Browsing by Subject "Glucocorticoids"
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Item Acute Biventricular Heart Failure After COVID-19 Infection in an Orthotropic Heart Transplant Patient: A Case Report(Elsevier, 2021-05) Berg, Nicholas; Ilonze, Onyedika; Bajpai, Vatsal; Guglin, Maya; Rao, Roopa; Medicine, School of MedicineThe cardiac effects of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) include myocarditis, takotsubo cardiomyopathy, pericardial effusion, and cardioembolic events in the general population. The effects of SARS-CoV-2 in heart transplant patients are unclear. We describe a case of myocarditis in the transplanted heart that responded to methylprednisolone.Item Antagonistic Interplay Between Mechanical Forces and Glucocorticoids in Bone: A Tale of Kinases(Wiley, 2010) Bellido, Teresita; Anatomy, Cell Biology and Physiology, School of MedicineThe contrasting actions of mechanical forces and glucocorticoids (GC) on bone have been long recognized. However, the cellular and molecular mechanisms by which these stimuli impact the skeleton remain only partially known. Recent evidence gained from studies on bone cell apoptosis has revealed that mechanical forces and GC exhibit converse effects on osteocyte and osteoblast survival resulting from divergent actions on the focal adhesion kinases FAK and Pyk2, molecules that regulate integrin-dependent interactions between bone cells and the extracellular matrix (ECM). This prospect reviews these findings and poses the possibility that similar opposing effects on kinase signaling are responsible for other actions of mechanical forces and GC on the skeleton, in particular on bone formation and the Wnt signaling pathway.Item The Canonical Wnt Signaling Pathway Inhibits the Glucocorticoid Receptor Signaling Pathway in the Trabecular Meshwork(Elsevier, 2021) Sugali, Chenna Kesavulu; Rayana, Naga Pradeep; Dai, Jiannong; Peng, Michael; Harris, Sherri L.; Webber, Hannah C.; Liu, Shaohui; Dixon, Stephan G.; Parekh, Priyanka H.; Martin, Elizabeth A.; Cantor, Louis B.; Fellman, Ronald L.; Godfrey, David G.; Butler, Michelle R.; Emanuel, Matthew E.; Grover, Davinder S.; Smith, Oluwatosin U.; Clark, Abbot F.; Raghunathan, Vijay Krishna; Mao, Weiming; Ophthalmology, School of MedicineGlucocorticoid-induced glaucoma is a secondary open-angle glaucoma. About 40% of the general population may develop elevated intraocular pressure on prolonged glucocorticoid treatment secondary to damages in the trabecular meshwork (TM), a tissue that regulates intraocular pressure. Therefore, identifying the key molecules responsible for glucocorticoid-induced ocular hypertension is crucial. In this study, Dickkopf-related protein 1 (Dkk1), a canonical Wnt signaling inhibitor, was found to be elevated in the aqueous humor and TM of glaucoma patients. At the signaling level, Dkk1 enhanced glucocorticoid receptor (GR) signaling, whereas Dkk1 knockdown or Wnt signaling activators decreased GR signaling in human TM cells as indicated by luciferase assays. Similarly, activation of the GR signaling inhibited Wnt signaling. At the protein level, glucocorticoid-induced extracellular matrix was inhibited by Wnt activation using Wnt activators or Dkk1 knockdown in primary human TM cells. In contrast, inhibition of canonical Wnt signaling by β-catenin knockdown increased glucocorticoid-induced extracellular matrix proteins. At the physiological level, adenovirus-mediated Wnt3a expression decreased glucocorticoid-induced ocular hypertension in mouse eyes. In summary, Wnt and GR signaling inhibit each other in the TM, and canonical Wnt signaling activators may prevent the adverse effect of glucocorticoids in the eye.Item A Case Series of Severe Hospitalized COVID-19 Patients Treated with Tocilizumab and Glucocorticoids: A Report from Saudi Arabian Hospital(Atlantis Press, 2021-01-22) Al Bahrani, Salma Yassin; Al-Tawfiq, Jaffar A.; Alshaer, Abdulaziz R.; Shilash, Amal; Alswefy, Khalid; Al-Zayer, Razan Salamah; Abouelela, Amr Mohamed; Medicine, School of MedicineBackground: The clinical spectrum of COVID-19 is variable and ranges from asymptomatic, mildly symptomatic, moderately severe and severe disease. A small proportion might develop severe disease and may have cytokine storm. One of the therapeutic options to treat such cases is Tocilizumab (TCZ). In this study, we present cases of severe COVID-19 treated with TCZ and glucocorticoids and discuss the treatment responses. Methods: This is a retrospective observational study of severe COVID-19 cases treated with TCZ and glucocorticoids. The case series examined the characteristics and outcome of those patients. Results: This study included 40 Severe Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) confirmed patients who received TCZ and glucocorticoids. The mean age of the included patients was 57.55 (±Standard deviation 12.86) years. There were 34 (85%) males, 19 (47.5%) were obese (BMI >30), 13 (32.5%) over weight, and five (12.5%) normal weight. The mean days from positive SARS-CoV-2 polymerase chain reaction (PCR) test to admission was 1.641 (±3.2) days. Of the patients, 18 (45%) had diabetes mellitus, 14 (35%) had hypertension. The mean days from hospital admission to ICU was 1.8 (±2.6), 20 (50%) required mechanical ventilation, 39 (97.5%) had received prone position, seven (17.5%) had renal replacement therapy, 13 (32.5%) required inotropes, four (10%) had plasmapheresis, one (2.5%) had intravenous immunoglobulin, all patients received steroid therapy, and the majority 31 (77.5%) did not receive any anti-viral therapy. Of all the patients, six (15%) died, 28 (70%) were discharged and six (15%) were still in hospital. Conclusion: The overall mortality rate was lower than those cited in meta-analysis. As our understanding of the COVID-19 continues, the approach and therapeutics are also evolving.Item Early Morning Cortisol Level as a Predictive Factor for Long-Term Glucocorticoid Replacement After Pituitary Surgery: A Systematic Review and Meta-Analysis(Elsevier, 2023-08) Abdollahifard, Saeed; Taherifard, Erfan; Sadeghi, Alireza; Farrokhi, Amirmohammad; Cohen-Gadol, Aaron A.; Palmisciano, Paolo; Neurosurgery, School of MedicineBackground A reliable strategy for predicting long-term adrenal insufficiency after pituitary surgery can reduce the risk of glucocorticoid overexposure or missing patients with pituitary insufficiency. For this purpose, we aimed to assess the predictive value of early postoperative morning serum cortisol level for the detection of hypothalamic-pituitary-adrenal axis dysfunction in patients who underwent pituitary surgery. Methods A Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)–based systematic review was conducted to include articles investigating morning blood cortisol levels after pituitary surgery for lesions of the pituitary gland as a determinant for administration of long-term supplemental glucocorticoids. Bayesian statistics were used to pool the sensitivity and specificity rates. Sensitivity and specificity were also determined for each potential cortisol level on postoperative day (POD) 1 and POD 2. Results The study included 17 articles encompassing 1648 patients. Morning cortisol levels on POD 1 and POD 2 showed pooled sensitivity rates of 86.4% and 86.6% and pooled specificity rates of 73.1% and 78.2%, respectively, for predicting long-term glucocorticoid replacement after surgery. A cortisol level of 2.1 μg/dL showed the highest sensitivity rate (98.78%), and 22.5 μg/dL showed the highest specificity rate (72.5%) on POD 1. Conclusions In this review and Bayesian meta-analysis, we found that postoperative serum cortisol measurement may have high accuracy in prediction of the long-term need for glucocorticoid administration in patients who underwent pituitary surgery.Item Glucocorticoid Excess in Bone and Muscle(Springer, 2018-03) Sato, Amy Y.; Peacock, Munro; Bellido, Teresita; Anatomy and Cell Biology, School of MedicineGlucocorticoids (GC), produced and released by the adrenal glands, regulate numerous physiological processes in a wide range of tissues. Because of their profound immunosuppressive and anti-inflammatory actions, GC are extensively used for the treatment of immune and inflammatory conditions, the management of organ transplantation, and as a component of chemotherapy regimens for cancers. However, both pathologic endogenous elevation and long-term use of exogenous GC are associated with severe adverse effects. In particular, excess GC has devastating effects on the musculoskeletal system. GC increase bone resorption and decrease formation leading to bone loss, microarchitectural deterioration and fracture. GC also induce loss of muscle mass and strength leading to an increased incidence of falls. The combined effects on bone and muscle account for the increased fracture risk with GC. This review summarizes the advance in knowledge in the last two decades about the mechanisms of action of GC in bone and muscle and the attempts to interfere with the damaging actions of GC in these tissues with the goal of developing more effective therapeutic strategies.Item Glucocorticoid hormone-induced chromatin remodeling enhances human hematopoietic stem cell homing and engraftment(Nature Publishing Group, 2017-04) Guo, Bin; Huang, Xinxin; Cooper, Scott; Broxmeyer, Hal E.; Microbiology and Immunology, School of MedicineEfficient hematopoietic stem cell (HSC) homing is important for hematopoietic cell transplantation (HCT), especially when HSC numbers are limited, as in the use of cord blood (CB). In a screen of small-molecule compounds, we identified glucocorticoid (GC) hormone signaling as an activator of CXCR4 expression in human CB HSCs and hematopoietic progenitor cells (HPCs). Short-term GC pretreatment of human CB HSCs and HPCs promoted SDF-1-CXCR4-axis-mediated chemotaxis, homing, and long-term engraftment when these cells were transplanted into primary- and secondary-recipient NSG mice. Mechanistically, activated glucocorticoid receptor binds directly to a glucocorticoid response element in the CXCR4 promoter and recruits the SRC-1-p300 complex to promote H4K5 and H4K16 histone acetylation, facilitating transcription of CXCR4. These results suggest a new and readily available means to enhance the clinical efficacy of CB HCT.Item Glucocorticoid Induced Leucine Zipper in Lipopolysaccharide Induced Neuroinflammation(Frontiers, 2019) Witek, Emily; Hickman, Debra; Lahiri, Debomoy K.; Srinivasan, Mythily; Oral Pathology, Medicine and Radiology, School of DentistryGlucocorticoids (GC) are steroid hormones secreted as the end-product of the neuroendocrine stress cascade. Both absence and elevated GC mediate neurotoxic responses, suggesting that a narrow window ranging from physiological to slightly high GC mediate protective responses. The beneficial effects of GC are attributed to the transactivation of regulatory proteins and inhibition mediated by glucocorticoid receptor interactions with other co-factors. The glucocorticoid induced leucine zipper (GILZ) is a gene strongly upregulated by GC and mediates many of the anti-inflammatory and anti-proliferative effects of GC. Although GILZ is constitutively expressed in many tissues including the brain, the expression has been shown to occur with varying dynamics suggesting that the local milieu modulates its expression with consequent effects on cellular responses. Here we investigated the expression profile of GILZ in lipopolysaccharide mediated neuroinflammation model of Alzheimer’s disease. Our data suggest that the GILZ expression is downregulated in neuroinflammation correlating inversely with the pro-inflammatory cytokines and innate immune responses.Item HSD3B1 genotype identifies glucocorticoid responsiveness in severe asthma(National Academy of Sciences, 2020-01-28) Zein, Joe; Gaston, Benjamin; Bazeley, Peter; DeBoer, Mark D.; Igo, Robert P., Jr; Bleecker, Eugene R.; Meyers, Deborah; Comhair, Suzy; Marozkina, Nadzeya V.; Cotton, Calvin; Patel, Mona; Alyamani, Mohammad; Xu, Weiling; Busse, William W.; Calhoun, William J.; Ortega, Victor; Hawkins, Gregory A.; Castro, Mario; Chung, Kian Fan; Fahy, John V.; Fitzpatrick, Anne M.; Israel, Elliot; Jarjour, Nizar N.; Levy, Bruce; Mauger, David T.; Moore, Wendy C.; Noel, Patricia; Peters, Stephen P.; Teague, W. Gerald; Wenzel, Sally E.; Erzurum, Serpil C.; Sharifi, Nima; Medicine, School of MedicineAsthma resistance to glucocorticoid treatment is a major health problem with unclear etiology. Glucocorticoids inhibit adrenal androgen production. However, androgens have potential benefits in asthma. HSD3B1 encodes for 3β-hydroxysteroid dehydrogenase-1 (3β-HSD1), which catalyzes peripheral conversion from adrenal dehydroepiandrosterone (DHEA) to potent androgens and has a germline missense-encoding polymorphism. The adrenal restrictive HSD3B1(1245A) allele limits conversion, whereas the adrenal permissive HSD3B1(1245C) allele increases DHEA metabolism to potent androgens. In the Severe Asthma Research Program (SARP) III cohort, we determined the association between DHEA-sulfate and percentage predicted forced expiratory volume in 1 s (FEV1PP). HSD3B1(1245) genotypes were assessed, and association between adrenal restrictive and adrenal permissive alleles and FEV1PP in patients with (GC) and without (noGC) daily oral glucocorticoid treatment was determined (n = 318). Validation was performed in a second cohort (SARP I&II; n = 184). DHEA-sulfate is associated with FEV1PP and is suppressed with GC treatment. GC patients homozygous for the adrenal restrictive genotype have lower FEV1PP compared with noGC patients (54.3% vs. 75.1%; P < 0.001). In patients with the homozygous adrenal permissive genotype, there was no FEV1PP difference in GC vs. noGC patients (73.4% vs. 78.9%; P = 0.39). Results were independently confirmed: FEV1PP for homozygous adrenal restrictive genotype in GC vs. noGC is 49.8 vs. 63.4 (P < 0.001), and for homozygous adrenal permissive genotype, it is 66.7 vs. 67.7 (P = 0.92). The adrenal restrictive HSD3B1(1245) genotype is associated with GC resistance. This effect appears to be driven by GC suppression of 3β-HSD1 substrate. Our results suggest opportunities for prediction of GC resistance and pharmacologic intervention.Item Multisystem Inflammatory Syndrome in Children — Initial Therapy and Outcomes(Massachusetts Medical Society, 2021-07-01) Son, Mary Beth F.; Murray, Nancy; Friedman, Kevin; Young, Cameron C.; Newhams, Margaret M.; Feldstein, Leora R.; Loftis, Laura L.; Tarquinio, Keiko M.; Singh, Aalok R.; Heidemann, Sabrina M.; Soma, Vijaya L.; Riggs, Becky J.; Fitzgerald, Julie C.; Kong, Michele; Doymaz, Sule; Giuliano, John S., Jr.; Keenaghan, Michael A.; Hume, Janet R.; Hobbs, Charlotte V.; Schuster, Jennifer E.; Clouser, Katharine N.; Hall, Mark W.; Smith, Lincoln S.; Horwitz, Steven M.; Schwartz, Stephanie P.; Irby, Katherine; Bradford, Tamara T.; Maddux, Aline B.; Babbitt, Christopher J.; Rowan, Courtney M.; McLaughlin, Gwenn E.; Yager, Phoebe H.; Maamari, Mia; Mack, Elizabeth H.; Carroll, Christopher L.; Montgomery, Vicki L.; Halasa, Natasha B.; Cvijanovich, Natalie Z.; Coates, Bria M.; Rose, Charles E.; Newburger, Jane W.; Patel, Manish M.; Randolph, Adrienne G.; Pediatrics, School of MedicineBackground: The assessment of real-world effectiveness of immunomodulatory medications for multisystem inflammatory syndrome in children (MIS-C) may guide therapy. Methods: We analyzed surveillance data on inpatients younger than 21 years of age who had MIS-C and were admitted to 1 of 58 U.S. hospitals between March 15 and October 31, 2020. The effectiveness of initial immunomodulatory therapy (day 0, indicating the first day any such therapy for MIS-C was given) with intravenous immune globulin (IVIG) plus glucocorticoids, as compared with IVIG alone, was evaluated with propensity-score matching and inverse probability weighting, with adjustment for baseline MIS-C severity and demographic characteristics. The primary outcome was cardiovascular dysfunction (a composite of left ventricular dysfunction or shock resulting in the use of vasopressors) on or after day 2. Secondary outcomes included the components of the primary outcome, the receipt of adjunctive treatment (glucocorticoids in patients not already receiving glucocorticoids on day 0, a biologic, or a second dose of IVIG) on or after day 1, and persistent or recurrent fever on or after day 2. Results: A total of 518 patients with MIS-C (median age, 8.7 years) received at least one immunomodulatory therapy; 75% had been previously healthy, and 9 died. In the propensity-score-matched analysis, initial treatment with IVIG plus glucocorticoids (103 patients) was associated with a lower risk of cardiovascular dysfunction on or after day 2 than IVIG alone (103 patients) (17% vs. 31%; risk ratio, 0.56; 95% confidence interval [CI], 0.34 to 0.94). The risks of the components of the composite outcome were also lower among those who received IVIG plus glucocorticoids: left ventricular dysfunction occurred in 8% and 17% of the patients, respectively (risk ratio, 0.46; 95% CI, 0.19 to 1.15), and shock resulting in vasopressor use in 13% and 24% (risk ratio, 0.54; 95% CI, 0.29 to 1.00). The use of adjunctive therapy was lower among patients who received IVIG plus glucocorticoids than among those who received IVIG alone (34% vs. 70%; risk ratio, 0.49; 95% CI, 0.36 to 0.65), but the risk of fever was unaffected (31% and 40%, respectively; risk ratio, 0.78; 95% CI, 0.53 to 1.13). The inverse-probability-weighted analysis confirmed the results of the propensity-score-matched analysis. Conclusions: Among children and adolescents with MIS-C, initial treatment with IVIG plus glucocorticoids was associated with a lower risk of new or persistent cardiovascular dysfunction than IVIG alone. (Funded by the Centers for Disease Control and Prevention.).