Origin of congenital coronary arterio-ventricular fistulae from anomalous epicardial and myocardial development.

Coronary Artery Fistulae (CAFs) are cardiac congenital anomalies consisting of an abnormal communication of a coronary artery with either a cardiac chamber or another cardiac vessel. In humans, these congenital anomalies can lead to complications such as myocardial hypertrophy, endocarditis, heart dilatation, and failure. Unfortunately, despite their clinical relevance, the aetiology of CAFs remains unknown. In this work, we have used two different species (mouse and avian embryos) to experimentally model CAFs morphogenesis. Both conditional Itga4 (alpha 4 integrin) epicardial deletion in mice and cryocauterisation of chick embryonic hearts disrupted epicardial development and ventricular wall growth, two essential events in coronary embryogenesis. Our results suggest that myocardial discontinuities in the embryonic ventricular wall promote the early contact of the endocardium with epicardial-derived coronary progenitors at the cardiac surface, leading to ventricular endocardial extrusion, precocious differentiation of coronary smooth muscle cells, and the formation of pouch-like aberrant coronary-like structures in direct connection with the ventricular lumen. The structure of these CAF-like anomalies was compared with histopathological data from a human CAF. Our results provide relevant information for the early diagnosis of these congenital anomalies and the molecular mechanisms that regulate their embryogenesis.

[Patient participation through active listening. About the remodeling of an extractions service]. / Participación del paciente a través de la escucha activa. A propósito de la remodelación de un servicio de extracciones.

BACKGROUND AND OBJECTIVE: From listening to patients there arises the possibility of improving both the care and the health infrastructure that users frequent. Our purpose of study was to explore the perception of users about the means and the care received involved in a hospital service through active listening, and to evaluate the satisfaction perceived after the opening of the renovated area. METHODS: A mixed methodology evaluative investigation was carried out within the context of the Extraction Service of the Costa del Sol Hospital, using qualitative methodology to assess the perception of users, and quantitative methodology through a satisfaction survey to identify the change after remodeling of the area. RESULTS: Through a qualitative approach, improvements have been identified in terms of the internal and external infrastructure of the center, highlighting the need to personalize spaces depending on the profile of the patient attended. In evaluating the impact after remodeling the area, patients have a higher overall satisfaction both from the healthcare professionals who attend them and from the healthcare center. CONCLUSIONS: Through the use of a mixed methodology, useful information has been incorporated for a project to improve a hospital infrastructure, and a subsequent evaluation of the positive impact on the satisfaction perceived by users after remodeling.

Dynamic Epicardial Contribution to Cardiac Interstitial c-Kit and Sca1 Cellular Fractions.

Background: The cardiac interstitial cellular fraction is composed of multiple cell types. Some of these cells are known to express some well-known stem cell markers such as c-Kit and Sca1, but they are no longer accepted to be true cardiac stem cells. Although their existence in the cardiac interstitium has not been disputed, their dynamic throughout development, specific embryonic origin, and potential heterogeneity remain unknown. In this study, we hypothesized that both c-KitPOS and Sca1POS cardiac interstitial cell (CIC) subpopulations are related to the Wilms' tumor 1 (Wt1) epicardial lineage. Methods: In this study, we have used genetic cell lineage tracing methods, immunohistochemistry, and FACS techniques to characterize cardiac c-KitPOS and Sca1POS cells. Results: Our data show that approximately 50% of cardiac c-KitPOS cells are derived from the Wt1-lineage at E15.5. This subpopulation decreased along with embryonic development, disappearing from P7 onwards. We found that a large proportion of cardiac c-KitPOS cells express specific markers strongly suggesting they are blood-borne cells. On the contrary, the percentage of Sca1POS cells within the Wt1-lineage increases postnatally. In accordance with these findings, 90% of adult epicardial-derived endothelial cells and 60% of mEFSK4POS cardiac fibroblasts expressed Sca1. Conclusion: Our study revealed a minor contribution of the Wt1-epicardial lineage to c-KitPOS CIC from embryonic stages to adulthood. Remarkably, a major part of the adult epicardial-derived cell fraction is enriched in Sca1, suggesting that this subpopulation of CICs is heterogeneous from their embryonic origin. The study of this heterogeneity can be instrumental to the development of diagnostic and prognostic tests for the evaluation of cardiac homeostasis and cardiac interstitium response to pathologic stimuli.

Early monitoring of infliximab serum trough levels predicts long-term therapy failure in patients with axial spondyloarthritis.

OBJECTIVE: To evaluate whether serum infliximab trough levels (ITL) during the early stages of treatment are predictive of long-term clinical failure in patients with axial spondyloarthritis (axSpA). METHODS: Longitudinal observational study involving 81 patients with axSpA monitored during infliximab therapy. Serum ITL were measured before starting infliximab treatment and at weeks 2 (W2), W6 and W12 of treatment. Disease activity was assessed by Ankylosing Spondylitis Disease Activity Score (ASDAS) at baseline, W24 and W52, and every 6 months thereafter until treatment discontinuation, regardless of the reason. Non-clinically important improvement was defined by ΔASDAS<1.1. The association between serum levels during the early stages and clinical outcomes (non-clinically important improvement at W52, drug survival and drop-out due to secondary inefficacy) was investigated through logistic regression models and Kaplan Meier curves. Receiver operating characteristic (ROC) curves were employed to determine the best cut-off for serum ITL. RESULTS: Out of the 81 patients, 45 (56%) did not achieve clinical improvement at W52. These patients had lower serum ITL at W12 compared to those who improved: ITL [median (IQR)]: 4.1(0.9-8.3) µg/mL vs 7.1 (4.3-11.3) µg/mL, respectively;p = 0.007). ITL<6.7 µg/mL at W12 was significantly associated with: i) not achieving clinical improvement at W52 (OR: 2.3; 95%CI: 1.3-3.9); ii) shorter drug survival (5.0 years (95% CI 3.8-6.2) vs 7.0 years (95% CI 4.8-6.9; p = 0.04), and iii) higher drop-out rates due to secondary inefficacy (OR: 3.5; 95% CI: 1.2-10.2). CONCLUSION: Low serum ITL at W12 were associated with long-term clinical failure in patients with axSpA, due to secondary inefficacy.

Delivery of cardiovascular progenitors with biomimetic microcarriers reduces adverse ventricular remodeling in a rat model of chronic myocardial infarction.

Despite tremendous progress in cell-based therapies for heart repair, many challenges still exist. To enhance the therapeutic potential of cell therapy one approach is the combination of cells with biomaterial delivery vehicles. Here, we developed a biomimetic and biodegradable micro-platform based on polymeric microparticles (MPs) capable of maximizing the therapeutic potential of cardiac progenitor cells (CPCs) and explored its efficacy in a rat model of chronic myocardial infarction. The transplantation of CPCs adhered to MPs within the infarcted myocardial microenvironment improved the long-term engraftment of transplanted cells for up to one month. Furthermore, the enhancement of cardiac cellular retention correlated with an increase in functional recovery. In consonance, better tissue remodeling and vasculogenesis were observed in the animals treated with cells attached to MPs, which presented smaller infarct size, thicker right ventricular free wall, fewer deposition of periostin and greater density of vessels than animals treated with CPCs alone. Finally, we were able to show that part of this beneficial effect was mediated by CPC-derived extracellular vesicles (EVs). Taken together, these findings indicate that the biomimetic microcarriers support stem cell survival and increase cardiac function in chronic myocardial infarction through modulation of cardiac remodeling, vasculogenesis and CPCs-EVs mediated therapeutic effects. The biomimetic microcarriers provide a solution for biomaterial-assisted CPC delivery to the heart. STATEMENT OF SIGNIFICANCE: In this study, we evaluate the possibility of using a biomimetic and biodegradable micro-platform to improve cardiovascular progenitor therapy. The strategy reported herein serves as an injectable scaffold for adherent cells due to their excellent injectability through cardiac catheters, capacity for biomimetic three-dimensional stem cell support and controllable biodegradability. In a rat model of chronic myocardial infarction, the biomimetic microcarriers improved cardiac function, reduced chronic cardiac remodeling and increased vasculogenesis through the paracrine signaling of CPCs. We have also shown that extracellular vesicles derived from CPCs cultured on biomimetic substrates display antifibrotic effects, playing an important role in the therapeutic effects of our tissue-engineered approach. Therefore, biomimetic microcarriers represent a promising and effective strategy for biomaterial-assisted CPC delivery to the heart.

Influence of land use on chlorpyrifos and persistent organic pollutant levels in honey bees, bee bread and honey: Beehive exposure assessment.

This work reports the spatial and temporal variations on the dynamics of OCPs, PCBs, PBDEs and chlorpyrifos in honey bee, bee bread and honey samples, as well as soil and flowers from the surrounding areas, considering, different land uses. Honey bee samples showed the highest pollutant levels, with a predominance of the industrial contaminants over pesticides. Chlorpyrifos showed the highest concentration during the application period in almost all samples from the soybean field (S2), in concordance with its current use. By other hand, the recalcitrant compounds such as, DDTs, BDE #47 and also light PCBs exhibited the highest levels in beehive samples from the field adjacent to urban disposal waste (S3). In both soils and flower samples a prevalence of obsolete compounds over chlorpyrifos was observed, and the 6-CB predominated among the homologous groups of PCBs These results highlights the importance of soils as sink of these persistent contaminants, which became available depending on environmental conditions. Results revealed that the land uses and seasonal variations have directly impacted on the levels of agrochemicals, PCBs and PBDEs found in the beehive matrixes. This survey provides novel evidence about the current situation of pollution on honey bee colonies under temperate climates and contributes to the knowledge of this poor studied topic in Argentina.

Single shot femtosecond laser nano-ablation of CVD monolayer graphene.

We investigate ablation of CVD monolayer graphene by femtosecond pulses in the single shot regime. We show that the ablation probability of flat graphene drastically reduces for small illumination diameters even if the ablation threshold is exceeded. However, the presence of graphene wrinkles enhances the ablation probability. This is interpreted in terms of electron and energy diffusion within the graphene layer. This differentiated behavior is a drawback for single shot laser nanopatterning. The morphology of the holes with minimal diameter depends on the fluence distribution at ablation threshold. Strong fluence gradients due to strong focussing produce an explosive folding of graphene during ablation.

Marteilia refringens and Marteilia pararefringens sp. nov. are distinct parasites of bivalves and have different European distributions.

Marteilia refringens causes marteiliosis in oysters, mussels and other bivalve molluscs. This parasite previously comprised two species, M. refringens and Marteilia maurini, which were synonymized in 2007 and subsequently referred to as M. refringens 'O-type' and 'M-type'. O-type has caused mass mortalities of the flat oyster Ostrea edulis. We used high throughput sequencing and histology to intensively screen flat oysters and mussels (Mytilus edulis) from the UK, Sweden and Norway for infection by both types and to generate multi-gene datasets to clarify their genetic distinctiveness. Mussels from the UK, Norway and Sweden were more frequently polymerase chain reaction (PCR)-positive for M-type (75/849) than oysters (11/542). We did not detect O-type in any northern European samples, and no histology-confirmed Marteilia-infected oysters were found in the UK, Norway and Sweden, even where co-habiting mussels were infected by the M-type. The two genetic lineages within 'M. refringens' are robustly distinguishable at species level. We therefore formally define them as separate species: M. refringens (previously O-type) and Marteilia pararefringens sp. nov. (M-type). We designed and tested new Marteilia-specific PCR primers amplifying from the 3' end of the 18S rRNA gene through to the 5.8S gene, which specifically amplified the target region from both tissue and environmental samples.

Long-term affected flat oyster (Ostrea edulis) haemocytes show differential gene expression profiles from naïve oysters in response to Bonamia ostreae.

European flat oyster (Ostrea edulis) production has suffered a severe decline due to bonamiosis. The responsible parasite enters in oyster haemocytes, causing an acute inflammatory response frequently leading to death. We used an immune-enriched oligo-microarray to understand the haemocyte response to Bonamia ostreae by comparing expression profiles between naïve (NS) and long-term affected (AS) populations along a time series (1 d, 30 d, 90 d). AS showed a much higher response just after challenge, which might be indicative of selection for resistance. No regulated genes were detected at 30 d in both populations while a notable reactivation was observed at 90 d, suggesting parasite latency during infection. Genes related to extracellular matrix and protease inhibitors, up-regulated in AS, and those related to histones, down-regulated in NS, might play an important role along the infection. Twenty-four candidate genes related to resistance should be further validated for selection programs aimed to control bonamiosis.