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Formononetin Inhibits Ige by Huplasma/Pbmcs and Mast Cells/Basophil Activation via JAK/STAT/PI3-Akt Pathways
No full textRationale: Food allergy is a prevalent disease in the U.S., affecting nearly 30 million people. The primary management strategy for this condition is food avoidance, as limited treatment options are available. The elevation of pathologic IgE and over-reactive mast cells/basophils is a central factor in food allergy anaphylaxis. This study aims to comprehensively evaluate the potential therapeutic mechanisms of a small molecule compound called formononetin in regulating IgE and mast cell activation. Methods: In this study, we determined the inhibitory effect of formononetin on the production of human IgE from peripheral blood mononuclear cells of food-allergic patients using ELISA. We also measured formononetin’s effect on preventing mast cell degranulation in RBL-2H3 and KU812 cells using beta-hexosaminidase assay. To identify potential targets of formononetin in IgE-mediated diseases, mast cell disorders, and food allergies, we utilized computational modeling to analyze mechanistic targets of formononetin from various databases, including SEA, Swiss Target Prediction, PubChem, Gene Cards, and Mala Cards. We generated a KEGG pathway, Gene Ontology, and Compound Target Pathway Disease Network using these targets. Finally, we used qRT-PCR to measure the gene expression of selected targets in KU812 and U266 cell lines. Results: Formononetin significantly decreased IgE production in IgE-producing human myeloma cells and PBMCs from food-allergic patients in a dose-dependent manner without cytotoxicity. Formononetin decreased beta-hexosaminidase release in RBL-2H3 cells and KU812 cells. Formononetin regulates 25 targets in food allergy, 51 in IgE diseases, and 19 in mast cell diseases. KEGG pathway and gene ontology analysis of targets showed that formononetin regulated disease pathways, primary immunodeficiency, Epstein-Barr Virus, and pathways in cancer. The biological processes regulated by formononetin include B cell proliferation, differentiation, immune response, and activation processes. Compound target pathway disease network identified NFKB1, NFKBIA, STAT1, STAT3, CCND1, TP53, TYK2, and CASP8 as the top targets regulated at a high degree by formononetin. TP53, STAT3, PTPRC, IL2, and CD19 were identified as the proteins mostly targeted by formononetin. qPCR validated genes of Formononetin molecular targets of IgE regulation in U266 cells and KU812 cells. In U266 cells, formononetin was found to significantly increase the gene expression of NFKBIA, TP53, and BCL-2 while decreasing the gene expression of BTK TYK, CASP8, STAT3, CCND1, STAT1, NFKB1, IL7R. In basophils KU812 cells, formononetin significantly increased the gene expression of NFKBIA, TP53, and BCL-2 while decreasing the gene expression of BTK, TYK, CASP8, STAT3, CCND1, STAT1, NFKB1, IL7R. Conclusion: These findings comprehensively present formononetin’s mechanisms in regulating IgE production in plasma cells and degranulation in mast cells
Beta2-Adrenergic Suppression of Neuroinflammation in Treatment of Parkinsonism, With Relevance for Neurodegenerative and Neoplastic Disorders
No full textThere is a preliminary record suggesting that β2-adrenergic agonists may have therapeutic value in Parkinson’s disease; recent studies have proposed a possible role of these agents in suppressing the formation of α-synuclein protein, a component of Lewy bodies. The present study focuses on the importance of the prototypical β2-adrenergic agonist epinephrine in relation to the incidence of Parkinson’s disease in humans, and its further investigation via synthetic selective β2-receptor agonists, such as levalbuterol. Levalbuterol exerts significant anti-inflammatory activity, a property that may suppress cytokine-mediated degeneration of dopaminergic neurons and progression of Parkinsonism. In a completely novel finding, epinephrine and certain other adrenergic agents modeled in the Harvard/MIT Broad Institute genomic database, CLUE, demonstrated strong associations with the gene-expression signatures of anti-inflammatory glucocorticoids. This prompted in vivo confirmation in mice engrafted with human peripheral blood mononuclear cells (PBMCs). Upon toxic activation with mononuclear antibodies, levalbuterol inhibited (1) the release of the eosinophil attractant chemokine eotaxin-1, which is implicated in CNS and peripheral inflammatory disorders, (2) elaboration of the tumor-promoting angiogenic factor VEGFa, and (3) release of the pro-inflammatory cytokine IL-13 from activated PBMCs. These observations suggest possible translation to Parkinson’s disease, other neurodegenerative syndromes, and malignancies, via several mechanisms
Knee Dislocations and Associated Fractures: Risk Factors for Surgical Reduction
No full textIntroduction: Dissociation of the knee joint, or knee dislocations (KD), can lead to severe complications, often resulting in multiligament injuries. A subset of these injuries are irreducible by closed reduction and require open reduction. Identifying KDs that necessitate surgical intervention is crucial for optimal outcomes. While previous studies have explored various risk factors, the influence of associated fractures is less understood. Materials and Methods: We queried the Trauma Quality Improvement Program (TQIP) database from 2017 to 2021, for non-congenital closed knee dislocations requiring surgery. Demographic variables were collected, and ICD-10 codes were used to identify associated tibia, femur, acetabular, and fibula fractures. ICD-10 codes were also used to identify nerve injuries and vascular injuries. Multivariate logistic regression was used to assess factors influencing the need for surgical reduction (SR). Results: A total of 1,467 patients with KDs were included in the study, of which 411 (28.0%) underwent open surgical reduction (SR) while 1,056 (72.0%) were treated with nonsurgical closed reduction (nSR). Factors associated with SR included concomitant tibia fracture (OR = 1.683, C.I: 1.255-2.256, p \u3c 0.001) and fibula fracture (OR = 1.457, C.I: 1.056-2.011, p = 0.022). Vascular injury had lower odds of SR (OR = 0.455, C.I: 0.292-0.708, p \u3c 0.001). Conclusion: Our study demonstrated that KDs presenting with concomitant tibia and/or fibula fractures are more likely to require SR. The difficulty posed to closed reduction may be due to the influence of these fracture patterns on surrounding soft tissue as well as the lack of a stable bone structure necessary for achieving proper reduction. Physicians should be aware of the potential risk of this fracture pattern when caring for patients with KDs
Safety and Tolerability of Continuous Inhaled Iloprost Therapy for Severe Pulmonary Hypertension in Neonates and Infants
No full textThis is a single-center retrospective study to assess the safety and tolerability of continuous inhaled iloprost use as rescue therapy for refractory pulmonary hypertension (PH) in critically ill neonates and infants. A retrospective chart review was performed on 58 infants and data were collected at baseline, 1, 6, 12, 24, 48 and 72 h of iloprost initiation. Primary outcomes were change in heart rate (HR), fraction of inspired oxygen (FiO2), mean airway pressures (MAP), blood pressure (BP) and oxygenation index (OI). Secondary outcomes were need for extracorporeal membrane oxygenation (ECMO) and death. 51 patients treated for \u3e6 h were analyzed in 2 age groups, neonate (≤28 days: n = 32) and infant (29–365 days: n = 19). FiO2 (p \u3c 0.001) and OI (p = 0.01) decreased, while there were no significant changes in MAP, BP and HR. Of the fifteen patients placed on ECMO, seven were bridged off ECMO on iloprost and eight died. Twenty-four out of fifty-one patients (47%) recovered without requiring ECMO, while twelve (23%) died. Iloprost as add-on therapy for refractory PH in critically ill infants in the NICU has an acceptable tolerability and safety profile. Large prospective multicenter studies using iloprost in the neonatal ICU are necessary to validate these results
Barriers to USMLE Step-1 Accommodations: Students With Type 1 Diabetes
No full textPurpose Students who earn their medical doctorate (MD) in the U.S. must pass the United States Medical Licensing Exam (USMLE) Step-1. The application process for students with disabilities who seek Step-1 accommodations can be arduous, barrier-ridden, and can impose a significant burden that may have long-lasting effects. We sought to understand the experiences of medical students with Type-1 Diabetes (T1D) who applied for Step-1 accommodations. Methods A Qualtrics survey was administered to students enrolled in Liaison Committee on Medical Education (LCME)-accredited MD programs who disclosed having a primary diagnosis of T1D. Basic counts and qualitative inductive analyses were conducted. Results Of the 21 surveys sent, 16 (76.2%) participants responded. Of the 16 respondents, 11 (68.8%) applied for USMLE Step-1 accommodations, whereas 5 (31.2%) did not. Of the 11 who applied for accommodations, 7 (63.6%) received the accommodations requested, while 4 (36.4%) did not. Of those who received the accommodations requested, 5/7 (71.4%) experienced at least one diabetes-related barrier on exam day. Of those who did not apply for Step-1 accommodations, 4/5 (80%) participants reported experiencing at least one diabetes- related barrier on exam day. Overall, 11/16 (68.8%) students experienced barriers on exam day with or without accommodations. Qualitative analysis revealed themes among participants about their experience with the process: frustration, anger, stress, and some areas of general satisfaction. Conclusions This study reports the perceptions of students with T1D about barriers and inequities in the Step-1 accommodations application process. Students with and without accommodations encountered T1D-related obstacles on test day
Socioeconomic Disparities in Pediatric Traumatic Brain Injury Transfer Patterns: An Analysis of Area Deprivation Index and Clinical Outcomes
No full textBackground: Traumatic brain injury (TBI) poses a significant health burden, particularly among pediatric populations, leading to long-term cognitive, physical, and psychosocial impairments. Timely transfer to specialized trauma centers is crucial for optimal management, yet the influence of socioeconomic factors, such as the Area Deprivation Index (ADI), on transfer patterns remains understudied. Methods: A retrospective study was conducted on pediatric TBI patients presenting to a Level I Pediatric Trauma Center between January 2012 and July 2023. Transfer status, distance, mode of transport, and clinical outcomes were analyzed in relation to ADI. Statistical analyses were performed using Student t-test and analysis of variance. Results: Of 359 patients, 53.5% were transferred from outside hospitals, with higher ADI scores observed in transfer patients (P \u3c 0.01). Air transport was associated with greater distances traveled and higher ADI compared to ground ambulance (P \u3c 0.01). Despite similarities in injury severity, intensive care unit admission rates differed between transfer modes, with no significant impact on mortality. Conclusions: High ADI patients were more likely to be transferred, suggesting disparities in access to specialized care. Differences in transfer modes highlight the influence of socioeconomic factors on logistical aspects. While transfer did not independently impact outcomes, disparities in intensive care unit admission rates were observed, possibly influenced by injury severity. Integrating socioeconomic data into clinical decision-making processes can inform targeted interventions to optimize care delivery and improve outcomes for all pediatric TBI patients. Prospective, multicenter studies are warranted to further elucidate these relationships
Selected 2023 Highlights in Congenital Cardiac Anesthesia
No full textThis article reviews the highlights of pertinent literature of interest to the congenital cardiac anesthesiologist published in 2023. After a search of the US National Library of Medicine PubMed database, several topics emerged where significant contributions were made in 2023. The authors of this article considered the following topics noteworthy to be included in this review: (1) advancements in percutaneous mechanical support in children with congenital heart disease, (2) children with pulmonary hypertension undergoing surgery for congenital heart disease, (3) dexmedetomidine in pediatric cardiac surgery, and (4) recommendations for pediatric heart surgery in the United States: Implications for pediatric cardiac anesthesia
Form, Function, Mind: What Doesn\u27t Compute (And What Might)
No full textThe applicability of computational and dynamical systems models to organisms is scrutinized, using examples from developmental biology and cognition. Developmental morphogenesis is dependent on the inherent material properties of developing animal (metazoan) tissues, a non-computational modality, but cell differentiation, which utilizes chromatin-based revisable memory banks and program-like function-calling, via the developmental gene co-expression system unique to the metazoans, has a quasi-computational basis. Multi-attractor dynamical models are argued to be misapplied to global properties of development, and it is suggested that along with computationalism, classic forms of dynamicism are similarly unsuitable to accounting for cognitive phenomena. Proposals are made for treating brains and other nervous tissues as novel forms of excitable matter with inherent properties which enable the intensification of cell-based basal cognition capabilities present throughout the tree of life. Finally, some connections are drawn between the viewpoint described here and active inference models of cognition, such as the Free Energy Principle
