Abstract
Aims
Cardiosphere-derived cells (CDCs) are cardiac progenitor cells that exhibit disease-modifying bioactivity in various models of cardiomyopathy and in previous clinical studies of acute ...myocardial infarction (MI), dilated cardiomyopathy, and Duchenne muscular dystrophy. The aim of the study was to assess the safety and efficacy of intracoronary administration of allogeneic CDCs in the multicentre, randomized, double-blinded, placebo-controlled, intracoronary ALLogeneic heart STem cells to Achieve myocardial Regeneration (ALLSTAR) trial.
Methods and results
We enrolled patients 4 weeks to 12 months after MI, with left ventricular ejection fraction (LVEF) ≤45% and LV scar size ≥15% of LV mass by magnetic resonance imaging (MRI). A pre-specified interim analysis was performed when 6-month MRI data were available. The trial was subsequently stopped due to the low probability of detecting a significant treatment effect of CDCs based on the primary endpoint. Patients were randomly allocated in a 2:1 ratio to receive CDCs or placebo in the infarct-related artery by stop-flow technique. The primary safety endpoint was the occurrence, during 1-month post-intracoronary infusion, of acute myocarditis attributable to allogeneic CDCs, ventricular tachycardia- or ventricular fibrillation-related death, sudden unexpected death, or a major adverse cardiac event (death or hospitalization for heart failure or non-fatal MI or need for left ventricular assist device or heart transplant). The primary efficacy endpoint was the relative percentage change in infarct size at 12 months post-infusion as assessed by contrast-enhanced cardiac MRI. We randomly allocated 142 eligible patients of whom 134 were treated (90 to the CDC group and 44 to the placebo group). The mean baseline LVEF was 40% and the mean scar size was 22% of LV mass. No primary safety endpoint events occurred. There was no difference in the percentage change from baseline in scar size (P = 0.51) between CDCs and placebo groups at 6 months. Compared with placebo, there were significant reductions in LV end-diastolic volume (P = 0.02), LV end-systolic volume (P = 0.02), and N-terminal pro b-type natriuretic peptide (NT-proBNP) (P = 0.02) at 6 months in CDC-treated patients.
Conclusion
Intracoronary infusion of allogeneic CDCs in patients with post-MI LV dysfunction was safe but did not reduce scar size relative to placebo at 6 months. Nevertheless, the reductions in LV volumes and NT-proBNP reveal disease-modifying bioactivity of CDCs.
Trial registration
Clinicaltrials.gov identifier: NCT01458405.
Prostate specific antigen (PSA) is the most widely used clinical biomarker for the diagnosis and monitoring of prostate cancer. Most available techniques for PSA quantification in human fluids ...require extensive sample processing and expensive immunoassays that are often unavailable in developing countries. The quantification of PSA in serum is the most common practice; however, PSA is also present in human urine, although less used in diagnosis. Herein we demonstrate the use of ionic-liquid-based aqueous biphasic systems (IL-based ABS) as effective pre-treatment strategies of human urine, allowing the PSA detection and quantification by more expedite equipment in a non-invasive matrix. If properly designed, IL-based ABS afford the simultaneous extraction and concentration of PSA (at least up to 250-fold) in the IL-rich phase. The best ABS not only allow to concentrate PSA but also other forms of PSA, which can be additionally quantified, paving the way to their use in differential prostate cancer diagnosis.
Woody invasive alien species can have profound impacts on ecosystem processes and functions, including fire regulation, which can significantly affect landscape resilience. Acacia dealbata, a ...widespread invasive alien plant in the Iberian Peninsula, holds well-known fire-adaptation traits (e.g., massive soil seed banks and heat-stimulated seed germination). In this study, we assess to what extent fire suppression and land-use strategies could affect the potential distribution of A. dealbata in a fire-prone transboundary protected mountain area of Portugal and Spain, using Habitat Suitability Models. Specifically, we predicted changes in habitat suitability for A. dealbata between years 2010 and 2050. We explored the potential impacts of two land-use strategies ('Business-as-usual' or 'High Nature Value farmlands') combined with three levels of fire suppression effectiveness using the biomod2 package in R. We also considered the potential effects of two climate change scenarios (RCP4.5 and RCP8.5). Our modeling approach demonstrated a strong capacity to predict habitat suitability using either climate or land-cover information alone (AUC climate = 0.947; AUC LC = 0.957). According to climate-based models, A. dealbata thrives under conditions characterized by higher precipitation seasonality, higher precipitation in the warmest month, and higher minimum temperature in the coldest month. Regarding land cover, A. dealbata thrives mainly in landscapes dominated by urban areas and evergreen forest plantations. Our models forecasted that habitat suitability by 2050 could either increase or decrease depending on the specific combinations of fire suppression, land-use, and climate scenarios. Thus, a combination of business-as-usual and fire-exclusion strategies would enhance habitat suitability for the species. Conversely, management promoting High Nature Value farmlands would decrease the available suitable habitat, particularly under low fire suppression efforts. These findings suggest that promoting sustainable farming activities could impede the spread of A. dealbata by reducing habitat availability, while strategies aiming at fire-exclusion could facilitate its expansion, likely by enabling establishment and large seed production. This study highlights the complex interplay between fire-prone invasive species, fire and land-use strategies, and climate change; and thus the need to consider the interactions between land-use and fire management to promote invasive species control and landscape resilience.
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•Many invasive species will expand towards conservation areas under future climates.•The study evaluates fire suppression and land-use effects on A. dealbata's habitat.•High Nature Value farmlands limit A. dealbata's habitat suitability the most.•High fire suppression creates a prevalence of land-uses that favor A. dealbata.•Invasive species control needs to consider the interactions of land-use and fire.
Evidence suggests an association between autonomical nervous system (ANS) function and atrial fibrillation (AF) development. We sought to examine the association of baseline resting heart rate (RHR) ...and short-term heart rate variability (HRV) as surrogates of (ANS) with incident AF in individuals without previous cardiovascular disease. A total of 6,261 participants of the Multi-Ethnic Study of Atherosclerosis who were free of AF and diagnosed cardiovascular disease were enrolled. Three standard 10-second, 12-lead electrocardiograms (ECG) were used to measure RHR, the standard deviation of normal-to-normal intervals (SDNN) and the root mean square of successive differences in RR intervals (RMSSD). Cox proportional hazards models adjusted for demographics, atrioventricular nodal agents, and known cardiovascular risk factors were used to examine the association of baseline RHR, and log transformed SDNN and RMSDD with incident AF. Over a mean follow-up of 11.3 ± 3.7 years, 754 (12%) participants developed AF. Spline curve analysis revealed a nonlinear association between RHR, HRV, and incident AF. In fully adjusted models higher (but not lower) baseline RHR (RHR >76 beats/min) was associated with incident AF (hazard ratio 1.48 95% confidence interval 1.18 to 1.86). Additionally, lower values of RMSDD and SDNN and higher values of RMSDD were independently associated with incident AF. In conclusion, cardiac ANS dysregulation indicated as higher RHR and lower HRV is associated with incident AF independent of known cardiovascular risk factors.
Serum N-terminal pro–B-type natriuretic peptide (NT-proBNP) is considered a marker that is expressed in response to myocardial strain and possibly fibrosis. However, the relationship to myocardial ...fibrosis in a community-based population is unknown.
The authors evaluated the relationship between cardiac magnetic resonance (CMR) measures of fibrosis and NT-proBNP levels in the MESA (Multi-Ethnic Study of Atherosclerosis) study.
A total of 1,334 participants (52% white, 23% black, 11% Chinese, 14% Hispanic, and 52% men with a mean age of 67.6 years) at 6 sites had both serum NT-proBNP measurements and CMR with T1 mapping of indices of fibrosis at 1.5 T. Univariate and multivariable regression analyses adjusting for demographics, cardiovascular risk factors, and left ventricular (LV) mass were performed to examine the association of log NT-proBNP with CMR T1 mapping indices.
In the fully adjusted model, each 1-SD increment (0.44 pg/ml) of log NT-proBNP was associated with a 0.62% increment in extracellular volume fraction (p < 0.001), 0.011 increment in partition coefficient (p < 0.001), and 4.7-ms increment in native T1 (p = 0.001). Results remained unchanged after excluding individuals with clinical cardiovascular disease or late gadolinium enhancement (n = 167), and after replacing LV mass by LV end-diastolic volume in the regression models.
Elevated NT-proBNP is related to subclinical fibrosis in a community-based setting. (Multi-Ethnic Study of Atherosclerosis MESA; NCT00005487)
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Purpose
Gadolinium‐based contrast agents (GBCAs) for MRI are generally administrated in direct relationship to body weight. Instead, we propose a model for GBCA dosing on the basis of blood volume. ...The new method was tested by exploring the associations between MRI T1 mapping indices and weight in the MESA (Multi‐Ethnic Study of Atherosclerosis.
Methods
Empirically derived methods based on sex and body habitus were used to calculate blood volumes. GBCA dose (in mL) in blood (in L) was calculated as the injected volume divided by the blood volume (i.e., DBV). Of the 1219 participants with cardiac MRI T1 mapping, 845 studies had standard dose of 0.15 mmol/kg (cohort 1) and 166 studies had 30 mL of GBCA regardless of weight (cohort 2). We also created a specific cohort with similar DBV (N = 357; cohort 3).
Results
Postcontrast blood relaxation rate R1blood and DBV were significantly correlated (R = 0.641; P < 0.001). R1blood was significantly associated with weight in cohort 1 and 2, but the correlation coefficient was positive for cohort 1 and negative for cohort 2, indicating GBCA overdosing in cohort 1 and underdosing in cohort 2 in heavy relative to lean subjects. R1blood was not associated with weight in cohort 3. Simulated results demonstrated that less contrast should be administrated for heavy subjects compared to the conventional weight‐based dose.
Conclusion
GBCA dosing on the basis of blood volume could improve the efficacy and safety of contrast‐enhanced MRI studies. This method could be implemented to standardize dose and augment precision in study comparisons.
Patients with chronic Chagas cardiomyopathy (CCC) have pronounced myocardial fibrosis, which may predispose to sudden cardiac death, despite well-preserved global left ventricular (LV) systolic ...function. Cardiac magnetic resonance can assess myocardial fibrosis by late gadolinium enhancement (LGE) sequences.
This prospective study evaluated if the presence of scar by LGE predicted hard adverse outcomes in a cohort of patients with CCC.
A prospective cohort of 140 patients with CCC (52.1% female; median age 57 years interquartile range: 45 to 67 years) were included. Cardiac magnetic resonance cine and LGE imaging were performed at enrollment with a 1.5-T scanner. The primary endpoint was the combination of cardiovascular death and sustained ventricular tachycardia. The secondary endpoint was the combination of cardiovascular death, sustained ventricular tachycardia, or cardiovascular hospitalization during follow-up.
After a median of 34 months (interquartile range: 24 to 49 months) of follow-up, 11 cardiovascular deaths, 3 episodes of sustained ventricular tachycardia, and 20 cardiovascular hospitalizations were recorded. LGE scar was present in 71.4% of the patients, with the lateral, inferolateral, and inferior walls most commonly affected. Patients with positive LGE had lower LV ejection fraction and higher LV end-diastolic volume and LV mass than patients without LGE. No difference in other cardiovascular risk factors was noted. Patients with scar had higher event rates compared with those without scar for the primary (p = 0.043) and the secondary (p = 0.016) endpoint. In multivariable analysis, age and LGE area were related to primary outcome; age and lower LV ejection fraction were related to the secondary outcome. The pattern of LGE myocardial fibrosis was transmural, focal, or diffuse scar in approximately one-third of patients with positive LGE, and no pattern was specifically related to outcomes.
In patients with CCC, presence of scar by LGE is common and is strongly associated with major adverse outcomes.
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•Novel ABS composed of phosphonium- and ammonium-based ionic liquids were investigated.•The performance of the studied ABS for the extraction of BSA was evaluated.•Extraction efficiencies of 100% of ...BSA were achieved in a single-step.•The recovery of the protein and the recyclability of the ionic liquids was demonstrated.•The stability of BSA after the extraction step was confirmed.
Novel aqueous biphasic systems (ABS) composed of phosphonium- or ammonium-based ionic liquids (ILs), combined with a buffered aqueous solution of potassium citrate/citric acid (pH=7.0), were investigated for the extraction of proteins. For that purpose, the phase diagrams, tie-lines and tie-line lengths were determined at 25°C, and the performance of these ABS for the extraction of bovine serum albumin (BSA) was then evaluated. The obtained results reveal that, with the exception of the more hydrophobic ILs, most of the systems investigated allow the complete extraction of BSA for the IL-rich phase in a single-step. These remarkable extraction efficiencies are far superior to those afforded by more conventional extraction systems previously reported. The composition of the biphasic systems, i.e., the amount of phase-forming components, was also investigated aiming at reducing the overall costs of the process without losing efficiency on the protein extraction. It is shown that the extraction efficiencies of BSA are maintained at 100% up to high protein concentrations (at least up to 10gL−1). The recovery of the BSA from the IL-rich phase by dialysis is also shown in addition to the demonstration of the IL recyclability and reusability, at least for 3 times. In the sequential three-step extractions (BSA recovery/IL reusability), the extraction efficiencies of BSA for the IL-rich phase were maintained at 100%. For the improved ABS, the preservation of the protein native conformation was confirmed by Size Exclusion High-Performance Liquid Chromatography (used also as the quantification method) and by Fourier Transform Infra-Red spectroscopy. According to the results herein reported, ABS composed of phosphonium- or ammonium-based ILs and a biodegradable organic salt represent an alternative and remarkable platform for the extraction of BSA and may be extended to other proteins of interest.
The liquid chromatography-mass spectrometry (LC-MS)-based metabolomics approach is a powerful technology for discovering novel biologically active molecules. In this study, we investigated the ...metabolic profiling of Orchidaceae species using LC-HRMS/MS data combined with chemometric methods and dereplication tools to discover antifungal compounds. We analyze twenty ethanolic plant extracts from
and
(Orchidaceae) genera. Molecular networking and chemometric methods were used to discriminate ions that differentiate healthy and fungal-infected plant samples. Fifty-three metabolites were rapidly annotated through spectral library matching and in silico fragmentation tools. The metabolomic profiling showed a large production of polyphenols, including flavonoids, phenolic acids, chromones, stilbenoids, and tannins, which varied in relative abundance across species. Considering the presence and abundance of metabolites in both groups of samples, we can infer that these constituents are associated with biochemical responses to microbial attacks. In addition, we evaluated the metabolic dynamic through the synthesis of stilbenoids in fungal-infected plants. The tricin derivative flavonoid- and the loliolide terpenoidfound only in healthy plant samples, are promising antifungal metabolites. LC-HRMS/MS, combined with state-of-the-art tools, proved to be a rapid and reliable technique for fingerprinting medicinal plants and discovering new hits and leads.
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