Caracterización del ruido de fase de los subsistemas que integran un oscilador sintetizado

A set of phase noise measurement techniques, based on the HP 3048A system, are compared in terms of major applications and limitations. To ilustrate the items, several significant measures are discussed.Peer ReviewedPostprint (published version

Serum Metabolomic Analysis Suggests Impairment of Myocardial Energy Production in Takotsubo Syndrome

Acute coronary syndromes; Takotsubo syndromeSíndromes coronarios agudos; Síndrome de TakotsuboSíndromes coronaris aguts; Síndrome de TakotsuboIntroduction: Takotsubo syndrome is a complex entity that, although it usually has a good prognosis, can be life threatening. While recent advances have improved the knowledge of takotsubo syndrome, many aspects of its etiology still remain uncertain. Metabolomics, a hypothesis generating approach, could provide novel pathophysiology information about this disease. Methods and Results: Serum samples were obtained from takotsubo (n = 19) and acute myocardial infarction patients (n = 8) at the cath lab and, in the case of takotsubo, again once the patient had recovered, 3 months after the main event. 1H NMR spectra of the serum were acquired at 9.4T using a CPMG pulse sequence (32 ms effective delay). Supervised and unsupervised pattern recognition approaches where applied to the data. Pattern recognition was able to differentiate between takotsubo and acute myocardial infarction during the acute phase with 95% accuracy. Myocardial infarction patients showed an increase in lipid signals, a known risk factor for the disease while takotsubo patients showed a relative increase in acetate that could suggest a reduced turnover of the Krebs cycle. When comparing acute and recovered phases, we could detect an increase in alanine and creatine once patients recovered. Conclusions: Our results demonstrate that takotsubo syndrome is metabolically different than AMI, showing limited myocardial energy production capacity during the acute phase. We achieved high classification success against AMI; however, this study should be considered as a proof of concept regarding clinical application of metabolic profiling in takotsubo cardiomyopathy.This work was supported by the Spanish Ministry of Economy and Competitiveness, Instituto de Salud Carlos III (Grants PI14/01431 and PI17/01397, SGR-1807, CIBER-CV, and CIBERESP), co-financed by the European Regional Development Fund (ERDF-FEDER, a way to build Europe)

Connexin 43 deficiency is associated with reduced myocardial scar size and attenuated tgfβ1 signaling after transient coronary occlusion in conditional knock-out mice

Funding: This research was funded by Fundació La Marató de TV3 (n◦. 201536-10) and the Spanish Ministry of Economy and Competitiveness, Instituto de Salud Carlos III (CIBERCV), cofinanced by the European Regional Development Fund (ERDF-FEDER, a way to build Europe). Antonio Rodríguez-Sinovas has a consolidated Miguel Servet contract.Previous studies demonstrated a reduction in myocardial scar size in heterozygous Cx43-mice subjected to permanent coronary occlusion. However, patients presenting with ST segment elevation myocardial infarction often undergo rapid coronary revascularization leading to prompt restoration of coronary flow. Therefore, we aimed to assess changes in scar size and left ventricular remodeling following transient myocardial ischemia (45 min) followed by 14 days of reperfusion using Cx43 (controls) and Cx43 inducible knock-out (Cx43 content: 50%) mice treated with vehicle or 4-hydroxytamoxifen (4-OHT) to induce a Cre-ER(T)-mediated global deletion of the Cx43 floxed allele. The scar area (picrosirius red), measured 14 days after transient coronary occlusion, was similarly reduced in both vehicle and 4-OHT-treated Cx43 mice, compared to Cx43 animals, having normal Cx43 levels (15.78% ± 3.42% and 16.54% ± 2.31% vs. 25.40% ± 3.14% and 22.43% ± 3.88% in vehicle and 4-OHT-treated mice, respectively, p = 0.027). Left ventricular dilatation was significantly attenuated in both Cx43-deficient groups (p = 0.037 for left ventricular end-diastolic diameter). These protective effects were correlated with an attenuated enhancement in pro-transforming growth factor beta 1 (TGFβ1) expression after reperfusion. In conclusion, our data demonstrate that Cx43 deficiency induces a protective effect on scar formation after transient coronary occlusion in mice, an effect associated with reduced left ventricular remodeling and attenuated enhancement in pro-TGFβ1 expression

Diffusion MRI signal cumulants and hepatocyte microstructure at fixed diffusion time: insights from simulations, 9.4T imaging, and histology

Histology; Liver; MicrostructureHistología; Hígado; MicroestructuraHistologia; Fetge; MicroestructuraPurpose Relationships between diffusion-weighted MRI signals and hepatocyte microstructure were investigated to inform liver diffusion MRI modeling, focusing on the following question: Can cell size and diffusivity be estimated at fixed diffusion time, realistic SNR, and negligible contribution from extracellular/extravascular water and exchange? Methods Monte Carlo simulations were performed within synthetic hepatocytes for varying cell size/diffusivity L / D0 , and clinical protocols (single diffusion encoding; maximum b-value: {1000, 1500, 2000} s/mm2; 5 unique gradient duration/separation pairs; SNR = { ∞ , 100, 80, 40, 20}), accounting for heterogeneity in (D0,L) and perfusion contamination. Diffusion ( D ) and kurtosis ( K ) coefficients were calculated, and relationships between (D0,L) and (D,K) were visualized. Functions mapping (D,K) to (D0,L) were computed to predict unseen (D0,L) values, tested for their ability to classify discrete cell-size contrasts, and deployed on 9.4T ex vivo MRI-histology data of fixed mouse livers Results Relationships between (D,K) and (D0,L) are complex and depend on the diffusion encoding. Functions mapping (D,K) to (D0,L) captures salient characteristics of D0(D,K) and L(D,K) dependencies. Mappings are not always accurate, but they enable just under 70% accuracy in a three-class cell-size classification task (for SNR = 20, bmax = 1500 s/mm2, δ = 20 ms, and Δ = 75 ms). MRI detects cell-size contrasts in the mouse livers that are confirmed by histology, but overestimates the largest cell sizes. Conclusion Salient information about liver cell size and diffusivity may be retrieved from minimal diffusion encodings at fixed diffusion time, in experimental conditions and pathological scenarios for which extracellular, extravascular water and exchange are negligible.This project was supported by Fundació La Caixa and by the investigator-initiated PREdICT study at the Vall d'Hebron Institute of Oncology (Barcelona), funded by AstraZeneca and supporting FG. FG has received funding from the postdoctoral fellowships programme Beatriu de Pinós (2020 BP 00117), funded by the Secretary of Universities and Research (Government of Catalonia). KB is funded by a Beatriu de Pinós post-doctoral grant (2019 BP 00182). RPL is supported by a CRIS Foundation Talent Award (TALENT19-05), the Instituto de Salud Carlos III-Investigación en Salud (PI18/01395), Spanish Ministry for Science, Innovation and Universities (RTI2018-095209-B-C21, FIS-G64384969), Prostate Cancer Foundation Young Investigator Award and Fero Foundation. ICS is supported by a fellowship from Fundació ”la Caixa” (ID 100010434) and the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 847648, fellowship code LCF/BQ/PI20/117600

Cardiomyocyte hypertrophy induced by Endonuclease G deficiency requires reactive oxygen radicals accumulation and is inhibitable by the micropeptide humanin

The endonuclease G gene (Endog), which codes for a mitochondrial nuclease, was identified as a determinant of cardiac hypertrophy. How ENDOG controls cardiomyocyte growth is still unknown. Thus, we aimed at finding the link between ENDOG activity and cardiomyocyte growth. Endog deficiency induced reactive oxygen species (ROS) accumulation and abnormal growth in neonatal rodent cardiomyocytes, altering the AKT-GSK3 beta and Class-II histone deacethylases (HDAC) signal transduction pathways. These effects were blocked by ROS scavengers. Lack of ENDOG reduced mitochondrial DNA (mtDNA) replication independently of ROS accumulation. Because mtDNA encodes several subunits of the mitochondrial electron transport chain, whose activity is an important source of cellular ROS, we investigated whether Endog deficiency compromised the expression and activity of the respiratory chain complexes but found no changes in these parameters nor in ATP content. MtDNA also codes for humanin, a micropeptide with possible metabolic functions. Nanomolar concentrations of synthetic humanin restored normal ROS levels and cell size in Endog-deficient cardiomyocytes. These results support the involvement of redox signaling in the control of cardiomyocyte growth by ENDOG and suggest a pathway relating mtDNA content to the regulation of cell growth probably involving humanin, which prevents reactive oxygen radicals accumulation and hypertrophy induced by Endog deficiency.This work was supported by Grant SAF2013-44942R from the Ministerio de Economia y Competitividad (MINECO) to DS, Grant 20153810 from Fundacio La Marato de TV3 to DS, Program ``Redes Tematicas de Investigacion Cooperativa en Salud´´ (RETICS) Grants RD12/0042/0035, RD12/0042/0056 and RD12/0042/0021, Red de Investigacion Cardiovascular (RIC) from the Institute de Salud Carlos-III (ISCIII) to DS, DG-D and JV, Grant 2009SGR-346 from the Agencia de Gestic d'Ajuts Universitaris i de Recerca (AGAUR) from the Government of Catalonia to DS. AB is supported by Fundacio La Marato de TV3 and GB is supported by a predoctoral contract from the Universitat de Lleida.S

Single Intracoronary Injection of Encapsulated Antagomir-92a Promotes Angiogenesis and Prevents Adverse Infarct Remodeling

Small and large preclinical animal models have shown that antagomir-92a-based therapy reduces early postischemic loss of function, but its effect on postinfarction remodeling is not known. In addition, the reported remote miR-92a inhibition in noncardiac organs prevents the translation of nonvectorized miR-targeted therapy to the clinical setting. We investigated whether a single intracoronary administration of antagomir-92a encapsulated in microspheres could prevent deleterious remodeling of myocardium 1 month after acute myocardial infarction AUTHOR: Should "acute" be added before "myocardial infarction" (since abbreviation is AMI)? Also check at first mention in main text (AMI) without adverse effects. In a percutaneous pig model of reperfused AMI, a single intracoronary administration of antagomir-92a encapsulated in specific microspheres (9 μm poly-d,-lactide-co-glycolide [PLGA]) inhibited miR-92a in a local, selective, and sustained manner (n=3 pigs euthanized 1, 3, and 10 days after treatment; 8×, 2×, and 5×-fold inhibition at 1, 3, and 10 days). Downregulation of miR-92a resulted in significant vessel growth (n=27 adult minipigs randomly allocated to blind receive encapsulated antagomir-92a, encapsulated placebo, or saline [n=8, 9, 9]; P =0.001), reduced regional wall-motion dysfunction (P =0.03), and prevented adverse remodeling in the infarct area 1 month after injury (P =0.03). Intracoronary injection of microspheres had no significant adverse effect in downstream myocardium in healthy pigs (n=2), and fluorescein isothiocyanate albumin-PLGA microspheres were not found in myocardium outside the left anterior descending coronary artery territory (n=4) or in other organs (n=2). Early single intracoronary administration of encapsulated antagomir-92a in an adult pig model of reperfused AMI prevents left ventricular remodeling with no local or distant adverse effects, emerging as a promising therapeutic approach to translate to patients who suffer a large AMI

1H-NMR Urinary Metabolic Profile, A Promising Tool for the Management of Infants with Human Cytomegalovirus-Infection

Abstract: Congenital human cytomegalovirus (HCMV) infection is the most common mother-to-child transmitted infection in the developed world. Certain aspects of its management remain a challenge. Urinary metabolic profiling is a promising tool for use in pediatric conditions. The aim of this study was to investigate the urinary metabolic profile in HCMV-infected infants and controls during acute care hospitalization. Urine samples were collected from 53 patients at five hospitals participating in the Spanish congenital HCMV registry. Thirty-one cases of HCMV infection and 22 uninfected controls were included. Proton nuclear magnetic resonance (1H-NMR) spectra were obtained using NOESYPR1D pulse sequence. The dataset underwent orthogonal projection on latent structures discriminant analysis to identify candidate variables affecting the urinary metabolome: HCMV infection, type of infection, sex, chronological age, gestational age, type of delivery, twins, and diet. Statistically significant discriminative models were obtained only for HCMV infection (p = 0.03) and chronological age (p < 0.01). No significant differences in the metabolomic profile were found between congenital and postnatal HCMV infection. When the HCMV-infected group was analyzed according to chronological age, a statistically significant model was obtained only in the neonatal group (p = 0.01), with the differentiating metabolites being betaine, glycine, alanine, and dimethylamine. Despite the considerable variation in urinary metabolic profiles in a real-life setting, clinical application of metabolomics to the study of HCMV infection seems feasible

Spontaneous reperfusion enhances succinate concentration in peripheral blood from stemi patients but its levels does not correlate with myocardial infarct size or area at risk

Cardiovascular biology; Diagnostic markers; Prognostic markersBiología cardiovascular; Marcadores de diagnóstico; Marcadores pronósticosBiologia cardiovascular; Marcadors diagnòstics; Marcadors pronòsticsSuccinate is enhanced during initial reperfusion in blood from the coronary sinus in ST-segment elevation myocardial infarction (STEMI) patients and in pigs submitted to transient coronary occlusion. Succinate levels might have a prognostic value, as they may correlate with edema volume or myocardial infarct size. However, blood from the coronary sinus is not routinely obtained in the CathLab. As succinate might be also increased in peripheral blood, we aimed to investigate whether peripheral plasma concentrations of succinate and other metabolites obtained during coronary revascularization correlate with edema volume or infarct size in STEMI patients. Plasma samples were obtained from peripheral blood within the first 10 min of revascularization in 102 STEMI patients included in the COMBAT-MI trial (initial TIMI 1) and from 9 additional patients with restituted coronary blood flow (TIMI 2). Metabolite concentrations were analyzed by 1H-NMR. Succinate concentration averaged 0.069 ± 0.0073 mmol/L in patients with TIMI flow ≤ 1 and was significantly increased in those with TIMI 2 at admission (0.141 ± 0.058 mmol/L, p < 0.05). However, regression analysis did not detect any significant correlation between most metabolite concentrations and infarct size, extent of edema or other cardiac magnetic resonance (CMR) variables. In conclusion, spontaneous reperfusion in TIMI 2 patients associates with enhanced succinate levels in peripheral blood, suggesting that succinate release increases overtime following reperfusion. However, early plasma levels of succinate and other metabolites obtained from peripheral blood does not correlate with the degree of irreversible injury or area at risk in STEMI patients, and cannot be considered as predictors of CMR variables. Trial registration: Registered at www.clinicaltrials.gov (NCT02404376) on 31/03/2015. EudraCT number: 2015-001000-58.This work was supported by the Spanish Ministry of Economy and Competitiveness, Instituto de Salud Carlos III (Grants PI17/01397 and CIBERCV) and the Spanish Society of Cardiology (Proyectos de la FEC para Investigación Básica en Cardiología 2018, Sociedad Española de Cardiología), and was cofinanced by the European Regional Development Fund (ERDF-FEDER, a way to build Europe). Antonio Rodríguez-Sinovas has a consolidated Miguel Servet contract