The ultradian rhythm of glucocorticoid secretion and the time course of target gene regulation

Glucocorticoid hormones (cortisol in humans and corticosterone in rodents) are secreted in discrete pulses during a day with a periodicityof approximately 1 h (ultradian rhythm), and this pattern is also maintained in plasma and extracellular fluid. However, the vast majority of studies on gene regulation by glucocorticoids typically assess gene responses regardless the ultradian rhythm. These experiments are usually performed using long-term stimulation with synthetic hormones (dexamethasone and triamcinolone), which form much more stable complexes with glucocorticoid receptor (GR) then natural hormones. This review summarizes the current scarce information, obtained in experiments mimicking the ultradian mode of natural hormone secretion in cultured cells and in animal models. The results of these experiments clearly demonstrate that ultradian stimulation by natural hormones induces rapid GR exchange with glucocorticoid response elements and leads to cyclic GR mediated transcriptional regulation (gene pulsing) at the level of nascent RNA. In contrast, synthetic glucocorticoids, having much higher receptor affinity, fail to disengage from nuclear receptors with sufficient speed to support the ultradian cycles, thereby uncoupling extracellular hormone fluctuations from appropriate receptor function at response elements. This alters RNA accumulation profiles dramatically. These findings suggest potentially important consequences of ultradian secretion. The transcriptional program induced by hormone pulses differs significantly from that generated by constant hormone treatment. Thus, treatment with synthetic glucocorticoids may not provide an accurate assessment of physiological hormone action

Glucocorticoid receptor: translocation from the cytoplasm to the nuclei, chromatin and intranuclear chaperone cycles

Glucocorticoid receptor (GR) is a ligand-dependent transcription factor, involved in the regulation of hundreds of genes. In the absence of any ligand, GR resides in the cytoplasm where it is sequestered in a multimeric chaperone complex consisting of hsp90, hsp70, p23, Hop, FKBP51, FKBP52, etc. As part of this multiprotein complex, GR undergoes conformational changes that allow glucocorticoid hormone binding. Upon ligand binding, GR dissociates from chaperon complex and translocates into the nucleus, where it interacts with specific DNA sequences (GREs) in the regulatory regions of target genes and modulates their expression. Then unliganded GR is exported to the cytoplasm, completing the nuclear-cytoplasmic cycle. Recent evidence suggests that, in addition to this cycle, chromatin and chaperone GR cycles exist within the nuclei. The chromatin cycle implies repeated interactions of ligand-bound GR with GREs in the chromatin context lasting for few seconds. The chaperone cycle starts after dissociation of the hormone–receptor complex, when GR binds to the nuclear chaperone machinery. As a result, its hormone-binding affinity is regained. Upon hormone binding, GR releases from chaperon complex and binds to GREs again. It is assumed that the chaperone cycle is mainly responsible for prolonged GR retention in nuclei (half-life within 8–12 h upon steroid withdrawal). In this review, we summarize and critically analyze the published data on chromatin and intranuclear chaperone GR cycles

Effect of neonatal dexamethasone treatment on cognitive abilities of adult male mice and gene expression in the hypothalamus

The early postnatal period is critical for the development of the nervous system. Stress during this period causes negative long-term effects, which are manifested at both behavioral and molecular levels. To simulate the elevated glucocorticoid levels characteristic of early-life stress, in our study we used the administration of dexamethasone, an agonist of glucocorticoid receptors, at decreasing doses at the first three days of life (0.5, 0.3, 0.1 mg/kg, s.c.). In adult male mice with neonatal dexamethasone treatment, an increase in the relative weight of the adrenal glands and a decrease in body weight were observed, while the basal level of corticosterone remained unchanged. Dexamethasone treatment in early life had a negative impact on the learning and spatial memory of adult mice in the Morris water maze. We analyzed the effect of elevated glucocorticoid levels in early life on the expression of the Crh, Avp, Gr, and Mr genes involved in the regulation of the HPA axis in the hypothalami of adult mice. The expression level of the mineralocorticoid receptor gene (Mr) was significantly downregulated, and the glucocorticoid receptor gene (Gr) showed a tendency towards decreased expression (p = 0.058) in male mice neonatally treated with dexamethasone, as compared with saline administration. The expression level of the Crh gene encoding corticotropin-releasing hormone was unchanged, while the expression of the vasopressin gene (Avp) was increased in response to neonatal administration of dexamethasone. The obtained results demonstrate a disruption of negative feedback regulation of the HPA axis, which involves glucocorticoid and mineralocorticoid receptors, at the level of the hypothalamus. Malfunction of the HPA axis as a result of activation of the glucocorticoid system in early life may cause the development of cognitive impairment in the adult mice

Prevention of Cardioembolic Complications in Patients with Atrial Fibrillation: Efficacy and Safety of Left Atrial Appendage Isolation and Oral Anticoagulants

Aim. To study the outcomes frequency and structure in patients with atrial fibrillation (AF) depending on the cardioembolic events preventing method: left atrial appendage (LAA) isolation, direct oral anticoagulants (DOACs) or warfarin.Material and methods. A prospective observational study included patients with AF and high risk of cardioembolic complications and without contraindications to anticoagulants. Patients who refused long-term oral anticoagulants taking underwent LAA isolation, the rest of the patients received DOACs or warfarin. The observation period was 3 years. Mortality, cardioembolic complications and major bleeding (according to GARFIELD criteria) cumulative incidence was assessed.Results. We included 245 patients: 46 patients were treated with LAA isolation, 100 with warfarin, and 99 with DOACs. Multivariate regression analysis demonstrated a statistically significant advantage of LAA occluder in terms of combined endpoint achieving frequency compared to warfarin (hazard ratio [HR] 3.10; 95% confidence interval [CI] 1.01-9.54; p=0.049), and to DOACs (HR 3.44, 95% CI 1.15-10.29; p=0.027). A similar result was obtained for all-cause mortality (HR 5.24; 95% CI 1.12-24.55; p=0.036 and HR 5.58; 95% CI 1.22-25.49; p=0.027, respectively). There were no significant differences in bleeding rates between the groups.Conclusion. This observational study demonstrates the superiority of LAA isolation as a first-line therapy over DOACs and warfarin in patients with AF and high risk of cardioembolic complications. Randomized trials are required to confirm these observations

Steps Toward Determination of the Size and Structure of the Broad-Line Region in Active Galactic Nuclei. XVI. A Thirteen-Year Study of Spectral Variability in NGC 5548

We present the final installment of an intensive 13-year study of variations of the optical continuum and broad H-beta emission line in the Seyfert 1 galaxy NGC 5548. The data base consists of 1530 optical continuum measurements and 1248 H-beta measurements. The H-beta variations follow the continuum variations closely, with a typical time delay of about 20 days. However, a year-by-year analysis shows that the magnitude of emission-line time delay is correlated with the mean continuum flux. We argue that the data are consistent with the simple model prediction that the size of the broad-line region is proportional to the square root of the ionizing luminosity. Moreover, the apparently linear nature of the correlation between the H-beta response time and the nonstellar optical continuum arises as a consequence of the changing shape of the continuum as it varies, specifically with the optical (5100 A) continuum luminosity proportional to the ultraviolet (1350 A) continuum luminosity to the 0.56 power.Comment: 20 pages plus 4 figures. Accepted for publication in The Astrophysical Journa

Efficacy and safety of left atrial appendage closure in patients with atrial fibrillation and high thromboembolic and bleeding risk

Aim. To compare the incidence of thromboembolic and hemorrhagic events after left atrial appendage occlusion (LAAO) or without prevention of thromboembolic events (TEEs) during prospective follow-up of patients with atrial fibrillation (AF) and a high risk of ischemic stroke (IS) who have contraindications to long-term anticoagulant therapy.Material and methods. The study included 134 patients with AF, a high risk of IS, and contraindications to long-term anticoagulation. Patients were divided into 2 groups as follows: the first group included patients who underwent LAAO (n=74), while the second one — those who did not undergo any TEE prevention (n=60). The follow-up period was 3 years. The cumulative rate of all-cause mortality, IS, transient ischemic attacks (TIA), and systemic embolism (SE) was taken as the primary efficacy endpoint. The primary safety endpoint included major bleeding according to GARFIELD registry criteria.Results.  The rate of composite efficacy endpoint in the LAAO group was significantly lower than in the group without thromboembolic prophylaxis (5,2 vs 17,4 per 100 patient-years; adjusted odds ratio (OR), 4,08; 95% confidence interval (CI): 1,7-9,5; p=0,001). The rate of major bleeding was comparable in both groups (2,4 in the LAAO group vs 1,3 per 100 patient-years in the group without thromboembolic prophylaxis; adjusted OR, 0,55; 95% CI: 0,1-3,09; p=0,509). In addition, the event rate of net clinical benefit (all-cause mortality + ischemic stroke/TIA/SE + major bleeding) in the LAAO group was also significantly lower (5,9 vs 18,2 per 100 patient-years; adjusted OR, 3,0; 95% CI: 1,47-6,36; p=0,003).Conclusion. Among patients with AF and contraindications to long-term anticoagulation after 3 years of follow-up, LAAO demonstrated the significant reduction of cumulative rate of all-cause mortality and non-fatal thromboembolic events. At the same time, the frequency of major bleeding was comparable between the groups, even taking into account access-site bleeding and postoperative antithrombotic therapy (ATT)-associated bleeding in the LAAO group. Further randomized clinical trials are required to confirm these data

The combination of traditional cardiorespiratory markers during treadmill testing “to failure” in athletes, depending on professional activity

Exercise tolerance test with the use of the spiroergometry technique is a reliable diagnostic method which provides objective information about cardiorespiratory system condition when performing physical activity. Both new and traditional, well-proven cardiorespiratory markers obtained in the process of treadmill testing “to failure”, are described in this article. The nature of the influence of physical exertion on the indicators of cardiorespiratory system functional activity is presented. The interpretation for planning and subsequent monitoring of the training process in athletes of various professional activities is proposed

A Spectroscopic and Photometric Study of Short-Timescale Variability in NGC5548

Results of a ground-based optical monitoring campaign on NGC5548 in June 1998 are presented. The broad-band fluxes (U,B,V), and the spectrophotometric optical continuum flux F_lambda(5100 A) monotonically decreased in flux while the broad-band R and I fluxes and the integrated emission-line fluxes of Halpha and Hbeta remained constant to within 5%. On June 22, a short continuum flare was detected in the broad band fluxes. It had an amplitude of about ~18% and it lasted only ~90 min. The broad band fluxes and the optical continuum F_lambda(5100 A) appear to vary simultaneously with the EUV variations. No reliable delay was detected for the broad optical emission lines in response to the EUVE variations. Narrow Hbeta emission features predicted as a signature of an accretion disk were not detected during this campaign. However, there is marginal evidence for a faint feature at lambda = 4962 A with FWHM=~6 A redshifted by Delta v = 1100 km/s with respect to Hbeta_narrow.Comment: 12 pages, 7 figures, accepted for publishing in A&

Study of the structure and kinematics of the NGC 7465/64/63 triplet galaxies

This paper is devoted to the analysis of new observational data for the group of galaxies NGC 7465/64/63, which were obtained at the 6-m telescope of the Special Astrophysical Observatory of the Russian Academy of Sciences (SAO RAS) with the multimode instrument SCORPIO and the Multi Pupil Fiber Spectrograph. For one of group members (NGC 7465) the presence of a polar ring was suspected. Large-scale brightness distributions, velocity and velocity dispersion fields of the ionized gas for all three galaxies as well as line-of-sight velocity curves on the basis of emission and absorption lines and a stellar velocity field in the central region for NGC 7465 were constructed. As a result of the analysis of the obtained information, we revealed an inner stellar disk (r ~ 0.5 kpc) and a warped gaseous disk in addition to the main stellar disk, in NGC 7465. On the basis of the joint study of photometric and spectral data it was ascertained that NGC 7464 is the irregular galaxy of the IrrI type, whose structural and kinematic peculiarities resulted most likely from the gravitational interaction with NGC 7465. The velocity field of the ionized gas of NGC 7463 turned out typical for spiral galaxies with a bar, and the bending of outer parts of its disk could arise owing to the close encounter with one of galaxies of the environment.Comment: 20 pages, 6 figure