Synthesis and Anti-Diabetic Activity of an 8-Purine Derivative as a Novel DPP-4 Inhibitor in Obese Diabetic Zücker Rats

Type 2 diabetes mellitus (T2DM) is one of the world’s principal metabolic diseases characterized by chronic hyperglycemia. The gut incretin hormones, glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP), which has been proposed as a new treatment for T2DM, are extensively metabolized by Dipeptidyl peptidase 4 (DPP-4). Inhibitors of DPP-4 block the degradation of GLP-1 and GIP and may increase their natural circulating levels, favoring glycemic control in T2DM. A novel and potent selective inhibitor of DPP-4 with an 8-purine derived structure (1) has been developed and tested in vitro and in vivo in Zücker obese diabetic fatty (ZDF) rats, an experimental model of the metabolic syndrome and T2DM to assess the inhibitory activity using vildagliptin as reference standard. ZDF rats were subdivided into three groups (n = 7/group), control (C-ZDF), and those treated with compound 1 (Compound1-ZDF) and with vildagliptin (V-ZDF), both at 10 mg/kg/d rat body weight, in their drinking water for 12 weeks, and a group of lean littermates (ZL) was used. ZDF rats developed DM (fasting hyperglycemia, 425 ± 14.8 mg/dL; chronic hyperglycemia, HbA1c 8.5 ± 0.4%), compared to ZL rats. Compound 1 and vildagliptin reduced sustained HbAl1c (14% and 10.6%, P < 0.05, respectively) and fasting hyperglycemia values (24% and 19%, P < 0.05, respectively) compared to C-ZDF group (P < 0.001). Compound 1 and vildagliptin have shown a potent activity with an IC50 value of 4.92 and 3.21 μM, respectively. These data demonstrate that oral compound 1 administration improves diabetes in ZDF rats by the inhibitory effect on DPP-4, and the potential to be a novel, efficient and tolerable approach for treating diabetes of obesity-related T2DM, in ZDF rats.Spanish Ministry of Science and Innovation through (grants PID2021.128109OB.I00 and PID2021-125900OB-I00)European Regional Development Fund (ERDF) as a way of making Europ

Ultrasonography-guided anterior approach for axillary nerve blockade: an anatomical study

Combined ultrasound-guided blockade of the suprascapular and axillary nerves has been proposed as an alternative to interscalene blockade for pain control in shoulder joint pathology or post-surgical care. This technique could help avoid respiratory complications and/or almost total upper limb palsy. Nowadays, the axillary nerve blockade is mostly performed using an in-plane caudal-to-cephalic approach from the posterior surface of the shoulder, reaching the nerve immediately after it exits the neurovascular quadrangular space (part of the spatium axillare). Despite precluding most respiratory complications, this approach has not made post-surgical pain relief any better than an interscalene blockade, probably because articular branches of the axillary nerve are not blocked. Cephalic to caudal Methylene Blue injections were placed in the first segment of the axillary nerve of six Thiel-embalmed cadavers using an ultrasound-guided anterior approach in order to compare the distribution with that produced by a posterior approach to the contralateral axillary nerve in the same cadaver. Another 21 formalin-fixed cadavers were bilaterally dissected to identify the articular branches of the axillary nerve. We found a good spread of the dye on the axillary nerve and a constant relationship of this nerve with the subscapularis muscle. The dye reached the musculocutaneous nerve, which also contributes to shoulder joint innervation. We describe the anatomical landmarks for an ultrasonography-guided anterior axillary nerve blockade and hypothesize that this anterior approach will provide better pain control than the posterior approach owing to complete blocking of the joint nerve. This article is protected by copyright. All rights reserved

Response of Horticultural Soil Microbiota to Different Fertilization Practices

Environmentally friendly agricultural production necessitates manipulation of microbe–plant interactions, requiring a better understanding of how farming practices influence soil microbiota. We studied the effect of conventional and organic treatment on soil bacterial richness, composition, and predicted functional potential. 16S rRNA sequencing was applied to soils from adjacent plots receiving either a synthetic or organic fertilizer, where two crops were grown within treatment, homogenizing for differences in soil properties, crop, and climate. Conventional fertilizer was associated with a decrease in soil pH, an accumulation of Ag, Mn, As, Fe, Co, Cd, and Ni; and an enrichment of ammonia oxidizers and xenobiotic compound degraders (e.g., Candidatus Nitrososphaera, Nitrospira, Bacillus, Pseudomonas). Soils receiving organic fertilization were enriched in Ti (crop biostimulant), N, and C cycling bacteria (denitrifiers, e.g., Azoarcus, Anaerolinea; methylotrophs, e.g., Methylocaldum, Methanosarcina), and disease-suppression (e.g., Myxococcales). Some predicted functions, such as glutathione metabolism, were slightly, but significantly enriched after a one-time manure application, suggesting the enhancement of sulfur regulation, nitrogen-fixing, and defense of environmental stressors. The study highlights that even a single application of organic fertilization is enough to originate a rapid shift in soil prokaryotes, responding to the differential substrate availability by promoting soil health, similar to recurrent applications.This work was supported by the Earth Microbiome Project; the METAMAHA project funded by the Basque Government’s Department of Industry, Trade, and Tourism (SAIOTEK program; S-PE13UN130); and IT1014-16 and IT1213-19 Consolidated Research Group Projects

Early transcontinental import of SARS-CoV-2 variant of concern 202012/01 (B.1.1.7) from Europe to Uruguay

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant B.1.1.7 causes a more transmissible and apparently more severe disease. We report its early introduction from Europe to South America from a traveler who arrived in Uruguay from the United Kingdom, even before B.1.1.7 was recognized as a variant of concern. This highlights the risk of introduction of SARS-CoV-2 variants despite strict contingency protocols and underscores the need of improving real-time surveillance worldwide.ANII: POS_NAC_2018_1_15149

Mitochondrial bioenergetics boost macrophage activation, promoting liver regeneration in metabolically compromised animals

Background and aims: Hepatic ischemia-reperfusion injury (IRI) is the leading cause of early posttransplantation organ failure as mitochondrial respiration and ATP production are affected. A shortage of donors has extended liver donor criteria, including aged or steatotic livers, which are more susceptible to IRI. Given the lack of an effective treatment and the extensive transplantation waitlist, we aimed at characterizing the effects of an accelerated mitochondrial activity by silencing methylation-controlled J protein (MCJ) in three preclinical models of IRI and liver regeneration, focusing on metabolically compromised animal models. Approach and results: Wild-type (WT), MCJ knockout (KO), and Mcj silenced WT mice were subjected to 70% partial hepatectomy (Phx), prolonged IRI, and 70% Phx with IRI. Old and young mice with metabolic syndrome were also subjected to these procedures. Expression of MCJ, an endogenous negative regulator of mitochondrial respiration, increases in preclinical models of Phx with or without vascular occlusion and in donor livers. Mice lacking MCJ initiate liver regeneration 12 h faster than WT and show reduced ischemic injury and increased survival. MCJ knockdown enables a mitochondrial adaptation that restores the bioenergetic supply for enhanced regeneration and prevents cell death after IRI. Mechanistically, increased ATP secretion facilitates the early activation of Kupffer cells and production of TNF, IL-6, and heparin-binding EGF, accelerating the priming phase and the progression through G1 /S transition during liver regeneration. Therapeutic silencing of MCJ in 15-month-old mice and in mice fed a high-fat/high-fructose diet for 12 weeks improves mitochondrial respiration, reduces steatosis, and overcomes regenerative limitations. Conclusions: Boosting mitochondrial activity by silencing MCJ could pave the way for a protective approach after major liver resection or IRI, especially in metabolically compromised, IRI-susceptible organs.Funding information: Supported by grants from Ministerio de Ciencia, Innovación y Universidades MICINN (PID2020-117116RB-100, RTI2018-096759-A-100, RTI2018-095114-B-I00, PID2019-108977RB-100 and RTI2018-095700-B100, integrado en el Plan Estatal de Investigación Científica y Técnica y Innovación, cofinanciado con Fondos FEDER, to M.L.M.-C., T.C.D., C.P., P.M.-S., and N.G.A.A., respectively), Subprograma Retos Colaboración RTC2019-007125-1; Fundación Científica de la Asociación Española Contra el Cáncer (AECC Scientific Foundation) Rare Tumor Calls 2017 (to M.L.M.-C.); Asociación Española contra el Cáncer (to T.C.D. and M.S.-M); La Caixa Foundation Program (HR17-00601, to M.L.M.-C.), Proyectos Investigación en Salud DTS20/00138 (to M.L.M.-C.); Departamento de Industria del Gobierno Vasco (to M.L.M.-C.); Departamento de Educación del Gobierno Vasco (to N.G.-U. and J.S.); Acción Estratégica Ciber Emergentes 2018 (Ciberehd-ISCIII) and Gilead Sciences International Research Scholars Program in Liver Disease (to M.V.-R.); Ciberehd_ISCIII_MINECO is funded by the Instituto de Salud Carlos IIIAcknowledgments: We thank MINECO for the Severo Ochoa Excellence Accreditation to CIC bioGUNE (SEV-2016-0644). We acknowledge Begoña Rodríguez Iruretagoyena for the technical support provided

Weasel exposure to the anticoagulant rodenticide bromadiolone in agrarian landscapes of southwestern Europe

Bromadiolone is an anticoagulant rodenticide (AR) commonly used as a plant protection product (PPP) against rodent pests in agricultural lands. ARs can be transferred trophically to predators/scavengers when they consume intoxicated live or dead rodents. ARs exposure in weasels Mustela nivalis, small mustelids specialized on rodent predation, is poorly known in southern Europe. Moreover, in this species there is no information on bioaccumulation of AR diastereomers e.g., cis- and trans-bromadiolone. Trans-bromadiolone is more persistent in the rodent liver and thus, is expected to have a greater probability of trophic transfer to predators. Here, we report on bromadiolone occurrence, total concentrations and diastereomers proportions (trans- and cis-bromadiolone) in weasels from Castilla y León (north-western Spain) collected in 2010–2017, where bromadiolone was irregularly applied to control outbreaks of common voles Microtus arvalis mainly with cereal grain bait distributed by the regional government. We also tested variables possibly associated with bromadiolone occurrence and concentration, such as individual features (e.g., sex), spatio-temporal variables (e.g., year), and exposure risk (e.g., vole outbreaks). Overall bromadiolone occurrence in weasels was 22% (n = 32, arithmetic mean of concentration of bromadiolone positives = 0.072 mg/kg). An individual showed signs of bromadiolone intoxication (i.e., evidence of macroscopic hemorrhages or hyperaemia and hepatic bromadiolone concentration > 0.1 mg/kg). All the exposed weasels (n = 7) showed only trans-bromadiolone diastereomer in liver, whilst a single analyzed bait from those applied in Castilla y León contained trans- and cis-bromadiolone at 65/35%. Bromadiolone occurrence and concentration in weasels varied yearly. Occurrence was higher in 2012 (100% of weasels), when bromadiolone was widely distributed, compared to 2016–2017 (2016: 20%; 2017: 8.33%) when bromadiolone was exceptionally permitted. The highest concentrations happened in 2014 and 2017, both years with vole outbreaks. Our findings indicate that specialist rodent predators could be exposed to bromadiolone in areas and periods with bromadiolone treatments against vole outbreaks.Francisco Díaz-Ruiz enjoyed a postdoctoral research contract “Juan de la Cierva” (ref: FJCI-2015-24949) from the Spanish Ministry of Economy, Industry, and Competitiveness and a postdoctoral contract funded by the University of Málaga through the grants programme ‘Ayudas para la Incorporación de Doctores del I Plan Propio de Investigación de la Universidad de Málaga’ (Call 2020). Julio Domínguez was supported by a predoctoral grant: “Programa Talento Formación” funded by Fondo Social Europeo (FSE) and Castilla La Mancha regional government (JCCM) (ref: SBPLY/16/180501/000205).Peer reviewe

Cancer impact prognosis on mortality in patients with acute heart failure: analysis of the epicter study

Introduction: Heart failure (HF) and cancer are currently the leading causes of death worldwide, with an increasing incidence with age. Little is known about the treatment received and the prognosis of patients with acute HF and a prior cancer diagnosis. Objective: to determine the clinical characteristics, palliative treatment received, and prognostic impact of patients with acute HF and a history of solid tumor. Methods: The EPICTER study ('Epidemiological survey of advanced heart failure') is a cross-sectional, multicenter project that consecutively collected patients admitted for acute HF in 74 Spanish hospitals. Patients were classified into two groups according to whether they met criteria for acute HF with and without solid cancer, and the groups were subsequently compared. A multivariable logistic regression analysis was conducted, using the forward stepwise method. A Kaplan-Meier survival analysis was performed to evaluate the impact of solid tumor on prognosis in patients with acute HF. Results: A total of 3127 patients were included, of which 394 patients (13%) had a prior diagnosis of some type of solid cancer. Patients with a history of cancer presented a greater frequency of weight loss at admission: 18% vs. 12% (p = 0.030). In the cancer group, functional impairment was noted more frequently: 43% vs. 35%, p = 0.039). Patients with a history of solid cancer more frequently presented with acute HF with preserved ejection fraction (65% vs. 58%, p = 0.048) than reduced or mildly reduced. In-hospital and 6-month follow-up mortality was 31% (110/357) in patients with solid cancer vs. 26% (637/2466), p = 0.046. Conclusion: Our investigation demonstrates that in-hospital mortality and mortality during 6-month follow-up in patients with acute HF were higher in those subjects with a history of concomitant solid tumor cancer diagnosis

Riesgo de subsidencia kárstica en áreas urbanas: el caso de Zaragoza

Parte del monográfico "Riesgos geológicos externos".[EN] This paper deals with the problems generated by karst in gypsum around Zaragoza, the development of alluvial sinkholes and the concomitant risks. Sinkhole geometry depends on the mechanical behaviour of the cover overlying the evaporitic bedrock: non-cohesive soils favour the development of basin and funnel shaped dolines, whereas cohesive covers lead to the development of well-shaped collapses. Surface survey in areas prone to develop dolines is based on aerial photographs, in situ features (such as topographic depressions, stepped ground, anomalous man-made fills, wet-ground vegetation), and location of building pathologies in urban areas. In some cases, the structure and geometry of dolines can be studied in section (road cuts, for instance), where the features of natural fills allow to characterize the evolutionary patterns and sedimentation- subsidence interactions. Through dating of such fills the rate of subsidence can be estimated, and linked to possible episodes of climate variations. Doline evolution through time, either by comparison of aerial photographs taken in different years or by instrumental survey, yields the scenario of a dynamic process with subsidence rates up to 12 cm/year, where cycles of steady subsidence periods and sudden collapse are identified. In the Zaragoza area, the consequences of karst subsidence are outstanding. They dramatically increased from the 70’s, when large portions of the territory, formerly of agricultural use, turned into urban, industrial and service uses. Prevention and hazard management of karstic risks on urban and peri-urban areas must include: 1) early detection of the problem, in surface as well as underground (by means of geophysical surveys), and 2) adaptation of land use to the degree of affection by karst and the potential susceptibility. Geology, geotechnics and engineering have specific roles on risk management strategies by diminishing either the exposition to karst hazard or the vulnerability of man made structures.[ES] Este trabajo analiza, desde múltiples puntos de vista, la problemática del karst en yesos en el entorno de Zaragoza, el desarrollo de dolinas aluviales y los riesgos que éstas conllevan. La morfología de las dolinas depende del comportamiento mecánico de la cobertera situada sobre el sustrato yesífero: en coberteras sin cohesión aparecen morfologías en embudo y en cubeta, producidas por subsidencia continuada, mientras en coberteras con cohesión se producen dolinas en ventana provocadas por colapso brusco. El reconocimiento superficial de las dolinas se basa en la observación de fotografías aéreas, en el análisis visual del terreno (depresiones topográficas, escalones, áreas de vegetación o rellenos antrópicos anómalos) y en la observación y análisis de daños en áreas urbanizadas. También pueden estudiarse la geometría y la estructura interna de las dolinas en secciones del terreno donde éstas hayan quedado expuestas. Así, las características de sus rellenos naturales permiten conocer las pautas y tasas de evolución y las interacciones entre la subsidencia kárstica y los procesos sedimentarios. El estudio de la evolución temporal de las dolinas, a partir de la comparación de fotografías aéreas de distintos años o del seguimiento instrumental de las mismas, ha permitido reconocer que se trata de un proceso dinámico que llega a alcanzar velocidades de hundimiento de 12 cm/año. En dicha evolución es frecuente la ocurrencia cíclica de periodos de subsidencia lenta y eventos de hundimiento brusco. La afección causada por la subsidencia kárstica en Zaragoza es muy significativa. Ésta se incrementó a partir de los años 70 del siglo pasado, cuando buena parte del suelo agrícola que circundaba la ciudad fue destinado a uso urbano, industrial y grandes infraestructuras. La prevención y manejo del riesgo kárstico en áreas urbanas y peri-urbanas debe contemplar: (1) la detección precoz de los fenómenos tanto en superficie como en profundidad (a partir de estudios geofísicos), y (2) la adaptación del uso del suelo a su grado de afección por fenómenos kársticos y a su susceptibilidad potencial a los mismos. La geología, la geotecnia y la ingeniería desempeñan, cada una, un papel específico en la estrategia para reducir el riesgo, bien sea evitando la exposición al peligro o disminuyendo la vulnerabilidad de las construcciones.Peer reviewe