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Cell Reports Jun 2024Addressing the mononuclear phagocyte system (MPS) and macrophage M1/M2 activation is important in diagnosing hematological disorders and inflammatory pathologies and...
Addressing the mononuclear phagocyte system (MPS) and macrophage M1/M2 activation is important in diagnosing hematological disorders and inflammatory pathologies and designing therapeutic tools. CSF1R is a reliable marker to identify all circulating MPS cells and tissue macrophages in humans using a single surface protein. CSF1R permits the quantification and isolation of monocyte and dendritic cell (DC) subsets in conjunction with CD14, CD16, and CD1c and is stable across the lifespan and sexes in the absence of overt pathology. Beyond cell detection, measuring M1/M2 activation in humans poses challenges due to response heterogeneity, transient signaling, and multiple regulation steps for transcripts and proteins. MPS cells respond in a conserved manner to M1/M2 pathways such as interleukin-4 (IL-4), steroids, interferon-γ (IFNγ), and lipopolysaccharide (LPS), for which we propose an ad hoc modular gene expression tool. Signature analysis highlights macrophage activation mosaicism in experimental samples, an emerging concept that points to mixed macrophage activation states in pathology.
Topics: Humans; Macrophage Activation; Macrophages; Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; Interferon-gamma; Lipopolysaccharides; Female; Mosaicism; Male; Monocytes; Lipopolysaccharide Receptors; Interleukin-4; Dendritic Cells; Receptors, IgG; Antigens, CD1; Mononuclear Phagocyte System; Glycoproteins; Receptor, Macrophage Colony-Stimulating Factor
PubMed: 38870011
DOI: 10.1016/j.celrep.2024.114352 -
Pediatric Quality & Safety 2024Asthma exacerbations are common presentations to pediatric emergency departments. Standard treatment for moderate-to-severe exacerbations includes administration of oral...
INTRODUCTION
Asthma exacerbations are common presentations to pediatric emergency departments. Standard treatment for moderate-to-severe exacerbations includes administration of oral corticosteroids concurrently with bronchodilators. Early administration of corticosteroids has been shown to decrease emergency department length of stay (LOS) and hospitalizations. Our SMART aim was to reduce the time from arrival to oral corticosteroids (dexamethasone) administration in pediatric patients ≥2 years of age with an initial Pediatric Asthma Severity Score >6 from 60 to 30 minutes within 6 months.
METHODS
We used the model for improvement with collaboration between ED physicians, nursing, pharmacy, and respiratory therapists. Interventions included nursing education, dosage rounding in the electronic medical record, supplying triage with 1-mg tablets and a pill crusher, updates to an asthma nursing order set and pertinent chief complaints triggering nurses to document a Pediatric Asthma Severity Score in the electronic medical record and use the order set. Our primary outcome measure was the time from arrival to dexamethasone administration. Secondary outcome measures included ED LOS for discharged patients and admission rate. We used statistical process control to analyze changes in measures over time.
RESULTS
From October 2021 to March 2022, the average time for dexamethasone administration decreased from 59 to 38 minutes. ED LOS for discharged asthma exacerbation patients rose with overall ED LOS for all patients during the study period. There was no change in the admission rate.
CONCLUSIONS
Using quality improvement methodology, we successfully decreased the time from ED arrival to administration of dexamethasone in asthma exacerbation patients from 59 to 38 minutes over 10 months.
PubMed: 38868756
DOI: 10.1097/pq9.0000000000000738 -
Cureus May 2024The occurrence of hypoglycemia in patients without diabetes is rare, and non-islet cell tumor hypoglycemia (NICTH) accounts for a small portion of these instances. One...
The occurrence of hypoglycemia in patients without diabetes is rare, and non-islet cell tumor hypoglycemia (NICTH) accounts for a small portion of these instances. One of the infrequent causes is associated with tumor cell production of Insulin-like growth factor (IGF)-2. Here is a case of a 66-year-old man with stage IV colon cancer who presented to the emergency department with breathlessness during chemotherapy (Bevacizumab plus FOLFOX4 regimen). He had undergone partial colectomy and chemotherapy three years prior but was recently diagnosed with metastatic liver disease. A CT scan revealed a 15 cm hepatic mass occupying the entire right hepatic lobe. Despite receiving dextrose infusions, he experienced persistent hypoglycemia after meals and during fasting. Given that he had no history of diabetes and denied using any oral hypoglycemic agents, the Endocrinology service was consulted for further evaluation. Plasma blood glucose (BG) was measured at 74 mg/dL (reference range 74-106) during dextrose administration. An 8 AM cortisol test yielded a result of 8.08 mcg/dL (4.30-22.40), ruling out adrenal insufficiency. A 72-hour fast was initiated but terminated at eight hours due to symptomatic hypoglycemia with a plasma BG of 48 mg/dL. C-peptide and Insulin levels were both low, measuring <0.05 ng/mL (0.48-5.05) and <1.0 mU/L (3.0-25), respectively, while beta-hydroxybutyrate (BHB) levels were normal at 1.1 mg/dL (0.2-2.8). Administration of 1 mg glucagon during the fast increased BG to 112 mg/dL within 2 hours. IGF-1 levels were undetectable (<1.9 nmol/L), while IGF-2 levels were at 23 nmol/L (44-129 nmol/L), resulting in an IGF2:IGF1 ratio of 12 (>10), confirming IGF-2 mediated NICTH. Treatment with dexamethasone 10 mg daily was initiated, maintaining blood glucose levels above 70 mg/dL without dextrose infusion. In approximately 50% of cases of NICTH, the tumor is detected before the onset of hypoglycemia, yet up to half the patients may remain asymptomatic despite having very low BG. Despite having a known hepatic lesion, our patient exhibited minimal symptoms despite severely low BG levels. The mechanisms underlying NICTH may involve tumor secretion of insulin, replacement of hepatic tissue, increased glucose utilization by the tumor, or, most commonly, secretion of IGF-2. In cases of IGF-2-mediated hypoglycemia, insulin, proinsulin, C-peptide, and β-hydroxybutyrate levels are typically low. IGF-2 stimulates the insulin receptors resulting in increased glucose uptake by skeletal muscles and suppression of gluconeogenesis, glycogenolysis, and ketogenesis by the liver. Insulin secretion from pancreatic β-cells is suppressed. IGF-1 levels are usually low, while IGF-2 levels may be high or normal, as many IGF-2omas produce IGF-2 precursors (pro-IGF-2). An elevated IGF-2:IGF-1 ratio (>10) confirms the diagnosis which may be helpful when IGF-2 levels are normal. The primary treatment is through surgical removal or debulking of the tumor. Neoadjuvant therapies such as radiation and chemotherapy may reduce occurrences of hypoglycemia, but only temporarily. Glucocorticoids may be used when the underlying malignancy cannot be treated.
PubMed: 38868260
DOI: 10.7759/cureus.60211 -
Cell Reports Jun 2024The human genome has many short tandem repeats, yet the normal functions of these repeats are unclear. The 5' untranslated region (UTR) of the fragile X messenger...
The human genome has many short tandem repeats, yet the normal functions of these repeats are unclear. The 5' untranslated region (UTR) of the fragile X messenger ribonucleoprotein 1 (FMR1) gene contains polymorphic CGG repeats, the length of which has differing effects on FMR1 expression and human health, including the neurodevelopmental disorder fragile X syndrome. We deleted the CGG repeats in the FMR1 gene (0CGG) in human stem cells and examined the effects on differentiated neurons. 0CGG neurons have altered subcellular localization of FMR1 mRNA and protein, and differential expression of cellular stress proteins compared with neurons with normal repeats (31CGG). In addition, 0CGG neurons have altered responses to glucocorticoid receptor (GR) activation, including FMR1 mRNA localization, GR chaperone HSP90α expression, GR localization, and cellular stress protein levels. Therefore, the CGG repeats in the FMR1 gene are important for the homeostatic responses of neurons to stress signals.
Topics: Humans; Fragile X Mental Retardation Protein; Neurons; RNA, Messenger; Receptors, Glucocorticoid; Stress, Physiological; 5' Untranslated Regions; HSP90 Heat-Shock Proteins; Trinucleotide Repeats; Trinucleotide Repeat Expansion
PubMed: 38865241
DOI: 10.1016/j.celrep.2024.114330 -
Bioscience Reports Jun 2024Tamoxifen (TAM) is a key player in estrogen receptor-positive (ER+) breast cancer (BC), however, ~30% of patients experience relapse and a lower survival rate due to TAM...
Tamoxifen (TAM) is a key player in estrogen receptor-positive (ER+) breast cancer (BC), however, ~30% of patients experience relapse and a lower survival rate due to TAM resistance. TAM resistance was related to the over expression of SOX-2 gene, which is regulated by the E2F3 transcription factor in the Wnt signaling pathway. It was suggested that SOX-2 overexpression was suppressed by dexamethasone (DEX), a glucocorticoid commonly prescribed to BC patients. The aim of the present study is to explore the effect of combining DEX and TAM on the inhibition of TAM-resistant LCC-2 cells (TAMR-1) through modulating the E2F3/SOX-2-mediated Wnt signaling pathway. The effect of the combination therapy on MCF-7 and TAMR-1 cell viability was assessed. Drug interactions were analyzed using CompuSyn and SynergyFinder softwares. Cell cycle distribution, apoptotic protein expression, gene expression levels of SOX-2 and E2F3, and cell migration were also assessed. Combining DEX with TAM led to synergistic inhibition of TAMR-1 cell proliferation and migration, induced apoptosis, reduced SOX-2 and E2F3 expression and was also associated with S and G2-M phase arrest. Therefore, combining DEX with TAM may present an effective therapeutic option to overcome TAM resistance, by targeting the E2F3/SOX-2/Wnt signaling pathway, in addition to its anti-inflammatory effect.
PubMed: 38864530
DOI: 10.1042/BSR20240367 -
Cureus May 2024Foreign body aspiration (FBA) is a significant cause of accidental death among children, with laryngeal FBA being relatively rare but potentially fatal due to airway...
Foreign body aspiration (FBA) is a significant cause of accidental death among children, with laryngeal FBA being relatively rare but potentially fatal due to airway obstruction. This report highlights a case of laryngeal FBA in an 11-month-old child, initially misdiagnosed as viral croup. Otolaryngological evaluation, particularly in the case of laryngeal FBA, may facilitate management. An 11-month-old male was brought to the emergency department, presenting with inspiratory stridor following a choking episode. A chest radiograph and CT scan of the chest were read as normal. He was suspected of having croup and treated with dexamethasone and racemic nebulized epinephrine, which led to temporary clinical improvement. The child returned with persistent stridor to the emergency department eight days after his initial visit, prompting an otolaryngological consultation. Flexible laryngoscopy ultimately identified a star-shaped sequin lodged in the glottis. The foreign body was successfully removed via direct laryngoscopy and bronchoscopy (DLB). Following the removal, the patient demonstrated significant improvement and eventually made a full recovery. This case emphasizes the difficulty in diagnosing laryngeal FBA due to its non-specific symptoms and the limitations of imaging techniques. The importance of a thorough clinical history, physical examination, and proper imaging combined with a high index of suspicion is crucial for early diagnosis and treatment. Additionally, the report discusses the potential for severe complications if diagnosis and treatment are delayed, highlighting the need for awareness and prompt intervention in suspected laryngeal FBA cases.
PubMed: 38864055
DOI: 10.7759/cureus.60144 -
Drug Design, Development and Therapy 2024Despite its extensive utilization in Chinese hospitals for treating acute pancreatitis (AP) and related acute respiratory distress syndrome (ARDS), the active components...
Mechanism Investigation and Clinical Retrospective Evaluation of Qingyi Granules: Pancreas Cleaner About Ameliorating Severe Acute Pancreatitis with Acute Respiratory Distress Syndrome.
BACKGROUND
Despite its extensive utilization in Chinese hospitals for treating acute pancreatitis (AP) and related acute respiratory distress syndrome (ARDS), the active components and mechanisms underlying the action of Qingyi Granule (QYKL) remain elusive.
METHODS
This study consists of four parts. First, we used Mendelian randomization (MR) to investigate the causal relationship between AP, cytokine, and ARDS. Next, 321 patients were collected to evaluate the efficacy of QYKL combined with dexamethasone (DEX) in treating AP. In addition, we used UHPLC-QE-MS to determine the chemical constituents of QYKL extract and rat serum after the oral administration of QYKL. The weighted gene coexpression network analysis (WGCNA) method was used to find the main targets of AP-related ARDS using the GSE151572 dataset. At last, a AP model was established by retrograde injection of 5% sodium taurocholate.
RESULTS
MR showed that AP may have a causal relationship with ARDS by mediating cytokine storms. Retrospective study results showed early administration of QYKL was associated with a lower incidence of ARDS, mortality, admissions to the intensive care unit, and length of stay in AP patients compared to the Control group. Furthermore, we identified 23 QYKL prototype components absorbed into rat serum. WGCNA and differential expression analysis identified 1558 APALI-related genes. The prototype components exhibited strong binding activity with critical targets. QYKL has a significant protective effect on pancreatic and lung injury in AP rats, and the effect is more effective after combined treatment with DEX, which may be related to the regulation of the IL-6/STAT3 signaling pathway.
CONCLUSION
By integrating MR, retrospective analysis, and systematic pharmacological methodologies, this study systematically elucidated the therapeutic efficacy of QYKL in treating AP-related ARDS, establishing a solid foundation for its medicinal use.
Topics: Drugs, Chinese Herbal; Respiratory Distress Syndrome; Pancreatitis; Animals; Rats; Humans; Retrospective Studies; Male; Rats, Sprague-Dawley; Dexamethasone; Acute Disease; Female; Middle Aged
PubMed: 38863767
DOI: 10.2147/DDDT.S454180 -
Paediatric & Neonatal Pain Jun 2024Postoperative care pathways for adolescent idiopathic scoliosis patients undergoing posterior spinal fusion have demonstrated decreases in postoperative opioid...
Postoperative care pathways for adolescent idiopathic scoliosis patients undergoing posterior spinal fusion have demonstrated decreases in postoperative opioid consumption, improved pain control, and lead to decreased lengths of stay. Our objective was to implement postoperative steroids to reduce acute postoperative opioid consumption, pain scores, and length of stay. Dosing consisted of intravenous dexamethasone 0.1 mg/kg up to 4 mg per dose for a total of three doses at 8, 16, and 24 h postoperatively. As part of a quality initiative, we compared three cohorts of patients. The initial retrospective epidural cohort (EPI) ( = 59) had surgeon placed epidural catheters with infusion of ropivacaine 0.1% postoperatively for 18-24 h. Following an institutional change in postoperative care, epidural use was discontinued. A second cohort ( = 149), with prospectively collected data, received a surgeon placed erector spinae plane block and wound infiltration with a combination of liposomal and plain bupivacaine (LB). A third cohort ( = 168) was evaluated prospectively. This cohort received a surgeon placed erector spinae plane block and wound infiltration with liposomal and plain bupivacaine and additionally received postoperative dexamethasone for three doses (LB + D). Compared to the LB cohort, the LB + D cohort demonstrated statistically significant decreases in oral milligram morphine equivalents per kilogram at 0-24, 24-48, and 48-72 h. There was a statistically significant difference in median pain scores at 24-48 and 48-72 h in LB + D versus LB. The LB + D cohort's median length of stay in hours was significantly less compared to the LB cohort (52 h vs. 70 h, < 0.0001). Postoperative intravenous dexamethasone was added to an established postoperative care pathway for patients undergoing posterior spinal fusion for idiopathic scoliosis resulting in decreased VAS pain scores, opioid consumption, and shorter length of stay.
PubMed: 38863457
DOI: 10.1002/pne2.12117 -
Molecular Plant-microbe Interactions :... Jun 2024Cyst nematodes co-opt plant developmental programs for the establishment of a permanent feeding site called a syncytium in plant roots. In recent years, the role of...
Cyst nematodes co-opt plant developmental programs for the establishment of a permanent feeding site called a syncytium in plant roots. In recent years, the role of plant developmental genes in syncytium formation has gained much attention. One main obstacle in studying the function of development-related genes in syncytium formation is that mutation or ectopic expression of such genes can cause pleiotropic phenotypes making it difficult to interpret nematode-related phenotypes, or in some cases, impossible to carry out infection assays due to aberrant root development. Here, we tested three commonly used inducible gene expression systems for their application in beet cyst nematode infection assays of the model plant Arabidopsis thaliana. We found that even a low amount of ethanol diminished nematode development, deeming the ethanol-based system unsuitable for use in cyst nematode infection assays; whereas treatment with estradiol or dexamethasone did not negatively affect cyst nematode viability. Dose and time course responses showed that in both systems, a relatively low dose of inducer (1 μM) is sufficient to induce high transgene expression within 24 hours of treatment. Transgene expression peaked at 3-5 days post induction and began to decline thereafter, providing a perfect window for inducible transgenes to interfere with syncytium establishment while minimizing any adverse effects on root development. These results indicate that both estradiol- and dexamethasone-based inducible gene expression systems are suitable for cyst nematode infection assays. The employment of such systems provides a powerful tool to investigate the function of development essential plant genes in syncytium formation.
PubMed: 38862124
DOI: 10.1094/MPMI-04-24-0042-TA -
Turkish Journal of Ophthalmology Jun 2024A 78-year-old man with a history of lung cancer, chemotherapy, radiotherapy, and coronavirus disease 2019 infection experienced visual deterioration of two-weeks’...
A 78-year-old man with a history of lung cancer, chemotherapy, radiotherapy, and coronavirus disease 2019 infection experienced visual deterioration of two-weeks’ duration in his right eye. There was multifocal, yellowish-white retinitis foci, vascular engorgement, and scattered intraretinal hemorrhages extending from posterior pole to retinal periphery in the right eye, whereas the left eye was normal. Intravitreal vancomycin, ceftazidime, clindamycin, and dexamethasone were given for endogenous endophthalmitis initially. Vitreous culture confirmed the presence of Aspergillus lentulus, and he was treated with intravitreal amphotericin-B and voriconazole injections together with systemic amphotericin-B, voriconazole, posaconazole, and micafungin therapy. During follow-up, vitreoretinal surgery was performed because of rhegmatogenous retinal detachment, and he received one additional cycle of chemotherapy due to recurrence of the cancer. Although the retina was attached, enucleation was eventually required due to painful red eye. Atypical squamous cells beneath the neurosensory retina suggesting metastasis were noted on histopathological examination. Timely ocular examination is crucial for any immunocompromised patient having ocular symptoms. High level of suspicion for a fungal etiology is a must in these patients.
Topics: Humans; Endophthalmitis; Male; Aged; Eye Infections, Fungal; Immunocompromised Host; Lung Neoplasms; Aspergillosis; Aspergillus; Antifungal Agents; COVID-19; Vitreous Body; Intravitreal Injections; SARS-CoV-2
PubMed: 38860516
DOI: 10.4274/tjo.galenos.2024.44045