Magnetic carbon Fe3O4 nanocomposites synthesized via Magnetic Induction Heating.

Magnetic Induction Heating (MIH) of magnetite nanoparticles is employed as a novel synthesis procedure of carbon based magnetic nanocomposites. Magnetic nanoparticles (Fe3O4) and fructose (1:2 weight ratio) were mechanically mixed and submitted to a RF magnetic field (305 kHz). The heat generated by the nanoparticles leads to the decomposition of the sugar and to the formation of an amorphous carbon matrix. Two sets of nanoparticles, with mean diameter sizes of 20 and 100 nm, are comparatively analysed. Structural (X-ray diffraction, Raman spectroscopy, Transmission Electron Microscopy (TEM)), electrical and magnetic (resistivity, SQUID magnetometry) characterizations confirm the nanoparticle carbon coating through the MIH procedure. The percentage of the carbonaceous fraction is suitably increased controlling the magnetic heating capacity of the magnetic nanoparticles. The procedure enables the synthesis of multifunctional nanocomposites with optimized properties to be applied in different technological fields. Particularly, Cr (VI) removal from aqueous media is presented employing the carbon nanocomposite with 20 nm Fe3O4 nanoparticles.

Recomendaciones para la realización de broncoscopia y técnicas pleurales en la pandemia COVID-19 / No disponible

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Macrocycle modeling in ICM: benchmarking and evaluation in D3R Grand Challenge 4.

Macrocycles represent a potentially vast extension of drug chemical space still largely untapped by synthetic compounds. Sampling of flexible rings is incorporated in the ICM-dock protocol. We tested the ability of ICM-dock to reproduce macrocyclic ligand-protein receptor complexes, first in a large retrospective benchmark (246 complexes), and next, in context of the D3R Grand Challenge 4 (GC4), where we modeled bound complexes and predicted activities for a series of macrocyclic BACE inhibitors. Sub-angstrom accuracy was achieved in ligand pose prediction both in cross-docking (D3R Challenge Stage 1A) and cognate (Stage 1B) setup. Stage 1B submission was top ranked by mean and average RMSDs, even though no ligand knowledge was used in our simulations on this Stage. Furthermore, we demonstrate successful receptor conformational selection in Stage 1A, aided by the enhanced '4D' multiple receptor conformation docking protocol with optimized scoring offsets. In the activity 3D QSAR modeling, predictivity of the BACE pKd model was modest, while for the second target (Cathepsin-S), leading performance was achieved. Difference in activity prediction performance between the targets is likely explained by the amount of available and relevant training data.

Molecular Basis of Action of a Small-Molecule Positive Allosteric Modulator Agonist at the Type 1 Cholecystokinin Holoreceptor.

Allosteric modulation of receptors provides mechanistic safety while effectively achieving biologic endpoints otherwise difficult or impossible to obtain by other means. The theoretical case has been made for the development of a positive allosteric modulator (PAM) of the type 1 cholecystokinin receptor (CCK1R) having minimal intrinsic agonist activity to enhance meal-induced satiety for the treatment of obesity, while reducing the risk of side effects and/or toxicity. Unfortunately, such a drug does not currently exist. In this work, we have identified a PAM agonist of the CCK1R, SR146131, and determined its putative binding mode and receptor activation mechanism by combining molecular modeling, chimeric CCK1R/CCK2R constructs, and site-directed mutagenesis. We probed the structure-activity relationship of analogs of SR146131 for impact on agonism versus cooperativity of the analogs. This identified structural features that might be responsible for binding affinity and potency while retaining PAM activity. SR146131 and several of its analogs were docked into the receptor structure, which had the natural endogenous peptide agonist, cholecystokinin, already in the bound state (by docking), providing a refined structural model of the intact CCK1R holoreceptor. Both SR146131 and its analogs exhibited unique probe-dependent cooperativity with orthosteric peptide agonists and were simultaneously accommodated in this model, consistent with the derived structure-activity relationships. This provides improved understanding of the molecular basis for CCK1R-directed drug development.

Hybrid receptor structure/ligand-based docking and activity prediction in ICM: development and evaluation in D3R Grand Challenge 3.

In context of D3R Grand Challenge 3 we have investigated several ligand activity prediction protocols that combined elements of a physics-based energy function (ICM VLS score) and the knowledge-based Atomic Property Field 3D QSAR approach. Activity prediction models utilized poses produced by ICM-Dock with ligand bias and 4D receptor conformational ensembles (LigBEnD). Hybrid APF/P (APF/Physics) models were superior to pure physics- or knowledge-based models in our preliminary tests using rigorous three-fold clustered cross-validation and later proved successful in the blind prediction for D3R GC3 sets, consistently performing well across four different targets. The results demonstrate that knowledge-based and physics-based inputs into the machine-learning activity model can be non-redundant and synergistic.

Incidencia real de cáncer de próstata en las áreas sanitarias de la comunidad autónoma de Castilla y León durante el año 2014. Datos del registro CAPCYL / Actual incidence of prostate cancer in healthcare areas of the autonomous community of Castilla-Leon during 2014. CAPCYL registry data

Objetivo: Conocer la incidencia real de cáncer de próstata (CP) en las áreas sanitarias de Castilla y León en el año 2014. Material y métodos: Estudio multicéntrico en el que participan 7 de las 9 áreas sanitarias de Castilla y León. Se recogen datos con carácter retrospectivo que incluyen el 87,8% de la población diana (varones diagnosticados de CP con confirmación histopatológica en el año 2014). Se calculan incidencias brutas e incidencias ajustadas por edad según el método directo. Los datos epidemiológicos comunitarios y nacionales son consultados en el Instituto Nacional de Estadística. Resultados: Se diagnosticaron 1.198 nuevos casos de CP. La tasa de incidencia bruta comunitaria es 109,54 casos por 100.000 varones. Las tasas ajustadas a población española y europea resultan en 115,41 y 110,07, respectivamente. El grupo etario de mayor concentración diagnóstica fue el de 60-70 años, con el 41,97% de los diagnósticos, y el que mostró mayor incidencia fue el comprendido entre 70 y 80años, con 438,87 casos por 100.000 habitantes. Se objetivan diferencias en las incidencias brutas y ajustadas por grupo de edad, así como en el factor edad al diagnóstico entre las diferentes áreas sanitarias incluidas. Conclusiones: La tasa de incidencia bruta comunitaria resultó ser mayor que la mayoría de datos existentes previamente. Se aprecian importantes diferencias entre las distintas áreas geográficas que pueden ser explicadas principalmente por la distribución del factor edad y las políticas de cribado oportunista en cada una de ellas

Objective: To determine the actual incidence of prostate cancer (PC) in the healthcare areas of Castilla-Leon in 2014. Material and methods: A multicentre study was conducted with the participation of 7 of the 9 healthcare areas of Castilla-Leon. We collected retrospective data that included 87.8% of the target population (men diagnosed with PC with histopathological confirmation in 2014). We calculated the raw and age-adjusted incidence rates based on the direct method and consulted the community and national epidemiological data in the Spanish National Institute of Statistics. Results: A total of 1198 new cases of PC were diagnosed, with a raw incidence rate in the community of 109.54 cases per 100,000 men. The adjusted rates for the Spanish and European populations were 115.41 and 110.07, respectively. The age group with the highest diagnostic concentration was the 60-70-year group, with 41.97% of the diagnoses. The group with the highest incidence was the 70-80-year group, with 438.87 cases per 100,000 inhabitants. There were differences in the raw and age-adjusted incidence rates and in the age at diagnosis among the various included healthcare areas. Conclusions: The community raw incidence rate was higher than most existing data. We observed significant differences among the various geographical areas, which could be explained mainly by the age distribution and the opportunistic screening policies for each area

Mental health in girls and boys exposed to intimate partner violence.

OBJECTIVES: Children of abused women have a greater risk of mental health problems. This study assesses the association between women's exposure to intimate partner violence (IPV) and the mental health of their children in the population of the Madrid Region. STUDY DESIGN: Cross-sectional. METHODS: Data were drawn from the '2014 Survey on Intimate Partner Violence against Women in the Madrid Region'. Women meeting the definition of IPV answered the Strengths and Difficulties Questionnaire (SDQ) on the mental health of one of their children aged 4-16 years. The comparison group was made up of mother-child dyads that had not been exposed to IPV. We used multivariate analysis to assess whether the children of abused women had a greater probability of having higher SDQ subscale and total scores. RESULTS: A total of 209 mother-child dyads were analyzed, 64 exposed (50% boys) and 145 unexposed to IPV (51% boys). Exposure to IPV was associated with a high SDQ score (greater risk of mental health problems), with a prevalence ratio of 3.6 (95% CI 1.2-10.3) in girls and 2.4 (95% CI 1.1-5.1) in boys. Among girls, moreover, exposure to IPV was significantly associated with behavioral and inattention/hyperactivity problems. In conclusion, exposure to IPV was associated with an increased frequency of mental health problems among children in general, and girls in particular. CONCLUSIONS: This study reinforces the recommendations to conduct studies with data disaggregated by sex and to address the impact of IPV in mothers and children jointly.

Obstrucción de la vía aérea central por enfermedad inflamatoria intestinal y rescate terapéutico con membrana de oxigenación extracorpórea / Central airway obstruction due to inflammatory bowel disease and rescue with extracorporeal membrane oxygenation

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Tromboelastometría como guía de administración de hemoderivados en cirugía cardiaca / Thromboelastometry as guidance for blood management in patients undergoing cardiac surgery

Objetivo. La tromboelastometría evalúa la coagulación analizando la viscoelasticidad de una muestra de sangre. Nuestro objetivo principal fue evaluar los resultados de su uso como guía de administración de hemoderivados en cirugía cardiaca y, secundariamente, las complicaciones postoperatorias y el tiempo de hospitalización en UCI. Material y método. Estudio analítico, de intervención, cuasiexperimental, comparativo, no aleatorizado, prospectivo, con un grupo control retrospectivo. Se incluyeron 80 pacientes reintervenidos de cualquier cirugía cardiaca, o cirugías por endocarditis o del arco aórtico. En 31 pacientes los hemoderivados intraoperatorios se administraron según pautas clínicas tradicionales (grupo A). Los 49 pacientes restantes recibieron hemoderivados siguiendo algoritmos basados en el análisis tromboelastométrico (grupo B). El objetivo principal fue la administración de hemoderivados y los objetivos secundarios fueron: estancia en UCI y complicaciones postoperatorias. Resultados. Hubo una importante disminución en la administración de plasma fresco congelado en el grupo B respecto al A (p<0,001), así como una disminución en la transfusión intraoperatoria de sangre: 3,9 concentrados de hematíes de media por paciente en el grupo A frente a 2,67 en el grupo B (p=0,125). Se incrementó la administración de fibrinógeno, con una p<0,019. Se encontró una menor tasa de complicaciones respiratorias (p=0,019) en el grupo B y una reducción significativa de las estancias mayores de 7 días en el grupo B respecto al A (p=0,031). Conclusiones. La tromboelastometría condujo a una importante disminución en la utilización de plasma fresco congelado, contribuyendo muy probablemente al descenso en la incidencia de complicaciones respiratorias y en la menor estancia en UCI (AU)

Objective. Thromboelastometry is a viscoelastometric method for haemostasis testing in a whole blood sample. The aim of this study was to assess the results of using thromboelastometry as guidance for blood management in cardiac surgery, postoperative adverse events and ICU stay. Material and method. Analytical and comparative non-randomised quasi-experimental prospective study with a retrospective control group. The inclusion criteria for the 80 patients were: patients undergoing cardiac surgery who had had prior cardiac surgery, endocarditis surgery or aortic arch surgery. Thirty-one patients were treated following routine transfusion practice during surgery (group A). The other 49 patients were treated with thromboelastometrically guided transfusion algorithms (group B). The main objective was blood products transfused, and postoperative adverse events and ICU stay were the secondary objectives. Results. Statistical analysis showed lower transfusion rates of fresh-frozen plasma in group B compared to group A (P<.001), as well as red blood cell transfusion during surgery with an average transfusion rate of 3.9 units in group A in comparison to 2.67 units in group B (P=.125). Moreover, fibrinogen infusion was increased in group B compared to group A (P=.019). In addition, a lower rate of respiratory adverse events was found in group B (P=.019). There was a significant decrease in ICU stays over 7 days in group B compared to group A (P=.031). Conclusions. Using thromboelastometry guidance for blood management led to a meaningful reduction of fresh frozen plasma transfusion during surgery. This probably resulted in a reduction in respiratory adverse events after surgery and length of ICU stay in our patients (AU)

Actual incidence of prostate cancer in healthcare areas of the autonomous community of Castilla-Leon during 2014. CAPCYL registry data. / Incidencia real de cáncer de próstata en las áreas sanitarias de la comunidad autónoma de Castilla y León durante el año 2014. Datos del registro CAPCYL.

OBJECTIVE: To determine the actual incidence of prostate cancer (PC) in the healthcare areas of Castilla-Leon in 2014. MATERIAL AND METHODS: A multicentre study was conducted with the participation of 7 of the 9 healthcare areas of Castilla-Leon. We collected retrospective data that included 87.8% of the target population (men diagnosed with PC with histopathological confirmation in 2014). We calculated the raw and age-adjusted incidence rates based on the direct method and consulted the community and national epidemiological data in the Spanish National Institute of Statistics. RESULTS: A total of 1198 new cases of PC were diagnosed, with a raw incidence rate in the community of 109.54 cases per 100,000 men. The adjusted rates for the Spanish and European populations were 115.41 and 110.07, respectively. The age group with the highest diagnostic concentration was the 60-70-year group, with 41.97% of the diagnoses. The group with the highest incidence was the 70-80-year group, with 438.87 cases per 100,000 inhabitants. There were differences in the raw and age-adjusted incidence rates and in the age at diagnosis among the various included healthcare areas. CONCLUSIONS: The community raw incidence rate was higher than most existing data. We observed significant differences among the various geographical areas, which could be explained mainly by the age distribution and the opportunistic screening policies for each area.

Thromboelastometry as guidance for blood management in patients undergoing cardiac surgery. / Tromboelastometría como guía de administración de hemoderivados en cirugía cardiaca.

OBJECTIVE: Thromboelastometry is a viscoelastometric method for haemostasis testing in a whole blood sample. The aim of this study was to assess the results of using thromboelastometry as guidance for blood management in cardiac surgery, postoperative adverse events and ICU stay. MATERIAL AND METHOD: Analytical and comparative non-randomised quasi-experimental prospective study with a retrospective control group. The inclusion criteria for the 80 patients were: patients undergoing cardiac surgery who had had prior cardiac surgery, endocarditis surgery or aortic arch surgery. Thirty-one patients were treated following routine transfusion practice during surgery (group A). The other 49 patients were treated with thromboelastometrically guided transfusion algorithms (group B). The main objective was blood products transfused, and postoperative adverse events and ICU stay were the secondary objectives. RESULTS: Statistical analysis showed lower transfusion rates of fresh-frozen plasma in group B compared to group A (P<.001), as well as red blood cell transfusion during surgery with an average transfusion rate of 3.9 units in group A in comparison to 2.67 units in group B (P=.125). Moreover, fibrinogen infusion was increased in group B compared to group A (P=.019). In addition, a lower rate of respiratory adverse events was found in group B (P=.019). There was a significant decrease in ICU stays over 7 days in group B compared to group A (P=.031). CONCLUSIONS: Using thromboelastometry guidance for blood management led to a meaningful reduction of fresh frozen plasma transfusion during surgery. This probably resulted in a reduction in respiratory adverse events after surgery and length of ICU stay in our patients.

Ligand-biased ensemble receptor docking (LigBEnD): a hybrid ligand/receptor structure-based approach.

Ligand docking to flexible protein molecules can be efficiently carried out through ensemble docking to multiple protein conformations, either from experimental X-ray structures or from in silico simulations. The success of ensemble docking often requires the careful selection of complementary protein conformations, through docking and scoring of known co-crystallized ligands. False positives, in which a ligand in a wrong pose achieves a better docking score than that of native pose, arise as additional protein conformations are added. In the current study, we developed a new ligand-biased ensemble receptor docking method and composite scoring function which combine the use of ligand-based atomic property field (APF) method with receptor structure-based docking. This method helps us to correctly dock 30 out of 36 ligands presented by the D3R docking challenge. For the six mis-docked ligands, the cognate receptor structures prove to be too different from the 40 available experimental Pocketome conformations used for docking and could be identified only by receptor sampling beyond experimentally explored conformational subspace.

Giant direct and inverse magnetocaloric effect linked to the same forward martensitic transformation.

Metamagnetic shape memory alloys have aroused considerable attraction as potential magnetic refrigerants due to the large inverse magnetocaloric effect associated to the magnetic-field-induction of a reverse martensitic transformation (martensite to austenite). In some of these alloys, the austenite phase can be retained on cooling under high magnetic fields, being the retained phase metastable after field removing. Here, we report a giant direct magnetocaloric effect linked to the anomalous forward martensitic transformation (austenite to martensite) that the retained austenite undergoes on heating. Under moderate fields of 10 kOe, an estimated adiabatic temperature change of 9 K has been obtained, which is (in absolute value) almost twice that obtained in the conventional transformation under higher applied fields. The observation of a different sign on the temperature change associated to the same austenite to martensite transformation depending on whether it occurs on heating (retained) or on cooling is attributed to the predominance of the magnetic or the vibrational entropy terms, respectively.

Gender-specific impairment of in vitro sinoatrial node chronotropic responses and of myocardial ischemia tolerance in rats exposed prenatally to betamethasone.

Excessive fetal glucocorticoid exposure has been linked to increased susceptibility to hypertension and cardiac diseases in the adult life, a process called fetal programming. The cardiac contribution to the hypertensive phenotype of glucocorticoid-programmed progeny is less known, therefore, we investigated in vitro cardiac functional parameters from rats exposed in utero to betamethasone. Pregnant Wistar rats received vehicle (VEH) or betamethasone (BET, 0.1mg/kg, i.m.) at gestational days 12, 13, 18 and 19. Male and female offspring were killed at post-natal day 30 and the right atrium (RA) was isolated to in vitro evaluation of drug-induced chronotropic responses. Additionally, whole hearts were retrograde-perfused in a Langendorff apparatus and infarct size in response to in vitro ischemia/reperfusion (I/R) protocol was evaluated. Male and female progeny from BET-exposed pregnant rats had reduced birth weight, a hallmark of fetal programming. Male BET-progeny had increased basal RA rate, impaired chronotropic responses to noradrenaline and adenosine, and increased myocardial damage to I/R. Though a 12-fold reduction in the negative chronotropic responses to adenosine, the effects of non-metabolisable adenosine receptor agonists 5'-(N-ethylcarboxamido)adenosine or 2-Chloro-adenosine were not different between VEH- and BET-exposed male rats. BET-exposed female offspring presented no cardiac dysfunction. Prenatal BET exposure engenders male-specific impairment of sinoatrial node function and on myocardial ischemia tolerance resulting, at least in part, from an increased adenosine metabolism in the heart. In light of the importance of adenosine in the cardiac physiology our results suggest a link between reduced adenosinergic signaling and the cardiac dysfunctions observed in glucocorticoid-induced fetal programming.

Personality traits and dental anxiety in self-reported bruxism. A cross-sectional study.

OBJECTIVES: The aim of this study was to investigate the association between psychological factors (Personality and Dental anxiety) with self-reported bruxism-related symptoms. METHODS: 526 subjects, over 18 years old and not seeking dental treatment, were recruited from the families and acquaintances of dental students from the University of Salamanca. Bruxism activity was estimated by means of a six-item questionnaire aimed at recording common bruxism-related symptoms and clenching/grinding awareness. The Spanish version of the modified dental anxiety scale (MDAS) was used to determine the level of anxiety perceived in 5 typical scenarios of dental assistance. The NEO-FFI inventory was applied to assess personality profiles associated with 5 different factors (neuroticism, extroversion, openness, agreeableness, and conscientiousness). Pearson correlations, Student T-tests, and logistic regression modelling were used for the statistical analyses. RESULTS: Thirty-five point nine percent of this adults sample was classified as being bruxers, where sleep bruxers comprised more than half of the sample at 20.2%. Bruxers tended to perceive more anxiety in all of the situations included within the MDAS, where they exhibited a higher level of phobia towards the teeth scaling and local anaesthetic injection. The risk of being considered a bruxer is reduced with age (OR: 0.99), and increases proportionally for some personality traits, such as neuroticism (OR: 1.06) and extraversion(OR: 1.04), to the MDAS total score (OR: 1.08) and in smokers (OR: 1.61), after controlling for all potentially confounding factors. CONCLUSIONS: Self-reported bruxism is significantly associated to several personality traits (mainly neuroticism and extraversion) and to the level of dental anxiety (MDAS score). CLINICAL SIGNIFICANCE: Clinicians should be aware of the typical psychological profiles of patients who experience bruxism and the relationship with dental phobias.

Bivalent Carbamates as Novel Control Agents of the Malaria Mosquito, Anopheles gambiae.

Widespread pyrethroid resistance has caused an urgent need to develop new insecticides for control of the malaria mosquito, Anopheles gambiae. Insecticide discovery efforts were directed towards the construction of bivalent inhibitors that occupy both the peripheral and catalytic sites of the mosquito acetylcholinesterase (AChE). It was hypothesized that this approach would yield a selective, high potency inhibitor that would also circumvent known catalytic site mutations (e.g. G119S) causing target site resistance. Accordingly, a series of bivalent phthalimide-pyrazole carbamates were prepared having an alkyl chain linker of varying length, along with other modifications. The most active compound was (1-(3-(1,3-dioxoisoindolin-2-yl)propyl)-1H-pyrazol-4-yl methylcarbamate, 8a), which has a chain length of three carbons, good mosquito anticholinesterase activity, and ca. 5-fold selectivity compared to human AChE. Moreover, this compound was toxic to mosquitoes by topical application (LD50 = 63 ng/female) with only 6-fold cross resistance in the Akron strain of Anopheles gambiae that showed 50- to 60-fold resistance to conventional carbamate insecticides. However, contact lethality in the WHO paper assay was disappointing. The implications of these results for design of new mosquitocides are discussed.

Use of Cysteine Trapping to Map Spatial Approximations between Residues Contributing to the Helix N-capping Motif of Secretin and Distinct Residues within Each of the Extracellular Loops of Its Receptor.

Amino-terminal regions of secretin-family peptides contain key determinants for biological activity and binding specificity, although the nature of interactions with receptors is unclear. A helix N-capping motif within this region has been postulated to directly contribute to agonist activity while also stabilizing formation of a helix extending toward the peptide carboxyl terminus and docking within the receptor amino terminus. We used cysteine trapping to systematically explore spatial approximations between cysteines replacing each residue in this motif of secretin (sec), Phe(6), Thr(7), and Leu(10), and cysteines incorporated into the extracellular face of the receptor. Each peptide was a full agonist for cAMP, but had a lower binding affinity than natural hormone. These bound to COS cells expressing 61 receptor constructs incorporating cysteines in every position along each extracellular loop (ECL) and adjacent parts of transmembrane (TM) segments. Patterns of covalent labeling were distinct for each probe, with Cys(6)-sec labeling multiple residues in the carboxyl-terminal half of ECL2 and throughout ECL3, Cys(7)-sec predominantly labeling only single residues in the carboxyl-terminal end of ECL2 and the amino-terminal end of ECL3, and Cys(10)-sec not efficiently labeling any of these residues. These spatial constraints were used to refine our model of secretin bound to its receptor, now bringing ECL3 above the amino terminus of the ligand and revealing possible charge-charge interactions between this part of secretin and receptor residues in TM5, TM6, ECL2, and ECL3, which can orient and stabilize the peptide-receptor complex. This was validated by testing predicted approximations by mutagenesis and residue-residue complementation studies.