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Abstract Efflux-mediated β-lactam resistance is a major public health concern, reducing the effectiveness of β-lactam antibiotics against many bacteria. Structural analyses show the efflux protein TolC in Gram-negative bacteria acts as a channel for antibiotics, impacting bacterial susceptibility and virulence. This study examines β-lactam drug efflux mediated by TolC using experimental and computational methods. Molecular dynamics simulations of drug-free TolC reveal essential movements and key residues involved in TolC opening. A whole-gene-saturation mutagenesis assay, mutating each TolC residue and measuring fitness effects under β-lactam selection, is performed. Here we show the TolC-mediated efflux of three antibiotics: oxacillin, piperacillin, and carbenicillin. Steered molecular dynamics simulations identify general and drug-specific efflux mechanisms, revealing key positions at TolC’s periplasmic entry affecting efflux motions. Our findings provide insights into TolC’s structural dynamics, aiding the design of new antibiotics to overcome bacterial efflux mechanisms.

Atrial Fibrillation (AF) induces proinflammatory processes which incite vascular endothelial activation and dysfunction. This study seeks to examine the potential relationship between various endothelial, inflammatory, thrombotic, and renin-angiotensin-system (RAS) biomarkers in AF patients. Blood samples were from AF patients (n = 110) prospectively enrolled in this study prior to their first AF ablation. Control plasma samples (n = 100) were used as reference. All samples were analyzed for endothelial (NO, ICAM-1, VEGF, TF, TFPI, TM, Annexin V), inflammatory (IL-6, TNFα, CRP), thrombotic (vWF, tPA, PAI-1, TAFI, D-dimer), and RAS (Renin, Ang-II) biomarkers using ELISA methods. Biomarker average comparisons and Spearman correlations were performed. AF patients showed varying levels of biomarker increase compared to controls. We observed a significant decrease of Ang-II in the AF population relative to controls when stratified for the use of angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB) upon study enrollment. AF patients showed statistically significant correlations between the following biomarkers: TNFα vs IL-6 (r s = 0.317, p = .004), ICAM-1 vs TNFα (r s = 0.527, p = .012), Annexin V vs VEGF (r s = 0.620, p

Malignant melanoma (MM) is an aggressive tumor that can metastasize to any organ, but biliary tract metastasis is scarce. We describe a very rare case of MM metastasis to the common bile duct (CBD), presented with only dyspeptic symptoms. The patient had mildly elevated alkaline phosphatase and gamma-glutamyl transferase levels. Magnetic resonance cholangiopancreatography demonstrated a dilated common bile duct with a distal stricture. The MM diagnosis was established with the ampulla of Vater biopsy specimens obtained by endoscopic retrograde cholangiopancreatography (ERCP), and the patient’s symptoms were resolved after biliary stenting. Both primary CBD cancer and other cancer types like MM that metastasize to CBD can cause obstruction and can be manifested only by dyspeptic symptoms. MM metastasis to CBD can cause obstruction manifested only by dyspeptic symptoms without obstructive jaundice. ERCP can be employed as a promising option for treatment and diagnosis. New-onset dyspeptic symptoms in patients with a history of MM should be investigated thoroughly, especially in the context of biliary metastasis.

In patients with end-stage renal disease (ESRD), heart failure with reduced ejection fraction (HFrEF) is a common comorbidity. Thromboinflammatory processes in both conditions represent complex pathophysiology, demonstrated by dysregulation of thromboinflammatory biomarkers, and commonly resulting in the combined pathology of cardiorenal syndrome. We sought to investigate the effects of HFrEF on these biomarkers in patients with ESRD, and observe the relationship to mortality. Blood samples from 73 patients with ESRD (mean age 67 ± 13 years, 56% male) and 40 healthy controls were analyzed via enzyme-linked immunosorbent assay and other chromogenic methods for angiopoietin-2 (Ang2), endogenous glycosaminoglycans, fatty acid binding protein, interleukin-6, lipopolysaccharide, free fatty acids, NT-pro B-type natriuretic peptide, tumor necrosis factor α, vascular endothelial growth factor, and von Willebrand factor. Patients were stratified into those with or without HFrEF (EF

Pulmonary embolism (PE) is a heterogenous condition with variable clinical presentations. Thrombin generation potential (TGP) and biomarkers, and blood cellular indices can reflect the underlying pathophysiology and risk stratification of PE. This case–control study analyzed TGP in 209 PE patients from Loyola University, Pulmonary Embolism Response Team program compared to normal human plasma (NHP) controls. The present study evaluates TGP and biomarkers, and cellular indices in relation to PE severity, according to the European Society of Cardiology (ESC) guidelines. Statistical analysis including median with interquartile range (IQR), 2-tailed Wilcoxon Mann–Whitney test, Chi-square test, and Spearman Correlational analysis were performed. There were 209 patients with PE, with an almost equal distribution between sex, and a median age of 63 years. Significant downregulation in peak thrombin and endogenous thrombin potential (ETP), as well as upregulation in lag time, were observed in PE patients versus controls. Biomarker analysis revealed pronounced elevations, with D-dimer demonstrating the most significant increase. Blood cellular indices also rose in PE patients, correlating with disease severity. PE severity was associated with higher TGP and biomarker levels. Mortality rates differed significantly across risk categories and were highest in patients with elevated cellular indices. TGP and biomarkers are intricately linked to PE severity and can aid in risk stratification. Elevated cellular indices are associated with increased mortality, highlighting their potential as prognostic markers. These findings could enhance the precision of PE management strategies.

Several risk stratification systems aid clinicians in classifying pulmonary embolism (PE) severity and prognosis. We compared 2 clinical PE scoring systems, the PESI and sPESI scores, with 2 comorbidity indices, the Charlson Comorbidity Index (CCI) and the val Walraven Elixhauser Comorbidity Index (ECI), to determine the utility of each in predicting mortality and hospital readmission. Information was collected from 436 patients presenting with PE via retrospective chart review. The PESI, sPESI, CCI, and ECI scores were calculated for each patient. Multivariate analysis was used to determine each system's ability to predict in-hospital mortality, 90-day mortality, overall mortality, and all-cause hospital readmission. The impact of various demographic and clinical characteristics of each patient on these outcomes was also assessed. The PESI score was found to be an independent predictor of in-hospital mortality and 90-day mortality. The PESI score and the CCI were able to independently predict overall mortality. None of the 4 risk scores independently predicted hospital readmission. Other factors including hypoalbuminemia, serum BNP, coagulopathy, anemia, and diabetes were associated with increased mortality and readmission at various endpoints. The PESI score was the best tool for predicting mortality at any endpoint. The CCI may have utility in predicting long-term outcomes. Further work is needed to better determine the roles of the CCI and ECI in predicting patient outcomes in PE. The potential prognostic implications of low serum albumin and anemia at the time of PE also warrant further investigation.

Objective: Wormwood (Artemisia absinthium L.) is a valuable medicinal plant that has been used for the wound healing since ancient times. Hydrogel dressings are often preferred for wound care in treatment. In this study, the effects of chit osanbased hydrogel dressings containing wormwood were investigated in rats with a burn wound model for the first time. Material-Method: Certain phenolic compounds in wormwood extracts were detected by LC-MS/MS and antioxidant activities were calculated using the DPPH. The antibacterial activity of the dressings was tested using the disk diffusion method. Tissues taken from 48 female Sprague-Dawley rats were histopathologically examined at days 3rd and 21st. Skin tissue Il-1α, Il-6, TNF-α and Il-10 levels were measured using ELISA. All data obtained from histopathological examination and cytokine levels were statistically evaluated. Results: Fifteen phenolic compounds were quantitatively determined in wormwood extracts. The antioxidant activities of high-, medium-, and low-dose wormwood extracts were 91.1% ± 0.054, 89.6% ± 0.012 and 84.1% ± 0.02, respectively. The hydrogel dressings showed no antibacterial activity against S. aureus (ATCC 29213) or P. aeruginosa (ATCC 27853). Granulation tissue formation, collagen increase, and regular scar appearance were higher in all three wormwood groups. Wound contraction was completed and remodeling phase started at day 21st, especially in the high-dose wormwood treatment group. Tissue cytokine levels were determined in pg/ml in all groups. Conclusion: It was determined that A. absinthium L. can promote wound healing through various mechanisms of action and shows immunomodulatory effects, and is appropriate for use as a wound dressing in the form of a chitosan -based hydrogel. [ABSTRACT FROM AUTHOR]

Aim: The aim of this study was to investigate the effects of chitosan-based hydrogel wound dressings containing different doses of wormwood (A. absinthium L.) extract on rat burn model. Material and Methods: Certain phenolic compounds in ethanolic wormwood extract were quantitatively determined by LC-MS/MS. Antioxidant activities of low (2%), medium (5%) and high (10%) dose wormwood extracts were measured by DPPH. The antimicrobial activity of the dressings was tested on Staphylococcus aureus (ATCC 29213) and Pseudomonas aureginosa (ATCC 27853) strains by disk diffusion. Tissues procured from 48 Sprague-Dawley female rats on the 3rd and 21st days of the experimental burn model were histopathologically examined in eleven categories. In addition, IL-1a, IL-6, IL-10 and TNF-a levels in the tissues were determined by ELISA. The data obtained from histopathologic examination and tissue cytokine levels were statistically evaluated. Results: Fifteen phenolic compounds in the wormwood extract were determined at the µg/L level. The antioxidant activities of high, medium and low dose wormwood extracts were 91.1 ± 0.054%, 89.6 ± 0.012% and 84.1 ± 0.02%, respectively. Hydrogel wound dressings did not show antimicrobial activity on the indicated bacterial strains. Fibrosis results obtained on the 21st day of the experiment were statistically significant. Although not statistically significant, granulation tissue formation, collagen increase and regular scar appearance were higher in the wormwood treatment groups compared to the other experimental groups. Wound contraction was completed in all three wormwood groups. The remodeling phase, which is the last step of healing, started on day 21 in the high dose wormwood group. Conclusion: Wormwood is quite rich in phenolic compounds and has strong antioxidant potential. It was concluded that it promotes wound healing through various mechanisms of action, shows immunomodulatory effects and is suitable for clinical use as a chitosan-based hydrogel wound dressing. [ABSTRACT FROM AUTHOR]