The mineralocorticoid receptor (MR), a member of the steroid receptor superfamily, regulates water-electrolyte balance and mediates pathophysiological effects in the renocardiovascular system. Previously, it was assumed that after binding aldosterone, the MR dissociates from HSP90, forms homodimers, and then translocates into the nucleus where it acts as a transcription factor (Guiochon-Mantel et al., 1989; Robertson et al., 1993; Savory et al., 2001). We found that, during aldosterone-induced nuclear translocation, MR is bound to HSP90 both in the cytosol and the nucleus. Homodimerization measured by eBRET and FRET takes place when the MR is already predominantly nuclear. In vitro binding of MR to DNA was independent of ligand but could be partially inhibited by geldanamycin. Overall, here we provide insights into classical MR signaling necessary for elucidating the mechanisms of pathophysiological MR effects and MR specificity.

Background: Reference values derived from existing diaphragm ultrasound protocols are inconsistent, and the association between sonographic measures of diaphragm function and volitional tests of respiratory muscle strength is still ambiguous. Objective: To propose a standardized and comprehensive protocol for diaphragm ultrasound in order to determine lower limits of normal (LLN) for both diaphragm excursion and thickness in healthy subjects and to explore the association between volitional tests of respiratory muscle strength and diaphragm ultrasound parameters. Methods: Seventy healthy adult subjects (25 men, 45 women; age 34 ± 13 years) underwent spirometric lung function testing, determination of maximal inspiratory and expiratory pressure along with ultrasound evaluation of diaphragm excursion and thickness during tidal breathing, deep breathing, and maximum voluntary sniff. Excursion data were collected for amplitude and velocity of diaphragm displacement. Diaphragm thickness was measured in the zone of apposition at total lung capacity (TLC) and functional residual capacity (FRC). All participants underwent invasive measurement of transdiaphragmatic pressure (Pdi) during different voluntary breathing maneuvers. Results: Ultrasound data were successfully obtained in all participants (procedure duration 12 ± 3 min). LLNs (defined as the 5th percentile) for diaphragm excursion were as follows: (a) during tidal breathing: 1.2 cm (males; M) and 1.2 cm (females; F) for amplitude, and 0.8 cm/s (M) and 0.8 cm/s (F) for velocity, (b) during maximum voluntary sniff: 2.0 cm (M) and 1.5 cm (F) for amplitude, and 6.7 (M) cm/s and 5.2 cm/s (F) for velocity, and (c) at TLC: 7.9 cm (M) and 6.4 cm (F) for amplitude. LLN for diaphragm thickness was 0.17 cm (M) and 0.15 cm (F) at FRC, and 0.46 Spiesshoefer et al. cm (M) and 0.35 cm (F) at TLC. Values for males were consistently higher than for females, independent of age. LLN for diaphragmatic thickening ratio was 2.2 with no difference between genders. LLN for invasively measured Pdi during different breathing maneuvers are presented. Voluntary Pdi showed only weak correlation with both diaphragm excursion velocity and amplitude during forced inspiration. Conclusions: Diaphragm ultrasound is an easy-to-perform and reproducible diagnostic tool for noninvasive assessment of diaphragm excursion and thickness. It supplements but does not replace respiratory muscle strength testing.

Use of BRV in GGE is well tolerated, and 50% responder rates are similar to those observed in the regulatory trials for focal epilepsies. An immediate switch from levetiracetam (LEV) to BRV at a ratio of 15:1 is feasible. The occurrence of psychobehavioral adverse events seems less prominent than under LEV, and a switch to BRV can be considered in patients with LEV-induced adverse events.

No abstract

Objective: To evaluate the efficacy and tolerability of brivaracetam (BRV) in a severely drug refractory cohort of patients with epileptic encephalopathies (EE).Method: A multicenter, retrospective cohort study recruiting all patients treated with EE who began treatment with BRV in an enrolling epilepsy center between 2016 and 2017.Results: Forty-four patients (27 male [61%], mean age 29 years, range 6 to 62) were treated with BRV. The retention rate was 65% at 3 months, 52% at 6 months and 41% at 12 months. A mean retention time of 5 months resulted in a cumulative exposure to BRV of 310 months. Three patients were seizure free during the baseline. At 3 months, 20 (45%, 20/44 as per intention-to-treat analysis considering all patients that started BRV including three who were seizure free during baseline) were either seizure free (n = 4; 9%, three of them already seizure-free at baseline) or reported at least 25% (n = 4; 9%) or 50% (n = 12; 27%) reduction in seizures. An increase in seizure frequency was reported in two (5%) patients, while there was no change in the seizure frequency of the other patients. A 50% long-term responder rate was apparent in 19 patients (43%), with two (5%) free from seizures for more than six months and in nine patients (20%, with one [2 %] free from seizures) for more than 12 months. Treatment-emergent adverse events were predominantly of psychobehavioural nature and were observed in 16%.Significance: In this retrospective analysis the rate of patients with a 50% seizure reduction under BRV proofed to be similar to those seen in regulatory trials for focal epilepsies. BRV appears to be safe and relatively well tolerated in EE and might be considered in patients with psychobehavioral adverse events while on levetiracetam.