Dronedarone for the Treatment of Atrial Fibrillation with Concomitant Heart Failure with Preserved and Mildly Reduced Ejection Fraction: Post-Hoc Analysis of the ATHENA Trial.

AIMS: Limited therapeutic options are available for the management of atrial fibrillation/flutter (AF/AFL) with concomitant heart failure with preserved and mildly reduced ejection fraction. (HFpEF and HFmrEF). Dronedarone reduces the risk of cardiovascular events in patients with AF, but sparse data are available examining its role in patients with AF complicated by HFpEF and HFmrEF. METHODS AND RESULTS: ATHENA was an international, multicenter trial that randomized 4,628 patients with paroxysmal or persistent AF/AFL and cardiovascular risk factors to dronedarone 400 mg twice daily versus placebo. We evaluated patients with 1) symptomatic HFpEF and HFmrEF (defined as LVEF>40%, evidence of structural heart disease, and New York Heart Association class II/III or diuretic use), 2) HF with reduced ejection fraction (HFrEF) or left ventricular dysfunction (LVEF≤40%), and 3) those without HF. We assessed effects of dronedarone vs placebo on death or cardiovascular hospitalization (primary endpoint), other key efficacy endpoints, and safety. Overall, 534 (12%) had HFpEF or HFmrEF, 422 (9%) had HFrEF or LV dysfunction, and 3,672 (79%) did not have HF. Patients with HFpEF and HFmrEF had a mean age of 73±9 years, 37% were women, and had a mean LVEF of 57±9%. Over 21±5 months mean follow-up, dronedarone consistently reduced risk of death or cardiovascular hospitalization (hazard ratio 0.76; 95% confidence interval 0.69-0.84) without heterogeneity based on HF status (Pinteraction >0.10). This risk reduction in the primary endpoint was consistent across the range of LVEF (as a continuous function) in HF without heterogeneity (Pinteraction =0.71). Rates of death, cardiovascular hospitalization, and HF hospitalization each directionally favored dronedarone vs. placebo in HFpEF and HFmrEF, but these treatment effects were not statistically significant. CONCLUSIONS: Dronedarone is associated with reduced cardiovascular events in patients with paroxysmal or persistent AF/AFL and HF across the spectrum of LVEF, including among those with HFpEF and HFmrEF. These data support a rationale for a future dedicated and powered clinical trial to affirm the net clinical benefit of dronedarone in this population

Comparison of Physical-chemical and Mechanical Properties of Chlorapatite and Hydroxyapatite Plasma Sprayed Coatings

Chlorapatite can be considered a potential biomaterial for orthopaedic applications. Its use as plasma-sprayed coating could be of interest considering its thermal properties and particularly its ability to melt without decomposition unlike hydroxyapatite. Chlorapatite (ClA) was synthesized by a high-temperature ion exchange reaction starting from commercial stoichiometric hydroxyapatites (HA). The ClA powder showed similar characteristics as the original industrial HA powder, and was obtained in the monoclinic form. The HA and ClA powders were plasma-sprayed using a low-energy plasma spraying system with identical processing parameters. The coatings were characterized by physical-chemical methods, i.e. X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR) and Raman spectroscopy, including distribution mapping of the main phases detected such as amorphous calcium phosphate (ACP), oxyapatite (OA), and HA or ClA. The unexpected formation of oxyapatite in ClA coatings was assigned to a side reaction with contaminating oxygenated species (O2, H2O). ClA coatings exhibited characteristics different from HA, showing a lower content of oxyapatite and amorphous phase. Although their adhesion strength was found to be lower than that of HA coatings, their application could be an interesting alternative, offering, in particular, a larger range of spraying conditions without formation of massive impurities.This study was carried out under a MNT ERA-Net Project named NANOMED. The authors gratefully thank the Midi-Pyrénées region (MNT ERA Net Midi-Pyrénées Région, NANOMED2 project) and the Institute National Polytechnique de Toulouse (BQR INPT 2011, BIOREVE project) for supporting this research work, especially the financial support for research carried out in the CIRIMAT and the LGP laboratories (France), and the Basque government and Tratamientos Superficiales Iontech, S.A. for their financial and technical support under the IG-2007/0000381 grant for the development of the LEPS device and deposition of the coatings carried out in Inasmet-Tecnalia. The French industrial collaborators (TEKNIMED SA and 2PS SA) were financed by the OSEO programs

Genomic and biochemical approaches in the discovery of mechanisms for selective neuronal vulnerability to oxidative stress

<p>Abstract</p> <p>Background</p> <p>Oxidative stress (OS) is an important factor in brain aging and neurodegenerative diseases. Certain neurons in different brain regions exhibit selective vulnerability to OS. Currently little is known about the underlying mechanisms of this selective neuronal vulnerability. The purpose of this study was to identify endogenous factors that predispose vulnerable neurons to OS by employing genomic and biochemical approaches.</p> <p>Results</p> <p>In this report, using <it>in vitro </it>neuronal cultures, <it>ex vivo </it>organotypic brain slice cultures and acute brain slice preparations, we established that cerebellar granule (CbG) and hippocampal CA1 neurons were significantly more sensitive to OS (induced by paraquat) than cerebral cortical and hippocampal CA3 neurons. To probe for intrinsic differences between <it>in vivo </it>vulnerable (CA1 and CbG) and resistant (CA3 and cerebral cortex) neurons under basal conditions, these neurons were collected by laser capture microdissection from freshly excised brain sections (no OS treatment), and then subjected to oligonucleotide microarray analysis. GeneChip-based transcriptomic analyses revealed that vulnerable neurons had higher expression of genes related to stress and immune response, and lower expression of energy generation and signal transduction genes in comparison with resistant neurons. Subsequent targeted biochemical analyses confirmed the lower energy levels (in the form of ATP) in primary CbG neurons compared with cortical neurons.</p> <p>Conclusion</p> <p>Low energy reserves and high intrinsic stress levels are two underlying factors for neuronal selective vulnerability to OS. These mechanisms can be targeted in the future for the protection of vulnerable neurons.</p

Método automático de clasificación de color en dientes humanos usando aprendizaje de máquina

Trabajo de InvestigaciónActualmente el proceso de identificación del color de los dientes para la fabricación de prótesis dentales es realizado manualmente por un experto que, utilizando un método de identificación visual, determina el color de las piezas dentales en la boca del paciente, usando guías de color como la VITA®. A pesar de que el método visual es el más utilizado para la identificación del color de dientes, este se ve afectado por distintas variables tales como: el cansancio del experto, la luminosidad en el ambiente, salud visual del especialista, entre otras que influyen en la identificación del color en los dientes. Los errores en la clasificación del color de los dientes pueden generar pérdidas de tiempo lo que implicaría en consecuencia sobrecostos que afectarían directamente al fabricante y la satisfacción final del cliente.1. Planteamiento del problema 2. Pregunta de investigación 3. Objetivos 4. Estado del arte 5. Marco de referencia 6. Alcances y limitaciones 7. Metodología 8. Diseño metodológico 9. Discusión y resultados 10. Conclusiones 11. Trabajos futuros 12. Bibliografía 13. ANEXOSPregradoIngeniero de Sistema

Ndufaf5 deficiency in the Dictyostelium model: new roles in autophagy and development

This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License.Ndufaf5 (also known as C20orf7) is a mitochondrial complex I (CI) assembly factor whose mutations lead to human mitochondrial disease. Little is known about the function of the protein and the cytopathological consequences of the mutations. Disruption of Dictyostelium Ndufaf5 leads to CI deficiency and defects in growth and development. The predicted sequence of Ndufaf5 contains a putative methyltransferase domain. Site-directed mutagenesis indicates that the methyltransferase motif is essential for its function. Pathological mutations were recreated in the Dictyostelium protein and expressed in the mutant background. These proteins were unable to complement the phenotypes, which further validates Dictyostelium as a model of the disease. Chronic activation of AMP-activated protein kinase (AMPK) has been proposed to play a role in Dictyostelium and human cytopathology in mitochondrial diseases. However, inhibition of the expression of AMPK gene in the Ndufaf5-null mutant does not rescue the phenotypes associated with the lack of Ndufaf5, suggesting that novel AMPK-independent pathways are responsible for Ndufaf5 cytopathology. Of interest, the Ndufaf5-deficient strain shows an increase in autophagy. This phenomenon was also observed in a Dictyostelium mutant lacking MidA (C2orf56/PRO1853/Ndufaf7), another CI assembly factor, suggesting that autophagy activation might be a common feature in mitochondrial CI dysfunction.This work was supported by Grants BFU2009-09050 and BFU2012-32536 from the Spanish Ministerio de Ciencia e Innovación.Peer Reviewe

VPS13A is closely associated with mitochondria and is required for efficient lysosomal degradation

Members of the VPS13 family are associated with various human diseases. In particular, the loss of function of VPS13A leads to chorea-acanthocytosis (ChAc), a rare neurodegenerative disease without available curative treatments. Autophagy has been considered a promising therapeutic target because the absence of VPS13A causes a defective autophagy flux. However, the mechanistic details of this deficiency are unknown. Here, we identified Rab7A as an interactor of one of the VPS13 family members in Dictyostelium discoideum and showed that this interaction is conserved between the human homologs VPS13A and RAB7A in HeLa cells. As RAB7A is a key player in endosome trafficking, we addressed the possible function of VPS13A in endosome dynamics and lysosome degradation. Our results suggest that the decrease in autophagy observed in the absence of VPS13A may be the result of a more general defect in endocytic trafficking and lysosomal degradation. Unexpectedly, we found that VPS13A is closely localized to mitochondria, suggesting that the role of VPS13A in the endolysosomal pathway might be related to inter-organelle communication. We show that VPS13A localizes at the interface between mitochondria-endosomes and mitochondria-endoplasmic reticulum and that the presence of membrane contact sites is altered in the absence of VPS13A. Based on these findings, we propose that therapeutic strategies aimed at modulating the endolysosomal pathway could be beneficial in the treatment of ChAc. This article has an associated First Person interview with the first author of the paper

Loaded microplasma-sprayed CaP-coated implants in vivo.

Microplasma spray equipment to deposit calcium phosphate ceramic (CaP) coatings has been developed. Fifty-six titanium implants were inserted into the mandibles of 7 adult beagle dogs. The implants were either acid-etched (NC), conventionally plasma-sprayed (PS), micro-plasma-sprayed (MPS), or micro-plasma-sprayed (aMPS) only at the apical part. After 6 weeks, implants in one half of the mandible were subjected to load. Fifty-two weeks thereafter, the animals were killed. Regardless of load, bone healing was comparable for all surfaces tested. It was concluded that loading of MPS CaP-coated implants evokes a favorable bone response, and that the bone response does not differ from that of PS CaP-coated implants. However, functional loading of PS as well as MPS CaP-coated implants might be associated with increased crestal bone maintenance as compared with non-coated implants

Effects of ion implantation on nano-topographic properties

It is well known that surface properties at nano-scale are determinant in a number of applications, such as sensors, biomedical and optical devices. Nevertheless, relations between surface treatment parameters and their effects on topography at the nano-scale, surface energy or light reflectivity are often poorly understood. In this study, a non fluorescent glass material (Knittel) was selected and subjected to ion implantation treatments with different parameters and species, including Ar, Ne, C, N, CO and NH2. The resulting surface topography at the nano-scale was studied by Atomic Force Microscopy (AFM) and the surface energy was evaluated with the contact angle method. Additionally, the modifications induced on optical properties, i.e. reflection, were evaluated with two different wavelength lasers. The results showed remarkable differences in surface nano-topographies and contact angles (from 15° to 70°) that were obtained. Furthermore, the effects of ion implantation parameters had also very significant consequences on background noise effects, of great importance for optical properties. It was found that the best implantation treatment corresponded to N2 + ions implanted to a dose of 3×1017 ions/cm2 at an energy of 30 keV. This treatment resulted in a adequate contact angle, producing a nano-textured surface with potential features for a good attachment and orientation of deposited bio-molecules, and a very low background fluorescence, hence allowing a high degree of scanning sensitivity, for application on DNA microarrays. The study has shown that ion implantation represents a powerful tool for modifying key properties on surfaces that play an important role in the response elicited on living tissue and bio-molecules, which is notoriously relevant for the application as bio-sensors.Spanish Ministry of Science and Technology MAT2002-04265-C03-02, Gobierno Vasco - Departamento de Industria MAAB-ETORTEK 2002-200

Establishment of a cellular model for the study of a VPS13A related disease

Trabajo presentado en SEFAGIA 2020, celebrado en Cáceres (España) del 4 al 6 de marzo de 2020