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Nature Communications Jun 2024Dexamethasone is the standard of care for critically ill patients with COVID-19, but the mechanisms by which it decreases mortality and its immunological effects in this...
Dexamethasone is the standard of care for critically ill patients with COVID-19, but the mechanisms by which it decreases mortality and its immunological effects in this setting are not understood. Here we perform bulk and single-cell RNA sequencing of samples from the lower respiratory tract and blood, and assess plasma cytokine profiling to study the effects of dexamethasone on both systemic and pulmonary immune cell compartments. In blood samples, dexamethasone is associated with decreased expression of genes associated with T cell activation, including TNFSFR4 and IL21R. We also identify decreased expression of several immune pathways, including major histocompatibility complex-II signaling, selectin P ligand signaling, and T cell recruitment by intercellular adhesion molecule and integrin activation, suggesting these are potential mechanisms of the therapeutic benefit of steroids in COVID-19. We identify additional compartment- and cell- specific differences in the effect of dexamethasone that are reproducible in publicly available datasets, including steroid-resistant interferon pathway expression in the respiratory tract, which may be additional therapeutic targets. In summary, we demonstrate compartment-specific effects of dexamethasone in critically ill COVID-19 patients, providing mechanistic insights with potential therapeutic relevance. Our results highlight the importance of studying compartmentalized inflammation in critically ill patients.
Topics: Dexamethasone; Humans; COVID-19 Drug Treatment; COVID-19; SARS-CoV-2; Lung; Cytokines; Critical Illness; Male; Single-Cell Analysis; Female; Middle Aged; T-Lymphocytes; Aged; Lymphocyte Activation
PubMed: 38942804
DOI: 10.1038/s41467-024-49756-2 -
British Journal of Hospital Medicine... Jun 2024A 37-year-old woman presented with nausea, vomiting and headache. She was found to be profoundly hyponatraemic with a sodium of 121 mmol/L, which deteriorated following...
A 37-year-old woman presented with nausea, vomiting and headache. She was found to be profoundly hyponatraemic with a sodium of 121 mmol/L, which deteriorated following a fluid challenge. An initial hyponatraemia screen identified adrenal insufficiency, with cortisol of 48 nmol/L. History confirmed she had been taking the herbal plant, ashwagandha. After 3 days of fluid restriction and steroid replacement, her sodium returned to normal (139 mmol/L). This article reviews the possible harmful effects of over-the-counter herbal remedies and highlights the importance of considering a wide differential diagnosis in patients presenting with non-specific symptoms.
Topics: Humans; Female; Adult; Adrenal Insufficiency; Hyponatremia; Phytotherapy; Plant Preparations; Diagnosis, Differential
PubMed: 38941978
DOI: 10.12968/hmed.2024.0038 -
Boletin Medico Del Hospital Infantil de... 2024Transverse myelitis (TM) is a demyelinating inflammatory disease that presents with motor, sensory, and autonomic dysfunction, which may be acute or subacute....
BACKGROUND
Transverse myelitis (TM) is a demyelinating inflammatory disease that presents with motor, sensory, and autonomic dysfunction, which may be acute or subacute. COVID-19-associated TM has been described in a scarce number of patients.
CLINICAL CASE
A 15-year-old previously healthy male patient with respiratory disease before his neurological deterioration presented to the emergency room after developing a complete medullary syndrome located at the cervical-dorsal level, with ascending and symmetric paraparesis that rapidly progressed to paraplegia, with sensory dysfunction from the T3 level, sphincter dysfunction and sudden ventilatory deterioration that required mechanical ventilation. Magnetic resonance imaging was compatible with acute TM. Inflammatory and non-inflammatory etiologies were discarded. In addition, a positive severe acute respiratory syndrome coronavirus 2 test was obtained. Treatment included steroid pulses and plasmapheresis, with an insidious evolution.
CONCLUSION
COVID-19 is an infrequent cause of TM and should be suspected when other etiologies have been ruled out.
Topics: Humans; Myelitis, Transverse; COVID-19; Male; Adolescent; Magnetic Resonance Imaging; Plasmapheresis; Respiration, Artificial; Paraplegia; Paraparesis
PubMed: 38941642
DOI: 10.24875/BMHIM.23000179 -
Sarcoidosis, Vasculitis, and Diffuse... Jun 2024Cardiac sarcoidosis is associated with significant morbidity and mortality. Immunosuppressive treatment focuses on suppressing myocardial inflammation, which can lead to...
Cardiac sarcoidosis is associated with significant morbidity and mortality. Immunosuppressive treatment focuses on suppressing myocardial inflammation, which can lead to major adverse events especially when progressing to fibrosis. Conventional management usually includes steroids and steroid sparing agents such as methotrexate and azathioprine. Tumour necrosis factor alpha inhibitors are often reserved for those with a worsening clinical status and/or evidence of persistent inflammatory activity despite conventional therapy. Refractory cardiac sarcoidosis (CS) can be defined as the persistence or progression of active disease, evidenced either by lack of clinical response or persistence or progression of imaging abnormalities, despite being on conventional therapy. In the United Kingdom, tumour necrosis factor alpha inhibitors are currently not licensed for cardiac sarcoidosis as there are no randomised controlled trials to assess the efficacy of infliximab in this patient cohort. In this study, we present the outcomes of six patients treated with infliximab for refractory cardiac sarcoidosis at Royal Brompton Hospital and performed a systematic review of the existing literature on use of infliximab in cardiac sarcoidosis. We searched the Cochrane Library, OVID Medline, OVID Embase, Web of Science and Pubmed to identify 7 full-text studies assessing the role of infliximab in the management of cardiac sarcoidosis. Infliximab was found to play a vital role in stabilising refractory cardiac sarcoidosis by stemming clinical deterioration, arrythmia burden and even reducing steroids requirements. Further prospective trial data is necessary to validate these findings.
PubMed: 38940716
DOI: 10.36141/svdld.v41i2.14484 -
Sarcoidosis, Vasculitis, and Diffuse... Jun 2024Sarcoidosis is a systemic disease of unknown etiology with diverse clinical manifestations. Disease may resolve spontaneously or require immunosuppression to control...
BACKGROUND AND AIM
Sarcoidosis is a systemic disease of unknown etiology with diverse clinical manifestations. Disease may resolve spontaneously or require immunosuppression to control progression. Currently, there is no predictive model to direct treatment, and management is guided by symptoms and functional impairment. This study examines the association between biopsy features and prognosis.
METHODS
This is a retrospective population-based cohort study. New cases of biopsy-proven sarcoidosis were divided into two groups: those with diffuse thoracic lymph nodes (TLN) involvement, versus partial TLN involvement (Defined as Non-necrotizing granuloma (NNG) found in some but not all sampled TLN). We compared outcomes one year after diagnosis. We assessed the need for immunosuppression, the number of hospitalizations, and lung function deterioration.
RESULTS
77 cases were included in the final analysis. 48.1% demonstrated extensive TLN involvement, and 51.9% demonstrated partial or non-involvement of sampled TLN. The partial positive group had a more aggressive disease, reflected by a significantly higher need for steroid therapy in the first year after diagnosis (45.0% vs. 18.9% p=0.015). The number of hospitalizations and lung functions were not significantly different between groups.
CONCLUSIONS
Our findings demonstrate a significantly increased need for steroidal therapy among sarcoidosis patients with a partial positivity of TLN. These findings suggest that the degree of TLN involvement can help predict worse outcome and guide therapeutic decisions.
PubMed: 38940712
DOI: 10.36141/svdld.v41i2.15336 -
Oncology Reports Aug 2024Intrahepatic cholangiocarcinoma (ICC) is a type of liver cancer associated with poor prognosis and increased mortality; the limited treatment strategy highlights the...
Intrahepatic cholangiocarcinoma (ICC) is a type of liver cancer associated with poor prognosis and increased mortality; the limited treatment strategy highlights the urgent need for investigation. Traditional Chinese Medicine (TCM), used alone or in combination with other treatments, can enhance therapeutic efficacy, improve life quality of patients and extend overall survival. In total, two rounds of screening of a TCM library of 2,538 active compounds were conducted using a Cell Counting Kit‑8 assay and ICC cell lines. Cell proliferation and migration abilities were assessed through colony formation, 5‑ethynyl‑2'‑deoxyuridine, would healing and Transwell assays. The impact of digitoxin (DT) on signaling pathways was initially investigated using RNA sequencing and further validated using reverse transcription‑quantitative PCR, western blotting, lectin blotting and flow cytometry. ICC cells stably overexpressing ST6 β‑galactoside α‑2,6‑sialyltransferase 1 (ST6GAL1) were generated through lentiviral transfection. It was shown that DT emerged as a highly effective anti‑ICC candidate from two rounds high‑throughput library screening. DT could inhibit the proliferation and migration of ICC cells by suppressing NF‑κB activation and reducing nuclear phosphorylated‑NF‑κB levels, along with diminishing ST6GAL1 mRNA and protein expression. The aforementioned biological effects and signal pathways of DT could be counteracted by overexpressing ST6GAL1 in ICC cells. In conclusion, DT suppressed ICC cell proliferation and migration by targeting the NF‑κB/ST6GAL1 signaling axis. The findings of the present study indicated the promising therapeutic effects of DT in managing ICC, offering new avenues for treatment strategies.
Topics: Humans; Signal Transduction; NF-kappa B; Cell Proliferation; Sialyltransferases; Digitoxin; Cholangiocarcinoma; Cell Movement; Cell Line, Tumor; Bile Duct Neoplasms; Antigens, CD; Gene Expression Regulation, Neoplastic; beta-D-Galactoside alpha 2-6-Sialyltransferase
PubMed: 38940341
DOI: 10.3892/or.2024.8762 -
Respirology (Carlton, Vic.) Jun 2024Asthma research and management needs to meet the priorities of the end user-patients, carers and clinicians. A better understanding of the natural history of asthma and... (Review)
Review
Asthma research and management needs to meet the priorities of the end user-patients, carers and clinicians. A better understanding of the natural history of asthma and the progression of disease has highlighted the importance of early identification of patients with asthma and the potential role of early intervention. Management of mild asthma requires a consistent approach with the same detail and consideration used when managing severe disease. Evidence around treatable traits approaches continues to evolve, supporting the role of a personalized medicine in asthma. Oral corticosteroid (OCS) stewardship continues to be an urgent issue in asthma management. Strategies to taper OCS doses and the implementation of biologic therapies for their steroid sparing benefits will be important steps to address this problem. The concept of remission in asthma provides an ambitious target and treatment outcome.
PubMed: 38940241
DOI: 10.1111/resp.14782 -
Case Reports in Neurological Medicine 2024The etiology of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) remains elusive and is believed to involve multiple contributing factors. There have...
The etiology of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) remains elusive and is believed to involve multiple contributing factors. There have been cases linking CIDP to the coronavirus disease 2019 (COVID-19) mRNA vaccine. However, there are no documented instances following alternative vaccines. We report a case of a 48-year-old woman, previously vaccinated with Pfizer-BioNTech's COVID-19 vaccine (BNT162b2), who subsequently received the Moderna mRNA-1273 vaccine. Within 2 days postvaccination, she developed diplopia and numbness in the lower limbs' distal extremities. Cerebrospinal fluid analysis exhibited protein-cell dissociation, while F-wave studies showed demyelinating activity in the bilateral tibial nerves. Given the disease's progressive nature, the patient was presumed to have CIDP and commenced steroid pulse therapy and intravenous immunoglobulin therapy. The onset of CIDP may be associated with variations in mRNA sequences and vaccine constituents.
PubMed: 38939233
DOI: 10.1155/2024/8584482 -
Case Reports in Dermatological Medicine 2024Granuloma annulare is a poorly understood dermatosis that, when generalized, can occur in up to 15 percent of patients. In these cases, treatment is frustrating and...
Granuloma annulare is a poorly understood dermatosis that, when generalized, can occur in up to 15 percent of patients. In these cases, treatment is frustrating and experimental. We report a case of a 60-year-old woman and a 41-year-old woman who demonstrated resolution of recalcitrant, generalized granuloma annulare (GA) following oral treatment with upadacitinib. After showing little to no response to other various treatments, such as steroids, antibiotic regimens, and systemic therapies, each patient was started on 15 mg of daily upadacitinib. At 2 months, one patient had complete clearance of all lesions while the other patient experienced noticeable improvement. Within 4 months, the other patient reached total resolution of her lesions. These cases provide evidence of a therapeutic option that may shorten disease duration and provide relief from cutaneous disease.
PubMed: 38939120
DOI: 10.1155/2024/8859178 -
Frontiers in Immunology 2024The primary treatment for acute relapses in multiple sclerosis (MS) is the intravenous administration of high-dose methylprednisolone (IVMP). However, the mechanisms...
BACKGROUND
The primary treatment for acute relapses in multiple sclerosis (MS) is the intravenous administration of high-dose methylprednisolone (IVMP). However, the mechanisms through which corticosteroid treatment impacts acute neuroinflammation in people with MS (pwMS) remain not fully understood. In particular, the changes induced by glucocorticoids (GCs) on cells of the innate immune system and the differences between patients with distinct immunotherapies have received little attention to date.
METHODS
We conducted immunophenotyping using flow cytometry on peripheral blood mononuclear cells of pwMS who received IVMP treatment during a relapse. We compared the impact of an IVMP treatment on a broad variety of immune cell subsets within three groups: twelve patients who were treatment-naïve to disease modifying therapies (wDMT) to ten patients on platform therapies (PT) and eighteen patients on fingolimod therapy (FTY).
RESULTS
We observed pronounced interindividual short- and intermediate-term effects of IVMP on distinct immune cells subsets. In addition to the well-documented decrease in T-helper cells (Th cells), we detected significant alterations after the first IVMP infusion within the innate immune response among neutrophil, eosinophil and basophil granulocytes, monocytes and plasmacytoid dendritic cells (pDCs). When comparing patients wDMT to the PT and FTY cohorts, we found that IVMP had a similar impact on innate immune cells across all treatment groups. However, we did not observe a significant further decline in T lymphocyte counts during IVMP in patients with pre-existing lymphopenia under FTY treatment. Although T cell apoptosis is considered the main mechanism of action of GCs, patients with FTY still reported symptom improvement following IVMP treatment.
CONCLUSION
In addition to T cell suppression, our data suggests that further immunoregulatory mechanisms of GC, particularly on cells of the innate immune response, are of greater significance than previously understood. Due to the regulation of the adaptive immune cells by DMTs, the impact of GC on these cells varies depending on the underlying DMT. Additional studies involving larger cohorts and cerebrospinal fluid samples are necessary to gain a deeper understanding of the immune response to GC in pwMS with different DMTs during relapse to define and explain differences in clinical response profiles.
Topics: Humans; Female; Male; Adult; Middle Aged; Multiple Sclerosis; Fingolimod Hydrochloride; Immunity, Innate; Methylprednisolone; Immunophenotyping; Leukocytes, Mononuclear; Adrenal Cortex Hormones; Immunosuppressive Agents; Glucocorticoids
PubMed: 38938576
DOI: 10.3389/fimmu.2024.1404316