Diagnostic Value of Delayed Contrast-Enhanced Cardiac Computed Tomography for Detecting Left Atrial Appendage Thrombus in Patients With Atrial Fibrillation.

Objective: Delayed enhancement cardiac CT is a reliable tool for the diagnosis of left atrial appendage thrombus but limited for scanning heterogeneity. We aimed to explore the improvement of the 1 and 3-min delay phase at the diagnostic level to detect left atrial appendage thrombus, in order to set up a reasonable CT scanning scheme. Materials and Methods: A total of 6,524 patients were continuously retrieved from January 2015 to September 2020 retrospectively. The patients had undergone Transesophageal echocardiography (TEE) and cardiac CT with complete period include the arterial enhancement phase, 1 and 3-min delay phase, TEE were used as the reference standard. The final study included 329 patients. Three experienced radiologists independently assessed each phase of the cardiac CT images for thrombus diagnosis. We explored the improvement of the diagnostic ability of different delayed contrast-enhanced phases for left atrial appendage thrombus detection. Multiple logistic regression analysis were used for further high-risk stratification to avoid an additional 1-min delayed scan. Results: In total, 29 thrombosis were detected at TEE. For all cardiac CT phases, sensitivity and negative predictive were 100%. The specificity were 0.54, 0.93, and 1.00, respectively; The positive predictive values (PPV) were 0.17, 0.57, and 1.00, respectively; Area under curve (AUC) were 0.75, 0.95, and 0.98, respectively. High risk factors that cannot be clearly diagnosed with 1-min delay phase included reduced cardiac function, increased CHA2DS2-VAScscore and left atrial enlargement. Compared with the arterial enhanced phase, increased radiation doses in the 1 and 3-min delay phases were 1.7 ± 1.3 msv and 1.5 ± 0.8 msv (mean ± standard deviation). Conclusion: Using TEE as the reference standard, early contrast-enhanced CT scanning with 1 and 3-min delay is necessary for the diagnosis of left appendage thrombus, which could significantly improve the diagnostic efficiency. Patients with high-risk stratification are suitable for direct 3-min delayed scanning.

Downregulation of MCM2 contributes to the reduced growth potential of epithelial progenitor cells in chronic nasal inflammation.

BACKGROUND: Recent studies have shown that human nasal epithelial progenitor cells (hNEPCs) are characterized by poor proliferation capacities during chronic nasal inflammation. OBJECTIVE: We sought to investigate the key molecular functions and candidates that contribute to the reduced growth potential of hNEPCs in chronically inflamed nasal mucosa. METHODS: Nasal biopsy specimens were obtained from 28 patients with nasal polyps (NPs) and 13 healthy controls. hNEPCs from nasal samples were cultured for 3 consecutive passages, and their molecular and functional profiles were analyzed by RNA sequencing. The minichromosome maintenance protein (MCM) family gene MCM2 was validated in hNEPCs and tissue samples from patients with NPs and control subjects by cell cycle, quantitative PCR, and Western blot analyses; small interfering RNA-mediated knockdown assay; and immunofluorescent staining. RESULTS: Compared with control hNEPCs, NP-derived hNEPCs showed (1) reduced growth kinetics, as evidenced by the colony-forming efficiency and doubling time; (2) inhibited cell cycle progression, as evidenced by gene ontology and/or pathway and cell cycle analyses; and (3) downregulated expression of MCM2, the key protein of the MCM complex, which is critical for DNA replication at the G1/S checkpoint. Moreover, hNEPCs with MCM2 knockdown showed a decreased proliferation rate, and the MCM2 protein level in basal cells was significantly lower in abnormally remodeled nasal epithelium than in normal epithelium. CONCLUSION: These results demonstrate inhibited cell cycle progression and MCM2 downregulation in basal or progenitor nasal epithelial cells from NP tissue, which may contribute to the decreased growth potential of hNEPCs in chronically inflamed upper airways.

Increase in IL-17-positive cells in sinonasal inverted papilloma.

OBJECTIVE: Neutrophil infiltration in patients with sinonasal inverted papilloma (SNIP) is significantly high. Whether IL-17, which is a potent factor mediating neutrophilic inflammation, is involved in the neutrophilic phenotype of SNIP is investigated in the current study. STUDY DESIGN: Laboratorial study. PARTICIPANTS: Nasal papilloma and inferior turbinate were collected from patients with SNIP (n = 50) and control subjects with septal deviation (n = 15). METHODS: IL-17 + cells were evaluated in tissues obtained from patients with SNIP and control subjects with septal deviation, by immunohistochemistry and flow cytometry. MAIN OUTCOME MEASURES: The IL-17 + cells were mainly localised in mononuclear cells and neutrophils, and were up-regulated in the SNIP samples compared with those in the controls. The IL-17 + T-cell subsets mainly included CD4+ (Th17, 60.0%) and CD8+ (Tc17, 30.0%), and both subsets were enhanced in the SNIP samples than controls. The total level of IL-17 + cells was significantly correlated with neutrophil infiltration in the SNIP tissues. Furthermore, the SNIP homogenates could significantly promote IL-17 production in peripheral blood mononuclear cells. CONCLUSIONS: An increase in IL-17 + cells is evident in SNIP and may be involved in neutrophil infiltration in local tissues. IL-17 could be a potential therapeutic target to relieve the neutrophilic pathological change in SNIP.

NOD-like receptor family, pyrin domain containing 3 (NLRP3) contributes to inflammation, pyroptosis, and mucin production in human airway epithelium on rhinovirus infection.

BACKGROUND: The airway epithelium maintains mucosal homeostasis and effectively responds to pathogens. The roles of the epithelial NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome in human rhinovirus (hRV) infection and its effects mediating epithelial functional changes remain poorly understood. OBJECTIVE: We investigated the mechanisms and cellular functions mediated by the epithelial NLRP3 inflammasome on hRV infection. METHODS: Using models of primary human nasal epithelial progenitor cells and differentiated human nasal epithelial cells (hNECs) infected by hRV, we functionally examined key factors for NLRP3 inflammasome activation, cell death, and mucus production. Furthermore, NLRP3 and IL-1ß in human epithelium from nasal mucosal inflammation induced by hRV were evaluated. RESULTS: The inflammasome-mediated IL-1ß secretion and pyroptosis in human nasal epithelial progenitor cells and hNECs on hRV infection were dependent on the DDX33/DDX58-NLRP3-caspase-1-GSDMD axis. In differentiated hNECs hRV could also promote major airway epithelial mucin (MUC5AC) production through this axis. Our results further confirmed that the NLRP3 inflammasome signaling pathway was responsible for suppressing hRV replication in airway epithelium. Finally, hRV infection in chronically inflamed nasal mucosa was associated with epithelial mucus hyperproduction, whereas NLRP3 and IL-1ß expression levels were significantly increased in hRV-infected epithelium with goblet cell hyperplasia compared with normal epithelium without viral infection. CONCLUSION: The current study showed that the NLRP3 inflammasome signaling axis could functionally mediate hRV-induced inflammation, pyroptosis, and mucus production in airway epithelium, which might be an essential mechanism associated with hRV-induced airway remodeling.

Tetrahydrocurcumin, a major metabolite of curcumin, ameliorates allergic airway inflammation by attenuating Th2 response and suppressing the IL-4Rα-Jak1-STAT6 and Jagged1/Jagged2 -Notch1/Notch2 pathways in asthmatic mice.

BACKGROUND: Curcumin (Cur), derived from Curcuma species, exhibits anti-inflammatory, antioxidant, and anticancer effects. Although Cur has some beneficial effects on asthma, its clinical application is limited by its low bioavailability. Tetrahydrocurcumin (THC), the major active metabolite of Cur, has multiple biological functions, similarly to Cur, and importantly, it showed enhanced bioavailability in tissues and plasma. However, the effect of THC on asthma has not been reported. OBJECTIVE: The current study sought to investigate the efficacy of dietary THC on allergic asthma compared to that of Cur in an animal model. METHODS: The anti-inflammatory effects of Cur and THC were evaluated in an ovalbumin-induced asthmatic mouse model. The nasal symptoms, pathological alterations of the lung tissues, oxidants and antioxidants, cytokine production, T cell subsets, and Th2-related signalling pathway activity were assessed. RESULTS: Both THC and Cur had beneficial effects on asthmatic mice with regard to nasal symptoms, pathological changes (eosinophils and mucus hyper-production), oxidative stress (malondialdehyde), cytokine production (IL-13), Th17 and cytotoxic T cell subsets, and Th2 signalling pathway (IL-4Rα-Jak1-STAT6 and Jagged1/Jagged2-Notch1/Notch2 axis) activity. THC was more effective than Cur in suppressing tissue eosinophilia, mucus production, and IL-4Rα/Jak1/STAT6 pathway activity. Furthermore, only THC inhibited peripheral eosinophil levels, Th2 cytokines (IL-4 and IL-5), and Th2 cell subsets and enhanced an antioxidant enzyme (glutathione). CONCLUSION AND CLINICAL RELEVANCE: The above results demonstrated for the first time that THC was superior to Cur in modulating allergic asthmatic phenotypes, especially attenuating the Th2 response. THC might be a potentially effective agent for asthma treatment.