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The mechanisms of spontaneous termination of reentrant supraventricular tachycardias. - International journal of cardiology
Atrioventricular nodal reentrant tachycardia (AVNRT) and atrioventricular reentrant tachycardia (AVRT) often terminate spontaneously, presumably due to changes in the electrophysiological properties of the reentrant circuit. However, the mechanism of spontaneous termination of these arrhythmias is incompletely understood.We included 70 consecutive patients with reentrant supraventricular tachycardias (35 AVNRT, 35 AVRT) in whom the arrhythmia ended spontaneously during the electrophysiologic study. We determined in each patient the duration of the induced arrhythmia, site of block, beat-to-beat oscillations in tachycardia cycle-length (CL), A-H, H-V, H-A and V-A intervals.In 21/34 (62%) patients with AVNRT and 19/30 (63%) with orthodromic AVRT, tachycardia termination was preceded by progressive increase in tachycardia CL due to prolongation of the A-H interval (Mobitz type-I pattern). In 13/34 patients with AVNRT (38%) and 11/30 with orthodromic AVRT (37%), termination occurred suddenly without a preceding change in CL, with block ensuing retrogradely either in the fast AV nodal pathway or the accessory pathway (Mobitz type-II pattern). In 4/5 patients with antidromic AVRT the tachycardia ended at the retrograde limb with previous prolongation of the VA interval.Spontaneous termination of AVNRT and AVRT is a time-related phenomenon. Despite different pathways being involved in these two reentrant tachycardias, termination can follow antegrade or retrograde block in similar ratio (60% antegradely and 40% retrogradely). Antegrade block is preceded by prolongation of the AH interval (Mobitz type-I), whereas retrograde block occurs unexpectedly in the retrograde limb (Mobitz type-II). Fatigue of conduction appears to be involved in this phenomenon.Copyright Â© 2015 Elsevier Ireland Ltd. All rights reserved.
Babelomics 5.0: functional interpretation for new generations of genomic data. - Nucleic acids research
Babelomics has been running for more than one decade offering a user-friendly interface for the functional analysis of gene expression and genomic data. Here we present its fifth release, which includes support for Next Generation Sequencing data including gene expression (RNA-seq), exome or genome resequencing. Babelomics has simplified its interface, being now more intuitive. Improved visualization options, such as a genome viewer as well as an interactive network viewer, have been implemented. New technical enhancements at both, client and server sides, makes the user experience faster and more dynamic. Babelomics offers user-friendly access to a full range of methods that cover: (i) primary data analysis, (ii) a variety of tests for different experimental designs and (iii) different enrichment and network analysis algorithms for the interpretation of the results of such tests in the proper functional context. In addition to the public server, local copies of Babelomics can be downloaded and installed. Babelomics is freely available at: http://www.babelomics.org.Â© The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.
Identification of potent and selective cathepsin S inhibitors containing different central cyclic scaffolds. - Journal of medicinal chemistry
Starting from the weakly active dual CatS/K inhibitor 5, structure-based design supported by X-ray analysis led to the discovery of the potent and selective (>50,000-fold vs CatK) cyclopentane derivative 22 by exploiting specific ligand-receptor interactions in the S2 pocket of CatS. Changing the central cyclopentane scaffold to the analogous pyrrolidine derivative 57 decreased the enzyme as well as the cell-based activity significantly by 24- and 69-fold, respectively. The most promising scaffold identified was the readily accessible proline derivative (e.g., 79). This compound, with an appealing ligand efficiency (LE) of 0.47, included additional structural modifications binding in the S1 and S3 pockets of CatS, leading to favorable in vitro and in vivo properties. Compound 79 reduced IL-2 production in a transgenic DO10.11 mouse model of antigen presentation in a dose-dependent manner with an ED50 of 5 mg/kg.
Inferring the functional effect of gene expression changes in signaling pathways. - Nucleic acids research
Signaling pathways constitute a valuable source of information that allows interpreting the way in which alterations in gene activities affect to particular cell functionalities. There are web tools available that allow viewing and editing pathways, as well as representing experimental data on them. However, few methods aimed to identify the signaling circuits, within a pathway, associated to the biological problem studied exist and none of them provide a convenient graphical web interface. We present PATHiWAYS, a web-based signaling pathway visualization system that infers changes in signaling that affect cell functionality from the measurements of gene expression values in typical expression microarray case-control experiments. A simple probabilistic model of the pathway is used to estimate the probabilities for signal transmission from any receptor to any final effector molecule (taking into account the pathway topology) using for this the individual probabilities of gene product presence/absence inferred from gene expression values. Significant changes in these probabilities allow linking different cell functionalities triggered by the pathway to the biological problem studied. PATHiWAYS is available at: http://pathiways.babelomics.org/.
Genome Maps, a new generation genome browser. - Nucleic acids research
Genome browsers have gained importance as more genomes and related genomic information become available. However, the increase of information brought about by new generation sequencing technologies is, at the same time, causing a subtle but continuous decrease in the efficiency of conventional genome browsers. Here, we present Genome Maps, a genome browser that implements an innovative model of data transfer and management. The program uses highly efficient technologies from the new HTML5 standard, such as scalable vector graphics, that optimize workloads at both server and client sides and ensure future scalability. Thus, data management and representation are entirely carried out by the browser, without the need of any Java Applet, Flash or other plug-in technology installation. Relevant biological data on genes, transcripts, exons, regulatory features, single-nucleotide polymorphisms, karyotype and so forth, are imported from web services and are available as tracks. In addition, several DAS servers are already included in Genome Maps. As a novelty, this web-based genome browser allows the local upload of huge genomic data files (e.g. VCF or BAM) that can be dynamically visualized in real time at the client side, thus facilitating the management of medical data affected by privacy restrictions. Finally, Genome Maps can easily be integrated in any web application by including only a few lines of code. Genome Maps is an open source collaborative initiative available in the GitHub repository (https://github.com/compbio-bigdata-viz/genome-maps). Genome Maps is available at: http://www.genomemaps.org.
Morphometric of blastomeres in Salmo salar. - Zygote (Cambridge, England)
For Salmo salar, there is a lack of information on the morphology of the first blastomeres formed during embryonic development and which could be used as a diagnostic tool for the first stages of development. The purpose of this investigation, therefore, was to characterize morphometrically the first blastomeres of S. salar. From a pool of eggs incubated at 7.5Â°C, 100 microphotographs of blastodiscs were extracted and analyzed at different incubation periods: 12, 14, 16, 20 or 24 h. Blastodiscs were characterized morphologically after 16, 20 or 24 h incubation, and classified into symmetric or asymmetric groups according to their morphology. The ratio of length (L) versus width (W) of each blastomere was determined, to establish its symmetry. In addition, 20 microphotographs of blastodiscs of normal appearance were analysed morphologically (control blastodisc: CB) for comparison (20 or 24 h). Results show that the first cleavage ends after 16 h of development. Seven categories were established during blastomere characterization: 47% normal (G1); 27% with dispersed margins (G2); 10% unequal (G3); 9% 'pie-shaped' (G4); 3% amorphous (G5); 2% three equal blastomeres and one different one (G6); and 2% with eccentric cleavage (G7). Although the incidence of abnormal cleavage in S. salar is uncertain, there is a potential for some asymmetries to be corrected during embryogenesis to generate viable individuals. More studies are necessary to correlate these abnormal cleavage patterns with indicators of quality in the later stages of embryogenesis in this species, to establish a quality assessment tool for gametes and/or embryos in salmonid species.
Right bundle branch block and middle septal fiber block with or without left anterior fascicular block manifested as aberrant conduction in apparent healthy individuals: Electro-vectorcardiographic characterization. - Journal of electrocardiology
Right bundle branch block (RBBB) evident in the precordial ECG leads may be associated with evidence of left bundle branch involvement in the limb leads. Any of the components of the left bundle can be involved, and this complex interventricular conduction abnormality has previously been described in patients with underlying heart disease.To analyze the electro-vectorcardiographic manifestations of RBBB with left middle septal fiber block (LMSFB), with or without left anterior fascicular block (LAFB) in premature atrial beats of patients without apparent structural heart disease.Twelve patients (8 men/4 women; mean age: 32Â±8years) with premature atrial contractions with this conduction abnormality were included. Surface 12 simultaneous lead ECG recordings and the corresponding vectorcardiographic loops were analyzed.The QRS complexes with RBBB and also LMSFB persisted for between 150 and 190ms. There were no q waves in lead I. The maximum spatial vector (72-86ms) was directed posteriorly, superiorly, and leftward, and the terminal forces were oriented anteriorly, inferiorly and rightward. In 10 patients, small q waves were apparent in leads V1-V2 and the frontal QRS axis was -60Â° and -70Â°, with the 46ms vector located at -50Â°Â±5. All of these patients most probably had LAFB in addition to LMSFB. In two patients, the initial electrical forces were directed anteriorly, inferiorly, and leftward, and the 46ms vector axis in the frontal plane was 6Â° and 11Â°, respectively, indicating absence of LAFB.The combination of RBBB and LMSFB occurring in patients without apparent structural heart disease may be related to the simultaneous occurrence of block of conduction through these components of the Purkinje network. The anterior fascicle of the left bundle may also be involved.Copyright Â© 2013 Elsevier Inc. All rights reserved.
Elevated serum levels of macrophage migration inhibitory factor are associated with progressive chronic cardiomyopathy in patients with Chagas disease. - PloS one
Clinical symptoms of chronic Chagas disease occur in around 30% of the individuals infected with Trypanosoma cruzi and are characterized by heart inflammation and dysfunction. The pathogenesis of chronic chagasic cardiomyopathy (CCC) is not completely understood yet, partially because disease evolution depends on complex host-parasite interactions. Macrophage migration inhibitory factor (MIF) is a pleiotropic proinflammatory cytokine that promotes numerous pathophysiological processes. In the current study, we investigated the link between MIF and CCC progression.Immunohistochemical analysis demonstrated MIF overexpression in the hearts from chronically T. cruzi-infected mice, particularly those showing intense inflammatory infiltration. We also found that MIF exogenously added to parasite-infected murine macrophage cultures is capable of enhancing the production of TNF-Î± and reactive oxygen species, both with pathogenic roles in CCC. Thus, the integrated action of MIF and other cytokines and chemokines may account for leukocyte influx to the infected myocardium, accompanied by enhanced local production of multiple inflammatory mediators. We further examined by ELISA the level of MIF in the sera from chronic indeterminate and cardiomyopathic chagasic patients, and healthy subjects. CCC patients displayed significantly higher MIF concentrations than those recorded in asymptomatic T. cruzi-infected and uninfected individuals. Interestingly, increased MIF levels were associated with severe progressive Chagas heart disease, in correlation with elevated serum concentration of high sensitivity C-reactive protein and also with several echocardiographic indicators of left ventricular dysfunction, one of the hallmarks of CCC. Our present findings represent the first evidence that enhanced MIF production is associated with progressive cardiac impairment in chronic human infection with T. cruzi, strengthening the relationship between inflammatory response and parasite-driven pathology. These observations contribute to unravel the elements involved in the pathogenesis of CCC and may also be helpful for the design of novel therapies aimed to control long-term morbidity in chagasic patients.
Discovery of highly selective and orally active lysophosphatidic acid receptor-1 antagonists with potent activity on human lung fibroblasts. - Journal of medicinal chemistry
Lysophosphatidic acid is a class of bioactive phospholipid that mediates most of its biological effects through LPA receptors, of which six isoforms have been identified. The recent results from LPA1 knockout mice suggested that blocking LPA1 signaling could provide a potential novel approach for the treatment of idiopathic pulmonary fibrosis. Here, we report the design and synthesis of pyrazole- and triazole-derived carbamates as LPA1-selective and LPA1/3 dual antagonists. In particular, compound 2, the most selective LPA1 antagonist reported, inhibited proliferation and contraction of normal human lung fibroblasts (NHLF) following LPA stimulation. Oral dosing of compound 2 to mice resulted in a dose-dependent reduction of plasma histamine levels in a murine LPA challenge model. Furthermore, we applied our novel antagonists as chemistry probes and investigated the contribution of LPA1/2/3 in mediating the pro-fibrotic responses. Our results suggest LPA1 as the major receptor subtype mediating LPA-induced proliferation and contraction of NHLF.
Morphometric characterization of the first blastomeres of rainbow trout (Oncorhynchus mykiss). - Zygote (Cambridge, England)
In the following investigation the morphometric characteristics of the first two blastomeres of rainbow trout (Oncorhynchus mykiss) were determined. Embryos were incubated at 9Â°C and then fixed in a Stockard solution every 30 min starting from 8.5 to 12.5 h of incubation post fertilization. Embryonic discs were extracted and microphotographs were taken with Q Capture Pro 5.0 software using a stereomicroscope Olympus SZX7. The average size of the blastodiscs was 941.22 Â± 160.42 Î¼m. The first cleavage finished after approximately 12 h of incubation. The first two blastomeres were regularly symmetrical in their morphology. Blastomere 1 had an average length (L) of 942.68 Â± 105.56 Î¼m and width (W) of 467.34 Â± 64.33 Î¼m. Blastomere 2 had an average length of 887.60 Â± 101.65 and width of 454.49 Â± 47.25 Î¼m (n = 91). Significant differences were found between the length and width of blastomeres 1 and 2. The proportion between the length of blastomeres 1 and 2 was 0.94 Â± 0.07 (n = 91); between the width of blastomeres 1 and 2 it was 0.88 Â± 0.11 (n = 91); and the width/length ratio was 0.51 Â± 0.09 (n = 182). It was concluded that rainbow trout blastomeres tend to be asymmetrical in length with a higher dispersion of widths.
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