to the Widrow-Hoff LMS algorithm with four tapped delays. The time for convergence, and the mean squared error (MSE) after convergence, were compared. The new LMS algorithm was also applied to lead aVF of the electrocardiogram in one patient with longstanding persistent AF, to enhance the F wave and to monitor extrinsic changes in signal shape. The average waveform over a 25 s interval was used as a prototypical reference signal for matching with the aVF lead. Based on the derivation equations, the y-shift and y-scale adjustments of the new LMS algorithm were shown to be equivalent to the scalar form of the Widrow-Hoff LMS algorithm. For x-shift and x-scale adjustments, rather than implementing a long tapped delay as in Widrow-Hoff LMS, the new method uses only two weights. After convergence, the MSE for matching paroxysmal CFAE averaged 0.46 ± 0.49 μV(2)/sample for the new LMS algorithm versus 0.72 ± 0.35 μV(2)/sample for Widrow-Hoff LMS. The MSE for matching persistent CFAE averaged 0.55 ± 0.95 μV(2)/sample for the new LMS algorithm versus 0.62 ± 0.55 μV(2)/sample for Widrow-Hoff LMS. There were no significant differences in estimation

  5. A new LMS algorithm for analysis of atrial fibrillation signals

    Directory of Open Access Journals (Sweden)

    Ciaccio Edward J

    2012-03-01

    Full Text Available Abstract Background A biomedical signal can be defined by its extrinsic features (x-axis and y-axis shift and scale and intrinsic features (shape after normalization of extrinsic features. In this study, an LMS algorithm utilizing the method of differential steepest descent is developed, and is tested by normalization of extrinsic features in complex fractionated atrial electrograms (CFAE. Method Equations for normalization of x-axis and y-axis shift and scale are first derived. The algorithm is implemented for real-time analysis of CFAE acquired during atrial fibrillation (AF. Data was acquired at a 977 Hz sampling rate from 10 paroxysmal and 10 persistent AF patients undergoing clinical electrophysiologic study and catheter ablation therapy. Over 24 trials, normalization characteristics using the new algorithm with four weights were compared to the Widrow-Hoff LMS algorithm with four tapped delays. The time for convergence, and the mean squared error (MSE after convergence, were compared. The new LMS algorithm was also applied to lead aVF of the electrocardiogram in one patient with longstanding persistent AF, to enhance the F wave and to monitor extrinsic changes in signal shape. The average waveform over a 25 s interval was used as a prototypical reference signal for matching with the aVF lead. Results Based on the derivation equations, the y-shift and y-scale adjustments of the new LMS algorithm were shown to be equivalent to the scalar form of the Widrow-Hoff LMS algorithm. For x-shift and x-scale adjustments, rather than implementing a long tapped delay as in Widrow-Hoff LMS, the new method uses only two weights. After convergence, the MSE for matching paroxysmal CFAE averaged 0.46 ± 0.49μV2/sample for the new LMS algorithm versus 0.72 ± 0.35μV2/sample for Widrow-Hoff LMS. The MSE for matching persistent CFAE averaged 0.55 ± 0.95μV2/sample for the new LMS algorithm versus 0.62 ± 0.55μV2/sample for Widrow

  6. Psoriasis is associated with subsequent atrial fibrillation in hypertensive patients with left ventricular hypertrophy

    DEFF Research Database (Denmark)

    Bang, Casper N; Okin, Peter M; Køber, Lars

    2014-01-01

    BACKGROUND: Inflammation contributes to the pathogenesis of psoriasis as well as atrial fibrillation. The impact of psoriasis and its association with new-onset atrial fibrillation was assessed in hypertensive patients with left ventricular hypertrophy (LVH). METHODS: The predictive value...... or developed psoriasis and new-onset atrial fibrillation occurred in 506 patients (7.1%) during a mean follow-up of 4.7 ± 1.1 years. At baseline, the psoriasis patients were younger (65 ± 7 vs. 67 ± 7 years) and had less left ventricle hypertrophy by ECG Sokolow-Lyon voltage (27.6 ± 9.7 vs. 30.1 ± 10.4 mm...... of baseline or incident psoriasis for new-onset atrial fibrillation was evaluated in 7099 hypertensive patients with electrocardiographic LVH with no history of atrial fibrillation or other cardiovascular disease, in sinus rhythm on their baseline electrocardiogram. RESULTS: A total of 154 patients (2.2%) had...

  7. NONPOTENTIALITY OF CHROMOSPHERIC FIBRILS IN NOAA ACTIVE REGIONS 11092 AND 9661

    International Nuclear Information System (INIS)

    Jing Ju; Yuan Yuan; Xu Yan; Wang Haimin; Reardon, Kevin; Wiegelmann, Thomas

    2011-01-01

    In this paper, we present a method to automatically segment chromospheric fibrils from Hα observations and further identify their orientation. We assume that chromospheric fibrils are aligned with the magnetic field. By comparing the orientation of the fibrils with the azimuth of the embedding chromospheric magnetic field extrapolated from a potential field model, the shear angle, a measure of nonpotentiality, along the fibrils is readily deduced. Following this approach, we make a quantitative assessment of the nonpotentiality of fibrils in two NOAA active regions (ARs): (1) the relatively simple AR 11092, observed with very high resolution by Interferometric Bidimensional Spectrometer, and (2) a β-γ-δ AR 9661, observed with median resolution by Big Bear Solar Observatory before and after an X1.6 flare.

  8. Polymorphism, metastable species and interconversion: the many states of glucagon fibrils

    DEFF Research Database (Denmark)

    Ghodke, Shirin D; Jensen, Grethe Vestergaard; Svane, Anna Sigrid P.

    2014-01-01

    physicochemical conditions such as high temperature, pressure, mechanical and chemical stress. Factors such as peptide concentration, accessible surface area, surface hydration of the glucagon molecular state, contact surface, temperature and ionic strength all contribute to fibrillar structure and stability...... fibril upon incubation at elevated temperatures (but not vice versa), indicating that fibrils are fundamentally malleable if they have not attained the most stable fibrillar state. While the effect of pressure on glucagon is complex (accelerating fibrillation at intermediate pressures and decelerating...... it at higher pressures), the thermal expansion coefficients obtained from these studies agree well with our previous calorimetric studies to reveal reduced or increased hydration of fibrils (leading to reduced or increased stability) depending on fibrillation conditions. Finally, we report...

  9. Conjugated Quantum Dots Inhibit the Amyloid β (1–42 Fibrillation Process

    Directory of Open Access Journals (Sweden)

    Garima Thakur

    2011-01-01

    Full Text Available Nanoparticles have enormous potential in diagnostic and therapeutic studies. We have demonstrated that the amyloid beta mixed with and conjugated to dihydrolipoic acid- (DHLA capped CdSe/ZnS quantum dots (QDs of size approximately 2.5 nm can be used to reduce the fibrillation process. Transmission electron microscopy (TEM and atomic force microscopy (AFM were used as tools for analysis of fibrillation. There is a significant change in morphology of fibrils when amyloid β (1–42 (Aβ (1–42 is mixed or conjugated to the QDs. The length and the width of the fibrils vary under modified conditions. Thioflavin T (ThT fluorescence supports the decrease in fibril formation in presence of DHLA-capped QDs.

  10. Angiotensinogen and ACE gene polymorphisms and risk of atrial fibrillation in the general population

    DEFF Research Database (Denmark)

    Ravn, Lasse S; Benn, Marianne; Nordestgaard, Børge G

    2008-01-01

    OBJECTIVES: The renin-angiotensin system may play a role in the pathogenesis of atrial fibrillation, and renin-angiotensin system blockers reduce the risk of atrial fibrillation. We hypothesized that polymorphisms in the angiotensinogen and angiotensin-converting enzyme (ACE) genes encoding...... in the ACE gene; rare allele frequencies were 0.16, 0.40, 0.12, 0.41, and 0.49, respectively. Participants had sinus rhythm at inclusion. During 26 years of follow-up, 968 individuals developed atrial fibrillation. Multifactorially adjusted hazard ratios for atrial fibrillation for a-20c ac and cc versus aa...... proteins in this system predict risk of atrial fibrillation. METHODS AND RESULTS: We genotyped 9235 individuals from the Danish general population, The Copenhagen City Heart Study, for the a-20c, g-6a, T174M, and M235T polymorphisms in the angiotensinogen gene and the insertion/deletion (I/D) polymorphism...

  11. Probability of atrial fibrillation after ablation: Using a parametric nonlinear temporal decomposition mixed effects model.

    Science.gov (United States)

    Rajeswaran, Jeevanantham; Blackstone, Eugene H; Ehrlinger, John; Li, Liang; Ishwaran, Hemant; Parides, Michael K

    2018-01-01

    Atrial fibrillation is an arrhythmic disorder where the electrical signals of the heart become irregular. The probability of atrial fibrillation (binary response) is often time varying in a structured fashion, as is the influence of associated risk factors. A generalized nonlinear mixed effects model is presented to estimate the time-related probability of atrial fibrillation using a temporal decomposition approach to reveal the pattern of the probability of atrial fibrillation and their determinants. This methodology generalizes to patient-specific analysis of longitudinal binary data with possibly time-varying effects of covariates and with different patient-specific random effects influencing different temporal phases. The motivation and application of this model is illustrated using longitudinally measured atrial fibrillation data obtained through weekly trans-telephonic monitoring from an NIH sponsored clinical trial being conducted by the Cardiothoracic Surgery Clinical Trials Network.

  12. Picosecond dissociation of amyloid fibrils with infrared laser: A nonequilibrium simulation study

    Energy Technology Data Exchange (ETDEWEB)

    Hoang Viet, Man; Roland, Christopher, E-mail: cmroland@ncsu.edu; Sagui, Celeste, E-mail: sagui@ncsu.edu [Department of Physics, North Carolina State University, Raleigh, North Carolina 27695-8202 (United States); Derreumaux, Philippe; Nguyen, Phuong H., E-mail: phuong.nguyen@ibpc.fr [Laboratoire de Biochimie Théorique, UPR 9080, CNRS Université Denis Diderot, Sorbonne Paris Cité IBPC, 13 rue Pierre et Marie Curie, 75005 Paris (France); Li, Mai Suan [Institute of Physics, Polish Academy of Sciences, Al. Lotnikow 32/46, 02-668 Warsaw (Poland); Institute for Computational Science and Technology, SBI Building, Quang Trung Software City, Tan Chanh Hiep Ward, District 12, Ho Chi Minh City (Viet Nam)

    2015-10-21

    Recently, mid-infrared free-electron laser technology has been developed to dissociate amyloid fibrils. Here, we present a theoretical framework for this type of experiment based on laser-induced nonequilibrium all-atom molecular dynamics simulations. We show that the fibril is destroyed due to the strong resonance between its amide I vibrational modes and the laser field. The effects of laser irradiation are determined by a balance between fibril formation and dissociation. While the overall rearrangements of the fibril finish over short time scales, the interaction between the peptides and the solvent continues over much longer times indicating that the waters play an important role in the dissociation process. Our results thus provide new insights into amyloid fibril dissociation by laser techniques and open up new venues to investigate the complex phenomena associated with amyloidogenesis.

  13. Intracellular Calcium Dynamics and Autonomic Stimulation in Atrial Fibrillation: Mechanisms and Implications

    Directory of Open Access Journals (Sweden)

    Chung-Chuan Chou, MD

    2008-01-01

    Full Text Available While atrial fibrillation is characterized by the co-existence of multiple activation waves within the atria, rapid activations in the pulmonary veins play an important role for the initiation and maintenance of atrial fibrillation. In addition to reentry, non-reentrant mechanisms resulting from abnormal intracellular calcium handling and intracellular calcium overload can also be responsible for these rapid activations in the pulmonary veins. Meanwhile, alterations of autonomic tone, involving both the sympathetic and parasympathetic nervous system, have been implicated in initiating paroxysmal atrial fibrillation. But the effectiveness of autonomic modulation as an adjunctive therapeutic strategy to catheter ablation of atrial fibrillation has been inconsistent. The interactions between the autonomic nervous system and atrial fibrillation are more complex than currently understood and further mechanistic and clinical studies are warranted.

  14. Atrial Fibrillation and Coronary Bypass Surgery – What Can Be Risk Factors for its' Appearance?

    Directory of Open Access Journals (Sweden)

    Slavenka Štraus

    2010-02-01

    Full Text Available The main goal of our study was to evalúate possible perioperative risk factors for occurrence of atrial fibrillation in the postoperative period in patients after CABG operations. The study included 140 patients after CABG, divided into two groups - Group I - 64 patients with new onset of POAF and Group II - 76 patients without postoperative atrial fibrillation occurrence. In both groups possible risk factors for atrial fibrillation onset (preoperative and postoperative were analyzed.Results showed that we can predict new onset of atrial fibrillation after CABG if the following preoperative factors are present - low ejection fraction (less than 40%, LAd > 40mm, higher body mass index (BMI over 30, presence of COPD and older age. Important perioperative factors for onset of atrial fibrillation in our study were longer extracorporeal circulation, increased dose/number of inotropic drugs, blood transfusion and elevated WBC count postoperatively.

  15. Atrial and ventricular function after cardioversion of atrial fibrillation.

    Science.gov (United States)

    Xiong, C.; Sonnhag, C.; Nylander, E.; Wranne, B.

    1995-01-01

    OBJECTIVE--Previous studies on atrial recovery after cardioversion of atrial fibrillation have not taken into account new knowledge about the pathophysiology of transmitral and transtricuspid flow velocity patterns. It is possible to shed further light on this problem if atrioventricular inflow velocity, venous filling pattern, and atrioventricular annulus motion are recorded and interpreted together. DESIGN--Prospective examinations of mitral and tricuspid transvalvar flow velocities, superior caval and pulmonary venous filling, and mitral and tricuspid annulus motion were recorded using Doppler echocardiography. Examinations were performed before and 24 hours, 1 month, and 20 months after cardioversion. SETTING--Tertiary referral centre for cardiac disease with facilities for invasive and non-invasive investigation. PATIENTS--16 patients undergoing cardioversion of atrial fibrillation in whom sinus rhythm had persisted for 24 hours or more. RESULTS--Before conversion there was no identifiable A wave in transvalvar flow recordings. The total motion of the tricuspid and mitral annulus was subnormal and there was no identifiable atrial component. Venous flow patterns in general showed a low systolic velocity. After conversion, A waves and atrial components were seen in all patients and increased significantly (P atrial components, an increased systolic component of venous inflow, an increased A wave velocity, and a decreased E/A ratio of the transvalvar velocity curves. The ventricular component of annulus motion was unchanged. Changes in general occurred earlier on the right side than the left. CONCLUSIONS--This study indicates that, in addition to the previously known electromechanical dissociation of atrial recovery that exists after cardioversion of atrial fibrillation, there may also be a transient deterioration of ventricular function modulating the transvalvar inflow velocity recordings. Function on the right side generally becomes normal earlier than on the

  16. Therapeutical considerations in associated atrial fibrillation and heart failure.

    Science.gov (United States)

    Mitu, O; Mitu, F; Constantin, S; Cojocaru, Elena; Leon, Maria-Magdalena

    2014-01-01

    Atrial fibrillation is a supraventricular tachyarrhythmia very common in medical practice, often associated with heart failure. Pathophysiological relationship between atrial fibrillation and heart failure is in the attention of numerous case studies, being incomplete elucidated. We made a retrospective study on patients with both diseases, hospitalized in Cardiovascular Rehabilitation Hospital, Iasi, during 01.01.2013 - 31.12.2013. The obtained data allowed the classification of patients according to gender distribution, age groups, area of origin, clinical aspects, and association with other diseases, instituted treatment and appreciation of CHADS2 score. Data interpretation was performed with appropriate statistical methods. We found a higher frequency of the disease among male patients, male: female ratio being 2:1; the most of the patients lived in urban area. The pick of diseases incidence was in patients over 65 years with a total percentage of 70.84% of cases. We noted that the most common symptoms were exertional dyspnea (in all patients), palpitations, dizziness, headache, fatigue, asthenia, dyspnea at rest and pain/chest pressure. In our study, the majority of patients received the beta-blocker--digoxin combination (46 patients, 40 patients respectively). The coexistence of the two disorders could be explained by identifying common risk factors. Beta blockers should be the first therapeutic option in patients with chronic heart failure and atrial fibrillation because they have the effect of controlling heart rate and improve survival in patients with these disorders. Meanwhile, digoxin is a drug, only certain conditions of high accuracy monitoring; whose major clinical indications are heart failure and atrial rhythm disturbances.

  17. A new therapeutic strategy for electrical cardioversion of atrial fibrillation.

    Science.gov (United States)

    de Luca, I; Sorino, M; Del Salvatore, B; de Luca, L

    2001-11-01

    The conventional approach to cardioversion of atrial fibrillation includes a period of anticoagulation with oral anticoagulant therapy (OAT) extending from 3 weeks precardioversion to 4 weeks postcardioversion. The protocol of rapid anticoagulation (such as that of the ACUTE study) consists of a precardioversion transesophageal echocardiography (TEE) followed by OAT for 4 weeks. In the last few years low-molecular-weight heparins have established themselves as a safe and efficacious alternative to traditional antithrombotic therapies. The aim of this study was to demonstrate that the exclusion of thrombi by precardioversion TEE together with the exclusion of atrial stunning by a second TEE performed after 1 week, to date not suggested in the literature, could reduce to 7 days the period of pericardioversion anticoagulation. This therapy would be carried out using low-molecular-weight heparins with no need for biological monitoring and with the possibility of self-administration. We have studied 57 consecutive patients who had atrial fibrillation or flutter with a history of atrial fibrillation lasting > 48 hours. All patients received enoxaparin at a dosage of 100 IU antiXa/kg twice daily before undergoing multiplane TEE. Previous informed consent and ethical committee authorization had been obtained. Twenty-four hours following TEE, in the absence of thrombi and/or spontaneous moderate/severe echocontrast in the atrial chambers, the patients underwent electrical cardioversion and were discharged within 24 hours of sinus rhythm restoration. These patients were prescribed enoxaparin at the indicated dosage twice daily until TEE, performed in an outpatients setting 7 days following cardioversion. In the absence of thrombi and/or atrial and/or left atrial appendage stunning, OAT was terminated. Enoxaparin was associated with OAT for the following 3 weeks if any of the following signs of stunning were present: A wave inferior to the normal value for age at transmitral

  18. Prospective randomized evaluation of the watchman left atrial appendage closure device in patients with atrial fibrillation versus long-term warfarin therapy: The PREVAIL trial.

    Science.gov (United States)

    Belgaid, Djouhar Roufeida; Khan, Zara; Zaidi, Mariam; Hobbs, Adrian

    2016-09-15

    Assessing the safety and effectiveness of left atrial appendage (LAA) (pouch found in the upper chambers of the heart) occlusion, using the Watchman device compared to long term warfarin therapy (drug that reduces clot formation), in preventing the risk of stroke in patients with atrial fibrillation (most common type of irregular heart beat). 90% of strokes in atrial fibrillation arise from clots forming in this pouch. By mechanically blocking it using the device less clots are suggested to be formed. This is an alternative to taking warfarin especially in patients who cannot take it. 50 sites in the United States enrolled 407 participants. After being randomly allocated, the device group had 269 participants and warfarin group (comparator)had 138 participants. Patients with atrial fibrillation and at high risk of stroke were randomly allocated a group after they were deemed eligible. Patients in the device group had to take warfarin and aspirin for 45days till the complete closure of the LAA. The oral anticoagulant was followed by dual antiplatelet therapy until 6months and then ASA. Patients in the warfarin group have to take it for life and were continually monitored. The study ran for 26months. The trial assessed the rate of adverse events using three endpoints: The PREVAIL trial was not designed to show superiority, but non-inferiority. It met the safety endpoint and one efficacy endpoint for the watchman device compared to long term warfarin for overall efficacy of the device. The results established that LAA occlusion is not worse than warfarin intake for the prevention of stroke more than 1week after randomization. Compared to previous trials, the safety of the device has also improved. LAA occlusion is a reasonable alternative to chronic warfarin therapy in stroke prevention for patients with atrial fibrillation. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  19. The immediate future for the medical treatment of atrial fibrillation

    DEFF Research Database (Denmark)

    Pedersen, Ole Dyg; Brendorp, Bente; Køber, Lars

    2002-01-01

    ) the rhythm causes loss of atrioventricular synchrony, which reduces diastolic filling and may lead to heart failure; and iii) atrial contraction is lost leading to stagnant blood that again may lead to atrial thrombi and peripheral embolism. Thus, the treatment of atrial fibrillation is focused...... on the maintenance of sinus rhythm, rate control and prevention of embolism. For the maintenance of sinus rhythm, all drugs under current development are potassium channel blockers; the so-called class III anti-arrhythmic drugs. Those which have been further investigated appear to be valuable for maintenance...

  20. Entropy measurements in paroxysmal and persistent atrial fibrillation

    International Nuclear Information System (INIS)

    Cervigón, R; Moreno, J; Pérez-Villacastín, J; Reilly, R B; Millet, J; Castells, F

    2010-01-01

    Recent studies on atrial fibrillation (AF) have identified different activation patterns in paroxysmal and persistent AF. In this study, bipolar intra-atrial registers from 28 patients (14 paroxysmal AF and 14 persistent AF) were analyzed in order to find out regional differences in the organization in both types of arrhythmias. The organization of atrial electrical activity was assessed in terms of nonlinear parameters, such as entropy measurements. Results showed differences between the atrial chambers with a higher disorganization in the left atrium in paroxysmal AF patients and a more homogenous behavior along the atria in persistent AF patients

  1. Cardioversion for atrial fibrillation in current European practice

    DEFF Research Database (Denmark)

    Hernández-Madrid, Antonio; Svendsen, Jesper Hastrup; Lip, Gregory Y.H.

    2013-01-01

    This survey was conducted to provide an insight into the current clinical practice regarding the use of cardioversion for atrial fibrillation (AF) in Europe. Responses were received from 57 centres across Europe, 71.9% of which were university hospitals. For electrical cardioversion, general...... anaesthesia was managed by an anaesthesiologist in 73.9% of centres and by a cardiologist in 37%. In the majority of centres, electrical cardioversion was performed using a biphasic defibrillator (85.1%). Antiarrhythmic drugs were routinely prescribed prior to electrical cardioversion by 54.3% of hospitals...

  2. Plasma YKL-40, a new biomarker for atrial fibrillation?

    DEFF Research Database (Denmark)

    Henningsen, Kristoffer Mads; Therkelsen, Susette Krohn; Johansen, Julia Sidenius

    2009-01-01

    AIMS: The aim of this study was to determine changes in a new potential biomarker plasma YKL-40 in patients with atrial fibrillation (AF) before and after electrical cardioversion (CV). METHODS AND RESULTS: Plasma concentrations of YKL-40 were measured in 56 patients (mean age 65 years, range 34......-84) with persistent AF (lasting mean 128 days, range 14-960), in 19 age-matched patients with permanent AF, and in 19 healthy subjects. The patients with persistent AF underwent CV. Plasma YKL-40 was measured prior to CV, and at follow-up after 24 h, 30 and 180 days. Patients with persistent AF had lower plasma YKL...

  3. Mass Determination of Entire Amyloid Fibrils by Using Mass Spectrometry.

    Science.gov (United States)

    Doussineau, Tristan; Mathevon, Carole; Altamura, Lucie; Vendrely, Charlotte; Dugourd, Philippe; Forge, Vincent; Antoine, Rodolphe

    2016-02-12

    Amyloid fibrils are self-assembled protein structures with important roles in biology (either pathogenic or physiological), and are attracting increasing interest in nanotechnology. However, because of their high aspect ratio and the presence of some polymorphism, that is, the possibility to adopt various structures, their characterization is challenging and basic information such as their mass is unknown. Here we show that charge-detection mass spectrometry, recently developed for large self-assembled systems such as viruses, provides such information in a straightforward manner. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  4. Exercise-Induced Ventricular Fibrillation: Seven Years Follow-Up

    Directory of Open Access Journals (Sweden)

    Gökmen Gemici

    2011-11-01

    Full Text Available We present a 7-year follow-up of a 55-year-old male who experienced ventricular fibrillation during the recovery period of exercise testing and refused implantation of an ICD. Normal left ventricular systolic function was found on echocardiographic examination, and coronary angiography revealed only a side branch disease with a vessel diameter of less than 2 millimeters. The patient was discharged on metoprolol and ASA in addition to his previous treatment with lisinopril and simvastatin. Outpatient cardiac evaluation by repeated 24-hour ECG monitorizations (Holter revealed normal findings. On follow up visits every six months for the past seven years, the patient was found to be asymptomatic.

  5. Atrial Fibrillation - A Common Ground for Neurology and Cardiology.

    Science.gov (United States)

    Abukhalil, Fawzi; Bodhit, Aakash; Cai, Peter Y; Ansari, Saeed; Thenkabail, Spandana; Ganji, Sarah; Saravanapavan, Pradeepan; Chandra Shekhar, Chandana; Waters, Michael F; Beaver, Thomas M; Shushrutha Hedna, Vishnumurthy

    2013-01-01

    Atrial fibrillation (AF) has a huge impact on clinical stroke because it is the primary cause of cardio-embolism, which constitutes ~20% of all strokes. As a result, there is a great need to explore safer and more effective primary and secondary prophylactic agents. In this article, we discuss the overlapping issues pertaining to AF from both a neurology and cardiology standpoint. We focus on the dynamic interplay of neurovascular and cardiovascular diseases in relation to AF, traditional and novel risk factors for AF leading to stroke, impact of AF on cognitive decline, and current upstream medical and surgical options for embolism prophylaxis.

  6. CT imaging of complications of catheter ablation for atrial fibrillation

    International Nuclear Information System (INIS)

    Shroff, G.S.; Guirguis, M.S.; Ferguson, E.C.; Oldham, S.A.A.; Kantharia, B.K.

    2014-01-01

    The complication rate following radiofrequency catheter ablation for atrial fibrillation is low (<5%). Complications include pericardial effusion, cardiac tamponade, pulmonary vein stenosis, oesophageal ulceration or perforation, atrio-oesophageal fistula formation, stroke/transient ischaemic attack, phrenic nerve injury, haematoma at the puncture site, and femoral arteriovenous fistula. Among available imaging tools, computed tomography (CT) can be very useful in diagnosing complications of the procedure, particularly in the subacute and delayed stages after ablation. This review illustrates CT imaging of several of the common and uncommon complications of radiofrequency catheter ablation

  7. Strain-induced internal fibrillation in looped aramid filaments

    DEFF Research Database (Denmark)

    Pauw, Brian Richard; Vigild, Martin Etchells; Mortensen, Kell

    2010-01-01

    in the scattering pattern is observed. One model capable of describing the intensity is a model of stacked cylinders. These cylinders could be part of the fibrillar structure present in the PPTA fibres, which consist of cylinder- to tape-like objects, the presence of which is supported by SEM images. One...... hypothetical physical interpretation presented here for the appearance of a regular internal structure is the occurrence of fibrillar separation in regions undergoing axially compressive strain, and the appearance of strain relief/slip planes between packs of fibrils in regions undergoing tensile strain...

  8. Fibril deformation under load of the rabbit Achilles tendon and medial collateral ligament femoral entheses.

    Science.gov (United States)

    Sevick, Johnathan L; Abusara, Ziad; Andrews, Stephen H; Xu, Minjia; Khurshid, Saad; Chatha, Jansher; Hart, David A; Shrive, Nigel G

    2018-04-10

    Microscopic visualization under load of the region connecting ligaments/tendons to bone, the enthesis, has been performed previously; however, specific investigation of individual fibril deformation may add insight to such studies. Detailed visualization of fibril deformation would inform on the mechanical strategies employed by this tissue in connecting two mechanically disparate materials. Clinically, an improved understanding of enthesis mechanics may help guide future restorative efforts for torn or injured ligaments/tendons, where the enthesis is often a point of weakness. In this study, a custom ligament/tendon enthesis loading device was designed and built, a unique method of sample preparation was devised, and second harmonic and two-photon fluorescence microscopy were used to capture the fibril-level load response of the rabbit Achilles tendon and medial collateral ligament femoral entheses. A focus was given to investigation of the mechanical problem of fibril embedment. Resultant images indicate a rapid (occurring over approximately 60 μm) change in fibril orientation at the interface of ligament/tendon and calcified fibrocartilage early in the loading regime, before becoming relatively constant. Such a change in fibril angle helps confirm the materially graded region demonstrated by others, while, in this case, providing additional insight into fibril bending. We speculate that the scale of the mechanical problem (i.e., fibril diameters being on the order of 250 nm) allows fibrils to bend over the small (relative to the imaging field of view, but large relative to fibril diameter) distances observed; thus, potentially lessening required embedment lengths. Nevertheless, this behavior merits further investigation to be confirmed. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.

  9. Surface characterization of insulin protofilaments and fibril polymorphs using tip-enhanced Raman spectroscopy (TERS).

    Science.gov (United States)

    Kurouski, Dmitry; Deckert-Gaudig, Tanja; Deckert, Volker; Lednev, Igor K

    2014-01-07

    Amyloid fibrils are β-sheet-rich protein aggregates that are strongly associated with a variety of neurodegenerative maladies, such as Alzheimer's and Parkinson's diseases. Even if the secondary structure of such fibrils is well characterized, a thorough understanding of their surface organization still remains elusive. Tip-enhanced Raman spectroscopy (TERS) is one of a few techniques that allow the direct characterization of the amino acid composition and the protein secondary structure of the amyloid fibril surface. Herein, we investigated the surfaces of two insulin fibril polymorphs with flat (flat) and left-twisted (twisted) morphology. It was found that the two differ substantially in both amino acid composition and protein secondary structure. For example, the amounts of Tyr, Pro, and His differ, as does the number of carboxyl groups on the respective surfaces, whereas the amounts of Phe and of positively charged amino and imino groups remain similar. In addition, the surface of protofilaments, the precursors of the mature flat and twisted fibrils, was investigated using TERS. The results show substantial differences with respect to the mature fibrils. A correlation of amino acid frequencies and protein secondary structures on the surface of protofilaments and on flat and twisted fibrils allowed us to propose a hypothetical mechanism for the propagation to specific fibril polymorphs. This knowledge can shed a light on the toxicity of amyloids and define the key factors responsible for fibril polymorphism. Finally, this work demonstrates the potential of TERS for the surface characterization of amyloid fibril polymorphs. Copyright © 2014 Biophysical Society. Published by Elsevier Inc. All rights reserved.

  10. Current concepts on ventricular fibrillation: A Vicious Circle of Cardiomyocyte Calcium Overload in the Initiation, Maintenance, and Termination of Ventricular Fibrillation

    Directory of Open Access Journals (Sweden)

    Christian E. Zaugg

    2004-04-01

    Full Text Available Based on recent experimental studies, this review article introduces the novel concept that cardiomyocyte Ca2+ and ventricular fibrillation (VF are mutually related, forming a self-maintaining vicious circle in the initiation, maintenance, and termination of VF. On the one hand, elevated myocyte Ca2+ can cause delayed afterdepolarizations, triggered activity, and consequently life-threatening ventricular tachyarrhythmias in various pathological conditions such as digitalis toxicity, myocardial ischemia, or heart failure. On the other hand, VF itself directly and rapidly causes progressive myocyte Ca2+ overload that maintains VF and renders termination of VF increasingly difficult. Accordingly, energy levels for successful electrical defibrillation (defibrillation thresholds increase as both VF and Ca2+ overload progress. Furthermore, VF-induced myocyte Ca2+ overload can promote re-induction of VF after defibrillation and/or postfibrillatory myocardial dysfunction (postresuscitation stunning due to reduced myofilament Ca2+ responsiveness. The probability of these adverse events is best reduced by early detection and rapid termination of VF to prevent or limit Ca2+ overload. Early additional therapy targeting transsarcolemmal Ca2+ entry, particularly during the first 2 min of VF, may partially prevent myocyte Ca2+ overload and thus, increase the likelihood of successful defibrillation as well as prevent postfibrillatory myocardial dysfunction.

  11. A model of insulin fibrils derived from the x-ray crystal structure of a monomeric insulin (despentapeptide insulin).

    Science.gov (United States)

    Brange, J; Dodson, G G; Edwards, D J; Holden, P H; Whittingham, J L

    1997-04-01

    The crystal structure of despentapeptide insulin, a monomeric insulin, has been refined at 1.3 A spacing and subsequently used to predict and model the organization in the insulin fibril. The model makes use of the contacts in the densely packed despentapeptide insulin crystal, and takes into account other experimental evidence, including binding studies with Congo red. The dimensions of this model fibril correspond well with those measured experimentally, and the monomer-monomer contacts within the fibril are in accordance with the known physical chemistry of insulin fibrils. Using this model, it may be possible to predict mutations in insulin that might alleviate problems associated with fibril formation during insulin therapy.

  12. Solution NMR structure and inhibitory effect against amyloid-β fibrillation of Humanin containing a D-isomerized serine residue

    Energy Technology Data Exchange (ETDEWEB)

    Alsanousi, Nesreen [Institute for Protein Research, Osaka University, 3-2 Yamadaoka, Suita, Osaka 565-0871 (Japan); Sugiki, Toshihiko, E-mail: sugiki@protein.osaka-u.ac.jp [Institute for Protein Research, Osaka University, 3-2 Yamadaoka, Suita, Osaka 565-0871 (Japan); Furuita, Kyoko; So, Masatomo; Lee, Young-Ho; Fujiwara, Toshimichi [Institute for Protein Research, Osaka University, 3-2 Yamadaoka, Suita, Osaka 565-0871 (Japan); Kojima, Chojiro, E-mail: kojima-chojiro-xk@ynu.ac.jp [Institute for Protein Research, Osaka University, 3-2 Yamadaoka, Suita, Osaka 565-0871 (Japan); Graduate School of Engineering, Yokohama National University, Tokiwadai 79-5, Hodogaya-ku, Yokohama 240-8501 (Japan)

    2016-09-02

    Humanin comprising 24 amino acid residues is a bioactive peptide that has been isolated from the brain tissue of patients with Alzheimer's disease. Humanin reportedly suppressed aging-related death of various cells due to amyloid fibrils and oxidative stress. There are reports that the cytoprotective activity of Humanin was remarkably enhanced by optical isomerization of the Ser14 residue from L to D form, but details of the molecular mechanism remained unclear. Here we demonstrated that Humanin D-Ser14 exhibited potent inhibitory activity against fibrillation of amyloid-β and remarkably higher binding affinity for amyloid-β than that of the Humanin wild-type and S14G mutant. In addition, we determined the solution structure of Humanin D-Ser14 by nuclear magnetic resonance (NMR) and showed that D-isomerization of the Ser14 residue enables drastic conformational rearrangement of Humanin. Furthermore, we identified an amyloid-β-binding site on Humanin D-Ser14 at atomic resolution by NMR. These biophysical and high-resolution structural analyses clearly revealed structure–function relationships of Humanin and explained the driving force of the drastic conformational change and molecular basis of the potent anti-amyloid-β fibrillation activity of Humanin caused by D-isomerization of the Ser14 residue. This is the first study to show correlations between the functional activity, tertiary structure, and partner recognition mode of Humanin and may lead to elucidation of the molecular mechanisms of the cytoprotective activity of Humanin. - Highlights: • Humanin D-Ser14 showed the strongest inhibitory activity against Aβ40 fibrillation. • NMR structure of Humanin D-Ser14 was determined in alcohol/water mixture solution. • Humanin D-Ser14 directly bound Aβ40 stronger than Humanin wild-type and Humanin S14G. • Aβ40 and zinc ion binding sites of Humanin D-Ser14 were identified. • Structure around Ser14 of Humanin is critical for Aβ40 binding and

  13. Modulation of human IAPP fibrillation: cosolutes, crowders and chaperones.

    Science.gov (United States)

    Gao, Mimi; Estel, Kathrin; Seeliger, Janine; Friedrich, Ralf P; Dogan, Susanne; Wanker, Erich E; Winter, Roland; Ebbinghaus, Simon

    2015-04-07

    The cellular environment determines the structure and function of proteins. Marginal changes of the environment can severely affect the energy landscape of protein folding. However, despite the important role of chaperones on protein folding, less is known about chaperonal modulation of protein aggregation and fibrillation considering different classes of chaperones. We find that the pharmacological chaperone O4, the chemical chaperone proline as well as the protein chaperone serum amyloid P component (SAP) are inhibitors of the type 2 diabetes mellitus-related aggregation process of islet amyloid polypeptide (IAPP). By applying biophysical methods such as thioflavin T fluorescence spectroscopy, fluorescence anisotropy, total reflection Fourier-transform infrared spectroscopy, circular dichroism spectroscopy and atomic force microscopy we analyse and compare their inhibition mechanism. We demonstrate that the fibrillation reaction of human IAPP is strongly inhibited by formation of globular, amorphous assemblies by both, the pharmacological and the protein chaperones. We studied the inhibition mechanism under cell-like conditions by using the artificial crowding agents Ficoll 70 and sucrose. Under such conditions the suppressive effect of proline was decreased, whereas the pharmacological chaperone remains active.

  14. Fibril orientation redistribution induced by stretching of cellulose nanofibril hydrogels

    International Nuclear Information System (INIS)

    Josefsson, Gabriella; Gamstedt, E. Kristofer; Ahvenainen, Patrik; Mushi, Ngesa Ezekiel

    2015-01-01

    The mechanical performance of materials reinforced by cellulose nanofibrils is highly affected by the orientation of these fibrils. This paper investigates the nanofibril orientation distribution of films of partly oriented cellulose nanofibrils. Stripes of hydrogel films were subjected to different amount of strain and, after drying, examined with X-ray diffraction to obtain the orientation of the nanofibrils in the films, caused by the stretching. The cellulose nanofibrils had initially a random in-plane orientation in the hydrogel films and the strain was applied to the films before the nanofibrils bond tightly together, which occurs during drying. The stretching resulted in a reorientation of the nanofibrils in the films, with monotonically increasing orientation towards the load direction with increasing strain. Estimation of nanofibril reorientation by X-ray diffraction enables quantitative comparison of the stretch-induced orientation ability of different cellulose nanofibril systems. The reorientation of nanofibrils as a consequence of an applied strain is also predicted by a geometrical model of deformation of nanofibril hydrogels. Conversely, in high-strain cold-drawing of wet cellulose nanofibril materials, the enhanced orientation is promoted by slipping of the effectively stiff fibrils

  15. Automatic detection of atrial fibrillation in cardiac vibration signals.

    Science.gov (United States)

    Brueser, C; Diesel, J; Zink, M D H; Winter, S; Schauerte, P; Leonhardt, S

    2013-01-01

    We present a study on the feasibility of the automatic detection of atrial fibrillation (AF) from cardiac vibration signals (ballistocardiograms/BCGs) recorded by unobtrusive bedmounted sensors. The proposed system is intended as a screening and monitoring tool in home-healthcare applications and not as a replacement for ECG-based methods used in clinical environments. Based on BCG data recorded in a study with 10 AF patients, we evaluate and rank seven popular machine learning algorithms (naive Bayes, linear and quadratic discriminant analysis, support vector machines, random forests as well as bagged and boosted trees) for their performance in separating 30 s long BCG epochs into one of three classes: sinus rhythm, atrial fibrillation, and artifact. For each algorithm, feature subsets of a set of statistical time-frequency-domain and time-domain features were selected based on the mutual information between features and class labels as well as first- and second-order interactions among features. The classifiers were evaluated on a set of 856 epochs by means of 10-fold cross-validation. The best algorithm (random forests) achieved a Matthews correlation coefficient, mean sensitivity, and mean specificity of 0.921, 0.938, and 0.982, respectively.

  16. Biophysical aspects and novel treatments of atrial fibrillation.

    Science.gov (United States)

    Gigli, Lorenzo; Rosa, Gian M; Tagliasacchi, Maria I; Bonaventura, Aldo; Liberale, Luca; Montecucco, Fabrizio; Carbone, Federico; Bertero, Giovanni; Brunelli, Claudio

    2017-04-01

    Atrial fibrillation (AF) is a cardiac arrhythmia caused by various mechanisms, such as multiple re-entering wavelets, high frequency activity, and rotor sources. This narrative review was based on papers found on PubMed and MEDLINE up to May 2016. The search terms were "atrial fibrillation" in combination with "catheter ablation, pathophysiology, antiarrhythmic drugs". Antiarrhythmic drugs are the cornerstone of therapy in AF, but their efficacy and safety might have to be improved. In case of failure of pharmacologic therapies, other treatments can be considered. A better understanding of the important role of the pulmonary veins has led to new approaches, such as ablation procedures, which were initially only surgical, while percutaneous options were later added. However, these strategies may present various technical complications also when performed by skilled operators. A promising field of investigation is the genetics of AF, as highlighted by studies on the role of micro-RNA. Relevant improvement on the knowledge of the electrophysiological basis of genesis and maintenance of AF has been done in order to treat a very common arrhythmia, but further studies, as those in the genetics field, can open new challenging therapeutic horizons.

  17. Iodine replition, thyrotoxicosis and fibrillation in Isfahan, Iran

    International Nuclear Information System (INIS)

    Aminorroaya, Ashraf; Rohani, Sina; Sattari, Goshtasb; Haghighi, Sasan; Amini, Masoud

    2004-01-01

    Iodized salt was reintroduced in Iran in 1989. Just before distribution of iodized salt, thyrotoxicosis was observed in 3.7% of the patients with atrial fibrillation (AF) in university teaching hospitals in Isfahan, a centrally located city in Iran. As repletion of iodine may increase the rate of autoimmune thyroid diseases and toxic multinodular goiter, this study was designed to evaluate the rate of thyrotoxicosis in patients with AF in the same hospitals after about a decade of iodide salt consumption. In a case- control study with convenience sampling, 100 patients with AF and an equal number of age and sex matched subjects taking the same medications were selected as case and control groups, respectively in university hospitals in 1997. 8% of patients with atrial fibrillation had overt thyrotoxicosis versus one percent in the control group (odds ratio =8.6, 95% CI =6.5 to 10.7, p<0.02). Thyrotoxicosis in patients with AF was 8 times higher than in control group without AF. In comparison with the period before use of iodized salt, AF more than doubled (8%vs. 3.7%). Thyroid function should be evaluated in all patients older than 40 years of age with AF. The benefits of iodine supplementation are great, but more attention should be paid to the complications of iodine repletion, including thyrotoxicosis and its frequent accompaniment, AF. (author)

  18. What patients want and need to know about atrial fibrillation

    Directory of Open Access Journals (Sweden)

    McCabe PJ

    2011-11-01

    Full Text Available Pamela J McCabe Saint Mary's Hospital, Mayo Clinic, Rochester, MN, USA Abstract: Clinicians in a variety of settings are called upon to care for patients diagnosed with atrial fibrillation (AF, a common chronic condition that affects up to 3 million people in the USA. Evidence-based guidelines provide clinicians with direction for treatment of AF, but recommended content for educating patients and counseling about self-management of AF is not included in published guidelines. When patients believe they have a good understanding of AF they report fewer symptoms, perceive greater control over AF, and attribute less emotional distress to AF. Thus, providing patients with information about AF and how to manage it is important for promoting positive outcomes. The purpose of this article is to offer evidence-based recommendations for content to include in self-management education and counseling for patients with AF. Approaches for educating and counseling patients related to AF pathophysiology, the nature of AF (its cause, consequences, and trajectory, treatments, action plans, and symptom management, and managing the psychosocial challenges of living with AF, are discussed. Keywords: atrial fibrillation, patient education, self-management education, counseling

  19. The effect of point mutations on structure and mechanical properties of collagen-like fibril: A molecular dynamics study

    International Nuclear Information System (INIS)

    Marlowe, Ashley E.; Singh, Abhishek; Yingling, Yaroslava G.

    2012-01-01

    Understanding sequence dependent mechanical and structural properties of collagen fibrils is important for the development of artificial biomaterials for medical and nanotechnological applications. Moreover, point mutations are behind many collagen associated diseases, including Osteogenesis Imperfecta (OI). We conducted a combination of classical and steered atomistic molecular dynamics simulations to examine the effect of point mutations on structure and mechanical properties of short collagen fibrils which include mutations of glycine to alanine, aspartic acid, cysteine, and serine or mutations of hydroxyproline to arginine, asparagine, glutamine, and lysine. We found that all mutations disrupt structure and reduce strength of the collagen fibrils, which may affect the hierarchical packing of the fibrils. The glycine mutations were more detrimental to mechanical strength of the fibrils (WT > Ala > Ser > Cys > Asp) than that of hydroxyproline (WT > Arg > Gln > Asn > Lys). The clinical outcome for glycine mutations agrees well with the trend in reduction of fibril's tensile strength predicted by our simulations. Overall, our results suggest that the reduction in mechanical properties of collagen fibrils may be used to predict the clinical outcome of mutations. Highlights: ► All mutations disrupt structure and bonding pattern and reduce strength of the collagen fibrils. ► Gly based mutations are worst to mechanical integrity of fibrils than that of Hyp. ► Lys and Arg mutations most dramatically destabilize collagen fibril properties. ► Clinical outcome of mutations may be related to the reduced mechanical properties of fibrils.

  20. The effect of point mutations on structure and mechanical properties of collagen-like fibril: A molecular dynamics study

    Energy Technology Data Exchange (ETDEWEB)

    Marlowe, Ashley E.; Singh, Abhishek; Yingling, Yaroslava G., E-mail: yara_yingling@ncsu.edu

    2012-12-01

    Understanding sequence dependent mechanical and structural properties of collagen fibrils is important for the development of artificial biomaterials for medical and nanotechnological applications. Moreover, point mutations are behind many collagen associated diseases, including Osteogenesis Imperfecta (OI). We conducted a combination of classical and steered atomistic molecular dynamics simulations to examine the effect of point mutations on structure and mechanical properties of short collagen fibrils which include mutations of glycine to alanine, aspartic acid, cysteine, and serine or mutations of hydroxyproline to arginine, asparagine, glutamine, and lysine. We found that all mutations disrupt structure and reduce strength of the collagen fibrils, which may affect the hierarchical packing of the fibrils. The glycine mutations were more detrimental to mechanical strength of the fibrils (WT > Ala > Ser > Cys > Asp) than that of hydroxyproline (WT > Arg > Gln > Asn > Lys). The clinical outcome for glycine mutations agrees well with the trend in reduction of fibril's tensile strength predicted by our simulations. Overall, our results suggest that the reduction in mechanical properties of collagen fibrils may be used to predict the clinical outcome of mutations. Highlights: Black-Right-Pointing-Pointer All mutations disrupt structure and bonding pattern and reduce strength of the collagen fibrils. Black-Right-Pointing-Pointer Gly based mutations are worst to mechanical integrity of fibrils than that of Hyp. Black-Right-Pointing-Pointer Lys and Arg mutations most dramatically destabilize collagen fibril properties. Black-Right-Pointing-Pointer Clinical outcome of mutations may be related to the reduced mechanical properties of fibrils.