Generation of Self-Induced Myocardial Ischemia in Large-Sized Cardiac Spheroids without Alteration of Environmental Conditions Recreates Fibrotic Remodeling and Tissue Stiffening Revealed by Constriction Assays.

A combination of human-induced pluripotent stem cells (hiPSCs) and 3D microtissue culture techniques allows the generation of models that recapitulate the cardiac microenvironment for preclinical research of new treatments. In particular, spheroids represent the simplest approach to culture cells in 3D and generate gradients of cellular access to the media, mimicking the effects of an ischemic event. However, previous models required incubation under low oxygen conditions or deprived nutrient media to recreate ischemia. Here, we describe the generation of large spheroids (i.e., larger than 500 µm diameter) that self-induce an ischemic core. Spheroids were generated by coculture of cardiomyocytes derived from hiPSCs (hiPSC-CMs) and primary human cardiac fibroblast (hCF). In the proper medium, cells formed aggregates that generated an ischemic core 2 days after seeding. Spheroids also showed spontaneous cellular reorganization after 10 days, with hiPSC-CMs located at the center and surrounded by hCFs. This led to an increase in microtissue stiffness, characterized by the implementation of a constriction assay. All in all, these phenomena are hints of the fibrotic tissue remodeling secondary to a cardiac ischemic event, thus demonstrating the suitability of these spheroids for the modeling of human cardiac ischemia and its potential application for new treatments and drug research.

Let's call! Using the phone to increase vaccine acceptance.

In the context of the COVID-19 pandemic, we develop and test experimentally three phone-based interventions to increase vaccine acceptance in Mozambique. The first endorses the vaccine with a simple positive message. The second adds the activation of social memory on the country's success in eradicating wild polio with vaccination campaigns. The third further adds a structured interaction with the participant to develop a critical view toward misleading information and minimize the sharing of fake news. We find that combining the endorsement with the stimulation of social memory and the structured interaction increases vaccine acceptance and trust in institutions.

Unveiling the biopathway for the design of novel COMT inhibitors.

Catechol-O-methyltransferase (COMT) is an enzyme responsible for the O-methylation of biologically active catechol-based molecules. It has been associated with several neurological disorders, especially Parkinson's disease (PD), because of its involvement in catecholamine metabolism, and has been considered an important therapeutic target for central nervous system disorders. In this review, we summarize the biophysical, structural, and therapeutical relevance of COMT; the medicinal chemistry behind the development of COMT inhibitors and the application of computer-aided design to support the design of novel molecules; current methodologies for the biosynthesis, isolation, and purification of COMT; and revise existing bioanalytical approaches for the assessment of enzymatic activity in several biological matrices.

10ß-Hydroxyestra-1,4-diene-3,17-dione as potential antiproliferative agent: in vitro biological evaluation and in silico studies.

10ß-Hydroxyestra-1,4-diene-3,17-dione (HEDD) is a natural product described as having neuroprotective activity. However, the cytotoxic properties of this quinol are barely studied. Thus, the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was performed in six cell lines (MCF-7, T47-D, LNCaP, HepaRG, Caco-2 and NHDF). Additionally, an in vitro estrogenicity assay and a cell viability analysis together with in silico molecular docking studies were carried out in order to understand the potential mechanism of cytotoxicity. Computational predictions of its pharmacokinetic and toxicity properties were also performed. Surprisingly, HEDD displayed marked cytotoxic activity, particularly against hormone-dependent cancer cells and the flow cytometry analysis revealed that HEDD markedly reduced the viability of hepatic cancer cells. Molecular docking studies suggested a high affinity towards the estrogen receptor α and 17ß-hydroxysteroid dehydrogenase type 1. Moreover, it was predicted that HEDD may have good oral bioavailability and a low maximum tolerated dose in humans.

Enhanced Stability of Detergent-Free Human Native STEAP1 Protein from Neoplastic Prostate Cancer Cells upon an Innovative Isolation Procedure.

BACKGROUND: The STEAP1 is a cell-surface antigen over-expressed in prostate cancer, which contributes to tumor progression and aggressiveness. However, the molecular mechanisms underlying STEAP1 and its structural determinants remain elusive. METHODS: The fraction capacity of Butyl- and Octyl-Sepharose matrices on LNCaP lysates was evaluated by manipulating the ionic strength of binding and elution phases, followed by a Co-Immunoprecipitation (Co-IP) polishing. Several potential stabilizing additives were assessed, and the melting temperature (Tm) values ranked the best/worst compounds. The secondary structure of STEAP1 was identified by circular dichroism. RESULTS: The STEAP1 was not fully captured with 1.375 M (Butyl), in contrast with interfering heterologous proteins, which were strongly retained and mostly eluted with water. This single step demonstrated higher selectivity of Butyl-Sepharose for host impurities removal from injected crude samples. Co-IP allowed recovering a purified fraction of STEAP1 and contributed to unveil potential physiologically interacting counterparts with the target. A Tm of ~55 °C was determined, confirming STEAP1 stability in the purification buffer. A predominant α-helical structure was identified, ensuring the protein's structural stability. CONCLUSIONS: A method for successfully isolating human STEAP1 from LNCaP cells was provided, avoiding the use of detergents to achieve stability, even outside a membrane-mimicking environment.

Recent Developments in New Therapeutic Agents against Alzheimer and Parkinson Diseases: In-Silico Approaches.

Neurodegenerative diseases (ND), including Alzheimer's (AD) and Parkinson's Disease (PD), are becoming increasingly more common and are recognized as a social problem in modern societies. These disorders are characterized by a progressive neurodegeneration and are considered one of the main causes of disability and mortality worldwide. Currently, there is no existing cure for AD nor PD and the clinically used drugs aim only at symptomatic relief, and are not capable of stopping neurodegeneration. Over the last years, several drug candidates reached clinical trials phases, but they were suspended, mainly because of the unsatisfactory pharmacological benefits. Recently, the number of compounds developed using in silico approaches has been increasing at a promising rate, mainly evaluating the affinity for several macromolecular targets and applying filters to exclude compounds with potentially unfavorable pharmacokinetics. Thus, in this review, an overview of the current therapeutics in use for these two ND, the main targets in drug development, and the primary studies published in the last five years that used in silico approaches to design novel drug candidates for AD and PD treatment will be presented. In addition, future perspectives for the treatment of these ND will also be briefly discussed.

Online monitoring of hiPSC expansion and hepatic differentiation in 3D culture by dielectric spectroscopy.

Hepatocyte-like cells derived from human-induced pluripotent stem cells (hiPSC-HLC) are expected to have important applications in drug screening and regenerative medicine. However, hiPSC-HLC are difficult to produce on a large-scale to obtain relevant numbers for such applications. The aim of this study was to implement a novel integrated strategy for scalable production of hiPSC-HLC and demonstrate the applicability of dielectric spectroscopy to monitor hiPSC expansion/differentiation processes. We cultured hiPSC as three-dimensional (3D) aggregates in stirred-tank bioreactors (STB) operated in perfusion with an in situ capacitance probe. Dissolved oxygen concentration and dilution rate were controlled along the process and after 5 days of cell expansion, the hepatic differentiation was integrated in sequential steps for 28 days. The hiPSC were able to grow as 3D aggregates and the expression of hepatic markers and albumin production after differentiation confirmed that hepatocyte differentiation improved when compared to 2D culture. These hiPSC-HLC exhibited functional characteristics of hepatocytes including glycogen storage and drug metabolization capacity. Our results also show a good correlation between the cell permittivity measured online and the aggregate biovolume measured by standard offline methods, demonstrating for the first time the potential of dielectric spectroscopy to monitor hiPSC expansion and differentiation in STB.

Recent Developments in the Determination of Biomarkers of Tobacco Smoke Exposure in Biological Specimens: A Review.

Environmental tobacco smoke exposure (ETS) and smoking have been described as the most prevalent factors in the development of certain diseases worldwide. According to the World Health Organization, more than 8 million people die every year due to exposure to tobacco, around 7 million due to direct ETS and the remaining due to exposure to second-hand smoke. Both active and second-hand exposure can be measured and controlled using specific biomarkers of tobacco and its derivatives, allowing the development of more efficient public health policies. Exposure to these compounds can be measured using different methods (involving for instance liquid- or gas-chromatographic procedures) in a wide range of biological specimens to estimate the type and degree of tobacco exposure. In recent years, a lot of research has been carried out using different extraction methods and different analytical equipment; this way, liquid-liquid extraction, solid-phase extraction or even miniaturized procedures have been used, followed by chromatographic analysis coupled mainly to mass spectrometric detection. Through this type of methodologies, second-hand smokers can be distinguished from active smokers, and this is also valid for e-cigarettes and vapers, among others, using their specific biomarkers. This review will focus on recent developments in the determination of tobacco smoke biomarkers, including nicotine and other tobacco alkaloids, specific nitrosamines, polycyclic aromatic hydrocarbons, etc. The methods for their detection will be discussed in detail, as well as the potential use of threshold values to distinguish between types of exposure.

Discovery of Small Molecules as Membrane-Bound Catechol-O-methyltransferase Inhibitors with Interest in Parkinson's Disease: Pharmacophore Modeling, Molecular Docking and In Vitro Experimental Validation Studies.

A pharmacophore-based virtual screening methodology was used to discover new catechol-O-methyltransferase (COMT) inhibitors with interest in Parkinson's disease therapy. To do so, pharmacophore models were constructed using the structure of known inhibitors and then they were used in a screening in the ZINCPharmer database to discover hit molecules with the desired structural moieties and drug-likeness properties. Following this, the 50 best ranked molecules were submitted to molecular docking to better understand their atomic interactions and binding poses with the COMT (PDB#6I3C) active site. Additionally, the hits' ADMET properties were also studied to improve the obtained results and to select the most promising compounds to advance for in-vitro studies. Then, the 10 compounds selected were purchased and studied regarding their in-vitro inhibitory potency on human recombinant membrane-bound COMT (MBCOMT), as well as their cytotoxicity in rat dopaminergic cells (N27) and human dermal fibroblasts (NHDF). Of these, the compound ZIN27985035 displayed the best results: For MBCOMT inhibition an IC50 of 17.6 nM was determined, and low cytotoxicity was observed in both cell lines (61.26 and 40.32 µM, respectively). Therefore, the promising results obtained, combined with the structure similarity with commercial COMT inhibitors, can allow for the future development of a potential new Parkinson's disease drug candidate with improved properties.

Markerless Eye-Hand Kinematic Calibration on the iCub Humanoid Robot.

Humanoid robots are resourceful platforms and can be used in diverse application scenarios. However, their high number of degrees of freedom (i.e., moving arms, head and eyes) deteriorates the precision of eye-hand coordination. A good kinematic calibration is often difficult to achieve, due to several factors, e.g., unmodeled deformations of the structure or backlash in the actuators. This is particularly challenging for very complex robots such as the iCub humanoid robot, which has 12 degrees of freedom and cable-driven actuation in the serial chain from the eyes to the hand. The exploitation of real-time robot sensing is of paramount importance to increase the accuracy of the coordination, for example, to realize precise grasping and manipulation tasks. In this code paper, we propose an online and markerless solution to the eye-hand kinematic calibration of the iCub humanoid robot. We have implemented a sequential Monte Carlo algorithm estimating kinematic calibration parameters (joint offsets) which improve the eye-hand coordination based on the proprioception and vision sensing of the robot. We have shown the usefulness of the developed code and its accuracy on simulation and real-world scenarios. The code is written in C++ and CUDA, where we exploit the GPU to increase the speed of the method. The code is made available online along with a Dataset for testing purposes.

Resultados negativos asociados a la medicación que son causa de visita al servicio de urgencias de un centro de atención primaria / Pharmacotherapy negative outcomes resulting in Primary Care Emergency visits

Objetivo: Analizar la prevalencia de los resultados negativos asociados a la medicación (RNM) que son causa de consulta en un servicio de urgencias de atención primaria (SUAP) en un entorno rural. Determinar la evitabilidad y la gravedad de los mismos. Diseño: Estudio observacional descriptivo transversal. Emplazamiento: SUAP de Mula. Murcia. Participantes: Un total de 330 pacientes, en un periodo de 33 semanas. Mediciones principales: Número y tipo de RNM: el farmacéutico, a través de los datos obtenidos de un cuestionario validado y la historia clínica, evaluó si existía relación entre los medicamentos que toma el paciente y el motivo de acudir a urgencias. En caso de sospecha de RNM se reevaluaba con el médico y se confirmaban o no los RNM identificados. Resultados: De los 330 pacientes fueron evaluables 317. La media de edad de los pacientes era de 39,63 años y el 51,42% eran mujeres. La media de medicamentos que utilizaban fue de 1,38. Se detectaron un 26,50% (IC 95% 21,94-31,62) de pacientes con RNM como causa de visita a urgencias. El 53,57% de los RNM detectados fue de la categoría de efectividad y el 40,48% de necesidad. El 77,41% (IC-95% 67,35-85,01) de las visitas causadas por RNM fueron evitables. En cuanto a la gravedad, el 92,986% de los RNM eran leves. Conclusiones: Una de cada 4 visitas al SUAP de Mula está causada por un RNM y, de ellas, el 77,41% son evitables(AU()

Objective: Our aim was to estimate the prevalence of Pharmacotherapy negative outcomes in Primary Care Emergency visits in a rural environment, and to determine their preventability and severity. Design: Descriptive study with an analytical component. Site: Primary Care Emergency Service (SUAP), Mula Murcia. Patients: The study consisted of 330 patients over a 33 week period. Method: Number and type of Pharmacotherapy negative outcomes: Pharmacist through the data, a validated questionnaire and medical history, assessing whether there was a relationship between the medications and the patient, and the reason for going to the Primary Care Emergency. In case of suspicion of Pharmacotherapy negative outcomes the patient is reassessed by the doctor, and the Pharmacotherapy negative outcomes confirmed or not identified. Results: Of the 330 patients, 317 were evaluable. The mean age of patients was 39.63 years and 51.42% were women. The mean number of drugs used was 1.38, and 26.50% (95% CI, 21.94% -31.62%) patients were detected with Pharmacotherapy negative outcomes as a cause of visiting the Primary Care Emergency. 53.57% of the detected Pharmacotherapy negative outcomes detected as regards efficacy was 53.75%, 40.48% as regards need. More than three-quarters (77.41%; 95% CI, 67.35% -85.01%) of emergency visits caused by Pharmacotherapy negative outcomes were avoidable. In terms of severity, 92.86% of the Pharmacotherapy negative outcomes were mild. Conclusions: One in four Mula SUAP visits are due to a Pharmacotherapy negative outcomes, and 77.41% of them are preventable(AU)

[Pharmacotherapy negative outcomes resulting in Primary Care Emergency visits]. / Resultados negativos asociados a la medicación que son causa de visita al servicio de urgencias de un centro de atención primaria.

OBJECTIVE: Our aim was to estimate the prevalence of Pharmacotherapy negative outcomes in Primary Care Emergency visits in a rural environment, and to determine their preventability and severity. DESIGN: Descriptive study with an analytical component. SITE: Primary Care Emergency Service (SUAP), Mula. Murcia. PATIENTS: The study consisted of 330 patients over a 33 week period. METHOD: Number and type of Pharmacotherapy negative outcomes: Pharmacist through the data, a validated questionnaire and medical history, assessing whether there was a relationship between the medications and the patient, and the reason for going to the Primary Care Emergency. In case of suspicion of Pharmacotherapy negative outcomes the patient is reassessed by the doctor, and the Pharmacotherapy negative outcomes confirmed or not identified. RESULTS: Of the 330 patients, 317 were evaluable. The mean age of patients was 39.63 years and 51.42% were women. The mean number of drugs used was 1.38, and 26.50% (95% CI, 21.94% -31.62%) patients were detected with Pharmacotherapy negative outcomes as a cause of visiting the Primary Care Emergency. 53.57% of the detected Pharmacotherapy negative outcomes detected as regards efficacy was 53.75%, 40.48% as regards need. More than three-quarters (77.41%; 95% CI, 67.35% -85.01%) of emergency visits caused by Pharmacotherapy negative outcomes were avoidable. In terms of severity, 92.86% of the Pharmacotherapy negative outcomes were mild. CONCLUSIONS: One in four Mula SUAP visits are due to a Pharmacotherapy negative outcomes, and 77.41% of them are preventable.

Using semantic technologies to promote interoperability between electronic healthcare records' information models.

There are currently different standards for representing electronic healthcare records (EHR). Each standard defines its own information models, so that, in order to promote the interoperability among standard-compliant information systems, the different information models must be semantically integrated. In this work, we present an ontological approach to promote interoperability among CEN- and OpenEHR-compliant information systems.

Incidencia de anemia al final de la gestacion y Evaluacion del Programa UNITAS (Hospital Materno Infantil German Urquidi de la ciudad de Cochabamba)

En el presente estudio se demuestra la persistencia de la anemia en el tercer trimestre del embarazo, a pesar de que existe un programa responsable de dar el suplemento de hierro (sulfato ferroso) a toda mujer embarazada a partir del quinto mes de gestacion y a la vez se evalua el cumplimiento y alcance del programa UNITAS

Organizaçäo e funcionamento de serviços de medicina do trabalho nas empresas / Organizational and functioning of occupational medicine services in enterprinses

Aborda a organizaçäo e funcionamento de serviços de medicina do trabalho nas empresas através da moderna concepçäo de segurança e saúde do trabalhador

Programas médicos específicos preventivos na empresa / Specific medical preventive program in the enterprise

Aborda os programas preventivos desenvolvidos para aplicaçäo na empresa (MC)

Organizaçäo de serviços de medicina do trabalho nas empresas / Organization of services of occupational medicine in enterprises

Esta publicaçäo está destinada aos profissionais médicos que se dedicam a prática da medicina ocupacional, e que muitas vezes säo convocados para organizá-la nas empresas. Pretendendo também, ser um manual prático e näo somente proporcionar conhecimentos teóricos aos iniciantes nos cursos de especializaçäo