Originally used as an antimalarial drug,hydroxychloroquine is now widely used in the treatment of rheumatic immune diseases due to its cost-effectiveness,safety,and efficacy.In addition to its immunomodulatory effects,hydroxychloroquine also exhibits anti thrombotic,anti-hypolipidemic,and anti-hypoglycemic properties.Hydroxychloroquine blood levels are correlated with clinical outcomes and adverse reactions,and can reflect patient compliance.However,due to the complex pharmacokinetic profile of hydroxychloroquine,significant inter-individual differences in blood concentration exist even with the administration of the same dosage.This study investigates the factors affecting the blood concentration of hydroxychloroquine in terms of physiological factors,pathological factors,metabolic enzyme gene polymorphisms,and drug-related factors.The aim is to provide a reference for rational clinical use and the development of individualized dosing.

Intestinal microorganisms and their metabolites are involved in the pathogenesis and progression of various cardiovascular diseases,especially in the progression of heart failure.This paper mainly discussed the gut microbial metabolites trimethylamine oxide(TMAO)participated in the pathological process of heart failure,and application value of TMAO in heart failure patients.This paper introduced the change characteristics of intestinal flora and its metabolites in heart failure patients,illu-minated the TMAO-mediated inflammatory response,and the related signal pathways and mechanism of myocardial hypertrophy and heart failure.High levels of TMAO are associated with poor outcomes in patients with heart failure indicating a good predictive value for the prognosis of heart failure.Regulating TMAO levels through diet,probiotics and prebiotics,antibiotics,fecal transplan-tation,and other pathways is expected to be a potential treatment for heart failure.

OBJECTIVE To investigate the mechanism of catalpol affecting the differentiation of helper T cell 17 （Th17） by interfering the expressions of pyruvate kinase M2 （PKM2） and lactate dehydrogenase A （LDHA）. METHODS The naive CD4+ T cells were selected from the spleen of C57BL/6 mice， and were differentiated into Th17 cells by adding directional differentiation stimulants for 72 hours. At the same time， the cells were treated with 0 （directed control）， 20， 40 and 80 μg/mL catalpol. The flow cytometry was used to detect the proportion of Th17 cell differentiation in cells； the colorimetric method was adopted to detect the levels of pyruvate and lactate in cell culture supernatant； mRNA expressions of retinoid-related orphan nuclear receptor gamma t （RORγt）， PKM2 and LDHA were detected by qRT-PCR method； Western blot was used to detect the expression levels of PKM2， LDHA， signal transducer and activator of transcription 3 （STAT3）， and phosphorylated STAT3 （p-STAT3） proteins in cells. RESULTS Compared with the directed control group， after 72 hours of treatment with 20， 40， 80 μg/mL catalpol， the differentiation ratio of Th17 cells were decreased by 6.74%， 8.41%， 9.24%， and the levels of pyruvate and lactate in the cell culture supernatant， the mRNA expressions of PKM2， LDHA and RORγt as well as the protein expressions of PKM2 and LDHA and the phosphorylation of STAT3 were significantly reduced （P＜0.05）. CONCLUSIONS Catalpol can reduce the glycolysis level by down-regulating the expressions of PKM2 and LDHA， thereby inhibiting the differentiation of Th17 cells.

OBJECTIVE To observe the regulation of aerobic oxidation mediated by HIF-1α/PDHK1 pathway by PNS, and to explore its mechanism of promoting the differentiation of Naive CD4+T cells into Treg cells. METHODS Naive CD4+T cells were isolated from the spleen of C57BL/6 mice by magnetic beads and induced to differentiate into Treg cells for in vitro culture. Naive CD4+T cells were divided into PNS treatment group(5, 10, 20 μg·mL−1), PNS combined with HIF-1α inhibitor(PX-478) group, and the control group was set up. The proportion of Treg cells differentiation was detected by flow cytometry. The expression of HIF-1α and PDHK1 protein was detected by Western blotting. The expression of HIF-1α, PDHK1 and FOXP3 mRNA was detected by real-time fluorescence quantitative PCR. The level of IL-10 in cell culture supernatant was detected by enzyme-linked immunosorbent assay. RESULTS PNS could significantly increase the proportion of Treg cells and the secretion level of IL-10, and increase the expression of FOXP3 mRNA in cells. At the same time, the expression of HIF-1α and PDHK1 protein and mRNA was inhibited. When the cells were treated with 10 μmol·L−1 PX-478 and then treated with 10 μg·mL−1 PNS, the expression of PDHK1 and FOXP3 and the differentiation ratio of Treg cells were not significantly different from those treated with 10 μmol·L−1 PX-478 alone. CONCLUSION PNS can reduce the expression level of PDHK1 by HIF-1α to enhance the aerobic oxidation of Naive CD4+T cells and promote their differentiation into Treg cells.

Objective:To investigate the clinicopathological features of Crooke cell tumor of adrenocorticotropic hormone differentiation specific transcription factor (TPIT, also known as transcription factor 19, TBX19) lineage neuroendocrine tumors.Methods:Six cases of Crooke cell tumor diagnosed at the First Affiliated Hospital of University of Science and Technology of China, Hefei, China from October 2019 to October 2023 were collected. The clinical and pathological features of these cases were analyzed.Results:Among the six cases, one was male and five were female, with ages ranging from 26 to 75 years, and an average age of 44 years. All tumors occurred within the sella turcica. Clinical presentations included visual impairment in two cases, menstrual disorders in one case, Cushing′s syndrome in one case, headache in one case, and one asymptomatic case discovered during a physical examination. Preoperative serum analyses revealed elevated levels of cortisol and adrenocorticotropic hormones in two cases, elevated cortisol in two cases, elevated adrenocorticotropic hormone in one case, and one case with a mild increase in prolactin due to the pituitary stalk effect. Magnetic resonance imaging revealed uneven enhancement of masses with maximum diameters ranging from 1.7 to 3.2 cm, all identified as macroadenomas. Microscopically, tumor cells exhibited irregular polygonal shapes, solid sheets, or pseudo-papillary arrangements around blood vessels. The cell nuclei were eccentric or centrally located, varying in size, with abundant cytoplasm. Some tumor cells showed perinuclear halo. Immunohistochemistry demonstrated diffuse strong positivity for TPIT in five cases, focal weak positivity for TPIT in one case, diffuse strong positivity for adrenocorticotropic hormone in all cases, and faint staining around the nuclei in a few cells. CK8/18 showed a strong positive ring pattern in more than 50% of tumor cells, focal weak positive expression of p53, and the Ki-67 positive index ranged 1%-5%. Periodic acid-Schiff staining revealed positive cytoplasm and negative perinuclear areas.Conclusions:Crooke cell tumor is a rare type of pituitary neuroendocrine tumors. Its pathological characteristics include a distinctive perinuclear clear zone and immunohistochemical markers, such as CK8/18 exhibiting a ring or halo pattern. This entity represents a high-risk subtype among pituitary neuroendocrine tumors, displaying a high risk of invasion and a propensity for recurrence. Accurate diagnosis is crucial for the postoperative follow-up and multimodal treatment planning.

Objective To evaluate the relationship between ceftazidime-avibactam(CAZ-AVI)blood concentrations and efficacy in critically ill patients and to investigate the factors influencing blood levels.Methods The CAZ-AVI trough concentrations(Cmin)were detected in 29 patients who received CAZ-AVI treatment for at least 48 hours.The clinical materials of the patients were collected together for retrospective analysis.Results The Cmin of ceftazidime(CAZ)and avibactam(AVI)were(50.95±5.17)and(7.52±0.96)mg·L-1 in the effective group and(31.16±7.03)and(5.37±1.32)mg·L-1 in the ineffective group,respectively.The Cmin of CAZ in the effective group was significantly higher than in the ineffective group(P<0.05),and there was no significant difference in AVI Cmin between the two groups(P>0.05).Spearman's correlation analysis showed that CAZ Cmin was positively correlated with clinical efficacy(P<0.05),and no correlation between AVI Cmin and clinical efficacy(P>0.05).The optimal CAZ Cmin threshold was 24.59 mg·L-1.Multiple linear regression analysis showed that age and creatinine clearance was significantly correlated with the Cmin of CAZ,and creatinine clearance was significantly correlated with AVI Cmin(P<0.05).Conclusions The Cmin of CAZ correlates with efficacy,and it may be more beneficial for clinical treatment to keep the concentration of CAZ-AVI always greater than the minimum inhibitory concentration during the dosing interval.The creatinine clearance should be fully considered when optimizing CAZ-AVI dosage in critically ill patients.

Objective:To explore the effect of short-chain fatty acid (SCFA) on acute lung injury (ALI) in sepsis via macrophage polarization.Methods:① Clinical trial: 30 sepsis patients admitted to the intensive care unit (ICU) of General Hospital of Ningxia Medical University from January to December in 2022 and 10 non-sepsis patients in the same period were enrolled, stool samples were collected on the first day of admission, and SCFA butyric acid level in the two groups were studied by targeted metabolomics. ② Animal experiment: male C57BL/6J mice were selected and randomly divided into sham operation group (Sham group), sepsis caused by cecal ligation and perforation (CLP group) and SCFA intervention group (SCFA group, sodium butyrate 25 mg/kg was given by gavage 1 hour after CLP), with 6 animals in each group. Twenty-four hours after molding, the state of mice was evaluated by mouse sepsis score (MSS), the degree of pulmonary edema was evaluated by calculating the wet/dry ratio (W/D), and the pathological changes of lung tissue were observed by hematoxylin-eosin (HE) staining, and lung injury score was performed. The serum levels of tumor necrosis factor-α (TNF-α), interleukins (IL-1β, IL-6, IL-10), nuclear factor-κB (NF-κB), and transforming growth factor-β (TGF-β) were detected by enzyme-linked immunosorbent assay (ELISA). Real-time fluorescence quantitative polymerase chain reaction (RT-qPCR) was used to measure the mRNA expressions of inflammatory factors TNF-α, IL-1β, IL-6 and antioxidant factor nuclear factor E2-related factor 2 (Nrf2) in lung tissue. The expressions of macrophage polarization markers arginin-1 (ARG-1), CD206, inducible nitric oxide synthase (iNOS) and IL-1β in lung tissue were detected by immunohistochemistry.Results:① Compared with non-sepsis patients, SCFA-butyric acid level was significantly reduced in patients with sepsis (μg/g: 34.56±6.61 vs. 1 150.67±381.90, P < 0.01). ② Compared with the Sham group, MSS, lung W/D ratio, lung injury score, the levels of serum inflammatory factors TNF-α, TGF-β, NF-κB, IL-10, IL-6, IL-1β, the mRNA expressions of lung tissue inflammatory factors and antioxidant factor Nrf2, M1 macrophage polarization markers ARG-1, CD206 and M2 macrophage polarization markers iNOS and IL-1β were significantly increased in the CLP group. Compared with the CLP group, MSS, lung W/D ratio, lung injury score, the levels of serum inflammatory factors TNF-α, TGF-β, NF-κB, IL-10, IL-6, IL-1β, the mRNA expressions of lung tissue inflammatory factors and antioxidant factors Nrf2, and M1 macrophage polarization markers ARG-1 and CD206 were significantly reduced [MSS: 14.50±3.16 vs. 20.00±1.55, lung W/D ratio: 4.60±0.18 vs. 5.51±0.59, lung injury score: 47.56±2.36 vs. 88.30±6.04, serum TNF-α (ng/L): 27.99±0.58 vs. 69.55±18.53, serum TGF-β (μg/L): 9.82±2.16 vs. 18.73±1.83, serum NF-κB (μg/L): 1.23±0.09 vs. 1.95±0.28, serum IL-10 (ng/L): 78.39±2.29 vs. 140.22±19.82, serum IL-6 (ng/L): 300.64±77.60 vs. 1 442.52±494.14, serum IL-1β (ng/L): 33.13±0.99 vs. 38.39±1.31, lung IL-1β mRNA expression (IL-1β/β-actin): 1.01±0.01 vs. 2.24±0.62, lung IL-6 mRNA expression (IL-6/β-actin): 0.63±0.09 vs. 1.46±0.31, lung TNF-α mRNA expression (TNF-α/β-actin): 0.81±0.33 vs. 2.57±0.64, lung Nrf2 mRNA expression (Nrf2/β-actin): 1.59±0.25 vs. 2.96±0.89, ARG-1 positive area: (36.27±2.89)% vs. (49.75±5.03)%, CD206 positive area: (20.02±3.26)% vs. (44.24±3.61)%, all P < 0.05]. However, there was no significant difference in M2 macrophage polarization markers iNOS and IL-1β expression [iNOS positive area: (18.32±2.23)% vs. (21.77±3.57)%, IL-1β positive area: (40.42±4.78)% vs. (42.14±4.22)%, both P > 0.05]. Conclusion:SCFA may alleviate ALI in sepsis by reducing M1 polarization of pulmonary macrophages.

Objective To investigate the predictive value of preoperative bi-parametric MRI radiomics for the International Society of Urological Pathology(ISUP)grading of prostate cancer(PCa).Methods One hundred and sixty-five patients with PCa confirmed by pathology were analyzed retrospectively.According to the ISUP grading system,PCa patients were divided into five subgroups:G1 group(Gleason score=6),G2 group(Gleason score=3+4),G3 group(Gleason score=4+3),G4 group(Gleason score=8)and G5 group(Gleason score=9 or 10).A total of 3 948 radiomics features were extracted from T2WI,diffusion weighted imaging(DWI),and apparent diffusion coefficient(ADC)images of each patient.Patients were classified into two categories based on Gleason score&ge;4+3 or ≤3+4.A radiomics signature(Rad-score)was constructed after reduction of dimension by the minimum redundancy maximum relevance(mRMR)and the least absolute shrinkage and selection operator(LASSO).The Spearman rank correlation test was used to evaluate the correlation between Rad-score and ISUP grading groups.The Kruskal-Wallis test was used to compare the difference of Rad-score among the five groups.Results Eleven most valuable features were selected as the Rad-score after reducing the dimension by mRMR and LASSO algorithm.Moderate correlation existed between Rad-score and ISUP grading(r=0.53,P＜0.05).There were significant differences in Rad-score between G1 and G2 groups and G3,G4 and G5 groups(P＜0.05),no significant difference existed between the remained two groups(P＞0.05).The area under the curve(AUC)of receiver operating characteristic(ROC)curve for Rad-score were 0.827,0.762,0.563,0.657,0.698 for G1,G2,G3,G4 and G5 groups,respectively.Conclusion The radiomics based on bi-parametric MRI can be used to predict grade 1,2 PCa patients in the ISUP grading system.

Objective:To investigate the microecological structure changes and correlation in blood, lung tissue and fecal intestine of mice with sepsis and acute lung injury.Methods:A total of 12 healthy male C57BL/6J mice were divided into the cecal ligation and perforation (CLP) group and sham operation (sham) group by random number table method, with six mice in each group. In the CLP group, acute lung injury model of sepsis mice was prepared by CLP method. In the sham group, only laparotomy but no perforation of cecal ligation was performed. Eye blood, lung tissue, and feces were collected from mice in each group 24 h after surgery. Lung tissue morphological changes were observed by HE staining, and 16s ribosome RNA sequencing was used to analyze the structural changes of microecology of the bacterial flora at each site in sepsis mice and find out the correlation.Results:(1) HE staining showed that mice in the CLP group had exudation into the alveolar cavity of the lung, disordered lung tissue structure, accompanied by a large number of inflammatory cell infiltration, and the lung histopathological score was significantly higher than that in the sham group ( P < 0.01). (2)α diversity analysis showed that there was no statistical significance in blood and fecal samples between the sham group and CLP group, while Ace index, Chao index and Simpson index in lung tissue samples were statistically significant ( P < 0.05). (3) β diversity analysis showed that the differences in blood and fecal samples were greater between the sham group and CLP group than that within the group, and analysis of Bray Curtis, weighted, and unweighted indexes were statistically significant ( P < 0.05). (4) At the phylum level, compared with the sham group, the abundance of Proteobacteria gradually increased, and the abundance of Firmicutes and actinobacteria was decreased in the CLP group. At the genus level, the sham group was dominated by Acinetobacter and Duchenne, while the CLP group was dominated by Escherichia coli and unclassified Enterobacter. Blood flora was more similar to lung tissue flora composition as compared with fecal flora. Conclusions:The distribution of bacterial flora in blood, lung tissue and intestine of sepsis mice with acute lung injury is partially overlapped.

Objective:To summarize and analyze the current application status of oral mucosal graft (OMG) technique in the repair of ureteral strictures in China, and clarify the feasibility, safety and effectiveness of this technique.Methods:The 175 patients who underwent repair of ureteral stricture using oral mucosal patches from June 2015 to February 2022 were etrospectively analyzed in 14 medical centers in China, including 49 cases in Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 32 cases in Affiliated Seventh Medical Center of PLA General Hospital, 3 cases in The Second Hospital of Anhui Medical University, 6 cases in The First Affiliated Hospital of Zhengzhou University, 56 cases in Peking University First Hospital, 3 cases in Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 3 cases in Shanghai Sixth People' s Hospital, 4 cases in General Hospital of Estern Theater Command, 4 cases in Lanzhou University Second Hospital, 2 cases in Guizhou Province People 's Hospital, 2 cases in Peking University People' s Hospital, 5 cases in Jinzhou First People's Hospital, 5 cases in The First Affiliated Hospital of Wannan Medical College, 1 case in Shandong Provincial Hospital. In this study, 127 patients (72.6%) used lingual mucosal patches, 32(18.3%) labial mucosa, and 16(9.1%) buccal mucosa. The surgical approach for OMG ureteral reconstruction was mainly minimally invasive, with robot-assisted laparoscopy in 84 patients (48.0%), traditional laparoscopic surgery in 87 patients (49.7%), and open surgery in only 4 patients (2.3%). There were 133 males and 42 females with an average age of (35.0±17.2) years. The mean body mass index (BMI) and stenosis length were (23.1±4.1) kg/m 2 and (4.7±1.8) cm, respectively. The stricture was located in the left ureter in 116 patients, right ureter in 58 case and bilateral ureter in 1 case. The most common causes of ureteral stricture were endoscopic surgery in 88(50.3%)patients, congenital stricture in 55(31.4%)patients, failed ureteroplasty in 29(16.6%)patients, history of extracorporeal shock wave lithotripsy in 13(7.4%)patients, radiotherapy history in 3(1.7%)patients and other causes in 6(3.4%)patients. Strictures were mainly located in the upper ureter, accounting for 61.7% (108/175 cases), followed by 36.0% (63/175) at the ureteropelvic junction and 2.3%(4/175)in the middle ureter. According to the surgical methods, the patients were divided into robot-assisted laparoscopic surgery group ( n=84), traditional laparoscopic surgery group ( n=87)and open surgery group ( n=4). Subgroup analysis of patients in robot-assisted laparoscopic and traditional laparoscopic surgery groups was performed. There were no significant difference in preoperative data between the two groups except for age (32.0±18.3) years vs.(37.0±15.9)years, P=0.040], BMI[(22.5±4.3)kg/m 2 vs. (23.7±3.6)kg/m 2, P=0.028], and etiology of stenosis [endoscopic injury, 34(40.5%) vs. 53(60.9%), P=0.012]. Preoperative hydronephrosis and stricture length were assessed by CTU and ureterography. Ureterography 7-9 weeks after surgery showed patency of the reconstructed segment, or no recurrence of hydronephrosis was judged as success. Evaluate the operation method, operation time, success rate, length of OMG in repairing ureteral stricture between laparoscopic and robot-assisted groups. Results:The overall success rate of oral mucosal graft repair surgery reached 97.7%(171/175). The success rate of ureteral reconstruction in the two groups were 96.4%(81/84)and 98.9%(86/87), respectively ( P=0.351), and the difference was not statistically significant. There was no significant difference for operation time, intraoperative blood loss, and mean oral mucosal length between the robotic and laparoscopic groups[(244.7±85.8) min and (222.7±83.5)min ( P=0.116), (58.9±38.6) ml and (68.4±45.5) ml ( P=0.217), (5.0±2.0) cm and (4.6±1.5) cm ( P=0.350)], respectively.Postoperative complications were reported in 23 (13.1%) patients, such as fever, urinary leakage, lymphatic leakage, infection, but only 2 (1.4%) cases patients had complications of Clavien-Dindo score &ge; Ⅲ. The two patients developed urinary stricture after surgery with failed conservative treatment, and no urinary stricture occurred following endoscopic treatment.The short-term (three months after surgery)incidence of complications in the site where the oral mucosa was taken, such as difficulty in opening mouth, pain, and swelling, was 12.0% (21/175), and there was no significant difference for oral complications between patients harvesting different length of mucosal graft. Conclusions:Ureteroplasty with oral mucosal graft is a safe, feasible and reliable technique for ureteral reconstruction. At present, minimally invasive technology is the main surgical approach for ureteroplasty, and there is no significant difference in operation time and success rate between robotic surgery and laparoscopic surgery.