Therapeutic Potential of Adipose-Derived Therapeutic Factor Concentrate for Treating Critical Limb Ischemia

Transplantation of adipose-derived stem cells (ADSCs) is an emerging therapeutic option for addressing intractable diseases such as critical limb ischemia (CLI). Evidence suggests that therapeutic effects of ADSCs are primarily mediated through paracrine mechanisms rather than transdifferentiation. These secreted factors can be captured in conditioned medium (CM) and concentrated to prepare a therapeutic factor concentrate (TFC) composed of a cocktail of beneficial growth factors and cytokines that individually and in combination demonstrate disease-modifying effects. The ability of a TFC to promote reperfusion in a rabbit model of CLI was evaluated. A total of 27 adult female rabbits underwent surgery to induce ischemia in the left hindlimb. An additional five rabbits served as sham controls. One week after surgery, the ischemic limbs received intramuscular injections of either (1) placebo (control medium), (2) a low dose of TFC, or (3) a high dose of TFC. Limb perfusion was serially assessed with a Doppler probe. Blood samples were analyzed for growth factors and cytokines. Tissue was harvested postmortem on day 35 and assessed for capillary density by immunohistochemistry. At 1 month after treatment, tissue perfusion in ischemic limbs treated with a high dose of TFC was almost double (p < 0.05) that of the placebo group [58.8 ± 23 relative perfusion units (RPU) vs. 30.7 ± 13.6 RPU; mean ± SD]. This effect was correlated with greater capillary density in the affected tissues and with transiently higher serum levels of the angiogenic and prosurvival factors vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF). The conclusions from this study are that a single bolus administration of TFC demonstrated robust effects for promoting tissue reperfusion in a rabbit model of CLI and that a possible mechanism of revascularization was promotion of angiogenesis by TFC. Results of this study demonstrate that TFC represents a potent therapeutic cocktail for patients with CLI, many of whom are at risk for amputation of the affected limb

Global guidelines for the sustainable use of non-native trees to prevent tree invasions and mitigate their negative impacts

Sustainably managed non-native trees deliver economic and societal benefits with limited risk of spread to adjoining areas. However, some plantations have launched invasions that cause substantial damage to biodiversity and ecosystem services, while others pose substantial threats of causing such impacts. The challenge is to maximise the benefits of non-native trees, while minimising negative impacts and preserving future benefits and options. A workshop was held in 2019 to develop global guidelines for the sustainable use of non-native trees, using the Council of Europe – Bern Convention Code of Conduct on Invasive Alien Trees as a starting point. The global guidelines consist of eight recommendations: 1) Use native trees, or non-invasive non-native trees, in preference to invasive non-native trees; 2) Be aware of and comply with international, national, and regional regulations concerning non-native trees; 3) Be aware of the risk of invasion and consider global change trends; 4) Design and adopt tailored practices for plantation site selection and silvicultural management; 5) Promote and implement early detection and rapid response programmes; 6) Design and adopt tailored practices for invasive non-native tree control, habitat restoration, and for dealing with highly modified ecosystems; 7) Engage with stakeholders on the risks posed by invasive non-native trees, the impacts caused, and the options for management; and 8) Develop and support global networks, collaborative research, and information sharing on native and non-native trees. The global guidelines are a first step towards building global consensus on the precautions that should be taken when introducing and planting non-native trees. They are voluntary and are intended to complement statutory requirements under international and national legislation. The application of the global guidelines and the achievement of their goals will help to conserve forest biodiversity, ensure sustainable forestry, and contribute to the achievement of several Sustainable Development Goals of the United Nations linked with forest biodiversity

The fingerprint of the summer 2018 drought in Europe on ground-based atmospheric CO2 measurements

During the summer of 2018, a widespread drought developed over Northern and Central Europe. The increase in temperature and the reduction of soil moisture have influenced carbon dioxide (CO2) exchange between the atmosphere and terrestrial ecosystems in various ways, such as a reduction of photosynthesis, changes in ecosystem respiration, or allowing more frequent fires. In this study, we characterize the resulting perturbation of the atmospheric CO2 seasonal cycles. 2018 has a good coverage of European regions affected by drought, allowing the investigation of how ecosystem flux anomalies impacted spatial CO2 gradients between stations. This density of stations is unprecedented compared to previous drought events in 2003 and 2015, particularly thanks to the deployment of the Integrated Carbon Observation System (ICOS) network of atmospheric greenhouse gas monitoring stations in recent years. Seasonal CO2 cycles from 48 European stations were available for 2017 and 2018.The UK sites were funded by the UK Department of Business, Energy and Industrial Strategy (formerly the Department of Energy and Climate Change) through contracts TRN1028/06/2015 and TRN1537/06/2018. The stations at the ClimaDat Network in Spain have received funding from the ‘la Caixa’ Foundation, under agreement 2010-002624

Rationale and design of a prospective, randomised study of retrograde application of bone marrow aspirate concentrate (BMAC) through coronary sinus in patients with congestive heart failure of ischemic etiology (the RETRO study)

Abstract Background Heart failure (HF) is a major chronic illness and results in high morbidity and mortality. The most frequent cause of HF with reduced ejection fraction (HFREF) is coronary artery disease (CAD). Although revascularisation of ischemic myocardium lead to improvements in myocardial contractility and systolic function, it cannnot restore the viability of the already necrotic myocardium. Methods/design The aim of our prospective randomised study is to assess the efficacy of the retrograde application of non-selected bone marrow autologous cells concentrate (BMAC) in patients with HFREF of ischemic aetiology. The evaluated preparation is concentrated BMAC, obtained using Harvest SmartPReP2 (Harvest Technologies, Plymouth, MA, USA). The study population will be a total of 40 patients with established CAD, systolic dysfunction with LV EF of ≤40% and HF in the NYHA class 3. Patients have been on standard HF therapy for 3 months and in a stabilised state for at least 1 month, before enrolling in the clinical study. Patients will be randomised 1:1 to either retrograde BMAC administration via coronary sinus or standard HF therapy. The primary end-points (left ventricular end-systolic and end-diastolic diameters [LVESd/EDd] and volumes [LVESV/EDV] and left ventricular ejection fraction [LV EF]) will be assessed by magnetic resonance imaging. The follow-up period will be 12 month. Discussion The application of bone marrow stem cells into affected areas of the myocardium seems to be a promising treatment of ischemic cardiomyopathy. The Harvest BMAC contains the entire population of nuclear cells from bone marrow aspirates together with platelets. The presence of both platelets and additional granulocytes can have a positive effect on the neovascularisation potential of the resulting concentrate. Our assumption is that retrograde administration on non-selected BMAC via coronary sinus, due to the content of platelets and growth factors, might improve left ventricular function and parameters compared to standard HF therapy. Furthermore, it will be associated with improved exercise tolerance in the six-minute corridor walk test and an improvement in the life quality of patients without increasing the incidence of severe ventricular arrythmias. Trial registration (ClinicalTrials.gov; https://clinicaltrials.gov; NCT03372954)

Magneto-responsive hyaluronan hydrogel for hyperthermia and bioprinting: Magnetic, rheological properties and biocompatibility

Magneto-responsive soft hydrogels are used for a number of biomedical applications, e.g., magnetic hyperthermia, drug delivery, tissue engineering, and neuromodulation. In this work, this type of hydrogel has been fabricated from hyaluronan (HA) filled with a binary system of Al2O3 nanoparticles and multicore magnetic particles (MCPs), which were obtained by clustering of superparamagnetic iron oxide FeOx NPs. It was established that the presence of diamagnetic Al2O3 has several positive effects: it enhances the hydrogel storage modulus and long-term stability in the cell cultivation medium; prevents the magnetic interaction among the MCPs. The HA hydrogel provides rapid heating of 0.3 °C per min under exposure to low amplitude radio frequency alternating magnetic field. Furthermore, the magneto-responsive hydrogel was successfully used to encapsulate cells and extrusion-based 3D printing with 87±6% cell viability, thus providing a bio-ink. The combination of high heating efficiency, softness, cytocompatibility, and 3D printability of magnetic HA hydrogel leads to a material suitable for biomedical applications

Retinol-binding protein 4 expression in visceral and subcutaneous fat in human obesity.

International audienceRetinol binding protein 4 (RBP4) is a novel adipokine which might be involved in the development of insulin resistance. The aim of the study was to investigate the expression of RBP4 mRNA in subcutaneous and visceral fat depots and the relationship between RBP4 plasma and mRNA levels relative to indices of adiposity and insulin resistance. In 59 Caucasian women (BMI 20 to 49 kg/m(2)) paired samples of subcutaneous and visceral fat were obtained for RBP4, leptin and GLUT 4 mRNA analysis using reverse transcription-quantitative PCR. Euglycemic hyperinsulinemic clamp and computed tomography scans were performed. RBP4 mRNA levels as well as GLUT 4 mRNA and leptin mRNA levels were lower (P<0.001, P<0.01 and P<0.001, respectively) in visceral compared to subcutaneous fat. No differences were found in RBP4 mRNA expression in the two fat depots or in RBP4 plasma levels between subgroups of non-obese subjects (n=26), obese subjects without metabolic syndrome (n=17) and with metabolic syndrome (n=16). No correlations between RBP4 mRNA or plasma levels relative to adiposity, glucose disposal rate and GLUT 4 mRNA expression in adipose tissue were found. There was a weak positive correlation between plasma RBP4 and plasma triglycerides (r = 0.30, p<0.05) and between plasma RBP4 and blood glucose (r = 0.26, p<0.05). Regardless of the state of adiposity or insulin resistance, RBP4 expression in humans was lower in visceral than in subcutaneous fat. We found no direct relationship between either RBP4 mRNA or its plasma levels and the adiposity or insulin resistance