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The Journal of Clinical Endocrinology... Dec 2023Determining the etiology of adrenocorticotropin (ACTH)-dependent Cushing's syndrome (CS) is often difficult. The gold standard test, inferior petrosal sinus sampling...
CONTEXT
Determining the etiology of adrenocorticotropin (ACTH)-dependent Cushing's syndrome (CS) is often difficult. The gold standard test, inferior petrosal sinus sampling (IPSS), is expensive and not widely available.
OBJECTIVE
Evaluate the performance of the corticotropin-releasing hormone stimulation test (CRH-ST) and the 8 mg high-dose dexamethasone suppression test (HDDST) in distinguishing Cushing's disease (CD) from ectopic ACTH syndrome (EAS).
METHODS
Retrospective review in a tertiary referral center. A total of 323 patients with CD or EAS (n = 78) confirmed by pathology or biochemical cure (n = 15) in 96% underwent CRH-ST and HDDST performed between 1986 and 2019. We calculated test sensitivity (Se), specificity (Sp), positive predictive value (PPV), negative predictive value, and diagnostic accuracy (DA) for the diagnosis of CD, and determined optimal response criteria for each test, alone and in combination.
RESULTS
The CRH-ST performed better than the HDDST (DA 91%, 95% CI 87-94% vs 75%, 95% CI 69-79%). Optimal response criteria were a ≥40% increase of ACTH and/or cortisol during the CRH test and a ≥69% suppression of cortisol during the HDDST. A ≥40% cortisol increase during the CRH test was the most specific measure, PPV 99%. Seventy-four percent of subjects had concordant positive CRH test and HDDST results, yielding Se 93%, Sp 98%, DA 95%, and PPV 99%, with a pretest likelihood of 85%. A proposed algorithm diagnosed 64% of patients with CD with near perfect accuracy (99%), obviating the need for IPSS.
CONCLUSION
CRH is a valuable tool to correctly diagnose the etiology of ACTH-dependent CS. Its current worldwide unavailability impedes optimal management of these patients.
Topics: Humans; Animals; Sheep; Cushing Syndrome; Adrenocorticotropic Hormone; Corticotropin-Releasing Hormone; Hydrocortisone; Diagnosis, Differential; ACTH Syndrome, Ectopic; Pituitary ACTH Hypersecretion; Dexamethasone
PubMed: 37531629
DOI: 10.1210/clinem/dgad454 -
Scientific Reports Nov 2023Extensive mechanical stress frequently causes micro-traumas in skeletal muscle, followed by a regeneration period. The effective removal of dead myofibers is a...
Extensive mechanical stress frequently causes micro-traumas in skeletal muscle, followed by a regeneration period. The effective removal of dead myofibers is a prerequisite for proper regeneration, and several cell types, including professional phagocytes, were reported to be active in this process. Myoblasts express several molecules of the phagocytic machinery, such as BAI1, stabilin-2, and TAM (Tyro3, Axl, Mertk) tyrosine kinase receptors, but these molecules were reported to serve primarily cell fusion and survival, and their role in the phagocytosis was not investigated. Therefore, we aimed to investigate the in vitro phagocytic capacity of the C2C12 mouse myoblast cell line. RNA sequencing data were analyzed to determine the level and changes of phagocytosis-related gene expression during the differentiation process of C2C12 cells. To study the phagocytic capacity of myoblasts and the effect of dexamethasone, all-trans retinoic acid, hemin, and TAM kinase inhibitor treatments on phagocytosis, C2C12 cells were fed dead thymocytes, and their phagocytic capacity was determined by flow cytometry. The effect of dexamethasone and all-trans retinoic acid on phagocytosis-related gene expression was determined by quantitative PCR. Both undifferentiated and differentiated cells engulfed dead cells being the undifferentiated cells more effective. In line with this, we observed that the expression of several phagocytosis-related genes was downregulated during the differentiation process. The phagocytosis could be increased by dexamethasone and all-trans retinoic acid and decreased by hemin and TAM kinase inhibitor treatments. Our results indicate that myoblasts not only express phagocytic machinery genes but are capable of efficient dead cell clearance as well, and this is regulated similarly, as reported in professional phagocytes.
Topics: Mice; Animals; Hemin; Phagocytosis; Cell Differentiation; Myoblasts; Tretinoin; Gene Expression; Dexamethasone
PubMed: 38017321
DOI: 10.1038/s41598-023-48492-9 -
Molecular Therapy : the Journal of the... Feb 2024Dexamethasone (dex) is a glucocorticoid that is a mainstay for the treatment of inflammatory pathologies, including immunotherapy-associated toxicities, yet the specific...
Dexamethasone (dex) is a glucocorticoid that is a mainstay for the treatment of inflammatory pathologies, including immunotherapy-associated toxicities, yet the specific impact of dex on the activity of CAR T cells is not fully understood. We assessed whether dex treatment given ex vivo or as an adjuvant in vivo with CAR T cells impacted the phenotype or function of CAR T cells. We demonstrated that CAR T cell expansion and function were not inhibited by dex. We confirmed this observation using multiple CAR constructs and tumor models, suggesting that this is a general phenomenon. Moreover, we determined that dex upregulated interleukin-7 receptor α on CAR T cells and increased the expression of genes involved in activation, migration, and persistence when supplemented ex vivo. Direct delivery of dex and IL-7 into tumor-bearing mice resulted in increased persistence of adoptively transferred CAR T cells and complete tumor regression. Overall, our studies provide insight into the use of dex to enhance CAR T cell therapy and represent potential novel strategies for augmenting CAR T cell function during production as well as following infusion into patients.
Topics: Humans; Animals; Mice; Receptors, Chimeric Antigen; Receptors, Antigen, T-Cell; Immunotherapy, Adoptive; Neoplasms; T-Lymphocytes; Dexamethasone; Receptors, Interleukin-7
PubMed: 38140726
DOI: 10.1016/j.ymthe.2023.12.017 -
Journal of Infection in Developing... Jul 2023The aim of this study was to demonstrate the purpose of adding antiviral (remdesivir) to the existing steroidal (dexamethasone) therapy in treating coronavirus disease... (Observational Study)
Observational Study
INTRODUCTION
The aim of this study was to demonstrate the purpose of adding antiviral (remdesivir) to the existing steroidal (dexamethasone) therapy in treating coronavirus disease 2019 (COVID-19).
METHODOLOGY
A retrospective observational case cohort study was carried out to compare the effect of dexamethasone alone and in combination with remdesivir in treating moderate and severe COVID-19 disease. The patients were divided into 2 groups: Group 1 included patients treated with dexamethasone alone, and Group 2 included patients treated with dexamethasone and remdesivir. Levels of inflammatory markers (C-reactive protein, D- dimer and lactate dehydrogenase), World Health Organization (WHO) ordinal scale scoring, symptomatic improvement in terms of fever, cough, shortness of breath, 6-minutes' walk test and SpO2 levels on day of admission (D0), 3 days and 5 days after admission (D3 and D5), and 10 days overall outcome (determined as death, or discharge with or without Long Term Oxygenation Therapy) were collected and analyzed.
RESULTS
Addition of remdesivir to dexamethasone in treating COVID 19 did not have any additional benefits. No additional role of remdesivir is seen in combating the disease except in case of 10 days outcome. However, the better 10-day outcome associated with the use of remdesivir was thought to be due to the patients who were on mechanical ventilation in the dexamethasone treated group at the time of inclusion.
CONCLUSIONS
Since a similar trend was seen in both groups, our study concluded no additional role of remdesivir in combating COVID-19.
Topics: Humans; COVID-19; SARS-CoV-2; Retrospective Studies; Cohort Studies; COVID-19 Drug Treatment; Antiviral Agents; Dexamethasone
PubMed: 37515802
DOI: 10.3855/jidc.17971 -
Blood Advances Oct 2023Although randomized controlled trial data suggest that the more intensive triplet bortezomib-lenalidomide-dexamethasone (VRd) is superior to the less intensive doublet... (Randomized Controlled Trial)
Randomized Controlled Trial
Although randomized controlled trial data suggest that the more intensive triplet bortezomib-lenalidomide-dexamethasone (VRd) is superior to the less intensive doublet lenalidomide-dexamethasone (Rd) in patients newly diagnosed with multiple myeloma (MM), guidelines have historically recommended Rd over VRd for patients who are frail and may not tolerate a triplet. We identified 2573 patients (median age, 69.7 years) newly diagnosed with MM who were initiated on VRd (990) or Rd (1583) in the national US Veterans Affairs health care System from 2004 to 2020. We measured frailty using the Veterans Affairs Frailty Index. To reduce imbalance in confounding, we matched patients for MM stage and 1:1 based on a propensity score. Patients who were moderate-severely frail had a higher prevalence of stage III MM and myeloma-related frailty deficits than patients who were not frail. VRd vs Rd was associated with lower mortality (hazard ratio [HR], 0.81; 95% confidence interval [CI], 0.70-0.94) in the overall matched population. Patients who were moderate-severely frail demonstrated the strongest association (HR 0.74; 95% CI, 0.56-0.97), whereas the association weakened in those who were mildly frail (HR, 0.80; 95% CI, 0.61-1.05) and nonfrail (HR, 0.86; 95% CI, 0.67-1.10). VRd vs Rd was associated with a modestly higher incidence of hospitalizations in the overall population, but this association weakened in patients who were moderate-severely frail. Our findings confirm the benefit of VRd over Rd in US veterans and further suggest that this benefit is strongest in patients with the highest levels of frailty, arguing that more intensive treatment of myeloma may be more effective treatment of frailty itself.
Topics: Humans; Aged; Multiple Myeloma; Lenalidomide; Frail Elderly; Frailty; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Dexamethasone
PubMed: 37582048
DOI: 10.1182/bloodadvances.2023011019 -
Journal of Investigative Surgery : the... Dec 2023Glucocorticoids are widely used in clinical practice; however, they can cause side effects, such as osteoporosis. Acteoside (ACT) from Cistanche has been used to combat...
OBJECTIVE
Glucocorticoids are widely used in clinical practice; however, they can cause side effects, such as osteoporosis. Acteoside (ACT) from Cistanche has been used to combat a variety of diseases. The study was conducted to evaluate the efficacy of ACT in glucocorticoid-induced osteoporosis (GIOP) and its potential mechanism.
METHODS
Dexamethasone (Dex) was injected intramuscularly to induce osteoporosis in a rat model, and ACT was given orally. ACT was supplemented in Dex-stimulated osteoblastic MC3T3-E1 cells. RT-qPCR was performed to assess the mRNA levels of bone formation (Runx2, CoL1A1), and bone resorption (OPG and RANKL). A commercial ELISA kit was applied to assess serum OC and CTX levels. Western blot was performed to assess protein levels in the PI3K/AKT/mTOR signaling pathway. CCK-8 assay and flow cytometry were performed to assess osteoblast viability and apoptosis.
RESULTS
ACT reduced Dex-induced bone microstructure deterioration, increased serum levels of OC, and decreased the levels of CTX ( < 0.05). In the MC3T3-E1 cells, Dex inhibited cell viability and promoted apoptosis; however, this effect was greatly attenuated by ACT ( < 0.05). Concurrently, ACT reversed the reduction in Runx2, osterix, CoL1A1, and OPG mRNA levels, ALP activity, and the promotion of RANKL by Dex. Additionally, ACT attenuated Dex-induced inhibition of p-AKT/AKT, p-mTOR/mTOR, and p-PI3K/PI3K protein levels by Dex ( < 0.05), while the PI3K/AKT/mTOR pathway inhibitor LY294002 diminished the potential effect of ACT ( < 0.05).
CONCLUSION
ACT from Cistanche may exert osteoprotective effects by activating the PI3K/AKT/mTOR signaling pathway to alleviate Dex-induced osteoporosis.
Topics: Rats; Animals; Glucocorticoids; Core Binding Factor Alpha 1 Subunit; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Cistanche; Dexamethasone; Osteoporosis; Osteoblasts; TOR Serine-Threonine Kinases; RNA, Messenger
PubMed: 36521840
DOI: 10.1080/08941939.2022.2154578 -
Journal of Cellular and Molecular... Dec 2023Steroid-induced femoral head necrosis (SIFHN) is a serious clinical complication that is caused by prolonged or excessive use of glucocorticoids (GCs). Osteoblast...
Steroid-induced femoral head necrosis (SIFHN) is a serious clinical complication that is caused by prolonged or excessive use of glucocorticoids (GCs). Osteoblast apoptosis and osteogenic differentiation dysfunction caused by GC-induced oxidative stress and mitochondrial impairment are strongly implicated in SIFHN. Apocynin (APO) is a kind of acetophenone extracted from an herb. In recent years, APO has received much attention for its antiapoptotic and antioxidant properties. This study aimed to investigate whether APO could protect against SIFHN and explore the mechanism. In our study, low-dose APO had no toxic effects on osteoblasts and restored dexamethasone (Dex)-treated osteoblasts by improving survival, inhibiting OS and restoring mitochondrial dysfunction. Mechanistically, APO alleviated Dex-induced osteoblast injury by activating the Nrf2 pathway, and the use of ML385 to block Nrf2 significantly eliminated the protective effect of APO. In addition, APO could reduce the formation of empty lacunae, restore bone mass and promote the expression of Nrf2 in SIFHN rats. In conclusion, APO protects osteoblasts from Dex-induced oxidative stress and mitochondrial dysfunction through activation of the Nrf2 pathway and may be a beneficial drug for the treatment of SIFHN.
Topics: Rats; Animals; Dexamethasone; NF-E2-Related Factor 2; Osteogenesis; Glucocorticoids; Oxidative Stress; Acetophenones; Apoptosis; Osteoblasts; Mitochondrial Diseases
PubMed: 37749949
DOI: 10.1111/jcmm.17974 -
Annals of Hematology Mar 2024This multicenter, open-label, single-arm trial (ClinicalTrials.gov, NCT05236621) was conducted to confirm the efficacy and safety of generic pomalidomide plus...
This multicenter, open-label, single-arm trial (ClinicalTrials.gov, NCT05236621) was conducted to confirm the efficacy and safety of generic pomalidomide plus dexamethasone in Chinese patients with relapsed or refractory multiple myeloma (RRMM). Total 79 eligible RRMM patients were planned to be included. Patients were treated with generic pomalidomide (4 mg daily on days 1-21, orally) and low-dose dexamethasone (40 mg/day on days 1, 8, 15, and 22, orally; 20 mg for patients aged > 75 years) in 28-day cycles until disease progression with a maximum treatment duration of 2 years. The primary endpoint is the overall response rate (ORR) assessed by the independent review committee per the 2016 International Myeloma Working Group guidelines. A total of 85 eligible patients were included in this study from 32 centers in China, with a median age of 62.0 (range, 39-76) years, a median prior line of therapy of 4 (range, 1-16), and 41.2% patients with high-risk cytogenetics. The ORR was 38.8% (95% confidence interval (CI), 28.44-50.01). The disease control rate was 67.1% (95% CI, 56.02-76.87), meanwhile, the median progression-free survival was 5.55 months (95% CI, 3.68-7.52). Among the treatment-related adverse events (TRAEs), infective pneumonia (17.6%) was the most frequent non-hematologic adverse event, while a decrease in neutrophil count (52.9%) was the most common grade ≥ 3 TRAE. The study results indicated that the generic pomalidomide demonstrated consistent efficacy and a safety profile similar to the branded pomalidomide when combined with low-dose dexamethasone in Chinese RRMM patients.Registration number ClinicalTrials.gov NCT05236621, retrospectively registered on February 11, 2022.
Topics: Humans; Adult; Middle Aged; Aged; Multiple Myeloma; Dexamethasone; Neoplasm Recurrence, Local; Antineoplastic Combined Chemotherapy Protocols; Thalidomide
PubMed: 38112795
DOI: 10.1007/s00277-023-05558-y -
Scientific Reports Oct 2023Cataract surgery can cause dry eye symptoms. One of the many factors compromising the ocular surface is the use of benzalkonium chloride (BAC)-preserved topical eye... (Randomized Controlled Trial)
Randomized Controlled Trial
Cataract surgery can cause dry eye symptoms. One of the many factors compromising the ocular surface is the use of benzalkonium chloride (BAC)-preserved topical eye drops administered during the postoperative period. In this open-label, prospective, randomized, comparative clinical trial, 40 patients not previously affected by dry eye disease were assigned to receive either preservative-free (PFD) or preserved (PD) dexamethasone 0.1% eye drops for two weeks after a standard phacoemulsification procedure. Fluorescein break-up time, ocular surface staining score, Schirmer test, Ocular Surface Disease Index and anterior chamber (AC) cells were evaluated at baseline prior to the surgery and 2 weeks after surgery. No statistically significant differences in baseline assessments were observed between groups. At week 2, a significant increase in corneal staining scores (p = 0.003) and foreign body sensation (p = 0.04) was observed for the PD group only. The conjunctival staining score was significantly higher in both groups. The mean AC cell grading was higher in the PFD group than in the PD group (0.28 ± 0.30 and 0.07 ± 0.18, respectively; p = 0.013). Preservative-free dexamethasone eye drops after cataract surgery caused milder dry eye symptoms as compared with preserved dexamethasone. The AC inflammation control comparison may require a larger study group. Trial registration: ClinicalTrials.gov identifier NCT05753787, 03/03/2023.
Topics: Humans; Prospective Studies; Preservatives, Pharmaceutical; Dry Eye Syndromes; Ophthalmic Solutions; Cataract; Dexamethasone
PubMed: 37903818
DOI: 10.1038/s41598-023-44939-1 -
Brain, Behavior, and Immunity Mar 2024Cognitive deficits are increasingly recognized as a long-term sequela of severe COVID-19. The underlying processes and molecular signatures associated with these...
BACKGROUND AND OBJECTIVES
Cognitive deficits are increasingly recognized as a long-term sequela of severe COVID-19. The underlying processes and molecular signatures associated with these long-term neurological sequalae of COVID-19 remain largely unclear, but may be related to systemic inflammation-induced effects on the brain. We studied the systemic inflammation-brain interplay and its relation to development of long-term cognitive impairment in patients who survived severe COVID-19. Trajectories of systemic inflammation and neuroaxonal damage blood biomarkers during ICU admission were analyzed and related to long-term cognitive outcomes.
METHODS
Prospective longitudinal cohort study of patients with severe COVID-19 surviving ICU admission. During admission, blood was sampled consecutively to assess levels of inflammatory cytokines and neurofilament light chain (NfL) using an ultrasensitive multiplex Luminex assay and single molecule array technique (Simoa). Cognitive functioning was evaluated using a comprehensive neuropsychological assessment six months after ICU-discharge.
RESULTS
Ninety-six patients (median [IQR] age 61 [55-69] years) were enrolled from March 2020 to June 2021 and divided into two cohorts: those who received no COVID-19-related immunotherapy (n = 28) and those treated with either dexamethasone or dexamethasone and tocilizumab (n = 68). Plasma NfL concentrations increased in 95 % of patients during their ICU stay, from median [IQR] 23 [18-38] pg/mL at admission to 250 [160-271] pg/mL after 28 days, p < 0.001. Besides age, glomerular filtration rate, immunomodulatory treatment, and C-reactive protein, more specific markers of systemic inflammation at day 14 (i.e., interleukin (IL)-8, tumour necrosis factor, and IL-1 receptor antagonist) were significant predictors of blood NfL levels at day 14 of ICU admission (R = 44 %, p < 0.001), illustrating the association between sustained systemic inflammation and neuroaxonal damage. Twenty-six patients (27 %) exhibited cognitive impairment six months after discharge from the ICU. NfL concentrations showed a more pronounced increase in patients that developed cognitive impairment (p = 0.03). Higher NfL predicted poorer outcome in information processing speed (Trail Making Test A, r = -0.26, p = 0.01; Letter Digit Substitution Test, r = -0.24, p = 0.02).
DISCUSSION
Prolonged systemic inflammation in critically ill COVID-19 patients is related to neuroaxonal damage and subsequent long-term cognitive impairment. Moreover, our findings suggest that plasma NfL concentrations during ICU stay may possess prognostic value in predicting future long-term cognitive impairment in patients that survived severe COVID-19.
Topics: Humans; Middle Aged; Longitudinal Studies; Prospective Studies; COVID-19; Cognitive Dysfunction; Inflammation; Dexamethasone
PubMed: 38336025
DOI: 10.1016/j.bbi.2024.02.002