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A non-toxic analgesic elicits cell-specific genomic and epigenomic modulation by targeting the PAG brain region
Get PDFAcetaminophen (ApAP) is widely used for pain management, but overuse or overdose leads to hepatotoxicity, making it the leading cause of acute liver failure globally. There is an urgent need for safer pain medications, as other non-opioid analgesics like non-steroidal anti-inflammatory drugs (NSAIDs) are nephrotoxic. We have identified SRP-001 as a safer, non-hepatotoxic, novel analgesic that overcomes ApAP\u27s limitations by avoiding NAPQI formation and preserving hepatic tight junctions. Using coupled RNA and ATAC sequencing, from the periaqueductal gray (PAG) midbrain region, we compared the genetic and epigenetic signatures of SRP-001 and ApAP treatments following complete Freund\u27s adjuvant (CFA)-induced inflammatory pain against no treatment and vehicle controls. Our analysis revealed differential activity in three transcription factor families (SOX, SP/KLF, and AP-1) with cell-specific patterns and altered neuron-neuron interactions through neurexin-neuregulin signaling. SRP-001 and ApAP demonstrated similar genetic and epigenetic outcomes, indicating that SRP-001 is a favorable alternative due to its non-hepatotoxic properties while maintaining the same antinociceptive effects as ApAP
Alternate functions of physiological anticoagulants
No full textThe anticoagulant proteins antithrombin, protein C, protein S, and tissue factor pathway inhibitor are physiological regulators of the blood coagulation pathway and have complex roles in causing or modifying the severity of bleeding and clotting disorders. The anticoagulant activity, as well as alternative physiological functions, of these proteins also impact many other diseases beyond bleeding and clotting disorders. We searched PubMed for articles published between 2018 and early 2025 that pertained to alternative functions of these physiological anticoagulants in clinical disease and selected therapeutic applications in the following categories: cancer, cardiovascular disease, novel therapeutics, pregnancy health, inflammation and infection, blood-brain barrier protection, stroke, novel developments in thrombosis, and endothelial and platelet interactions. This review highlights recently identified physiological implications of antithrombin, protein C, protein S, and tissue factor pathway inhibitor functions that present an exciting therapeutic avenue for a diverse array of human diseases
Avoiding Electrocautery: Hemostatic Agents for Perioperative Bleeding in Mohs Micrographic Surgery
No full textBACKGROUND Bleeding remains a frequent complication during Mohs micrographic surgery, particularly among patients receiving anticoagulant or antiplatelet therapy. The growing use of these medications has prompted increased exploration of adjunctive methods to improve perioperative hemostasis. OBJECTIVE To systematically review the literature on topically and locally administered hemostatic agents used to reduce bleeding in Mohs micrographic surgery. METHODS A systematic search of PubMed, Scopus, Cochrane, and EMBASE was conducted through March 2024. Original studies evaluating hemostatic agents applied topically or by local injection during Mohs micrographic surgery were included. RESULTS Seven studies met inclusion criteria, encompassing 458 patients. Agents evaluated included tranexamic acid, brimonidine gel, hemostatic powders, and microporous polysaccharide materials. These agents were generally well tolerated and associated with reductions in intraoperative and postoperative bleeding. CONCLUSION Locally administered hemostatic agents offer a promising adjunct to improve bleeding control in Mohs micrographic surgery. Their use may be particularly beneficial in patients at elevated bleeding risk and warrants further investigation in larger, controlled studies
Area deprivation and pediatric cancer mortality: An analysis of 2000-2020 state cancer registry data
No full textBACKGROUND: Compared to adult cancers, less research has been conducted on health disparities in pediatric cancer outcomes. The effect of neighborhood deprivation, as measured by the Area Deprivation Index (ADI), on pediatric cancer survival is not well understood, especially among diverse populations. METHODS: We conducted a population-based longitudinal study using data from the Iowa Cancer Registry and Louisiana Tumor Registry. The study included children diagnosed with cancer in the two states ages 0-19 years from 2000 to 2020. The primary exposure was ADI, and the primary outcome was cancer-specific mortality. Cox regression models with shared frailty to account for the geographic clustering of individuals were used to compute the association between ADI and mortality. RESULTS: A total of 6,982 children were included between the two states: 2,939 in Iowa and 4,043 in Louisiana. In the adjusted analysis, higher deprivation was positively associated with poorer pediatric cancer survival. Compared to children in the least deprived neighborhoods, those in the most deprived neighborhoods had a 50% higher risk of cancer death (95% CI: 1.18-1.89) and a 3.15 times greater risk of early cancer death (95% CI: 1.39-7.16). Among children with extracranial solid tumors, those in the most deprived neighborhoods had a 54% higher risk of cancer death (95% CI: 1.04-2.27) compared to those in the least deprived neighborhoods. CONCLUSIONS: Higher ADI is associated with higher pediatric cancer mortality, highlighting the importance of social drivers of health on pediatric cancer outcomes. IMPACT: Neighborhood-level interventions will likely be needed to improve pediatric cancer outcomes
Complete genome sequence of Rothia mucilaginosa D1, a genetically amenable strain
No full textHere, we report the complete genome sequence of Rothia mucilaginosa D1. Unlike many other strains that have been sequenced, R. mucilaginosa D1, a clinical isolate, is genetically amenable. The complete sequencing of the genome provides potential for further studies on the genetics and pathophysiology of this emerging pathobiont
Effects of LSVT BIG on Bradykinesia During Activities of Daily Living
No full textBradykinesia in Parkinson\u27s disease (PD) can limit activities of daily living (ADL) through disruption of roles and routines. Lee Silverman Voice Treatment (LSVT BIG) is a commonly used program for persons with PD but it is not known if LSVT BIG can impact bradykinesia. This preliminary study sought to determine if LSVT BIG participation would impact bradykinesia during ADL. Sixty patient charts were reviewed following participation in the LSVT BIG program. Time to perform three functional tasks was recorded before and after participation. A significant decrease in time, on average, of 14.5 s to don/doff a jacket (p = .009), 18.3 s to don/doff socks (p = .01), and 21.4 s to insert a pillow into a pillowcase (p \u3c .01) was observed. Speed of performance during three ADL tasks improved significantly following LSVT BIG participation; therefore, this program may positively impact bradykinesia and task performance in Parkinson\u27s
Dysregulated Protein s-Nitrosylation Promotes Nitrosative Stress and Disease Progression in Heart Failure With Preserved Ejection Fraction
No full textBACKGROUND: Recent studies suggest aberrant elevation of iNOS (inducible NO synthase) expression and excessive protein s-nitrosylation promote the pathogenesis of heart failure with preserved ejection fraction (HFpEF). However, the interplay between NO bioavailability, enzymatic regulation of protein s-nitrosylation by transnitrosylase and denitrosylase, and HFpEF progression remains poorly defined. We investigated the molecular basis of nitrosative stress in HFpEF, focusing on alterations in NO signaling and regulation of protein s-nitrosylation. METHODS: Circulating nitrite (NO bioavailability) and nitrosothiols were quantified in patients with HFpEF. Parallel studies using rodent models of cardiometabolic HFpEF were performed to evaluate cardiac function, NO signaling, and total nitroso species during disease progression. Single-nucleus RNA sequencing and proteomic analysis were conducted to identify regulatory genes and cellular targets of pathological s-nitrosylation. RESULTS: In patients with HFpEF, circulating nitrosothiols were significantly elevated, indicating heightened nitrosative stress, whereas nitrite levels remained unchanged. In ZSF1 Obese (ob) rats, NO bioavailability declined with age, whereas total nitroso species progressively increased as HFpEF worsened. Transcriptomic analysis revealed marked upregulation of a transnitrosylase HBb (hemoglobin-β subunit), validated in both rat and human HFpEF hearts. Enzymatic assays demonstrated aberrant functions of Trx2 (thioredoxin 2) and GSNOR (S-nitrosoglutathione reductase) in ZSF1 Ob hearts. Cell-based experiments confirmed that altered expression or function of HBb, Trx2, and GSNOR resulted in elevated cellular RxNO. Additionally, similar dysregulation of s-nitrosylation dynamics was observed in the peripheral organs, such as the kidneys and liver, in HFpEF. CONCLUSIONS: These data demonstrate that nitrosative stress, evidenced by dysregulated protein s-nitrosylation occurs in the heart and peripheral organs in cardiometabolic HFpEF. Pathological alterations in NO bioavailability resulting from alterations in NOS expression or function alone do not account for this phenotype. Instead, pathological protein s-nitrosylation results in part from the imbalance between transnitrosylase and denitrosylase function. Restoration of physiological levels of protein s-nitrosylation and NO signaling may represent an effective therapeutic target for HFpEF
OphthoSearch: An AI-Driven Searchbot Tool for Quick, Automated Patient Data Retrieval and Multi-Patient Analysis
No full textAssociation for Research in Vision and Ophthalmology Annual Meeting, ARVO 2025, May 4-8, 2025, Salt Lake City, U
Targeting Neutrophil Integrin a9 Enhances Microglial Efferocytosis and Improves Sensorimotor and Cognitive Recovery Following Subarachnoid Hemorrhage in Mice
No full textAmerican Stroke Association\u27s 2025 International Stroke Conference and State-of-the-Science Stroke Nursing Symposium 2025, February 5 - 7, 2025, Los Angeles, C