ABSTRACT
Invasive fungal infections (IFIs) have been associated with high mortality, highlighting the urgent need for developing novel antifungal strategies. Herein the first light-responsive antifungal agents were designed by optical control of fungal ergosterol biosynthesis pathway with photocaged triazole lanosterol 14α-demethylase (CYP51) inhibitors. The photocaged triazoles completely shielded the CYP51 inhibition. The content of ergosterol in fungi before photoactivation and after photoactivation was 4.4% and 83.7%, respectively. Importantly, the shielded antifungal activity (MIC80 ≥ 64 μg/mL) could be efficiently recovered (MIC80 = 0.5-8 μg/mL) by light irradiation. The new chemical tools enable optical control of fungal growth arrest, morphological conversion and biofilm formation. The ability for high-precision antifungal treatment was validated by in vivo models. The light-activated compound A1 was comparable to fluconazole in prolonging survival in Galleria mellonella larvae with a median survival of 14 days and reducing fungal burden in the mouse skin infection model. Overall, this study paves the way for precise regulation of antifungal therapy with improved efficacy and safety.
ABSTRACT
Objective:To observe the relationship between inducible carbon monoxide synthase (iNOS) and delayed encephalopathy after acute carbon monoxide poisoning (DEACMP), and explore its mechanism of action in DEACMP.Methods:This study was designed as prospective cohort study. Patients with acute carbon monoxide poisoning who met the diagnostic criteria and were admitted to Emergency Intensive Care Unit(EICU) of our hospital from June 2019 to June 2021 were selected as subjects. Patients were divided into the DEACMP group and non-DEACMP group according to the occurrence of DEACMP. Serum samples were collected on the first 24 h after admission and on day 7 and 14 after admission, and the serum nitric oxide (NO), neuronal nitric oxide synthase (nNOS), inducible carbon monoxide synthase (iNOS), and endothelial nitric oxide synthase (eNOS) level were measured by enzyme-linked immunosorbent assay. The generalized estimating equation was used to estimate the difference of NO, nNOS, iNOS and eNOS between DEACMP and non-DEACMP patients.Results:A total of 78 patients with carbon monoxide poisoning were included in our study finally, including 49 (62.82%) males and 29 (37.18%) females, with an average age of (53.96±14.95) years, 20 (25.64%) patients with DEACMP, and 1 (1.28%) death. Univariate analysis showed that patients with DEACMP had an average increase of 3 h (95% CI: 1.00, 5.00) in carbon monoxide exposure time and a 5-point decrease in GCS score (95% CI: 1.00, 6.00) than the patients without DEACMP, and the proportion of patients with severe carbon monoxide poisoning in the DEACMP group was higher than that of the non-DEACMP group (90.00% vs. 32.76%). According to the analysis of generalized estimation equation, on day 7 and 14 after admission, Compared with non-DEACMP patients, neither by performing unadjusted nor adjusted analysis with the iNOS of DEACMP patients was significantly higher than that in non-DEACMP patients regardless of whether exposure time, GCS score, coma time or severity of carbon monoxide poisoning were adjusted or not ( P <0.01 or P <0.05). Except for the level of nNOS in the GEE model adjusted with carbon monoxide exposure time, the levels of NO, nNOS and eNOS showed no significant difference between DEACMP and non-DEACMP patients ( P >0.05). Conclusions:The expression of iNOS level is increased in DEACMP patients, and its continuous expression may be involved in the pathogenesis of DEACMP.
ABSTRACT
Objective@#To investigate the effect of incisor retraction on three-dimensional morphology of upper airway and fluid dynamics in class Ⅰ adult patients with bimaxillary protrusion.@*Methods@#Thirty class Ⅰ patients with bimaxillary protrusion that received fixed orthodontic treatment in Department of Stomatology, The First Affiliated Hospital of Wenzhou Medical University from January 2011 to September 2014 were selected using random number table. All the patients were treated with extraction of four first premolars and retraction of anterior teeth using implant anchorage. Cone-beam CT (CBCT) scans were performed before and after incisor retraction for all patients. The CBCT data of the upper airway were constructed using Mimics 16.0, and the flow field characteristics inside the upper airway were simulated using Ansys 14.0. The changes of volume (V), mean cross-sectional area (mCSA), maximum lateral diameters/maximum anteroposterior diameters (LP/AP) of cross section, the maximum pressure of airflow (Pmax), the minimum pressure of airflow (Pmin) and pressure drop (△P) of nasopharynx, oropharynx and hypopharynx before and after incisor retraction were measured and compared using paired t test. The correlation between the variation of △P in the most significant pharyngeal part and the morphological variables after incisor retraction was analyzed using Pearson correlation test.@*Results@#No statistical differences were observed in the morphology and flow field in nasopharynx before and after incisor retraction (P>0.05). Before incisor retraction, the oropharyngeal volume and mCSA were (7 580±622) mm3 and (217±40) mm2, respectively, and the hypopharyngeal volume and mCSA were (2 564±162) mm3, and (239±43) mm2, respectively. After incisor retraction, the volumes of oropharynx and hypopharynx were (6 885±601) mm3 and (2 535±156) mm3, respectively, and mCSA of oropharynx and hypopharynx were (197±37) mm2 and (236±42) mm2, respectively. The volume and mCSA of oropharynx and hypopharynx were significantly decreased after incisor retraction (P<0.05). The greatest changes in pharyngeal volume and mCSA occurred in the oropharynx. In addition, the LP/AP of oropharynx after incisor retraction was changed from 1.9±0.6 to 2.1±0.7, which was significantly increased compared with the levels before incisor retraction (P<0.05). After simulation of pharyngeal airflow, the oropharyngeal Pmin, hypopharyngeal Pmax and Pmin were (-13.7±4.3), (-8.3±3.8) and (-42.8±9.5) Pa, respectively, whereas the values turned to (-16.4±6.5), (-11.9±3.6) and (-46.0±11.0) Pa, respectively after incisor retraction, which was significantly reduced (P<0.05). △P of oropharynx was significantly increased from (42.7±10.1) Pa to (45.2±13.0) Pa after incisor retraction (P<0.05) and the variation of oropharyngeal △P was negatively correlated with the variation of V and mCSA in oropharynx before and after incisor retraction (r=-0.681, P=0.001; r=-0.844, P=0.000).@*Conclusions@#The oropharynx was constricted and the pharyngeal resistance was increased after incisor retraction in adult class Ⅰ patients with bimaxillary protrusion. A comprehensive and systematic evaluation of the pharyngeal morphology and ventilatory function were very important for making a scientific and rational clinical treatment plan.