Electrophysiological effects of extracellular vesicles secreted by cardiosphere-derived cells: Unraveling the antiarrhythmic properties of cell therapies

This article belongs to the Special Issue Advances in Regenerative Medicine and Tissue Engineering.Although cell-based therapies show potential antiarrhythmic effects that could be mediated by their paracrine action, the mechanisms and the extent of these effects were not deeply explored. We investigated the antiarrhythmic mechanisms of extracellular vesicles secreted by cardiosphere-derived cell extracellular vesicles (CDC-EVs) on the electrophysiological properties and gene expression profile of HL1 cardiomyocytes. HL-1 cultures were primed with CDC-EVs or serum-free medium alone for 48 h, followed by optical mapping and gene expression analysis. In optical mapping recordings, CDC-EVs reduced the activation complexity of the cardiomyocytes by 40%, increased rotor meandering, and reduced rotor curvature, as well as induced an 80% increase in conduction velocity. HL-1 cells primed with CDC-EVs presented higher expression of SCN5A, CACNA1C, and GJA1, coding for proteins involved in INa, ICaL, and Cx43, respectively. Our results suggest that CDC-EVs reduce activation complexity by increasing conduction velocity and modifying rotor dynamics, which could be driven by an increase in expression of SCN5A and CACNA1C genes, respectively. Our results provide new insights into the antiarrhythmic mechanisms of cell therapies, which should be further validated using other models.This research was funded by the Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación, Spain: PI16/01123, PI17/01059, Red de Terapia Celular-Tercel-RD16.0011.0029 and CIBERCV-CB16.11.00292

Fabrication of human myocardium using multidimensional modelling of engineered tissues

Biofabrication of human tissues has seen a meteoric growth triggered by recent technical advancements such as human induced pluripotent stem cells (hiPSCs) and additive manufacturing. However, generation of cardiac tissue is still hampered by lack of adequate mechanical properties and crucially by the often unpredictable post-fabrication evolution of biological components. In this study we employ melt electrowriting (MEW) and hiPSC-derived cardiac cells to generate fibre-reinforced human cardiac minitissues. These are thoroughly characterized in order to build computational models and simulations able to predict their post-fabrication evolution. Our results show that MEW-based human minitissues display advanced maturation 28 post-generation, with a significant increase in the expression of cardiac genes such as MYL2, GJA5, SCN5A and the MYH7/MYH6 and MYL2/MYL7 ratios. Human iPSC-cardiomyocytes are significantly more aligned within the MEW-based 3D tissues, as compared to conventional 2D controls, and also display greater expression of C ×43. These are also correlated with a more mature functionality in the form of faster conduction velocity. We used these data to develop simulations capable of accurately reproducing the experimental performance. In-depth gauging of the structural disposition (cellular alignment) and intercellular connectivity (C ×43) allowed us to develop an improved computational model able to predict the relationship between cardiac cell alignment and functional performance. This study lays down the path for advancing in the development of in silico tools to predict cardiac biofabricated tissue evolution after generation, and maps the route towards more accurate and biomimetic tissue manufacture

Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

Funder: European Society of Intensive Care Medicine; doi: http://dx.doi.org/10.13039/501100013347Funder: Flemish Society for Critical Care NursesAbstract: Purpose: Intensive care unit (ICU) patients are particularly susceptible to developing pressure injuries. Epidemiologic data is however unavailable. We aimed to provide an international picture of the extent of pressure injuries and factors associated with ICU-acquired pressure injuries in adult ICU patients. Methods: International 1-day point-prevalence study; follow-up for outcome assessment until hospital discharge (maximum 12 weeks). Factors associated with ICU-acquired pressure injury and hospital mortality were assessed by generalised linear mixed-effects regression analysis. Results: Data from 13,254 patients in 1117 ICUs (90 countries) revealed 6747 pressure injuries; 3997 (59.2%) were ICU-acquired. Overall prevalence was 26.6% (95% confidence interval [CI] 25.9–27.3). ICU-acquired prevalence was 16.2% (95% CI 15.6–16.8). Sacrum (37%) and heels (19.5%) were most affected. Factors independently associated with ICU-acquired pressure injuries were older age, male sex, being underweight, emergency surgery, higher Simplified Acute Physiology Score II, Braden score 3 days, comorbidities (chronic obstructive pulmonary disease, immunodeficiency), organ support (renal replacement, mechanical ventilation on ICU admission), and being in a low or lower-middle income-economy. Gradually increasing associations with mortality were identified for increasing severity of pressure injury: stage I (odds ratio [OR] 1.5; 95% CI 1.2–1.8), stage II (OR 1.6; 95% CI 1.4–1.9), and stage III or worse (OR 2.8; 95% CI 2.3–3.3). Conclusion: Pressure injuries are common in adult ICU patients. ICU-acquired pressure injuries are associated with mainly intrinsic factors and mortality. Optimal care standards, increased awareness, appropriate resource allocation, and further research into optimal prevention are pivotal to tackle this important patient safety threat

Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

Funder: European Society of Intensive Care Medicine; doi: http://dx.doi.org/10.13039/501100013347Funder: Flemish Society for Critical Care NursesAbstract: Purpose: Intensive care unit (ICU) patients are particularly susceptible to developing pressure injuries. Epidemiologic data is however unavailable. We aimed to provide an international picture of the extent of pressure injuries and factors associated with ICU-acquired pressure injuries in adult ICU patients. Methods: International 1-day point-prevalence study; follow-up for outcome assessment until hospital discharge (maximum 12 weeks). Factors associated with ICU-acquired pressure injury and hospital mortality were assessed by generalised linear mixed-effects regression analysis. Results: Data from 13,254 patients in 1117 ICUs (90 countries) revealed 6747 pressure injuries; 3997 (59.2%) were ICU-acquired. Overall prevalence was 26.6% (95% confidence interval [CI] 25.9–27.3). ICU-acquired prevalence was 16.2% (95% CI 15.6–16.8). Sacrum (37%) and heels (19.5%) were most affected. Factors independently associated with ICU-acquired pressure injuries were older age, male sex, being underweight, emergency surgery, higher Simplified Acute Physiology Score II, Braden score 3 days, comorbidities (chronic obstructive pulmonary disease, immunodeficiency), organ support (renal replacement, mechanical ventilation on ICU admission), and being in a low or lower-middle income-economy. Gradually increasing associations with mortality were identified for increasing severity of pressure injury: stage I (odds ratio [OR] 1.5; 95% CI 1.2–1.8), stage II (OR 1.6; 95% CI 1.4–1.9), and stage III or worse (OR 2.8; 95% CI 2.3–3.3). Conclusion: Pressure injuries are common in adult ICU patients. ICU-acquired pressure injuries are associated with mainly intrinsic factors and mortality. Optimal care standards, increased awareness, appropriate resource allocation, and further research into optimal prevention are pivotal to tackle this important patient safety threat

Correction to: Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

The original version of this article unfortunately contained a mistake

The Essential Need for a Validated Potency Assay for Cell-Based Therapies in Cardiac Regenerative and Reparative Medicine. A Practical Approach to Test Development

Biological treatments are one of the medical breakthroughs in the twenty-first century. The initial enthusiasm pushed the field towards indiscriminatory use of cell therapy regardless of the pathophysiological particularities of underlying conditions. In the reparative and regenerative cardiovascular field, the results of the over two decades of research in cell-based therapies, although promising still could not be translated into clinical scenario. Now, when we identified possible deficiencies and try to rebuild its foundations rigorously on scientific evidence, development of potency assays for the potential therapeutic product is one of the steps which will bring our goal of clinical translation closer. Although, highly challenging, the potency tests for cell products are considered as a priority by the regulatory agencies. In this paper we describe the main characteristics and challenges for a cell therapy potency test focusing on the cardiovascular field. Moreover, we discuss different steps and types of assays that should be taken into consideration for an eventual potency test development by tying together two fundamental concepts: target disease and expected mechanism of action

Ultrafine particle and fine trace metal (As, Cd, Cu, Pb and Zn) pollution episodes induced by industrial emissions in Huelva, SW Spain

Urban air quality impairment by ultrafine particles has become a matter of concern due to the adverse effects on human health. Most of the studies of ultrafine particles in urban air quality have focused on vehicle exhaust emissions. We studied how industrial emissions contribute to ultrafine particle concentrations in downwind urban ambient air. This research is based on experimental data collected in the ambient air of the industrial city of Huelva (SW Spain) over April 2008–December 2009 period (particle number, gaseous pollutants and black carbon concentrations and levels and chemical composition of PM10 and PM2.5 with daily and hourly resolution). This city is affected by emissions from the second largest Cu-smelter in Europe, phosphoric acid and fertilizer production plants and an oil refinery and petrochemical plant. Industrial emissions are the main cause of ultrafine particle episodes. When vehicle exhaust emissions are the main source, ultrafine particles typically show (24-h mean) concentrations within the range 14,700–5000 cm−3 (50th–1st), with 60% of these linked to this source and 30% to industrial emissions. In contrast, when daily mean levels of N are within the range 50,000–25,500 cm−3 (100th–70th), industrial and vehicle exhaust emissions accounted for 49 and 30%, respectively. High concentrations of toxic trace metals (As, Cu, Cd, Zn and Pb) were recorded when the study city suffered fumigations of the Cu-smelter plumes (e.g. 10–25 ng m−3 As, 1–2 ng m−3 Cd and >105 cm−3 of ultrafine particles). Because of these industrial emissions, ultrafine particle concentrations during daylight are about two times higher than those observed in other European cities. Recently, ultrafine particle emissions in vehicle exhausts have been subject to limit values in a recent stage of the EURO standards. Industrial emissions should also be considered. and 30% to industrial emissions. In contrast, when daily mean levels of N are within the range 50,000 e25,500 cm 3 (100the70th), industrial and vehicle exhaust emissions accounted for 49 and 30%, respectively. High concentrations of toxic trace metals (As, Cu, Cd, Zn and Pb) were recorded when the study city suffered fumigations of the Cu-smelter plumes (e.g. 10e25 ng m 3 As, 1e2 ng m 3 Cd and >105 cm 3 of ultrafine particles). Because of these industrial emissions, ultrafine particle concentrations during daylight are about two times higher than those observed in other European cities. Recently, ultrafine particle emissions in vehicle exhausts have been subject to limit values in a recent stage of the EURO standards. Industrial emissions should also be considered

Levels and chemical composition of PM in a city near a large Cu-smelter in Spain

A long-term series (2001–2008) of chemical analysis of atmospheric particulate matter (PM10 and PM2.5) collected in the city of Huelva (SW Spain) is considered in this study. The impact of emission plumes from one of the largest Cu-smelters in the world on air quality in the city of Huelva is evidenced by the high daily and hourly levels of As, other potentially toxic elements (e.g. Cu, Zn, Cd, Se, Bi, and Pb) in particulate matter, as well as the high levels of some gaseous pollutants (NO2 and SO2). Mean arsenic levels in the PM10 fraction were higher than the target value set by European Directive 2004/ 107/EC (6 ngAs m 3) for 1st January 2013. Hourly peak concentrations of As and other metals and elements (Zn, Cu, P and Se) analyzed by PIXE can reach maximum hourly levels as high as 326 ngAs m 3, 506 ngZn m 3, 345 ngCu m 3, 778 ngP m 3 and 12 ngSe m 3. The contribution of Cu-smelter emissions to ambient PM is quantified on an annual basis in 2.0–6.7 mg m 3 and 1.8–4.2 mg m 3 for PM10 and PM2.5, respectively. High resolution outputs of the HYSPLIT dispersion model show the geographical distribution of the As ambient levels into the emission plume, suggesting that the working regime of the Cu-smelter factory and the sea breeze circulation are the main factors controlling the impact of the Cu-smelter on the air quality of the city. The results of this work improve our understanding of the behaviour of industrial emission plumes and their impact on air quality of a city, where the population might be exposed to very high ambient concentrations of toxic metals during a few hours.This work was developed within the framework of project CGL2005-05693-C03-01 and was funded by the Spanish Ministry of Science and Innovation, and Project CS2007-0067 GRACCIE by the Spanish Ministry of Science and Innovation. Also, we would like to thank the Autonomous Government of Andalusia for financing this work (Projects 2007-RNM 02729 and RNM-03125). We would like to thank the NOAA Air Resources Laboratory (ARL) for providing the HYSPLIT transport and dispersion model. Thanks also go to the NASA/Goddard Space Flight Center, Laboratory for Atmospheres, Greenbelt (MD, USA), the Atmospheric Modeling and Weather Forecasting Group from the University of Athens and NASA's SeaWIFS Project for the valuable information supplied by the TOMS and SKIRON aerosol maps and satellite images