clinicaltrials.gov Identifier: NCT1874431.
AimsTo evaluate oral doses of the non-steroidal mineralocorticoid receptor antagonist finerenone given for 90 days in patients with worsening heart failure and reduced ejection fraction and chronic kidney disease and/or diabetes mellitus.Methods and resultsMiner Alocorticoid Receptor antagonist Tolerability Study-Heart Failure (ARTS-HF) was a randomized, double-blind, phase 2b multicentre study (ClinicalTrials.gov: NCT01807221). Of 1286 screened patients, 1066 were randomized. Patients received oral, once-daily finerenone (2.5, 5, 7.5, 10, or 15 mg, uptitrated to 5, 10, 15, 20, or 20 mg, respectively, on Day 30) or eplerenone (25 mg every other day, increased to 25 mg once daily on Day 30, and to 50 mg once daily on Day 60) for 90 days. The primary endpoint was the percentage of individuals with a decrease of >30% in plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) from baseline to Day 90. A key exploratory endpoint was a composite clinical endpoint of death from any cause, cardiovascular hospitalizations, or emergency presentation for worsening HF until Day 90. Mean age ranged from 69.2 to 72.5 years in different treatment groups (standard deviation 9.7–10.6 years). Decreases in NT-proBNP of >30% from baseline occurred in 37.2% of patients in the eplerenone group and 30.9, 32.5, 37.3, 38.8, and 34.2% in the 2.5→5, 5→10, 7.5→15, 10→20, and 15→20 mg finerenone groups, respectively (P = 0.42–0.88). Except for the 2.5→5 mg finerenone group, the composite clinical endpoint occurred numerically less frequently in finerenone-treated patients compared with eplerenone; this difference reached nominal statistical significance in the 10→20 mg group (hazard ratio 0.56, 95% confidence interval, CI, 0.35; 0.90; nominal P = 0.02), despite the fact that this phase 2 study was not designed to detect statistical significant differences. A potassium level increase to ≥5.6 mmol/L at any time point occurred in 4.3% of patients, with a balanced distribution among all treatment groups.ConclusionFinerenone was well tolerated and induced a 30% or greater decrease in NT-proBNP levels in a similar proportion of patients to eplerenone. The finding of reduced clinical events in the finerenone 10→20 mg group should be further explored in a large outcomes trial.
‘Tomacula’ and myelin outfoldings are striking neuropathological features of a diverse group of inherited demyelinating neuropathies. Whereas the underlying genetic defects are well known, the molecular mechanisms of tomacula formation have remained obscure. We hypothesized that they are caused by uncontrolled, excessive myelin membrane growth, a process, which is regulated in normal development by neuregulin-1/ErbB2, PI3 Kinase signalling and ERK/MAPK signalling. Here, we demonstrate by targeted disruption of Pten in Schwann cells that hyperactivation of the endogenous PI3 Kinase pathway causes focal hypermyelination, myelin outfoldings and tomacula, even when induced in adult animals by tamoxifen, and is associated with progressive peripheral neuropathy. Activated AKT kinase is associated with PtdIns(3,4,5)P3 at paranodal loops and Schmidt–Lanterman incisures. This striking myelin pathology, with features of human CMT type 4B1 and HNPP, is dependent on AKT/mTOR signalling, as evidenced by a significant amelioration of the pathology in mice treated with rapamycin. We suggest that regions of non-compact myelin are under lifelong protection by PTEN against abnormal membrane outgrowth, and that dysregulated phosphoinositide levels play a critical role in the pathology of tomaculous neuropathies.
In the peripheral nervous system, the 'trigger' of myelination is axon size (>1µm), a threshold mediated by Nrg1 type III on the axon surface 1 . Since Nrg1 is not required for CNS myelination 2 , we asked whether axon size can be experimentally increased here by the absence of PTEN 3 , i.e. with PI(3,4,5)P3 stimulating the AKT1/mTOR pathway ( Fig.1a). To specifically enlarge cerebellar granule cells (GC) and their naturally unmyelinated parallel fiber (Pf) axons, we generated Tg (m6) (Fig.1d).Mutant mice appeared healthy (Supplementary Video1), but cerebellar GC layer (GL) and molecular layer (ML) progressively enlarged ( Fig.1e; Supplementary Fig.1a).Immunostaining of GABAA receptor 6 revealed a gradual size increase of GC somata ( Supplementary Fig.1b). Older mice developed ataxia and tremor (Supplementary Video2), possibly due to hamartomas at advanced age (Supplementary Fig.2; Supplementary Information).The diameter of Pf also increased over time, as quantified by electron microscopy (EM), reaching 0.61±0.009µm in mutants over 0.16±0.002 µm in controls at 1 year of age ( Fig.1f,g; Supplementary Fig.1c). Importantly, radial Pf growth in mutant brains was associated with significant myelination beginning at age P40 (2.30.6% myelinated Pf) and progressing over time (3 months: 9.51% myelinated Pf), up to 3 403% of Pf being myelinated at 1 year with an average g-ratio of 0.84. Myelination was visualized by Gallyas silver impregnation ( Supplementary Fig.3a), anti-CNP immunohistochemistry ( Fig.1h, Supplementary Fig.3b), including whole-mount immunolabelling combined with light sheet and 2-photon microscopy (Supplementary Video3), as well as EM (Fig.1i-k). We determined a 'size threshold' of approximately 0.25 µm for myelination at all ages tested (Fig.1k,l). Myelinated Pf segments were very rarely seen in controls.De novo myelination included the formation of nodes and paranodes with septate -like junctions ( Fig.1j) and the clustering of Caspr and NaV1.6 on axons (Fig.1m,n). GC synaptic contacts to Purkinje cell dendrites were restricted to Pf 'nodal' regions ( Fig.1o; Supplementary Fig.4).The ML harbors normally very few oligodendrocytes and only scattered OPC s, as demonstrated in Plp1-DsRed*Ng2-EYFP double-transgenic mice (Fig.2a). In Pten mutants at P45, mature oligodendrocytes were increased in the GL (+33%) and more prominent in the ML (+750%), yet unaltered in cerebellar white matter (WM) (Fig.2b).To determine whether OPCs proliferate in the ML or are recruited from the GL, we combined immunostaining with BrdU labeling (Fig.2c). After 20 days of daily BrdU injections (P25-45), OPC proliferation (BrdU+,Olig2+) was the same in GL or WM of mutants and controls (Fig.2d). However, OPC proliferation in the mutant ML was 4.4 -fold increased. Even at age 6-7 months, we found a 4.7-fold increase of BrdU+,Olig2+ cells. This suggests that local proliferation is stimulated (directly or indirectly) by GC axon-derived signals, which must still be present at older ages. At that time, oligodendrocyte lineage cel...
Establishment of long-range fiber tracts by neocortical projection neurons is fundamental for higher brain functions. The molecular control of axon tract formation, however, is still poorly understood. Here, we have identified basic helix-loop-helix (bHLH) transcription factors Neurod2 and Neurod6 as key regulators of fasciculation and targeted axogenesis in the mouse neocortex. In Neurod2/6 double-mutant mice, callosal axons lack expression of the cell adhesion molecule Contactin2, defasciculate in the subventricular zone, and fail to grow toward the midline without forming Probst bundles. Instead, mutant axons overexpress Robo1 and follow random trajectories into the ipsilateral cortex. In contrast to long-range axogenesis, generation and maintenance of pyramidal neurons and initial axon outgrowth are grossly normal, suggesting that these processes are under distinct transcriptional control. Our findings define a new stage in corpus callosum development and demonstrate that neocortical projection neurons require transcriptional specification by neuronal bHLH proteins to execute an intrinsic program of remote connectivity.
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