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

Formation of ultrapotassic magma via crustal contamination and hybridization of mafic magma: an example from the Stomanovo monzonite, Central Rhodope Massif, Bulgaria

Generally all orogenic ultrapotassic rocks are formed after melting of metasomatized sub-continental lithospheric mantle via subducted crustal mica-bearing lithologies. Here we present another possible model, based on the study of the small Stomanovo ultrapotassic monzonite porphyry intrusion in the Central Rhodope Massif, Bulgaria. The monzonite dated at 30.50 ± 0.46 Ma is intruded into the voluminous Oligocene (31.63 ± 0.40 Ma) Bratsigovo–Dospat ignimbrite. The monzonite hosts both normally and reversely zoned clinopyroxene phenocrysts. The normally zoned clinopyroxene is characterized by gradually diminishing core-to-rim Mg no. (89–74), whereas the reversely zoned clinopyroxene has green Fe-rich cores (Mg no. 71–55) mantled by normally zoned clinopyroxene (Mg no. 87–74). Neither the core of the normally zoned clinopyroxene nor the Fe-rich green cores are in equilibrium with the host monzonite. This ultrapotassic monzonite shows more radiogenic Sr isotopes ((87Sr/86Sr)i = 0.71066) and ϵNd(t) = −7.8 to −8.0 that are distinct from the host ignimbrites with (87Sr/86Sr)i = 0.70917–0.70927 and ϵNd(t) = −4.6 to −6.5. The Sr–Nd isotopic data and the presence of copious zircon xenocrysts from the underlying metamorphic basement suggest extensive crustal assimilation. Our observations indicate that the Stomanovo ultrapotassic monzonite formed after extensive lower or middle crustal fractional crystallization from an evolved magma producing cumulates. The process was followed by hybridization with primitive mantle-derived magma and subsequent continuous crustal contamination. We suggest that instead of inheriting their high K2O and large-ion lithophile element enrichments from slab-derived/metasomatic fluids, the Stomanovo ultrapotassic monzonite may owe some of its unusually high alkalinity to the assimilation of potassium-rich phases from the Rhodope Massif basement rocks

Adipogenic potential of stem cells derived from rabbit subcutaneous and visceral adipose tissue in vitro

Rabbits are considered as appropriate animal models to study some obesity-associated abnormalities because of the similarity of their blood lipid profile and metabolism to humans. The current study was focused on comparison of adipose differentiation ability in rabbit adipose-derived stem cells (ADSC) in vitro. Subcutaneous and visceral stromal vascular fractions (SVF) were isolated from three 28-d-old New Zealand rabbits by collagenase digestion. Supernatants from both isolates were collected 24 h after the initial plating. On the fourth passage, all isolated cell types undergo triplicate adipogenic induction. The adipose induction potential was calculated as percentage of increasing optical density (OD) values. The data revealed that with increasing the number of induction cycles, the induction tendency in visceral ADSC decreased in contrast to the subcutaneous ones. Although the supernatants did not reach induction levels of their relevant precursors, they follow the same pattern in both subcutaneous and visceral ADSC. All cell types successfully passed osteogenic and chondrogenic differentiation. In conclusion, the best adipose induction ability was observed in directly plated subcutaneous cell population. The increase of induction numbers depressed adipose induction ability in cell populations derived from visceral fat depots

Effect of subcutaneous insulin on intestinal adaptation in a rat model of short bowel syndrome

Insulin has been shown to influence intestinal structure and absorptive function. The purpose of the present study was to evaluate the effects of parenteral insulin on structural intestinal adaptation, cell proliferation, and apoptosis in a rat model of short bowel syndrome (SBS). Male Sprague-Dawley rats were divided into three experimental groups: sham rats underwent bowel transection and reanastomosis, SBS rats underwent a 75% small bowel resection, and SBS-INS rats underwent a 75% small bowel resection and were treated with insulin given subcutaneously at a dose of 1 U/kg, twice daily, from day 3 through day 14. Parameters of intestinal adaptation, enterocyte proliferation, and enterocyte apoptosis were determined on day 15 following operation. SBS rats demonstrated a significant increase in jejunal and ileal bowel and mucosal weight, villus height and crypt depth, and cell proliferation index compared with the sham group. SBS-INS animals demonstrated higher jejunal and ileal bowel and mucosal weights, jejunal and ileal mucosal DNA and protein, and jejunal and ileal crypt depth compared with SBS animals. SBS-INS rats also had a greater cell proliferation index in both jejunum and ileum and a trend toward a decrease in enterocyte apoptotic index in jejunum and ileum compared with the SBS untreated group. In conclusion, parenteral insulin stimulates structural intestinal adaptation in a rat model of SBS. Increased cell proliferation is the main mechanism responsible for increased cell mass.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47170/1/383_2004_Article_1308.pd

Systemic autoimmune disease induced by dendritic cells that have captured necrotic but not apoptotic cells in susceptible mouse strains

Systemic lupus erythematosus (SLE) is an autoimmune disorder of a largely unknown etiology. Anti-double-stranded (ds) DNA antibodies are a classic hallmark of the disease, although the mechanism underlying their induction remains unclear. We demonstrate here that, in both lupus-prone and normal mouse strains, strong anti-dsDNA antibody responses can be induced by dendritic cells (DC) that have ingested syngeneic necrotic (DC/nec), but not apoptotic (DC/apo), cells. Clinical manifestations of lupus were evident, however, only in susceptible mouse strains, which correlate with the ability of DC/nec to release IFN-c and to induce the pathogenic IgG2a anti-dsDNA antibodies. Injection of DC/nec not only accelerated disease progression in the MRL/MpJ-lpr/lpr lupus-prone mice but also induced a lupus-like disease in the MRL/MpJ-+/+ wild-type control strain. Immune complex deposition was readily detectable in the kidneys, and the mice developed proteinuria. Strikingly, female MRL/MpJ-+/+ mice that had received DC/nec, but not DC/apo, developed a 'butterfly' facial lesion resembling a cardinal feature of human SLE. Our study therefore demonstrates that DC/nec inducing a Th1 type of responses, which are otherwise tightly regulated in a normal immune system, may play a pivotal role in SLE pathogenesis