Circadian regulation of hippocampal function is disrupted with corticosteroid treatment.

Disrupted circadian activity is associated with many neuropsychiatric disorders. A major coordinator of circadian biological systems is adrenal glucocorticoid secretion which exhibits a pronounced preawakening peak that regulates metabolic, immune, and cardiovascular processes, as well as mood and cognitive function. Loss of this circadian rhythm during corticosteroid therapy is often associated with memory impairment. Surprisingly, the mechanisms that underlie this deficit are not understood. In this study, in rats, we report that circadian regulation of the hippocampal transcriptome integrates crucial functional networks that link corticosteroid-inducible gene regulation to synaptic plasticity processes via an intrahippocampal circadian transcriptional clock. Further, these circadian hippocampal functions were significantly impacted by corticosteroid treatment delivered in a 5-d oral dosing treatment protocol. Rhythmic expression of the hippocampal transcriptome, as well as the circadian regulation of synaptic plasticity, was misaligned with the natural light/dark circadian-entraining cues, resulting in memory impairment in hippocampal-dependent behavior. These findings provide mechanistic insights into how the transcriptional clock machinery within the hippocampus is influenced by corticosteroid exposure, leading to adverse effects on critical hippocampal functions, as well as identifying a molecular basis for memory deficits in patients treated with long-acting synthetic corticosteroids.

Natural Polyphenol Delivered Methylprednisolone Achieve Targeted Enrichment for Acute Spinal Cord Injury Therapy.

The strong anti-inflammatory effect of methylprednisolone (MP) is a necessary treatment for various severe cases including acute spinal cord injury (SCI). However, concerns have been raised regarding adverse effects from MP, which also severely limits its clinical application. Natural polyphenols, due to their rich phenolic hydroxyl chemical properties, can form dynamic structures without additional modification, achieving targeted enrichment and drug release at the disease lesion, making them a highly promising carrier. Considering the clinical application challenges of MP, a natural polyphenolic platform is employed for targeted and efficient delivery of MP, reducing its systemic side effects. Both in vitro and SCI models demonstrated polyphenols have multiple advantages as carriers for delivering MP: (1) Achieved maximum enrichment at the injured site in 2 h post-administration, which met the desires of early treatment for diseases; (2) Traceless release of MP; (3) Reducing its side effects; (4) Endowed treatment system with new antioxidative properties, which is also an aspect that needs to be addressed for diseases treatment. This study highlighted a promising prospect of the robust delivery system based on natural polyphenols can successfully overcome the barrier of MP treatment, providing the possibility for its widespread clinical application.

Melatonin synergistically potentiates the effect of methylprednisolone on reducing neuroinflammation in the experimental autoimmune encephalomyelitis mouse model of multiple sclerosis.

Multiple sclerosis (MS) is an autoimmune neurodegenerative disease of unknown etiology characterized by infiltration of encephalitogenic cells in the central nervous system (CNS) resulting in the presence of multifocal areas of demyelination leading to neurodegeneration. The infiltrated immune cells population is composed mainly of effector CD4+ and CD8+ T lymphocytes, B cells, macrophages, and dendritic cells that secrete pro-inflammatory factors that eventually damage myelin leading to axonal damage. The most common clinical form of MS is relapsing-remitting (RR), characterized by neuroinflammatory episodes followed by partial or total recovery of neurological deficits. The first-line treatment for RRMS relapses is a high dose of glucocorticoids, especially methylprednisolone, for three to five consecutive days. Several studies have reported the beneficial effects of melatonin in the context of neuroinflammation associated with MS or experimental autoimmune encephalomyelitis (EAE), the preclinical model for MS. Therefore, the objective of this study was to evaluate the effect of the combined treatment of melatonin and methylprednisolone on the neuroinflammatory response associated with the EAE development. This study shows for the first time the protective synergistic effect of co-treatment with melatonin and methylprednisolone on reducing the severity of EAE by decreasing CD4 lymphocytes, B cells, macrophages and dendritic cells in the CNS, as well as modulating the population of infiltrated T and B cells toward regulatory phenotypes to the detriment of pro-inflammatory effector functions. In addition to the potentiation of the protective role of methylprednisolone, treatment with melatonin from the clinical onset of EAE improves the natural course of the EAE and the response to a subsequent treatment with methylprednisolone in a later relapse of the disease, pointing melatonin as potential therapeutic tool in combination with methylprednisolone for the treatment of relapses in MS.

Effectiveness of intravenous methylprednisolone pulse in patients with severe microscopic polyangiitis and granulomatosis with polyangiitis.

OBJECTIVES: To evaluate the effectiveness and safety of two different intravenous methylprednisolone (IVMP) pulse doses in patients with severe microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA). METHODS: We emulated a target trial using observational data from the nationwide registry in Japan. Patients with severe glomerulonephritis or diffuse alveolar haemorrhage were selected and pseudo-randomised into three groups using propensity score-based overlap weighting as follows: non-IVMP, IVMP 0.5 g/day, and IVMP 1.0 g/day. The primary outcome was all-cause death, and the secondary outcomes were composite all-cause death and kidney failure, severe relapse, and serious infection from 2 to 48 weeks after treatment initiation. To estimate the treatment effects, the Cox proportional hazard model and Fine-Gray subdistribution hazard model were used. RESULTS: In this emulated target trial, of 201 eligible patients (MPA, 175; GPA, 26), 6 (2.8%) died, 4 (2.0%) had kidney failure, 11 (5.3%) had severe relapse, and 40 (19.8%) had severe infections. Hazard ratios (HR) for IVMP 0.5 g/day and IVMP 1.0 g/day pulse groups compared with non-IVMP pulse were as follows: all-cause death = 0.46 (95% confidence interval [95%CI]: 0.07-2.81) and 0.07 (95%CI: 0.01-0.41); all-cause death/kidney failure = 1.18 (95%CI: 0.26-5.31) and 0.59 (95%CI: 0.08-4.52); subdistribution HRs for severe relapse = 1.26 (95%CI: 0.12-13.70) and 3.36 (95%CI: 0.49-23.29); and serious infection = 1.88 (95%CI: 0.76-4.65) and 0.94 (95%CI: 0.28-3.13). CONCLUSIONS: IVMP 1.0 g/day pulse may improve 48-week mortality in patients with severe MPA/GPA.

Dexamethasone versus methylprednisolone for multiple organ dysfunction in COVID-19 critically ill patients: a multicenter propensity score matching study.

BACKGROUND: Dexamethasone usually recommended for patients with severe coronavirus disease 2019 (COVID-19) to reduce short-term mortality. However, it is uncertain if another corticosteroid, such as methylprednisolone, may be utilized to obtain better clinical outcome. This study assessed dexamethasone's clinical and safety outcomes compared to methylprednisolone. METHODS: A multicenter, retrospective cohort study was conducted between March 01, 2020, and July 31, 2021. It included adult COVID-19 patients who were initiated on either dexamethasone or methylprednisolone therapy within 24 h of intensive care unit (ICU) admission. The primary outcome was the progression of multiple organ dysfunction score (MODS) on day three of ICU admission. Propensity score (PS) matching was used (1:3 ratio) based on the patient's age and MODS within 24 h of ICU admission. RESULTS: After Propensity Score (PS) matching, 264 patients were included; 198 received dexamethasone, while 66 patients received methylprednisolone within 24 h of ICU admission. In regression analysis, patients who received methylprednisolone had a higher MODS on day three of ICU admission than those who received dexamethasone (beta coefficient: 0.17 (95% CI 0.02, 0.32), P = 0.03). Moreover, hospital-acquired infection was higher in the methylprednisolone group (OR 2.17, 95% CI 1.01, 4.66; p = 0.04). On the other hand, the 30-day and the in-hospital mortality were not statistically significant different between the two groups. CONCLUSION: Dexamethasone showed a lower MODS on day three of ICU admission compared to methylprednisolone, with no statistically significant difference in mortality.

Methylprednisolone dosing for pediatric critical asthma: a single-center cohort study.

OBJECTIVE: We aimed to characterize intravenous (IV) methylprednisolone (MP) dosing regimens and clinical outcomes for children hospitalized for critical asthma (CA). METHODS: A single-center, retrospective review was performed of children admitted to the pediatric intensive care unit (PICU) for CA between September 2015 and October 2019. Patients 5-to 17-year-olds, initiated on continuous nebulized albuterol, and prescribed at least one dose of IV MP were included. The primary outcome was to characterize PICU MP dosing. Cohorts were then compared by MP dosing: conservative-dose methylprednisolone (CDMP, ≤ 0.5 mg/kg/dose every 6 h) and standard-dose methylprednisolone (SDMP, > 0.5 mg/kg/dose every 6 h). Clinical efficacy endpoints were the duration of continuous nebulized albuterol and PICU length of stay (LOS). Safety endpoints included corticosteroid-related adverse events. RESULTS: Of 168 children studied, 50 (29.8%) were prescribed CDMP and 118 (70.2%) SDMP. The overall mean MP dose was 31.3 ± 19.6 mg (weight-adjusted: 0.77 ± 0.32 mg/kg/dose). Compared to those prescribed SDMP, those prescribed CDMP had a shorter median duration of continuous nebulized albuterol (12.8 [IQR: 10.5-20] versus 17.3 [IQR: 11.3-29.7] hours, p = 0.019) and median PICU LOS (0.9 [IQR: 0.7-1.4] versus 1.2 [IQR: 0.9-1.8] days, p = 0.012). No corticosteroid-related adverse events were observed. In adjusted models, weight-adjusted IV MP dose was not associated with PICU LOS or duration of continuous nebulized albuterol. CONCLUSIONS: Intravenous MP dosing for pediatric CA varied widely in our study sample. Prospective, controlled trials are required to validate our observations including clinical efficacy and safety endpoints.

Efficacy of rituximab and risk factors for poor prognosis in patients with childhood-onset steroid-resistant nephrotic syndrome: a multicenter study.

BACKGROUND: The efficacy of rituximab in steroid-resistant nephrotic syndrome (SRNS) is controversial. We previously reported that rituximab in combination with methylprednisolone pulse therapy (MPT) and immunosuppressants was associated with favorable outcomes. We determined risk factors for poor response following rituximab treatment, which remains unknown. METHODS: This retrospective study included 45 patients with childhood-onset SRNS treated with rituximab across four pediatric kidney facilities. Treatment effects were categorized as complete remission (CR), partial remission (PR), and no remission (NR) at one year after rituximab treatment. The primary outcome was the rate of CR, PR, and NR. Risk factors for non-CR were calculated with multivariate logistic regression. Adverse events and the relationship between disease status at one year and long-term prognosis were also evaluated. RESULTS: The rates of CR, PR, and NR at one year were 69%, 24%, and 7%, respectively. The median time from rituximab administration to CR was 90 days. The median follow-up period after rituximab administration was 7.4 years. In multivariate analysis, significant risk factors for poor response were the pathologic finding of focal segmental glomerular sclerosis and a long interval between SRNS diagnosis and rituximab administration. The rates of CR were 90.3% and 21.4% in patients receiving rituximab within and after 6 months following SRNS diagnosis, respectively (p < 0.001). Five patients developed chronic kidney disease stage G5, including 2 of the 11 patients with PR and all 3 patients with NR, whereas none of the 31 patients with CR developed chronic kidney disease stage G5. CONCLUSION: Early administration of rituximab in combination with MPT and immunosuppressants might achieve favorable outcomes in patients with SRNS.

Glucocorticoid-induced adrenal insufficiency after therapy with intravenous methylprednisolone in patients with moderate-to-severe and active Graves' orbitopathy: assessment with a low-dose corticotropin test.

PURPOSE: We aimed to assess adrenal function following treatment of moderate-to-severe and active Graves' orbitopathy (GO) with intravenous methylprednisolone (IVMP) in weekly pulses in a cumulative dose of 4.5 or 7.5 g. We evaluated the impact of IVMP pulses on adrenal reserve using a low-dose (1 µg) ACTH stimulation test (LDT) for the first time. METHODS: In this prospective study we evaluated adrenal function in 21 patients with moderate-to-severe and active GO treated with 12 weekly IVMP pulses according to the European Group on Graves' Orbitopathy (EUGOGO) recommendations. We assessed serum cortisol, plasma adrenocorticotropic hormone (ACTH), and dehydroepiandrosterone sulfate (DHEA-S) levels before the 1st and 12th IVMP pulse. We performed dynamic testing using LDT before the 12th IVMP pulse in all patients. In those who failed LDT, adrenal function was reassessed with LDT and the overnight metyrapone test after 4-7 weeks. RESULTS: Two patients failed to achieve serum cortisol levels ≥ 18.1 µg/dL at 30 and 60 min in LDT and were diagnosed with glucocorticoid-induced adrenal insufficiency (GC-induced AI). They were recommended to take hydrocortisone in situations of acute stress. Both patients were reassessed within 4-7 weeks after treatment cessation and showed an adequate response in LDT and overnight metyrapone test. We observed a statistically significant decrease in DHEA-S levels (p = 0.004) before the 12th IVMP pulse compared to baseline in all patients. CONCLUSION: For the first time, our research shows that administering IVMP in 12 weekly pulses can result in GC-induced AI. We suggest that patients should undergo careful evaluation for GC-induced AI, including LDT, after therapy with IVMP according to EUGOGO guidelines. Screening for altered adrenal reserve could prevent life-threatening complications, particularly during acute stress situations.

Rituximab in combination with cyclosporine and steroid pulse therapy for childhood-onset multidrug-resistant nephrotic syndrome: a multicenter single-arm clinical trial (JSKDC11 trial).

BACKGROUND: Only 80% of children with idiopathic nephrotic syndrome respond well to glucocorticoid therapy. Multidrug-resistant nephrotic syndrome (MRNS) is associated with a poor kidney prognosis. Several retrospective studies have identified rituximab as an effective treatment for MRNS; however, prospective studies are required to assess its efficacy and safety. METHODS: We conducted a multicenter, non-blinded, single-arm trial to investigate the efficacy and safety of rituximab in patients with childhood-onset MRNS who were resistant to cyclosporine and more than three courses of steroid pulse therapy. The enrolled patients received four 375 mg/m2 doses of rituximab in combination with baseline cyclosporine and steroid pulse therapy. The primary endpoint was a > 50% reduction in the urinary protein/creatinine ratio from baseline on day 169. Complete and partial remissions were also evaluated. RESULTS: Six patients with childhood-onset MRNS were enrolled. All patients were negative for pathogenic variants of podocyte-related genes. On day 169, five patients (83.3%) showed a > 50% reduction in the urinary protein/creatinine ratio, two patients showed partial remission, and two patients showed complete remission. No deaths occurred and severe adverse events occurred in two patients (infection in one patient and acute kidney injury in one patient). Three patients needed treatment for moderate-to-severe infection. CONCLUSIONS: The study treatment effectively reduced the urinary protein/creatinine ratio in patients with childhood-onset MRNS. The adverse events in this study were within the expected range; however, attention should be paid to the occurrence of infections.

Visual recovery after oral high-dose methylprednisolone in acute inflammatory optic neuropathy.

PURPOSE: High doses of venous corticosteroids are currently the only validated treatment for the management of optic neuritis (ON). The objective is to assess the changes in visual function parameters after oral high-dose methylprednisolone in patients with ON. METHODS: A retrospective analysis of patients with acute ON was performed. Patients received 1 g per day of oral methylprednisolone for 3 to 5 days. Visual function was measured using the ETDRS test for visual acuity, 30-2 automated visual field test, contrast sensitivity test, and color vision test before treatment, 4 days, 2 weeks, 1 month and 3 months, and 6 months following treatment. To assess anatomical changes, optical coherence tomography of the ganglion cells was performed at various timepoints. RESULTS: Between September 2014 and September 2016, a total of 29 patients were included in the study. More than 80% of patients had recovered normal visual acuity after 3 and 6 months. This recovery of all parameters of visual function was observed as early as 4 days but occurred predominantly within 15 days after the initiation of treatment. We observed a thinning of the ganglion cell layer during the follow-up, which mainly occurs within one month. The P100 wave of visually evoked potentials was discernible in all patients at 6 months. During the 6 years of follow-up, 2 patients had experienced a relapse of ON. No serious adverse effects were observed. CONCLUSION: This study demonstrated a rapid recovery of all visual function parameters after oral high-dose methylprednisolone ON with no serious adverse effects.

Methylprednisolone Does Not Enhance Paraoxonase 1 Activity During Cardiopulmonary Bypass Surgery-A Randomized, Controlled Clinical Trial.

OBJECTIVES: Cardiopulmonary bypass (CPB) is linked to systemic inflammatory responses and oxidative stress. Paraoxonase 1 (PON1) is an antioxidant enzyme with a cardioprotective role whose activity is decreased in systemic inflammation and in patients with acute myocardial and global ischemia. Glucocorticoids counteract the effect of oxidative stress by upregulating PON1 gene expression. The authors aimed to determine the effect of methylprednisolone on PON1 activity during cardiac surgery on CPB. DESIGN: Prospective, randomized, controlled clinical trial. SETTING: The University Medical Center Ljubljana, Slovenia. PARTICIPANTS: Forty adult patients who underwent complex cardiac surgery on CPB between February 2016 and December 2017 were randomized into methylprednisolone and control groups (n = 20 each). INTERVENTIONS: Patients in the methylprednisolone group received 1 g of methylprednisolone in the CPB priming solution, whereas patients in the control group were not given methylprednisolone during CPB. MEASUREMENTS AND MAIN RESULTS: The effect of methylprednisolone from the CPB priming solution was compared with standard care during CPB on PON1 activity until postoperative day 5. Correlations of PON1 activity with lipid status, mediators of inflammation, and hemodynamics were analyzed also. No significant differences were found between study groups for PON1 activity, high-density lipoprotein, and low-density lipoprotein in any of the measurement intervals (p > 0.016). The methylprednisolone group had significantly lower tumor necrosis factor alpha (p < 0.001) and interleukin-6 (p < 0.001), as well as C-reactive protein and procalcitonin (p < 0.016) after surgery. No significant difference was found between groups for hemodynamic parameters. A positive correlation existed between PON1 and lipid status, whereas a negative correlation was found between PON1 activity and tumor necrosis factor alpha, interleukin-6, and CPB duration. CONCLUSIONS: Methylprednisolone does not influence PON1 activity during cardiac surgery on CPB.

Neuroprotective macromolecular methylprednisolone prodrug nanomedicine prevents glucocorticoid-induced muscle atrophy and osteoporosis in a rat model of spinal cord injury.

To address the adverse side effects associated with systemic high-dose methylprednisolone (MP) therapy for acute spinal cord injury (SCI), we have developed a N-2-hydroxypropyl methacrylamide copolymer-based MP prodrug nanomedicine (Nano-MP). Intravenous Nano-MP selectively targeted to the inflamed SCI lesion and significantly improved neuroprotection and functional recovery after acute SCI. In the present study, we comprehensively assessed the potential adverse side effects associated with the treatment in the SCI rat models, including reduced body weight and food intake, impaired glucose metabolism, and reduced musculoskeletal mass and integrity. In contrast to free MP treatment, intravenous Nano-MP after acute SCI not only offered superior neuroprotection and functional recovery but also significantly mitigated or even eliminated the aforementioned adverse side effects. The superior safety features of Nano-MP observed in this study further confirmed the clinical translational potential of Nano-MP as a highly promising drug candidate for better clinical management of patients with acute SCI.

Targeted-delivery of nanomedicine-enabled methylprednisolone to injured spinal cord promotes neuroprotection and functional recovery after acute spinal cord injury in rats.

To date, no therapy has been proven to be efficacious in fully restoring neurological functions after spinal cord injury (SCI). Systemic high-dose methylprednisolone (MP) improves neurological recovery after acute SCI in both animal and human. MP therapy remains controversial due to its modest effect on functional recovery and significant adverse effects. To overcome the limitation of MP therapy, we have developed a N-(2-hydroxypropyl) methacrylamide copolymer-based MP prodrug nanomedicine (Nano-MP) that can selectively deliver MP to the SCI lesion when administered systemically in a rat model of acute SCI. Our in vivo data reveal that Nano-MP is significantly more effective than free MP in attenuating secondary injuries and neuronal apoptosis. Nano-MP is superior to free MP in improving functional recovery after acute SCI in rats. These data support Nano-MP as a promising neurotherapeutic candidate, which may provide potent neuroprotection and accelerate functional recovery with improved safety for patients with acute SCI.

Comparison of side effects of different steroids used in intratympanic injections.

OBJECTIVES: This study aimed to compare the side effects of different steroids used in the intratympanic injections (IT). METHODS: One hundred and sixty patients diagnosed with sudden sensorineural hearing loss and undergoing IT were assigned to four groups based on the type or concentration of steroids administered (Group DM5: 5 mg/ml Dexamethasone sodium phosphate; Group DM10: 10 mg/ml Dexamethasone sodium phosphate; Group MP: 40 mg/ml Methylprednisolone sodium succinate; Group BM: 4 mg/ml Betamethasone sodium phosphate). Each group comprised 40 patients, and all participants received IT six times. The study assessed and compared the degrees and duration of pain, dizziness, and tympanic membrane damage following IT. Patients were asked to report the pain they felt using the numeric rating scale (NRS). RESULTS: NRS scores for pain after IT showed significant differences among the four groups (p < 0.001). The average NRS scores for pain in each group were as follows: Group DM5: 1.53 ± 1.04; Group DM10: 1.45 ± 1.30; Group MP: 4.33 ± 2.22; Group BM: 6.03 ± 1.46. The durations of pain after IT also exhibited significant differences among the four groups (p < 0.001), with the longest duration observed in Group MP at 31.93 ± 15.20 min. CONCLUSION: Different types of steroids could lead to varying degrees of pain when used in IT. Betamethasone could cause the most severe pain, and methylprednisolone could result in the longest duration of pain.

Endolymphatic duct blockage surgery vs. intratympanic steroids for treatment of refractory Ménière's disease.

PURPOSE: To compare the effectiveness of the Endolymphatic duct blockage (EDB) and intratympanic methylprednisolone(ITMP) injection to control refractory Ménière's disease(MD) symptoms and evaluate their impact on hearing level. STUDY DESIGN: Retrospective study in a tertiary care center. METHODS: 36 received ITMP injection and 52 EDB. Mean outcome measures at 24 months included vertigo control, tinnitus, aural fullness and hearing level: pure-tone average (PTA), bone conduction average(BCA) and speech discrimination score(SDS). RESULTS: At 24 months postoperatively, 90.4% of the EDB group had complete control of vertigo and 43.4% of the ITMP group (p = 0.001). There was no significant difference in tinnitus or aural fullness control (p = 0.34 and p 0.21 respectively). In each group, the drop in tinnitus and aural fullness frequency at 24 months were significant for EDB (p = 0.03; p < 0.001 respectively) and for ITMP group in tinnitus (p = 0.03) but not aural fullness (p = 0.063). At 24 months, PTA, BCA and SDS were significantly worst in the ITMP group when compared to preoperative levels (p = 0.038, p = 0.027, p = 0.016). PTA in the EDB group was stable with no difference compared to ITMP group (p = 0.48). BCA and SDS in the EDB group were stable and better than the ITMP group (p = 0.032; p = 0.036). In each group, vestibular paresis was not significantly different before (p = 0.06) and after treatment (p = 0.68). CONCLUSION: EDB is more effective than the ITMP for controlling the vertigo symptoms of Ménière's disease and in preserving hearing function. It is a novel surgical technique with promising results for a complete treatment of Ménière's disease. ITMP decreases the frequency and the severity of the symptoms but only control vertigo in 27.8% of cases.

Methylprednisolone taper is an effective addition to multimodal pain regimens after total shoulder arthroplasty: results of a randomized controlled trial: 2022 Neer Award winner.

BACKGROUND: Perioperative corticosteroids have shown potential as nonopioid analgesic adjuncts for various orthopedic pathologies, but there is a lack of research on their use in the postoperative setting after total shoulder arthroplasty (TSA). The purpose of this study was to assess the effect of a methylprednisolone taper on a multimodal pain regimen after TSA. METHODS: This study was a randomized controlled trial (clinicaltrials.gov NCT03661645) of opioid-naive patients undergoing TSA. Patients were randomly assigned to receive intraoperative dexamethasone only (control group) or intraoperative dexamethasone followed by a 6-day oral methylprednisolone (Medrol) taper course (treatment group). All patients received the same standardized perioperative pain management protocol. Standardized pain journal entries were used to record visual analog pain scores (VAS-pain), VAS-nausea scores, and quantity of opioid tablet consumption during the first 7 postoperative days (POD). Patients were followed for at least one year postoperatively for clinical evaluation, collection of patient-reported outcomes, and observation of complications. RESULTS: A total of 67 patients were enrolled in the study; 32 in the control group and 35 in the treatment group. The groups had similar demographics and comorbidities. The treatment group demonstrated a reduction in mean VAS pain scores over the first 7 POD. Between POD 1 and POD 7, patients in the control group consumed an average of 17.6 oxycodone tablets while those in the treatment group consumed an average of 5.5 tablets. This equated to oral morphine equivalents of 132.1 and 41.1 for the control and treatment groups, respectively. There were fewer opioid-related side effects during the first postoperative week in the treatment group. The treatment group reported improved VAS pain scores at 2-week, 6-week, and 12-week postoperatively. There were no differences in Europe Quality of Life, shoulder subjective value (SSV), at any time point between groups, although American Shoulder and Elbow Surgeons questionnaire scores showed a slight improvement at 6-weeks in the treatment group. At mean follow-up, (control group: 23.4 months; treatment group:19.4 months), there was 1 infection in the control group and 1 postoperative cubital tunnel syndrome in the treatment group. No other complications were reported. CONCLUSIONS: A methylprednisolone taper course shows promise in reducing acute pain and opioid consumption as part of a multimodal regimen following TSA. As a result of this study, we have included this 6-day methylprednisolone taper course in our multimodal regimen for all primary shoulder arthroplasties. We hope this trial serves as a foundation for future studies on the use of low-dose oral corticosteroids and other nonnarcotic modalities to control pain after shoulder surgeries.

Gli1+ Progenitors Mediate Glucocorticoid-Induced Osteoporosis In Vivo.

For a wide range of chronic autoimmune and inflammatory diseases in both adults and children, synthetic glucocorticoids (GCs) are one of the most effective treatments. However, besides other adverse effects, GCs inhibit bone mass at multiple levels, and at different ages, especially in puberty. Although extensive studies have investigated the mechanism of GC-induced osteoporosis, their target cell populations still be obscure. Here, our data show that the osteoblast subpopulation among Gli1+ metaphyseal mesenchymal progenitors (MMPs) is responsive to GCs as indicated by lineage tracing and single-cell RNA sequencing experiments. Furthermore, the proliferation and differentiation of Gli1+ MMPs are both decreased, which may be because GCs impair the oxidative phosphorylation(OXPHOS) and aerobic glycolysis of Gli1+ MMPs. Teriparatide, as one of the potential treatments for GCs in bone mass, is sought to increase bone volume by increasing the proliferation and differentiation of Gli1+ MMPs in vivo. Notably, our data demonstrate teriparatide ameliorates GC-caused bone defects by targeting Gli1+ MMPs. Thus, Gli1+ MMPs will be the potential mesenchymal progenitors in response to diverse pharmaceutical administrations in regulating bone formation.

Intravenous methylprednisolone-induced hypokalaemic periodic paralysis in a thyrotoxic patient: a case report and literature review.

Hypokalaemic periodic paralysis (HPP) is an uncommon complication of corticosteroid therapy, which may also be seen in thyrotoxicosis. It was mostly described in the Asian population, and it is rare in other ethnic groups. We present the case of a poorly controlled thyrotoxic Caucasian male with thyroid eye disease (TED) who suffered an acute quadriplegic episode caused by severe hypokalaemia and was admitted to the intensive care unit (ITU) within 24 hours of initiating intravenous methylprednisolone (IVMP) infusion. Once his potassium blood levels were repleted, he completely recovered from the episode. Although HPP is rare in the Caucasian population, it can be precipitated in thyrotoxic patients by systemic steroids. Caution should be exercised when administering IVMP in poorly controlled thyrotoxic patients, and we suggest monitoring the potassium levels at regular intervals with ECG monitoring for at least 24 hours in at-risk individuals.

Diagnosis and treatment of allograft rejection in islet transplantation.

Islet transplantation stabilizes glycemic control in patients with complicated diabetes mellitus. Rapid functional decline could be due to islet allograft rejection. However, there is no reliable method to assess rejection, and treatment protocols are absent. We aimed to characterize diagnostic features of islet allograft rejection and assess effectiveness of high-dose methylprednisolone treatment. Over a median follow-up of 61.8 months, 22% (9 of 41) of islet transplant recipients experienced 10 suspected rejection episodes (SREs). All first SREs occurred within 18 months after transplantation. Important features were unexplained hyperglycemia (all cases), unexplained C-peptide decrease (ΔC-peptide, 77.1% [-59.1% to -91.6%]; ΔC-peptide:glucose, -76.3% [-49.2% to -90.4%]), predisposing event (5 of 10 cases), and increased immunologic risk (5 of 10 cases). At 6 months post-SRE, patients who received protocolized methylprednisolone (n = 4) had significantly better islet function than untreated patients (n = 4), according to C-peptide (1.39 ± 0.59 vs 0.14 ± 0.19 nmol/L; P = .007), Igls score (good [4 of 4 cases] vs failure [3 of 4 cases] or marginal [1 of 4 cases]; P = .018) and ß score (6.0 [6.0-6.0] vs 1.0 [0.0-3.5]; P = .013). SREs are prevalent among islet transplant recipients and are associated with loss of islet graft function. Timely treatment with high-dose methylprednisolone mitigates this loss. Unexplained hyperglycemia, unexpected C-peptide decrease, a predisposing event, and elevated immunologic risk are diagnostic indicators for SRE.

Protective effects of methylprednisolone-cyclophosphamide treatment on bleomycin-induced pulmonary fibrosis.

BACKGROUND: Methylprednisolone (MP) and cyclophosphamide (CTX) combination treatment has shown great benefits in improving pulmonary fibrosis (PF) and high safety. Currently, the mechanism underlying the effects of MP-CTX on improving PF remains unclear. This study determined the effects of MP-CTX combination treatment on the modulation of inflammation, oxidative stress, and T-cell immunity in PF. METHODS: PF rat models were induced by bleomycin stimulation. MP (3 mg/kg) and MP-CTX (MP: 3 mg/kg; CTX: 8 mg/kg) combination were administered in the PF + MP and PF + MP + CTX groups, respectively. Transmission electron microscopy, hematoxylin and eosin staining, Ashcroft score, and Masson trichrome staining were performed to measure lung morphology in PF. Enzyme-linked immunosorbent assay and quantitative polymerase chain reaction assay were performed to quantify inflammatory factors. Malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione peroxidase (GSH-PX) levels were determined using commercial kits. α-Smooth muscle actin (SMA) and collagen I levels were determined using western blotting and immunohistochemistry. The T-cell count was evaluated using flow cytometry. RESULTS: MP-CTX reduced lung injury, collagen deposition, and α-SMA and collagen I levels in a bleomycin-induced PF rat model. Additionally, MP-CTX decreased the levels of MDA and inflammatory factors (tumor necrosis factor-α, interleukin-1ß, and interleukin-6) but increased the activities of SOD and GSH-PX. Furthermore, MP-CTX changed T-cell types in lung tissues, such as increasing CD4+CD25+Foxp3+ cell count. CONCLUSIONS: MP-CTX combination treatment improved the degree of PF by reducing inflammation and oxidative stress and improving T-cell immunity. These findings provide novel insights into the mechanisms underlying the effects of MP-CTX on PF.