Utilización de recursos sanitarios y costes asociados al diagnóstico y tratamiento de cada episodio de trombosis venosa profunda y sangrado en pacientes intervenidos de cirugía ortopédica de cadera o rodilla

Objective: To determine the use of healthcare resources and costs associated with the diagnosis and treatment of thrombosis and bleeding patients who have undergone elective hip or knee replacement surgery, in routine clinical practice conditions. Patients and methods: This multicentre observational and retrospective study extracted data from the medical records of three Spanish public hospitals (2010). Patients ≥40 years who had received prophylaxis-anticoagulation were included. They were randomised into three groups: (a) control (no hospital complications), (b) bleeding, and (c) thrombosis. General variables, use of resources and costs were analysed. Statistical analysis: logistic regression and ANCOVA for model correction (P < .05) was included. Results: A total of 141 patients (control: 60; bleeding: 60; and thrombosis: 21), with a mean age 68.7 (SD: 10.4) years, and 68.1% females were identified. Hip arthroplasty was more frequent (71.6%). The bleeding risk was associated with age (OR = 1.1) and thrombosis with COPD (OR = 1.8); P < .05). The average length of stay for the thrombosis, bleeding and control groups was 13.9, 11.5 and 7.4 days, respectively; P < .001). The total costs for each group were D10,484.3; D8766.4 and D6496.1 respectively; P < .05. All grouped results were comparable between them according to the hospital analysed and the type of replacement. Conclusions: Costs were higher for thrombosis and bleeding patients, respectively. Costs were associated with length of stay and hospital-acquired infections.Objetivo: Conocer la utilización de recursos sanitarios y los costes asociados al diagnóstico y tratamiento de la trombosis y sangrado en pacientes intervenidos de artroplastia primaria total de cadera (ATC) o rodilla (ATR), durante 3 meses de seguimiento. Pacientes y método: Estudio observacional de carácter multicéntrico y retrospectivo, realizado a partir de los registros médicos de pacientes pertenecientes a 3 centros hospitalarios-públicos espanoles ˜ (ano˜ 2010). Se consideraron aleatoriamente 3 grupos de pacientes: a) control (sin complicaciones hospitalarias); b) sangrado, y c) trombosis. Se incluyeron variables generales, de utilización de recursos y sus costes. Análisis estadístico: regresión logística y ANCOVA, p < 0,05. Resultados: Se incluyeron pacientes ≥ 40 anos ˜ y que hubieran recibido profilaxis anticoagulante. Se incluyó un total de 141 pacientes (control: 60; sangrado: 60; y trombosis: 21). La edad media fue de 68,7 (DE: 10,4) anos ˜ y el 68,1% fueron mujeres. La ATR fue la técnica más frecuente (71,6%). El riesgo de sangrado se relacionó con la edad (OR = 1,1) y el de trombosis con la EPOC (OR = 1,8), p < 0,05. El promedio de días de estancia de los grupos de trombosis, sangrado y control fue de 13,9; 11,5 y 7,4 días, respectivamente, p < 0,001). Los costes totales fueron: 10.484,3 D; 8.766,4 D, y 6.496,1 D, respectivamente, p < 0,05. Todos los resultados agrupados fueron comparables entre ellos según el hospital analizado y el tipo de artroplastia. Conclusiones: Los costes más elevados se producen en los pacientes que habían desarrollado una trombosis y sangrado, respectivamente. Los costes se relacionaron con la prolongación de los días de estancia y las infecciones intrahospitalariasMedicin

Tuning Single-Molecule Conductance in Metalloporphyrin-Based Wires via Supramolecular Interactions.

Nature has developed amazing supramolecular constructs to deliver outstanding charge transport capabilities using metalloporphyrin-based supramolecular stacks.1 Here we are incorporating simple, naturally inspired supramolecular interactions via the axial complexation of metalloporphyrins into the formation of a single-molecule wire in a nanoscale gap to dissect the resulting electron pathways through the final chemical adduct. We observe that small structural changes in the axial coordinating linkers result in dramatic changes in the transport properties through the metalloporphyrin-based wire. The increased flexibility of a pyridine-4-yl-methanethiol ligand due to an extra methyl group as compared to a more rigid mercaptopyridine linker allows the former to adopt an unexpected highly conductive stacked structure between the two junction electrodes and the metalloporphyrin ring. DFT calculations reveal a molecular junction structure composed of a shifted stack of the three molecular backbones; the two pyridine ligands sandwiching the metalloporphyrin ring, which is stabilized by a combination of the porphyrin metal center coordinating the pyridinic N and the pyridine/porphyrin overlapping. Contrarily, the more rigid 4-mercaptopyridine ligand presents a more expected octahedral coordination of the metalloporphyrin metal center, leading to much lower conductance. Furthermore, we show that a mechanical forced imposed along the molecular wire axis results in a variety of more extended supramolecular structures between the pyridine linkers and the porphyrin ring spanning the tunneling gap and scoring relatively high conductance values. This works sets an example of the use of supramolecular chemistry in the construction of efficient molecular conduits towards the development of supramolecular electronics, a concept already exploited in natural organisms

Prevention of diabetes in overweight/obese children through a family based intervention program including supervised exercise (PREDIKID project): study protocol for a randomized controlled trial

Background: The global pandemic of obesity has led to an increased risk for prediabetes and type-2 diabetes (T2D). The aims of the current project are: (1) to evaluate the effect of a 22-week family based intervention program, including supervised exercise, on insulin resistance syndrome (IRS) risk in children with a high risk of developing T2D and (2) to identify the profile of microRNA in circulating exosomes and in peripheral blood mononuclear cells in children with a high risk of developing T2D and its response to a multidisciplinary intervention program including exercise. Methods: A total of 84 children, aged 8-12 years, with a high risk of T2D will be included and randomly assigned to control (N = 42) or intervention (N = 42) groups. The control group will receive a family based lifestyle education and psycho-educational program (2 days/month), while the intervention group will attend the same lifestyle education and psycho-educational program plus the exercise program (3 days/week, 90 min per session including warm-up, moderate to vigorous aerobic activities, and strength exercises). The following measurements will be evaluated at baseline prior to randomization and after the intervention: fasting insulin, glucose and hemoglobin A1c; body composition (dual-energy X-ray absorptiometry); ectopic fat (magnetic resonance imaging); microRNA expression in circulating exosomes and in peripheral blood mononuclear cells (MiSeq; Illumina); cardiorespiratory fitness (cardiopulmonary exercise testing); dietary habits and physical activity (accelerometry). Discussion: Prevention and identification of children with a high risk of developing T2D could help to improve their cardiovascular health and to reduce the comorbidities associated with obesity.The Spanish Ministry of Industry and Competitiveness (DEP2016-78377-R), by “Fondos Estructurales de la Unión Europea (FEDER), Una manera de hacer Europa.” and by the University of the Basque Country (GIU14/21). This work was also supported by grants from Spanish Ministry of Economy and Competitiveness (RYC-2010-05957; RYC- 2011-09011), Spanish Ministry of Education, Culture and Sports (FPU14/ 03329) and by the Education, Linguistic Policy and Culture Department of the Government of the Basque Country (PRE_2016_1_0057)

Grafting Snake Melon [Cucumis melo L. subsp. melo Var. flexuosus (L.) Naudin] in Organic Farming: Effects on Agronomic Performance; Resistance to Pathogens; Sugar, Acid, and VOC Profiles; and Consumer Acceptance

The performance of snake melon [Cucumis melo var. flexuosus (L.)] in organic farming was studied under high biotic and salt stress conditions. Soilborne diseases (mainly caused by Macrophomina phaseolina and Neocosmospora falciformis), combined with virus incidence [Watermelon mosaic virus (WMV), Zucchini yellow mosaic virus (ZYMV), and Tomato leaf curl New Delhi virus (ToLCNDV)] and Podosphaera xanthii attacks, reduced yield by more than 50%. Snake melon susceptibility to M. phaseolina and Monosporascus cannonballus was proved in pathogenicity tests, while it showed some degree of resistance to Neocosmospora keratoplastica and N. falciformis. On the contrary, salt stress had a minor impact, although a synergic effect was detected: yield losses caused by biotic stress increased dramatically when combined with salt stress. Under biotic stress, grafting onto the melon F1Pat81 and wild Cucumis rootstocks consistently reduced plant mortality in different agroecological conditions, with a better performance compared to classic Cucurbita commercial hybrids. Yield was even improved under saline conditions in grafted plants. A negative effect was detected, though, on consumer acceptability, especially with the use of Cucurbita rootstocks. Cucumis F1Pat81 rootstock minimized this side effect, which was probably related to changes in the profile of sugars, acids, and volatiles. Grafting affected sugars and organic acid contents, with this effect being more accentuated with the use of Cucurbita rootstocks than with Cucumis. In fact, the latter had a higher impact on the volatile organic compound profile than on sugar and acid profile, which may have resulted in a lower effect on consumer perception. The use of Cucumis rootstocks seems to be a strategy to enable organic farming production of snake melon targeted to high-quality markets in order to promote the cultivation of this neglected crop.

Uncovering de novo gene birth in yeast using deep transcriptomics

De novo gene origination has been recently established as an important mechanism for the formation of new genes. In organisms with a large genome, intergenic and intronic regions provide plenty of raw material for new transcriptional events to occur, but little is know about how de novo transcripts originate in more densely-packed genomes. Here, we identify 213 de novo originated transcripts in Saccharomyces cerevisiae using deep transcriptomics and genomic synteny information from multiple yeast species grown in two different conditions. We find that about half of the de novo transcripts are expressed from regions which already harbor other genes in the opposite orientation; these transcripts show similar expression changes in response to stress as their overlapping counterparts, and some appear to translate small proteins. Thus, a large fraction of de novo genes in yeast are likely to co-evolve with already existing genes

Interferon-stimulated gene 15 pathway is a novel mediator of endothelial dysfunction and aneurysms development in angiotensin II infused mice through increased oxidative stress

AIMS: Interferon-stimulated gene 15 (ISG15) encodes a ubiquitin-like protein that induces a reversible post-translational modification (ISGylation) and can also be secreted as a free form. ISG15 plays an essential role as host-defence response to microbial infection; however, its contribution to vascular damage associated with hypertension is unknown. METHODS AND RESULTS: Bioinformatics identified ISG15 as a mediator of hypertension-associated vascular damage. ISG15 expression positively correlated with systolic and diastolic blood pressure and carotid intima-media thickness in human peripheral blood mononuclear cells. Consistently, Isg15 expression was enhanced in aorta from hypertension models and in angiotensin II (AngII)-treated vascular cells and macrophages. Proteomics revealed differential expression of proteins implicated in cardiovascular function, extracellular matrix and remodelling, and vascular redox state in aorta from AngII-infused ISG15-/- mice. Moreover, ISG15-/- mice were protected against AngII-induced hypertension, vascular stiffness, elastin remodelling, endothelial dysfunction, and expression of inflammatory and oxidative stress markers. Conversely, mice with excessive ISGylation (USP18C61A) show enhanced AngII-induced hypertension, vascular fibrosis, inflammation and reactive oxygen species (ROS) generation along with elastin breaks, aortic dilation, and rupture. Accordingly, human and murine abdominal aortic aneurysms showed augmented ISG15 expression. Mechanistically, ISG15 induces vascular ROS production, while antioxidant treatment prevented ISG15-induced endothelial dysfunction and vascular remodelling. CONCLUSION: ISG15 is a novel mediator of vascular damage in hypertension through oxidative stress and inflammation.This work was supported by the Ministerio de Ciencia e Innovación and Fondo Europeo de Desarrollo Regional (FEDER)/FSE (SAF2016-80305P; SAF2017-88089-R; SAF2016-79151-R; RTI2018-099246-B-I00), Ministerio de Innovación, Cultura y Deportes (PGC2018-097019-B-I00), Instituto de Salud Carlos III (ISCIII; FIS PI18/0919); Comunidad de Madrid (CM) (AORTASANA B2017/BMD-3676) FEDER-a way to build Europe, Bayer AG (2019-09-2433), CM-Universidad Autónoma de Madrid (SI1-PJI-2019-00321), and British Heart Foundation (CH/12/4/29762; RE//18/6/34217). M.G.-A. was supported by an FPI-UAM fellowship, R.R.-D. by a Juan de la Cierva contract (IJCI-2017-31399), and A.C.M. by a Walton Fellowship, University of Glasgow. The CNIC is supported by ISCIII, the Ministerio de Ciencia e Innovación, and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015-0505)

Regulation of cell death receptor S-nitrosylation and apoptotic signaling by Sorafenib in hepatoblastoma cells

Nitric oxide (NO) plays a relevant role during cell death regulation in tumor cells. The overexpression of nitric oxide synthase type III (NOS-3) induces oxidative and nitrosative stress, p53 and cell death receptor expression and apoptosis in hepatoblastoma cells. S-nitrosylation of cell death receptor modulates apoptosis. Sorafenib is the unique recommended molecular-targeted drug for the treatment of patients with advanced hepatocellular carcinoma. The present study was addressed to elucidate the potential role of NO during Sorafenib-induced cell death in HepG2 cells. We determined the intra- and extracellular NO concentration, cell death receptor expression and their S-nitrosylation modifications, and apoptotic signaling in Sorafenib-treated HepG2 cells. The effect of NO donors on above parameters has also been determined. Sorafenib induced apoptosis in HepG2 cells. However, low concentration of the drug (10nM) increased cell death receptor expression, as well as caspase-8 and -9 activation, but without activation of downstream apoptotic markers. In contrast, Sorafenib (10 µM) reduced upstream apoptotic parameters but increased caspase-3 activation and DNA fragmentation in HepG2 cells. The shift of cell death signaling pathway was associated with a reduction of S-nitrosylation of cell death receptors in Sorafenib-treated cells. The administration of NO donors increased S-nitrosylation of cell death receptors and overall induction of cell death markers in control and Sorafenib-treated cells. In conclusion, Sorafenib induced alteration of cell death receptor S-nitrosylation status which may have a relevant repercussion on cell death signaling in hepatoblastoma cells.Instituto de Salud Carlos III PI13/00021Ministerio de Economía y Competitividad BFU2012-32056Consejería de Economía, Innovación, Ciencia y Empleo, Junta de Andalucía BIO-0216Consejería de Economía, Innovación, Ciencia y Empleo, Junta de Andalucía CTS-6264Consejería de Salud, Junta de Andalucía PI13/ 0002

Identification of a novel polyfluorinated compound as a lead to inhibit human enzymes aldose reductase and AKR1B10 : structure determination of both ternary complexes and implications for drug design

Aldo-keto reductases (AKRs) are mostly monomeric enzymes which fold into a highly conserved ([alpha]/[beta])8 barrel, while their substrate specificity and inhibitor selectivity are determined by interaction with residues located in three highly variable external loops. The closely related human enzymes aldose reductase (AR or AKR1B1) and AKR1B10 are of biomedical interest because of their involvement in secondary diabetic complications (AR) and in cancer, e.g. hepatocellular carcinoma and smoking-related lung cancer (AKR1B10). After characterization of the IC50 values of both AKRs with a series of polyhalogenated compounds, 2,2',3,3',5,5',6,6'-octafluoro-4,4'-biphenyldiol (JF0064) was identified as a lead inhibitor of both enzymes with a new scaffold (a 1,1'-biphenyl-4,4'-diol). An ultrahigh-resolution X-ray structure of the AR-­NADP+-JF0064 complex has been determined at 0.85 Å resolution, allowing it to be observed that JF0064 interacts with the catalytic residue Tyr48 through a negatively charged hydroxyl group (i.e. the acidic phenol). The non-competitive inhibition pattern observed for JF0064 with both enzymes suggests that this acidic hydroxyl group is also present in the case of AKR1B10. Moreover, the combination of surface lysine methylation and the introduction of K125R and V301L mutations enabled the determination of the X-ray crystallo­graphic structure of the corresponding AKR1B10-NADP+-JF0064 complex. Comparison of the two structures has unveiled some important hints for subsequent structure-based drug-design efforts

Comparación de los índices PROFUND y PALIAR en pacientes pluripatológicos con enfermedad crónica no oncológica en fase avanzada

Background and objective: To compare the discrimination power of PROFUND and PALIAR indexes for predicting mortality in polypathological patients with advanced non-oncologic chronic disease. Material and methods: Prospective multicentre cohort study. We included polypathological patients with advanced non-oncologic chronic disease, who were admitted to internal medicine departments between July 1 st and December 31th, 2014. Data was collected from each patient on age, sex, categories of polypathology, advanced disease, comorbidity, functional and cognitive assessment, terminal illness symptoms, need for caregiver, hospitalisation in the past three and 12 months and number of drugs. We calculated the PROFUND and PALIAR indexes and conducted a 12-month follow-up. We assessed mortality with the Kaplan-Meier survival curves and the discrimination of indexes with the ROC curves. Results: We included 213 patients with a mean (standard deviation) age of 83.0 (7.0) years, 106 (49.8%) of whom were female. Mortality at six months was 40.4% and at 12 months 50.2%. Deceased patients scored higher scores on the PROFUND [11.2(4.2) vs 8.5(3.9); P <.001] and PALIAR [6.7 (4.6) vs 3.6(3.1); p < 0, 001] indexes. The discrimination of PALIAR index at six months (under the curve area 0.734 95%CI 0.665-0.803) was higher than of PROFUND, and there was no difference at 12 months. Conclusions: In polypathological patients with advanced non-oncologic chronic disease, the PALIAR index had better discrimination power than PROFUND index at 66 months and there were no differences at 12 months