Distinguishing pathophysiological features of heart failure with reduced and preserved ejection fraction: A comparative analysis of two mouse models.

Heart failure (HF) is a heterogeneous condition that can be categorized according to the left ventricular ejection fraction (EF) into HF with reduced (HFrEF) or preserved (HFpEF) EF. Although HFrEF and HFpEF share some common clinical manifestations, the mechanisms underlying each phenotype are often found to be distinct. Identifying shared and divergent pathophysiological features might expand our insights on HF pathophysiology and assist the search for therapies for each HF subtype. In this study, we evaluated and contrasted two new murine models of non-ischaemic HFrEF and cardiometabolic HFpEF in terms of myocardial structure, left ventricular function, gene expression, cardiomyocyte calcium handling, mitochondrial polarization and protein acetylation in a head-to-head fashion. We found that in conditions of similar haemodynamic stress, the HFrEF myocardium underwent a more pronounced hypertrophic and fibrotic remodelling, whereas inflammation was greater in the HFpEF myocardium. We observed opposing features on calcium release, which was diminished in the HFrEF cardiomyocyte but enhanced in the HFpEF cardiomyocyte. Mitochondria were less polarized in both HFrEF and HFpEF cardiomyocytes, reflecting similarly impaired metabolic capacity. Hyperacetylation of cardiac proteins was observed in both models, but it was more accentuated in the HFpEF heart. Despite shared features, unique triggering mechanisms (neurohormonal overactivation in HFrEF vs. inflammation in HFpEF) appear to determine the distinct phenotypes of HF. The findings of the present research stress the need for further exploration of the differential mechanisms underlying each HF subtype, because they might require specific therapeutic interventions. KEY POINTS: The mechanisms underlying heart failure with either reduced (HFrEF) or preserved (HFpEF) ejection fraction are often found to be different. Previous studies comparing pathophysiological traits between HFrEF and HFpEF have been conducted on animals of different ages and strains. The present research contrasted two age-matched mouse models of non-ischaemic HFrEF and cardiometabolic HFpEF to uncover divergent and shared features. We found that upon similar haemodynamic stress, the HFrEF heart experienced a more pronounced hypertrophic and fibrotic remodelling, whereas inflammation appeared to be greater in the HFpEF myocardium. Calcium release was diminished in the HFrEF cardiomyocyte and enhanced in the HFpEF cardiomyocyte. Mitochondria were comparably less polarized in both HFrEF and HFpEF myocytes. Hyperacetylation of proteins was common to both models, but stronger in the HFpEF heart. Casting light on common and distinguishing features might ease the quest for phenotype-specific therapies for heart failure patients.

The retinoic acid response is a minor component of the cardiac phenotype in H9c2 myoblast differentiation.

The H9c2 myoblast cell line, isolated from the left ventricular tissue of rat, is currently used in vitro as a mimetic for skeletal and cardiac muscle due to its biochemical, morphological, and electrical/hormonal signaling properties. During culture, H9c2 cells acquire a myotube phenotype, where a critical component is the inclusion of retinoic acid (RA). The results from some authors on H9c2 suggested that thousands of genes respond to RA stimuli, while others report hundreds of genes responding to RA over different cell types. In this article, using a more appropriate experimental design, we first confirm the H9c2 cardiac phenotype with and without RA and report transcriptomic and physiological changes regarding calcium handling, bioenergetics, and other biological concepts. Interestingly, of the 2360 genes showing a transcriptional change, 622 genes were statistically associated with the RA response. Of these genes, only 305 were RA-specific, and the rest also showed a culture-time component. Thus, the major expression changes (from 74 to 87%) were indeed due to culture conditions over time. Unexpectedly, only a few components of the retinol pathway in KEGG responded to RA. Our results show the role of RA in the H9c2 cultures impacting the interpretation using H9c2 as an in vitro model.

Integrative analysis reveals novel pathways mediating the interaction between adipose tissue and pancreatic islets in obesity in rats.

AIMS/HYPOTHESIS: Comprehensive characterisation of the interrelation between the peripancreatic adipose tissue and the pancreatic islets promises novel insights into the mechanisms that regulate beta cell adaptation to obesity. Here, we sought to determine the main pathways and key molecules mediating the crosstalk between these two tissues during adaptation to obesity by the way of an integrated inter-tissue, multi-platform analysis. METHODS: Wistar rats were fed a standard or cafeteria diet for 30 days. Transcriptomic variations by diet in islets and peripancreatic adipose tissue were examined through microarray analysis. The secretome from peripancreatic adipose tissue was subjected to a non-targeted metabolomic and proteomic analysis. Gene expression variations in islets were integrated with changes in peripancreatic adipose tissue gene expression and protein and metabolite secretion using an integrated inter-tissue pathway and network analysis. RESULTS: The highest level of data integration, linking genes differentially expressed in both tissues with secretome variations, allowed the identification of significantly enriched canonical pathways, such as the activation of liver/retinoid X receptors, triacylglycerol degradation, and regulation of inflammatory and immune responses, and underscored interaction network hubs, such as cholesterol and the fatty acid binding protein 4, which were unpredicted through single-tissue analysis and have not been previously implicated in the peripancreatic adipose tissue crosstalk with beta cells. CONCLUSIONS/INTERPRETATION: The integrated analysis reported here allowed the identification of novel mechanisms and key molecules involved in peripancreatic adipose tissue interrelation with beta cells during the development of obesity; this might help the development of novel strategies to prevent type 2 diabetes.

Previous cardiovascular injury is a prerequisite for immune checkpoint inhibitor-associated lethal myocarditis in mice.

AIMS: Immune checkpoint inhibitors (ICIs) are antineoplastic drugs designed to activate the immune system's response against cancer cells. Evidence suggests that they may lead to immune-related adverse events, particularly when combined (e.g., anti-CTLA-4 plus anti-PD-1), sometimes resulting in severe conditions such as myocarditis. We aimed to investigate whether a previously sustained cardiac injury, such as pathological remodelling due to hypertension, is a prerequisite for ICI therapy-induced myocarditis. METHODS: We evaluated the cardiotoxicity of ICIs in a hypertension (HTN) mouse model (C57BL/6). Weekly doses were administered up to day 21 after the first administration. Our analysis encompassed the following parameters: (i) survival and cardiac pathological remodelling, (ii) cardiac function assessed using pressure-volume (PV)-loops, with brain natriuretic peptide (BNP) serving as a marker of haemodynamic dysfunction and (iii) cardiac inflammation (cytokine levels, infiltration, and cardiac antigen autoantibodies). RESULTS: After the first administration of ICI combined therapy, the treated HTN group showed a 30% increased mortality (P = 0.0002) and earlier signs of hypertrophy and pathological remodelling compared with the untreated HTN group. BNP (P = 0.01) and TNF-α (<0.0001) increased 2.5- and 1.7-fold, respectively, in the treated group, while IL-6 (P = 0.8336) remained unchanged. Myocarditis only developed in the HTN group treated with ICIs on day 21 (score >3), characterised by T cell infiltration and increased cardiac antigen antibodies (86% showed a titre of 1:160). The control group treated with ICI was unaffected in any evaluated feature. CONCLUSIONS: Our findings indicate that pre-existing sustained cardiac damage is a necessary condition for ICI-induced myocarditis.

Mitochondrial Ca2+ Uniporter-Dependent Energetic Dysfunction Drives Hypertrophy in Heart Failure.

The role of the mitochondrial calcium uniporter (MCU) in energy dysfunction and hypertrophy in heart failure (HF) remains unknown. In angiotensin II (ANGII)-induced hypertrophic cardiac cells we have shown that hypertrophic cells overexpress MCU and present bioenergetic dysfunction. However, by silencing MCU, cell hypertrophy and mitochondrial dysfunction are prevented by blocking mitochondrial calcium overload, increase mitochondrial reactive oxygen species, and activation of nuclear factor kappa B-dependent hypertrophic and proinflammatory signaling. Moreover, we identified a calcium/calmodulin-independent protein kinase II/cyclic adenosine monophosphate response element-binding protein signaling modulating MCU upregulation by ANGII. Additionally, we found upregulation of MCU in ANGII-induced left ventricular HF in mice, and in the LV of HF patients, which was correlated with pathological remodeling. Following left ventricular assist device implantation, MCU expression decreased, suggesting tissue plasticity to modulate MCU expression.

Measles-an ENT diagnosis?

Ear, Nose and Throat (ENT) should remain vigilant about the emergence of measles in non-endemic countries. Clinical suspicion is crucial in identifying this disease, with Koplik's spots being a pathognomonic sign. Forming part of the differential diagnosis and helping to prevent potential outbreaks.

Drivers of Insect Community Change along the Margins of Mountain Streams in Serra da Estrela Natural Park (Portugal).

Mountain ecosystems are important biodiversity hotspots and valuable natural laboratories to study community assembly processes. Here, we analyze the diversity patterns of butterflies and odonates in a mountainous area of high conservation value-Serra da Estrela Natural Park (Portugal)-and we assess the drivers of community change for each of the two insect groups. The butterflies and odonates were sampled along 150 m transects near the margins of three mountain streams, at three elevation levels (500, 1000, and 1500 m). We found no significant differences in odonate species richness between elevations, but marginal differences (p = 0.058) were found for butterflies due to the lower number of species at high altitudes. Both insect groups showed significant differences in beta diversity (ßtotal) between elevations, with species richness differences being the most important component for odonates (ßrich = 55.2%), while species replacement drove the changes between butterfly assemblages (ßrepl = 60.3%). Climatic factors, particularly those depicting harsher conditions of temperature and precipitation, were the best predictors of total beta diversity (ßtotal) and its components (ßrich, ßrepl) for the two study groups. The study of insect biodiversity patterns in mountain ecosystems and of the role played by different predictors contribute to further our understanding on the community assembly processes and may help to better predict environmental change impacts on mountain biodiversity.

Exploring the mechanisms underlying stroke volume variability reduction in a murine model of heart failure with reduced ejection fraction.

Heart failure with reduced ejection fraction (HFrEF) is accompanied by disregulation of cardiovascular function. Heart rate variability (HRV) is commonly used to assess autonomic dysfunction in HFrEF. However, analysis of stroke volume variability (SVV) may provide additional insights. We examined HRV and SVV in a mouse model of HFrEF. HFrEF mice exhibited reduced stroke volume and ejection fraction versus controls, confirming cardiac contractile dysfunction. HRV was preserved in HFrEF mice. However, SVV was markedly diminished, indicating dissociation between HRV and SVV regulation. Using a mathematical model, we propose that Frank-Starling mechanism abnormalities in HFrEF disrupt SVV independent of HRV. Assessing SVV could thus provide unique insights beyond HRV into cardiovascular control deficits in HFrEF.

Standardised inventories of lepidopterans and odonates from Serra da Estrela Natural Park (Portugal) - setting the scene for mountain biodiversity monitoring.

Background: Mountain insect biodiversity is unique, but is menaced by different drivers, particularly climate and land-use changes. In mainland Portugal, the highest mountain - Serra da Estrela - is one of the most important biodiversity hotspots, being classified as Natural Park since 1976. Many lepidopteran and odonate species, including rare and protected species, are known to occur in Serra da Estrela, but basic knowledge on their abundance, distribution and ecology is still lacking. Standardised sampling of these communities is crucial to provide valuable biological information to support short-term decision-making for conservation management, setting simultaneously the standards for mountain biodiversity monitoring aiming to tackle the effects of environmental change in the long-term. New information: This study reports novel information on lepidopteran and odonate species diversity, distribution and abundance from Serra da Estrela Natural Park (Portugal). Seventy-two lepidopteran and 26 odonate species were sampled in this protected area, including the first findings of Apaturailia (Denis & Schiffermüller, 1775), Macromiasplendens (Pictet, 1843) and Vanessavirginiensis (Drury, 1773). New populations of Euphydriasaurinia (Rottemburg, 1775) and Oxygastracurtisii (Dale, 1834), protected species under the Habitats Directive, were found in this Natural Park and novel distribution and ecological data were collected for most species, including several rare species and subspecies [e.g. Aeshnajuncea (Linnaeus, 1758), Coenonymphaglycerioniphioides Staudinger, 1870, Cyanirissemiargus (Rottemburg, 1775) and Sympetrumflaveolum (Linnaeus, 1758)]. All data were collected using standardised sampling allowing its use as a baseline for biodiversity monitoring in Serra da Estrela.

Direct reprogramming of human fibroblasts into insulin-producing cells using transcription factors.

Direct lineage reprogramming of one somatic cell into another without transitioning through a progenitor stage has emerged as a strategy to generate clinically relevant cell types. One cell type of interest is the pancreatic insulin-producing ß cell whose loss and/or dysfunction leads to diabetes. To date it has been possible to create ß-like cells from related endodermal cell types by forcing the expression of developmental transcription factors, but not from more distant cell lineages like fibroblasts. In light of the therapeutic benefits of choosing an accessible cell type as the cell of origin, in this study we set out to analyze the feasibility of transforming human skin fibroblasts into ß-like cells. We describe how the timed-introduction of five developmental transcription factors (Neurog3, Pdx1, MafA, Pax4, and Nkx2-2) promotes conversion of fibroblasts toward a ß-cell fate. Reprogrammed cells exhibit ß-cell features including ß-cell gene expression and glucose-responsive intracellular calcium mobilization. Moreover, reprogrammed cells display glucose-induced insulin secretion in vitro and in vivo. This work provides proof-of-concept of the capacity to make insulin-producing cells from human fibroblasts via transcription factor-mediated direct reprogramming.

Optimization of production of extracellular polymeric substances by Arthrobacter viscosus and their interaction with a 13X zeolite for the biosorption of Cr(VI).

In this work we aimed to optimize the production of extracellular polymeric substances (EPS) by an Arthrobacter viscosus biofilm supported on 13X zeolite to be used in the biosorption of Cr(VI). The optimization parameters were agitation rate, work volume, pH and glucose concentration. Following the optimization of EPS production, the biofilm was used in the biosorption of hexavalent Cr from liquid solutions. Differences between the use of dead or active biomass and between the performance of zeolite in powder or in pellet form were also studied. The optimized EPS production allowed values of metal uptake between 2.72 mg/g(biosorbent) and 7.88 mg/g(biosorbent) for initial Cr(VI) concentrations of 20-60 mg/L. For an initial concentration of 20 mg/L, the optimal conditions of EPS production allowed an increase of 10% on the removal percentage of total Cr, and the use of zeolite as a powder rather than the pelleted form produced an increase of 46.5% in the removal percentage. For the initial concentration of 60 mg/L, the use of active biomass compared to dried biomass allowed a reduction of the time required for the total removal of Cr(VI) from 20 to 13 days.

Rheologically Assisted Design of Conductive Adhesives for Stencil Printing on PCB.

Driven by the need to deliver new, lead-free, eco-friendly solder pastes for soldering electronic components to Printed Circuit Boards (PCB), electrically conductive adhesives (ECAs) based on epoxy, carbon nanotubes (CNT), and exfoliated graphite (EG) were designed. The rheology of the adhesives prepared is paramount for the success of the deposition process, which is based on stencil printing. Thus, a rheological analysis of the process was first performed. Then, an experimental protocol was defined to assess the relevant viscoelastic characteristics of the adhesives for stencil printing application. Different composite formulations of epoxy/CNT/EG were produced. Their rheological characteristics were established following the designed protocol and benchmarked with a commercial solder paste. The thermal and electrical properties of the composite formulations were also characterized. As a result, a new, electrically conductive adhesive was delivered with potential to be an eco-friendly alternative to the solder paste currently used in stencil printing of PCB.

Removal of organic compounds by a biofilm supported on GAC: modelling of batch and column data.

The performance of a biofilm of Arthrobacter viscosus supported on granular activated carbon on the retention of organic compounds was evaluated. The presence of functional groups on the cell wall surface of the biomass that may interact with the organic compounds was confirmed by Fourier transform infrared spectroscopy, to assess the applicability of this system to the removal of those compounds. The batch assays showed that the removal percentage decreases with the increasing initial concentration. The removal of phenol ranged from 99.5 to 93.4%, the chlorophenol removal ranged from 99.3 to 61.6% and the o-cresol removal ranged from 98.7 to 73.5%, for initial concentrations between 100 and 1,700 mg/L. The batch data were described by Freundlich, Langmuir, Redlich-Peterson, Dubinin-Radushkevich, Sips and Toth model isotherms and the best fit for the retention of phenol and for the retention of o-cresol was obtained with the Sips model, while for chlorophenol, the best fit was obtained with the Freundlich model. The column tests showed that the retention performance followed the order: phenol > chlorophenol > o-cresol, and increased with the increasing initial organic compound concentration. Data from column runs were described by Adams-Bohart, Wolborska and Yoon and Nelson models with good fitting for all the models.

[Physician-pharmacist collaboration: a way to improve the quality of drug prescribing]. / Qualité de la prescription médicamenteuse: des progrès grâce a la collaboration médecins- pharmaciens.

The medical prescription is the end-result of a structured process. It is, in effect, a medicolegal document that binds the physician who writes it as well as the pharmacist who delivers it, with a civil duty of care that is protected by penal sanction. Moreover, prescriptions carry important costs, and can be the source of errors, especially where there are breakdowns in the continuity of patient care. These features underline the importance of the act of "prescribing", and the need for ways to improve its quality through increased efficiency and safety. The Swiss experience of physicians-pharmacists Quality Circles for drug prescription in the community and in the nursing homes, represent with the medication review, one method of safeguarding quality prescribing.

Targeting pancreatic islet PTP1B improves islet graft revascularization and transplant outcomes.

Deficient vascularization is a major driver of early islet graft loss and one of the primary reasons for the failure of islet transplantation as a viable treatment for type 1 diabetes. This study identifies the protein tyrosine phosphatase 1B (PTP1B) as a potential modulator of islet graft revascularization. We demonstrate that grafts of pancreatic islets lacking PTP1B exhibit increased revascularization, which is accompanied by improved graft survival and function, and recovery of normoglycemia and glucose tolerance in diabetic mice transplanted with PTP1B-deficient islets. Mechanistically, we show that the absence of PTP1B leads to activation of hypoxia-inducible factor 1α-independent peroxisome proliferator-activated receptor γ coactivator 1α/estrogen-related receptor α signaling and enhanced expression and production of vascular endothelial growth factor A (VEGF-A) by ß cells. These observations were reproduced in human islets. Together, these findings reveal that PTP1B regulates islet VEGF-A production and suggest that this phosphatase could be targeted to improve islet transplantation outcomes.

Nanoencapsulated Quercetin Improves Cardioprotection during Hypoxia-Reoxygenation Injury through Preservation of Mitochondrial Function.

The effective delivery of antioxidants to the cells is hindered by their high metabolization rate. In this work, quercetin was encapsulated in poly(lactic-co-glycolic) acid (PLGA) nanoparticles. They were characterized in terms of its physicochemical properties (particle size distribution, ζ-potential, encapsulation efficiency, quercetin release and biological interactions with cardiac cells regarding nanoparticle association, and internalization and protective capability against relevant challenges). A better delivery of quercetin was achieved when encapsulated versus free. When the cells were challenged with antimycin A, it resulted in lower mitochondrial O2 - (4.65- vs. 5.69- fold) and H2O2 rate production (1.15- vs. 1.73- fold). Similarly, under hypoxia-reoxygenation injury, a better maintenance of cell viability was found (77 vs. 65%), as well as a reduction of thiol groups (~70 vs. 40%). Therefore, the delivery of encapsulated quercetin resulted in the preservation of mitochondrial function and ATP synthesis due to its improved oxidative stress suppression. The results point to the potential of this strategy for the treatment of oxidative stress-based cardiac diseases.

Taurine Treatment Modulates Circadian Rhythms in Mice Fed A High Fat Diet.

Close ties have been made among certain nutrients, obesity, type 2 diabetes and circadian clocks. Among nutrients, taurine has been documented as being effective against obesity and type 2 diabetes. However, the impact of taurine on circadian clocks has not been elucidated. We investigated whether taurine can modulate or correct disturbances in daily rhythms caused by a high-fat diet in mice. Male C57BL/6 mice were divided in four groups: control (C), control + taurine (C+T), high-fat diet (HFD) and HFD + taurine (HFD+T). They were administered 2% taurine in their drinking water for 10 weeks. Mice were euthanized at 6:00, 12:00, 18:00, and 24:00. HFD mice increased body weight, visceral fat and food intake, as well as higher levels of glucose, insulin and leptin, throughout the 24 h. Taurine prevented increments in food intake, body weight and visceral fat, improved glucose tolerance and insulin sensitivity and reduced disturbances in the 24 h patterns of plasma insulin and leptin. HFD downregulated the expression of clock genes Rev-erbα, Bmal1, and Per1 in pancreatic islets. Taurine normalized the gene and protein expression of PER1 in beta-cells, which suggests that it could be beneficial for the correction of daily rhythms and the amelioration of obesity and diabetes.

Tailored zeolites for the removal of metal oxyanions: overcoming intrinsic limitations of zeolites.

This review aims to present a global view of the efforts conducted to convert zeolites into efficient supports for the removal of heavy metal oxyanions. Despite lacking affinity for these species, due to inherent charge repulsion between zeolite framework and anionic species, zeolites have still received considerable attention from the scientific community, since their versatility allowed tailoring them to answer specific requirements. Different processes for the removal and recovery of toxic metals based on zeolites have been presented. These processes resort to modification of the zeolite surface to allow direct adsorption of oxyanions, or by combination with reducing agents for oxyanions that allow ion-exchange with the converted species by the zeolite itself. In order to testify zeolite versatility, as well as covering the wide array of physicochemical constraints that oxyanions offer, chromium and arsenic oxyanions were selected as model compounds for a review of treatment/remediation strategies, based on zeolite modification.

The effect of clay treatment on remediation of diethylketone contaminated wastewater: uptake, equilibrium and kinetic studies.

The ability of four different clays to adsorb diethylketone was investigated in batch experiments aiming to treat wastewater with low solvent concentrations. The adsorption performance in terms of uptake followed the sequence: vermiculite>sepiolite=kaolinite=bentonite, for all the adsorbent doses tested (from 0.1 to 1.5 g) in 150 mL of ketone solution (800 mg/L). The equilibrium data in the batch systems were described by Sips and Dubinin-Raduskevich isotherms. The best fits for bentonite and kaolinite clays were obtained with the Sips isotherm and for sepiolite and vermiculite the best fits were obtained with the Dubinin-Raduskevich model. Kinetic data were described by pseudo-first and pseudo-second order kinetics models. The best fit was obtained for the pseudo-first order model which assumed that the interaction rate was limited only by one process or mechanism on a single class of sorbing sites and that all sites were time dependent. The presence of functional groups on the clay surface that might have interacted with the solvent was confirmed by FTIR. XRD analysis was also performed. This study showed that the tested clays are very effective for the removal of diethylketone from industrial effluents.

Adherence: a review of education, research, practice and policy in Switzerland.

Nonadherence to medication treatment regimens is a major preventable risk behavior in both acute and chronic diseases. Community pharmacists are facilitators in community care for promoting medication adherence and they should implement interdisciplinary medication adherence programs. To do so, pharmacists should be educated in medication adherence, and new pharmaceutical care policies should be implemented. The healthcare system should evolve to better meet the specific needs of patients. AIMS: this article describes what has been undertaken in the last decade in medication adherence in terms of education, research, practice and policy in Switzerland. METHODS: Medline was searched, with the search limited to Switzerland. The three Swiss pharmacy schools were also contacted to collect information about the medication adherence content of both their courses and research programs. National policies related to medication adherence were also reviewed for relevant content. EDUCATION: two pharmacy schools offer courses devoted specifically to medication adherence. The number of hours dedicated to the topic varies between 4 to13. RESEARCH: a total of 16 studies met the inclusion criteria. Chronic patients were the focus of 9 studies. Medication adherence was the primary outcome of all studies; 10 studies also measured clinical outcomes. Nine studies evaluated the prevalence of medication nonadherence; three studies evaluated the feasibility of new technologies for monitoring adherence; three studies evaluated medication adherence enhancing programs. Policies: three cognitive pharmaceutical services are reimbursed by healthcare insurers, which are directly related to medication adherence. CONCLUSIONS: Pharmacists in Switzerland have been actively involved in medication adherence research since the mid '90s. Specific medication adherence courses have entered the curriculum of pharmacy schools, and policies in Switzerland are slowly beginning to meet needs of chronic patients by the introduction of pharmaceutical cognitive services and reimbursement fees.