Euthyroid graves' ophthalmopathy in a Chinese population: A cross-sectional follow-up study.

OBJECTIVES: A subtype of patients with thyroid eye disease (TED) were found to be euthyroid without prior thyroid dysfunction or treatment, known as Euthyroid Graves' Ophthalmopathy (EGO). We report the prevalence, clinical and serological phenotypes of EGO in a Chinese population. METHODS: A cross-sectional follow-up study. Ethnic Chinese TED patients were managed at the Thyroid Eye Clinic(TEC), Prince of Wales Hospital and TEC, the Chinese University of Hong Kong between September 2007 and July 2021. RESULTS: A total of 66 (5%) patients among the 1266 ethnic Han Chinese TED cohort were diagnosed as EGO, and 6 (9%)of them become dysthyroid over an average of 74-month follow-up. EGO patients were associated with a longer duration between onset of the symptoms to our first consultation (P < 0.0001), a higher male-to-female ratio (P = 0.0045) and a higher age of disease onset (P = 0.0092). Family history of thyroid disease was more common in TED patients (P = 0.0216) than in EGO patients. EGO patients were more likely to present unilaterally (P < 0.0001), and they have a larger difference in MRD1 (P < 0.0001), and extraocular motility (P < 0.0001) between the 2 eyes when compared to the TED patients. Notably, the extraocular motility restriction of the worst eye was more affected in EGO patients (P = 0.0113). The percentages of patients who received IVMP, ORT and emergency or elective surgeries(decompression or squint operation) between EGO and TED were similar. CONCLUSIONS: Understanding the important clinical phenotypes of EGO may help the clinician to make the correct diagnosis. Further study to compare EGO and TED is warranted.

Effectiveness of Modalities to Teach Evidence Based Medicine to Pediatric Clerkship Students: A Randomized Controlled Trial.

OBJECTIVE: To evaluate the effectiveness of a traditional didactic session (TDS) as compared to a self-paced, interactive, multimedia module (SPM) on the application of evidence-based medicine (EBM) skills among medical students during their inpatient pediatric rotation. METHODS: We conducted a randomized controlled trial from June, 2017 to June, 2018 at a quaternary care children's hospital. Students were randomized to TDS or SPM during each 2-week block. All students completed a critical appraisal tool (CAT) of evidence related to a clinical question in a standardized appraisal form and self-reflected about the EBM process. The primary outcome was the numeric score of the CAT derived by using the validated Fresno tool. Secondary outcomes of knowledge, attitudes, confidence, and self-reported behaviors related to EBM were measured using validated surveys. Statistical analysis was performed using Student's t test for CAT scores and mixed-model procedure (PROC MIXED), with subject as random effect and time as repeated measure for the secondary outcomes. RESULTS: One hundred twenty-seven clerkship students were included. Overall, there was no significant difference in mean CAT scores for TDS (n = 59) versus SPM (n = 66) groups (90.3 vs 92.0, P = .65). There were no significant differences between SPM and TDS groups for knowledge (P = .66), attitudes (P = .97), confidence (P  = .55), and accessing evidence (P = .27). Both groups showed significant gains in knowledge, attitudes, confidence, and accessing evidence from baseline to postcourse. Improvements in knowledge and confidence were sustained at 3-months. CONCLUSION: A SPM learning module is as effective as a TDS module for application of EBM concepts and knowledge to patient care.

beta-Arrestin scaffolding of the ERK cascade enhances cytosolic ERK activity but inhibits ERK-mediated transcription following angiotensin AT1a receptor stimulation.

beta-Arrestins are cytosolic proteins that mediate homologous desensitization of G protein-coupled receptors (GPCRs) by binding to agonist-occupied receptors and by uncoupling them from heterotrimeric G proteins. The recent finding that beta-arrestins bind to some mitogen-activated protein (MAP) kinases has suggested that they might also function as scaffolds for GPCR-stimulated MAP kinase activation. To define the role of beta-arrestins in the regulation of ERK MAP kinases, we examined the effect of beta-arrestin overexpression on ERK1/2 activation and nuclear signaling in COS-7 cells expressing angiotensin II type 1a receptors (AT1aRs). Expression of either beta-arrestin1 or beta-arrestin2 reduced angiotensin-stimulated phosphatidylinositol hydrolysis but paradoxically increased angiotensin-stimulated ERK1/2 phosphorylation. The increase in ERK1/2 phosphorylation in beta-arrestin-expressing cells correlated with activation of a beta-arrestin-bound pool of ERK2. The beta-arrestin-dependent increase in ERK1/2 phosphorylation was accompanied by a significant reduction in ERK1/2-mediated, Elk1-driven transcription of a luciferase reporter. Analysis of the cellular distribution of phospho-ERK1/2 by confocal immunofluorescence microscopy and cellular fractionation revealed that overexpression of beta-arrestin resulted in a significant increase in the cytosolic pool of phospho-ERK1/2 and a corresponding decrease in the nuclear pool of phospho-ERK1/2 following angiotensin stimulation. beta-Arrestin overexpression resulted in formation of a cytoplasmic pool of beta-arrestin-bound phospho-ERK, decreased nuclear translocation of phospho-ERK1/2, and inhibition of Elk1-driven luciferase transcription even when ERK1/2 was activated by overexpression of cRaf-1 in the absence of AT1aR stimulation. These data demonstrate that beta-arrestins facilitate GPCR-mediated ERK activation but inhibit ERK-dependent transcription by binding to phospho-ERK1/2, leading to its retention in the cytosol.

The stability of the G protein-coupled receptor-beta-arrestin interaction determines the mechanism and functional consequence of ERK activation.

By binding to agonist-activated G protein-coupled receptors (GPCRs), beta-arrestins mediate homologous receptor desensitization and endocytosis via clathrin-coated pits. Recent data suggest that beta-arrestins also contribute to GPCR signaling by acting as scaffolds for components of the ERK mitogen-activated protein kinase cascade. Because of these dual functions, we hypothesized that the stability of the receptor-beta-arrestin interaction might affect the mechanism and functional consequences of GPCR-stimulated ERK activation. In transfected COS-7 cells, we found that angiotensin AT1a and vasopressin V2 receptors, which form stable receptor-beta-arrestin complexes, activated a beta-arrestin-bound pool of ERK2 more efficiently than alpha 1b and beta2 adrenergic receptors, which form transient receptor-beta-arrestin complexes. We next studied chimeric receptors in which the pattern of beta-arrestin binding was reversed by exchanging the C-terminal tails of the beta2 and V2 receptors. The ability of the V2 beta 2 and beta 2V2 chimeras to activate beta-arrestin-bound ERK2 corresponded to the pattern of beta-arrestin binding, suggesting that the stability of the receptor-beta-arrestin complex determined the mechanism of ERK2 activation. Analysis of covalently cross-linked detergent lysates and cellular fractionation revealed that wild type V2 receptors generated a larger pool of cytosolic phospho-ERK1/2 and less nuclear phospho-ERK1/2 than the chimeric V2 beta 2 receptor, consistent with the cytosolic retention of beta-arrestin-bound ERK. In stably transfected HEK-293 cells, the V2 beta 2 receptor increased ERK1/2-mediated, Elk-1-driven transcription of a luciferase reporter to a greater extent than the wild type V2 receptor. Furthermore, the V2 beta 2, but not the V2 receptor, was capable of eliciting a mitogenic response. These data suggest that the C-terminal tail of a GPCR, by determining the stability of the receptor-beta-arrestin complex, controls the extent of beta-arrestin-bound ERK activation, and influences both the subcellular localization of activated ERK and the physiologic consequences of ERK activation.