Estrogen inhibits GH signaling by suppressing GH-induced JAK2 phosphorylation, an effect mediated by SOCS-2

Oral estrogen administration attenuates the metabolic action of growth hormone (GH) in humans. To investigate the mechanism involved, we studied the effects of estrogen on GH signaling through Janus kinase (JAK)2 and the signal transducers and activators of transcription (STATs) in HEK293 cells stably expressing the GH receptor (293GHR), HuH7 (hepatoma) and T-47D (breast cancer) cells. 293GHR cells were transiently transfected with an estrogen receptor-α expression plasmid and luciferase reporters with binding elements for STAT3 and STAT5 or the β-casein promoter. GH stimulated the reporter activities by four- to sixfold. Cotreatment with 17β-estradiol (E2) resulted in a dose-dependent reduction in the response of all three reporters to GH to a maximum of 49-66% of control at 100 nM (P < 0.05). No reduction was seen when E2 was added 1-2 h after GH treatment. Similar inhibitory effects were observed in HuH7 and T-47D cells. E2 suppressed GH-induced JAK2 phosphorylation, an effect attenuated by actinomycin D, suggesting a requirement for gene expression. Next, we investigated the role of the suppressors of cytokine signaling (SOCS) in E2 inhibition. E2 increased the mRNA abundance of SOCS-2 but not SOCS-1 and SOCS-3 in HEK293 cells. The inhibitory effect of E2 was absent in cells lacking SOCS-2 but not in those lacking SOCS-1 and SOCS-3. In conclusion, estrogen inhibits GH signaling, an action mediated by SOCS-2. This paper provides evidence for regulatory interaction between a sex steroid and the GH/JAK/STAT pathway, in which SOCS-2 plays a central mechanistic role

The Protective Effect of Glibenclamide in a Model of Hemorrhagic Encephalopathy of Prematurity

brain science

Transfer of Patients with Spontaneous Intracranial Hemorrhage who Need External Ventricular Drain: Does Admission Location Matter?

Introduction: Patients with spontaneous intracranial hemorrhage (sICH) are associated with high mortality and require early neurosurgical interventions. At our academic referral center, the neurocritical care unit (NCCU) receives patients directly from referring facilities. However, when no NCCU bed is immediately available, patients are initially admitted to the critical care resuscitation unit (CCRU). We hypothesized that the CCRU expedites transfer of sICH patients and facilitates timely external ventricular drain (EVD) placement comparable to the NCCU.Methods: This is a pre-post study of adult patients transferred with sICH and EVD placement. Patients admitted between January 2011–July 2013 (2011 Control) were compared with patients admitted either to the CCRU or the NCCU (2013 Control) between August 2013–September 2015. The primary outcome was time interval from arrival at any intensive care units (ICU) to time of EVD placement (ARR-EVD). Secondary outcomes included time interval from emergency department transfer request to arrival, and in-hospital mortality. We assessed clinical association by multivariable logistic regressions.Results: We analyzed 259 sICH patients who received EVDs: 123 (48%) CCRU; 81 (31%) 2011 Control; and 55 (21%) in the 2013 Control. The groups had similar characteristics, age, disease severity, and mortality. Median ARR-EVD time was 170 minutes [106-311] for CCRU patients; 241 minutes [152-490] (p &lt; 0.01) for 2011 Control; and 210 minutes [139-574], p = 0.28) for 2013 Control.&nbsp; Median transfer request-arrival time for CCRU patients was significantly less than both control groups. Multivariable logistic regression showed each minute delay in ARR-EVD was associated with 0.03% increased likelihood of death (odds ratio 1.0003, 95% confidence interval, 1.0001-1.006, p = 0.043).Conclusion: Patients admitted to the CCRU had shorter transfer times when compared to patients admitted directly to other ICUs. Compared to the specialty NCCU, the CCRU had similar time interval from arrival to EVD placement. A resuscitation unit like the CCRU can complement the specialty unit NCCU in caring for patients with sICH who require EVDs

Strain-related regional alterations of calcium-handling proteins in myocardial remodeling

BackgroundCardiac remodeling has been shown to have deleterious effects at both the global and local levels. The objective of this study is to investigate the role of strain in the initiation of structural and functional changes of myocardial tissue and its relation to alteration of calcium-handling proteins during cardiac remodeling after myocardial infarction.MethodsSixteen sonomicrometry transducers were placed in the left ventricular free wall of 9 sheep to measure the regional strain in the infarct, adjacent, and remote myocardial regions. Hemodynamic, echocardiographic, and sonomicrometry data were collected before myocardial infarction, after infarction, and 2, 6, and 8 weeks after infarction. Regional myocardial tissues were collected for calcium-handling proteins at the end study.ResultsAt time of termination, end-systolic strains in 3 regionally distinct zones (remote, adjacent, and infarct) of myocardium were measured to be −14.65 ± 1.13, −5.11 ± 0.60 (P ≤ .05), and 0.92 ± 0.56 (P ≤ .05), respectively. The regional end-systolic strain correlated strongly with the abundance of 2 major calcium-handling proteins: sarcoplasmic reticulum Ca2+ adenosine triphosphatase subtype 2a (r2 = 0.68, P ≤ .05) and phospholamban (r2 = 0.50, P ≤ .05). A lesser degree of correlation was observed between the systolic strain and the abundance of sodium/calcium exchanger type 1 protein (r2 = 0.17, P ≤ .05).ConclusionsRegional strain differences can be defined in the different myocardial regions during postinfarction cardiac remodeling. These differences in regional strain drive regionally distinct alterations in calcium-handling protein expression