Design and baseline characteristics of the finerenone in reducing cardiovascular mortality and morbidity in diabetic kidney disease trial

Background: Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. Patients and Methods: The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate >= 25 mL/min/1.73 m(2) and albuminuria (urinary albumin-to-creatinine ratio >= 30 to <= 5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level alpha = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Conclusions: FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049

A new role of hindbrain boundaries as pools of neural stem/progenitor cells regulated by Sox2

Background: Compartment boundaries are an essential developmental mechanism throughout evolution, designated to act as organizing centers and to regulate and localize differently fated cells. The hindbrain serves as a fascinating example for this phenomenon as its early development is devoted to the formation of repetitive rhombomeres and their well-defined boundaries in all vertebrates. Yet, the actual role of hindbrain boundaries remains unresolved, especially in amniotes. Results: Here, we report that hindbrain boundaries in the chick embryo consist of a subset of cells expressing the key neural stem cell (NSC) gene Sox2. These cells co-express other neural progenitor markers such as Transitin (the avian Nestin), GFAP, Pax6 and chondroitin sulfate proteoglycan. The majority of the Sox2+ cells that reside within the boundary core are slow-dividing, whereas nearer to and within rhombomeres Sox2+ cells are largely proliferating. In vivo analyses and cell tracing experiments revealed the contribution of boundary Sox2+ cells to neurons in a ventricular-to-mantle manner within the boundaries, as well as their lateral contribution to proliferating Sox2+ cells in rhombomeres. The generation of boundary-derived neurospheres from hindbrain cultures confirmed the typical NSC behavior of boundary cells as a multipotent and self-renewing Sox2+ cell population. Inhibition of Sox2 in boundaries led to enhanced and aberrant neural differentiation together with inhibition in cell-proliferation, whereas Sox2 mis-expression attenuated neurogenesis, confirming its significant function in hindbrain neuronal organization. Conclusions: Data obtained in this study deciphers a novel role of hindbrain boundaries as repetitive pools of neural stem/progenitor cells, which provide proliferating progenitors and differentiating neurons in a Sox2-dependent regulation. Electronic supplementary material The online version of this article (doi:10.1186/s12915-016-0277-y) contains supplementary material, which is available to authorized users

Wireless Optogenetic Stimulation of Oxytocin Neurons in a Semi-natural Setup Dynamically Elevates Both Pro-social and Agonistic Behaviors

Complex behavioral phenotyping techniques are becoming more prevalent in the field of behavioral neuroscience, and thus methods for manipulating neuronal activity must be adapted to fit into such paradigms. Here, we present a head-mounted, magnetically activated device for wireless optogenetic manipulation that is compact, simple to construct, and suitable for use in group-living mice in an enriched semi-natural arena over several days. Using this device, we demonstrate that repeated activation of oxytocin neurons in male mice can have different effects on pro-social and agonistic behaviors, depending on the social context. Our findings support the social salience hypothesis of oxytocin and emphasize the importance of the environment in the study of social neuromodulators. Our wireless optogenetic device can be easily adapted for use in a variety of behavioral paradigms, which are normally hindered by tethered light delivery or a limited environment

Additional file 7: of A new role of hindbrain boundaries as pools of neural stem/progenitor cells regulated by Sox2

Expression of neural-differentiation markers in the hindbrain. A. (a) Representative flow cytometry plot from 18 HH hindbrain stained with Sox2 and Tuj1. Quantification of relative abundance of Sox2/Tuj1-expressing cells is shown. (b) Graphic representation of Sox2/Tuj1 distribution as percentage of total stained cells. B. Representative flat-mounted views of 15HH and 18HH hindbrains in situ hybridized with RNA probes against NeuroD, NSCL1 and Brn3a, or immunostained for HuC/D (n = 10/marker) (e-h). Expression of NSCL1 and HuC/D shifts from punctuated rhombomeric expression in 15HH to boundary-enhanced expression at 18HH. C. (a-c) Representative flat-mounted views of 18HH hindbrains stained for Sox2 and HuC/D (n = 10). Merged image is shown in (c). (d-g) Sequential Z-stack analysis from 0 to –20 μm of a boundary area. Arrows indicate site of neural differentiation. Scale bars = 100 μm. D. Scheme of the clonal-analysis of HB cell-labeling experiment using injection of AFP plasmid into single cells and harvesting at two time points. (TIF 4496 kb

Additional file 6: of A new role of hindbrain boundaries as pools of neural stem/progenitor cells regulated by Sox2

CM-DiI labeling of boundary and rhombomere cells. Representative flat-mount confocal views of CM-DiI labelled rhombomere (a,b) or boundary (c,d) (n = 5 hindbrains). Arrows indicate injection site, yellow lines indicate boundaries. Outlined areas in (b,d) show dye expansion. (TIF 11336 kb

Additional file 9: of A new role of hindbrain boundaries as pools of neural stem/progenitor cells regulated by Sox2

Detailed description of clones and plasmids used in this study. (DOCX 13 kb