Metabotropic Ca2+ channel-induced Ca2+ release and ATP-dependent facilitation of arterial myocyte contraction

Voltage-gated Ca2_ channels in arterial myocytes can mediate Ca2_ release from the sarcoplasmic reticulum and, thus, induce contraction without the need of extracellular Ca2_ influx. This metabotropic action of Ca2_ channels (denoted as calcium-channelinduced calcium release or CCICR) involves activation of G proteins and the phospholipase C-inositol 1,4,5-trisphosphate pathway. Here, we show a form of vascular tone regulation by extracellular ATP that depends on the modulation of CCICR. In isolated arterial myocytes, ATP produced facilitation of Ca2_-channel activation and, subsequently, a strong potentiation of CCICR. The facilitation of L-type channel still occurred after full blockade of purinergic receptors and inhibition of G proteins with GDP_S, thus suggesting that ATP directly interacts with Ca2_ channels. The effects of ATP appear to be highly selective, because they were not mimicked by other nucleotides (ADP or UTP) or vasoactive agents, such as norepinephrine, acetylcholine, or endothelin-1. We have also shown that CCICR can trigger arterial cerebral vasoconstriction in the absence of extracellular calcium and that this phenomenon is greatly facilitated by extracellular ATP. Although, at low concentrations, ATP does not induce arterial contraction per se, this agent markedly potentiates contractility of partially depolarized or primed arteries. Hence, the metabotropic action of L-type Ca2_ channels could have a high impact on vascular pathophysiology, because, even in the absence of Ca2_ channel opening, it might mediate elevations of cytosolic Ca2_ and contraction in partially depolarized vascular smooth muscle cells exposed to small concentrations of agonists

Stip: un espacio para la participación, la formación y la investigación co-protagonizado por estudiantes y profesorado desde la didáctica de las Ciencias Sociales

Existe una demanda creciente por parte de maestros y maestras en formación inicial hacia una mayor implicación en procesos formativos y de investigación que implemente el contenido de las asignaturas. También se hacen necesarios otros entornos de trabajo y aprendizaje de carácter más dinámico, horizontal y participativo que tengan a profesorado y estudiantes como elementos motores de la comunidad educativa. La educación democrática y la investigación-acción-participativa son fuentes de conocimiento y metodologías que nos facilitan la toma en consideración de los intereses, necesidades, sueños, dudas e incertidumbres que estudiantes y profesorado necesitamos compartir. El Seminario de Trabajo e Investigación Permanente “STIP” surge con esta pretensión en marzo de 2014 como laboratorio de iniciativas y proyectos, y lo hace como cierre de la asignatura de Conocimiento del Entorno Social en el Grado de Educación Infantil, en la Facultad de Ciencias de la Educación, Universidad de Sevilla.There is a growing demand by teachers in initial training for more involvement in the training processes and research that implements the content of the subjects. Also necessary make other environments of work and learning more dynamic, horizontal and participatory character having the teachers and students working together in the educational community. Democratic education and action research - participatory are sources of knowledge and methodologies that facilitate the taking into account of the interests, needs, dreams, doubts and uncertainties that students and teachers need to share. Seminar work and research permanent "STIP" cames with this claim in March 2014 as a laboratory for initiatives and projects, and maked it as a closure of the subject's knowledge of the Social environment in the degree of early childhood education in the Faculty of Sciences of Education, University of Seville

Post-Graduate Course in Selection and Management with Antimicrobial in Respiratory and Urinary Infections

Background: one of the pharmacologic groups of bigger prescription and use in Primary Health Attention, for his efficacy in the treatment of multiple infections constitute the antimicrobial. Previous studies evidence that there are difficulties in their prescription by doctors of this level of attention. Objective: designing a post-graduate course about the suitable selection and management of the antimicrobial in respiratory and urinary infections in primary health attention. Methods: a descriptive study, accomplished at the University of Medical Sciences of Cienfuegos, shaped for three stages: diagnosis of the level of knowledge taking as sample 113 comprehensive general doctors of all the health areas of Cienfuegos; the course's design, and its validation by consulting experts. They were considered the recommendations of the guides and protocols with the best available scientific evidences about the theme. Results: the majority of the inquired individuals presented a level of knowledge between middle and low about the theme. The course was structured in five themes, with its respective objectives, organizational teaching forms, methodological guidelines, methods and teaching aids. The experts validated the course and considered it feasible, pertinent and of lofty quality. Conclusions: the course can contribute to the increment of doctor’s knowledge of the family about a selection and management of antimicrobial in the most frequent infections in Primary Health Attention, and therefore, to upgrade medical attention to the patient

Post-Graduate Course in Selection and Management with Antimicrobial in Respiratory and Urinary Infections

Background: one of the pharmacologic groups of bigger prescription and use in Primary Health Attention, for his efficacy in the treatment of multiple infections constitute the antimicrobial. Previous studies evidence that there are difficulties in their prescription by doctors of this level of attention. Objective: designing a post-graduate course about the suitable selection and management of the antimicrobial in respiratory and urinary infections in primary health attention. Methods: a descriptive study, accomplished at the University of Medical Sciences of Cienfuegos, shaped for three stages: diagnosis of the level of knowledge taking as sample 113 comprehensive general doctors of all the health areas of Cienfuegos; the course's design, and its validation by consulting experts. They were considered the recommendations of the guides and protocols with the best available scientific evidences about the theme. Results: the majority of the inquired individuals presented a level of knowledge between middle and low about the theme. The course was structured in five themes, with its respective objectives, organizational teaching forms, methodological guidelines, methods and teaching aids. The experts validated the course and considered it feasible, pertinent and of lofty quality. Conclusions: the course can contribute to the increment of doctor’s knowledge of the family about a selection and management of antimicrobial in the most frequent infections in Primary Health Attention, and therefore, to upgrade medical attention to the patient

Bronchopulmonary Penetration of Isavuconazole in Pulmonary Transplant Recipients (PBISA01): Protocol for a Phase IV Clinical Trial With a Single Treatment Arm

Background: Aspergillosis is the most frequently observed invasive fungal disease (IFD) in lung transplant recipients. Isavuconazole (ISA) has shown a better safety profile and noninferiority to voriconazole in the treatment of patients with IFD. Objective: The aim of this study is to describe the bronchopulmonary pharmacokinetic profile of oral ISA by analyzing the degree of penetration in the epithelial lining fluid and alveolar macrophages in patients receiving lung transplantation with a diagnosis of IFD. Methods: A total of 12 patients aged ≥18 years receiving a lung transplant with an IFD diagnosis and indication for ISA treatment and follow-up bronchoscopy will be included in the study. After 5 days of treatment with ISA and before the treatment is discontinued, the patients will be randomized (1:1:1:1) to perform the scheduled bronchoscopy at various times after the administration of ISA (2, 4, 8, and 12 hours). In total, 4 blood samples will be obtained per patient: at 72 hours after treatment initiation, on the day of the bronchoscopy, at the time of the bronchoalveolar lavage (simultaneously), and at 7 days after treatment initiation, to analyze tacrolimus and ISA plasma levels. ISA concentrations will be measured in plasma, epithelial lining fluid, and alveolar macrophages by a high-performance liquid chromatography/UV coupled to fluorescence method. Results: Enrollment for the PBISA01 trial began in October 2020 and was completed in October 2021. All samples will be analyzed once recruitment is complete, and the results are expected to be published in October 2022. Conclusions: There are no clinical studies that analyze the bronchopulmonary penetration of ISA. Bronchoalveolar lavage performed routinely in the follow-up of lung transplant recipients constitutes an opportunity to analyze the bronchopulmonary penetration of ISA. Trial registration: European Clinical Trials Register 2019-004240-30; www.clinicaltrialsregister.eu/ctr-search/trial/2019-004240-30/ES. International registered report identifier (irrid): DERR1-10.2196/37275.This work is supported funded by Pfizer (grant 54685521). Pfizer will have no role in the study’s design; the collection, management, analysis, and interpretation of data; writing of the report; and the decision to submit the report for publication.S

Bronchopulmonary penetration of isavuconazole in lung transplant recipients

Isavuconazole's (ISA) pharmacokinetics was studied among lung transplant recipients to evaluate its bronchopulmonary penetration. This study included 13 patients and showed mean serum concentrations of 3.30 (standard deviation [SD] 0.45), 5.12 (SD 1.36), and 6.31 (SD 0.95) at 2 h, 4 h, and 24 h respectively. Mean concentrations in the epithelial lining fluid were 0.969 (SD 0.895), 2.141 (SD 1.265), and 2.812 (SD 0.693) at the same time points. ISA is a drug with a tolerable safety profile that achieves adequate concentrations in the lung.This work was partially supported and funded by Pfizer (grant 54685521). Pfizer had no role in the study’s design; the collection, management, analysis, and interpretation of data; writing of the report; and the decision to submit the report for publicationS

Multicomponent Synthesis of Unsaturated γ-Lactam Derivatives. Applications as Antiproliferative Agents through the Bioisosterism Approach: Carbonyl vs. Phosphoryl Group

We report efficient synthetic methodologies for the preparation of 3-amino and 3-hydroxy 3-pyrrolin-2-ones (unsaturated γ-lactams) through a multicomponent reaction of amines, aldehydes and acetylene or pyruvate derivatives. The densely substituted γ-lactam substrates show in vitro cytotoxicity, inhibiting the growth of the carcinoma human tumor cell lines RKO (human colon epithelial carcinoma), SKOV3 (human ovarian carcinoma) and A549 (carcinomic human alveolar basal epithelial cell). In view of the possibilities for the diversity of the substituents that offer a multicomponent, synthetic methodology, an extensive structure–activity profile is presented. In addition, the bioisosteric replacement of the flat ester group by a tetrahedral phosphonate or phosphine oxide moiety in γ-lactam substrates leads to increased growth inhibition activity. Cell morphology analysis and flow cytometry assays indicate that the main pathway by which our compounds induce cytotoxicity is based on the activation of the intracellular apoptotic mechanism.Financial support by Ministerio de Economía, Industria y Competividad (MINECO) (RTI2018-101818-B-I00) and Gobierno Vasco (GV, IT 992-16) is gratefully acknowledged. X.d.C. and A.L.-F. thank the Basque Country Government for a predoctoral grant. I.V.-B. thanks the University of the Basque Country (UPV/EHU) for a postdoctoral fellowship (ESPDOC19/47). M.S.-R. thanks the University of the Basque Country (UPV/EHU) for a pre-doctoral fellowship (PIF17/79)

Curso abierto de ayuda para la elaboración del Trabajo Fin de Grado en los Grados en Química e Ingeniería Química

Este proyecto llevará a cabo el desarrollo de un curso abierto que sirva a los estudiantes como guía de ayuda a la hora de elaborar su Trabajo Fin de Grado (TFG) en los Grados de Química e Ingeniería Química. Se incluirá una descripción de herramientas que los estudiantes puedan emplear en el desarrollo de sus TFG. Éstas serán seleccionadas de acuerdo con la experiencia de los miembros del Grupo y en función de las necesidades de los estudiantes. El curso resultante se editará para libre acceso a través del portal iTunes U, de ámbito internacional, convirtiéndose en el primer curso UCM ofertado en esta plataforma (tras consulta y aprobación del Vicerrectorado de Innovación; de no ser así, se alojará en alguna otra plataforma de amplia difusión). Se aprovechará la accesibilidad ofertada a los estudiantes por iTunes U para poner a su disposición el material elaborado logrando una gran difusión, incrementándose la visibilidad internacional de la UCM. El material de ayuda elaborado para el curso se presentará tanto en español como en inglés, para facilitar su uso por alumnos visitantes de la UCM, favoreciendo la movilidad de los estudiantes en el marco del EEES. Este material también se adaptará para poder ser empleado de forma directa, totalmente o en forma de módulos, en el Campus Virtual UCM

Effect of a Pulmonary Embolism Diagnostic Strategy on Clinical Outcomes in Patients Hospitalized for COPD Exacerbation. A Randomized Clinical Trial

SLICE Trial Group.[Importance] Active search for pulmonary embolism (PE) may improve outcomes in patients hospitalized for exacerbations of chronic obstructive pulmonary disease (COPD).[Objective] To compare usual care plus an active strategy for diagnosing PE with usual care alone in patients hospitalized for COPD exacerbation.[Design, Setting, and Participants] Randomized clinical trial conducted across 18 hospitals in Spain. A total of 746 patients were randomized from September 2014 to July 2020 (final follow-up was November 2020).[Interventions] Usual care plus an active strategy for diagnosing PE (D-dimer testing and, if positive, computed tomography pulmonary angiogram) (n = 370) vs usual care (n = 367).[Main Outcomes and Measures] The primary outcome was a composite of nonfatal symptomatic venous thromboembolism (VTE), readmission for COPD, or death within 90 days after randomization. There were 4 secondary outcomes, including nonfatal new or recurrent VTE, readmission for COPD, and death from any cause within 90 days. Adverse events were also collected.[Results] Among the 746 patients who were randomized, 737 (98.8%) completed the trial (mean age, 70 years; 195 [26%] women). The primary outcome occurred in 110 patients (29.7%) in the intervention group and 107 patients (29.2%) in the control group (absolute risk difference, 0.5% [95% CI, −6.2% to 7.3%]; relative risk, 1.02 [95% CI, 0.82-1.28]; P = .86). Nonfatal new or recurrent VTE was not significantly different in the 2 groups (0.5% vs 2.5%; risk difference, −2.0% [95% CI, −4.3% to 0.1%]). By day 90, a total of 94 patients (25.4%) in the intervention group and 84 (22.9%) in the control group had been readmitted for exacerbation of COPD (risk difference, 2.5% [95% CI, −3.9% to 8.9%]). Death from any cause occurred in 23 patients (6.2%) in the intervention group and 29 (7.9%) in the control group (risk difference, −1.7% [95% CI, −5.7% to 2.3%]). Major bleeding occurred in 3 patients (0.8%) in the intervention group and 3 patients (0.8%) in the control group (risk difference, 0% [95% CI, −1.9% to 1.8%]; P = .99).[Conclusions and Relevance] Among patients hospitalized for an exacerbation of COPD, the addition of an active strategy for the diagnosis of PE to usual care, compared with usual care alone, did not significantly improve a composite health outcome. The study may not have had adequate power to assess individual components of the composite outcome.[Trial Registration] ClinicalTrials.gov Identifier: NCT02238639.Peer reviewe