Background Manganese is an essential trace element for the human body and maintains normal development of many organs including the brain. However, long-term exposure to a high manganese environment or excessive manganese intake will lead to manganese poisoning and result in neurological diseases, and currently no effective treatment plan is available. Objective To develop an animal model for subchronic manganese exposure and assess the impact of Dendrobium nobile Lindl. alkaloids (DNLA) on manganese associated behavioral and hippocampal effects in rats. Methods Fifty male SPF SD rats were randomly allocated into a control group (0.9% normal saline by intraperitoneal injection), two experimental groups [7.5 mg·kg⁻¹ (low) or 15 mg·kg⁻¹ (high) of MnCl₂·4H₂O by intraperitoneal injection], and two DNLA antagonistic groups [15 mg·kg⁻¹ MnCl₂·4H₂O by intraperitoneal injection then either 20 mg·kg⁻¹ (low) or 40 mg·kg⁻¹ (high) DNLA by oral administration]. All groups of rats were adminaistered 5 d per wek, once a day, for consecutive 13 weeks. Following modeling, neurobehavioral assessments were conducted using open field, Morris water maze, and Y maze. Inductively coupled plasma mass spectrometry (ICP-MS) was utilized to measure manganese levels in the blood and brain tissues of the rats, and hematoxylin-eosin (HE) staining was employed to examine neuronal morphological changes in the hippocampal tissues of the rats. Results The neurobehavioral tests revealed that the manganese-exposed rats exhibited decreased total movement distance, prolonged central zone dwelling time, and reduced motor activity in the open field test, indicating tendencies toward depression and anxiety (P<0.05). In the Y-maze test, the mean exploration distance in the novel arm, the number of entries into the novel arm, and the time spent in the novel arm of the managanses-exposed rats were all reduced, while the latency period increased, suggesting impaired spatial exploration and learning-memory functions (P<0.05). In the Morris water maze navigation test, the escape latency was significantly longer in the manganese-exposed rats compared to the control group, and the number of platform crossings decreased in the spatial probe test, indicating a significant decline in spatial learning and memory (P<0.05). The ICP-MS analysis showed elevated manganese concentrations in the blood and hippocampus of the exposed rats (P<0.05), and the histopathological observation revealed hippocampal damage. Following the DNLA intervention, the manganese-exposed rats showed increased total movement distance and reduced central zone dwelling time in the open field test (P<0.05). In the Y-maze test, the mean exploration distance in the novel arm, the number of entries into the novel arm, and the time spent in the novel arm increased, while the latency period decreased, suggesting alleviation of anxiety and improved exploratory behavior (P<0.05). In the Morris water maze test, the escape latency gradually shortened, and both the number of platform crossings and the percentage of time spent in the target quadrant increased, indicating improved spatial learning and memory (P<0.05). Additionally, the manganese levels in the blood and hippocampus decreased (P<0.05), and the hippocampal pathological changes were partially restored. Conclusion DNLA demonstrates the ability to counteract multiple neurotoxic effects following the elevation of manganese levels in the blood and hippocampal tissues of rats induced by subchronic manganese exposure. Specifically, DNLA is shown to ameliorate the behavioral alterations observed in rats after manganese exposure, and mitigate the hippocampal damage in manganese-exposed rats.

Background Exposure to benzo[a]pyrene (BaP) may impair lung function through various mechanisms; however, it remains uncertain whether BaP induces ferroptosis in lung tissue cells, resulting in lung function impairment. Objective To investigate the ferroptosis of lung tissue cells triggered by subchronic BaP exposure in mice and its correlation with lung injury, and to explore the function of ferroptosis in BaP-induced lung tissue damage. Method Seventy-two healthy 3-weeks-old male C57BL/6J mice were acclimatized for 1 week and then randomly divided into six groups: control group (corn oil 10 mL·kg⁻¹), low-dose BaP group (2.5 mg·kg⁻¹), medium-dose BaP group (5 mg·kg⁻¹), high-dose BaP group (10 mg·kg⁻¹), BaP+ferrostatin-1 (Fer-1) group (10 mg·kg⁻¹+1 mg·kg⁻¹), and Fer-1 group (1 mg·kg⁻¹), with 12 mice each group. Corn oil and BaP were administered via gavage every other day, followed by an intraperitoneal injection of Fer-1 the subsequent day, throughout a period of 90 d. Whole-body plethysmography was applied to detect lung function; hematoxylin-eosin staining (HE) and Masson staining were used to observe lung tissue injury and fibrosis; microscopy of alveolar epithelial cells was conducted to reveal mitochondrial morphology; biochemical assays were used to measure the content of tissue iron, malondialdehyde (MDA), and glutathione (GSH), as well as the activity of glutathione peroxidase (GSH-Px); Western blotting and real-time quantitative PCR (RT-qPCR) analyses were performed to reveal the protein and mRNA expression of ferroptosis markers. Results Compared to the control group, the high-dose BaP group showed a significant increase in expiration time (Te) (P<0.01), and a significant decrease in ratio rate of achieving peak expiratory flow (Rpef), tidal volume (TVb), peak inspiratory flow (PIF), minute volume (MVb), and peak expiratory flow (PEF) (P<0.05 or 0.01). Based on the results of HE and Masson staining, partial destruction of alveolar structures, thickening of alveolar walls, infiltration of inflammatory cells, significant thickening of tracheal walls and a large deposition of collagen fibers in lung tissue were observed in the medium- and high-dose BaP groups. By microscopy, the alveolar epithelial cells exposed to low-dose BaP showed condensed chromatin, and the mitochondria exposed to medium and high-dose BaP showed wrinkles, increased mitochondrial membrane density, and diminished mitochondrial cristae. Compared to the control group, in the medium- and high-dose BaP groups, the lung tissue iron content and the expression levels of ACSL4 protein and mRNA significantly elevated (P<0.01 or 0.05), while the mRNA expression level of SLC7A11 significantly decreased (P<0.05); in the high-dose BaP group, the MDA content, COX2 protein, and PTGS2 mRNA expression levels significantly increased (P<0.05 or 0.01), GSH content and GSH-Px activity, GPX4 protein and mRNA expression levels, and the expression level of SLC7A11 protein significantly decreased (P<0.01 or 0.05). The ferroptosis inhibitor Fer-1 markedly reversed respiratory function, morphology, mitochondrial alterations, and the aforementioned ferroptosis-related biochemical indicators. Conclusion Subchronic exposure to BaP can induce ferroptosis in mice lung tissue cells, resulting in compromised lung function.

OBJECTIVE To evaluate the cost-effectiveness of ivabradine in the treatment of chronic heart failure （CHF） in the context of “Quadruple Therapy” from the perspective of the health system. METHODS Based on real-world cohort data， the Markov model was constructed according to the natural progression of CHF， with a cycle time of 3 months， a study timeframe of 20 years， and a discount rate of 5%. Using quality-adjusted life year （QALY） and incremental cost-effectiveness ratios （ICER） as the output indexes， the cost-utility analysis was used to evaluate the cost-effectiveness of ivabradine in combination with the “Quadruple Therapy” regimen， compared with the “Quadruple Therapy” regimen for the treatment of CHF， and the robustness of the results of the base analysis was verified by univariate sensitivity analysis and probabilistic sensitivity analysis. RESULTS The results of the base analysis showed that the ICER of ivabradine combined with the “Quadruple Therapy” regimen was 165 065.54 yuan/QALY， compared with the “Quadruple Therapy” regimen， which was lower than the willingness-to-pay （WTP） threshold （257 094 yuan/QALY） based on 3 times of China’s gross domestic product （GDP） per capita in 2022. The results of the univariate sensitivity analysis showed that the discount rate had the greatest impact on the robustness of the model. The probabilistic sensitivity analysis showed that the probability that the ivabradine combined with the “Quadruple Therapy” regimen was cost-effective under the WTP threshold in this study was 59.50%. CONCLUSIONS When using 3 times China’s 2022 GDP per capita （257 094 yuan/ QALY） as the WTP threshold， the combination of ivabradine and the “Quadruple Therapy” regimen for treating CHF is cost- effective.

Humans ; Adolescent ; Acne Vulgaris/therapy* ; Skin Care ; Surveys and Questionnaires ; Cognition ; China ; Skin

This study examines inhibiting galectin 1 (Gal1) as a treatment option for hepatocellular carcinoma (HCC). Gal1 has immunosuppressive and cancer-promoting roles. Our data showed that Gal1 was highly expressed in human and mouse HCC. The levels of Gal1 positively correlated with the stages of human HCC and negatively with survival. The roles of Gal1 in HCC were studied using overexpression (OE) or silencing using Igals1 siRNA delivered by AAV9. Prior to HCC initiation induced by RAS and AKT mutations, lgals1-OE and silencing had opposite impacts on tumor load. The treatment effect of lgals1 siRNA was further demonstrated by intersecting HCC at different time points when the tumor load had already reached 9% or even 42% of the body weight. Comparing spatial transcriptomic profiles of Gal1 silenced and OE HCC, inhibiting matrix formation and recognition of foreign antigen in CD45⁺ cell-enriched areas located at tumor-margin likely contributed to the anti-HCC effects of Gal1 silencing. Within the tumors, silencing Gal1 inhibited translational initiation, elongation, and termination. Furthermore, Gal1 silencing increased immune cells as well as expanded cytotoxic T cells within the tumor, and the anti-HCC effect of lgals1 siRNA was CD8-dependent. Overall, Gal1 silencing has a promising potential for HCC treatment.

OBJECTIVE To evaluate the effects of ivabradine on vascular endothelial function in patients with coronary artery disease. METHODS PubMed， Embase， the Cochrane Library， Web of Science， CNKI， Wanfang Data， VIP and CBM databases were retrieved to collect randomized controlled trials （RCTs） about ivabradine （intervention group） versus placebo or β-blocker （control group） from the inception to Mar. 20th 2023. The meta-analysis was performed by using RevMan 5.4 software after literature screening， data extraction and quality evaluation. RESULTS A total of 12 RCTs were included， involving 1 206 patients. The results of meta-analysis showed that the levels of flow-mediated dilation （FMD） [MD＝1.71， 95%CI （0.96， 2.46）， P＜0.000 01] and nitric oxide （NO） [MD＝5.80， 95%CI （5.02， 6.59）， P＜0.000 01] in the intervention group were significantly higher than control group， while endothelin-1（ET-1） level was significantly lower than control group [MD＝－7.45， 95%CI （－8.42， －6.47）， P＜0.000 01]. There was no statistical significance in nitroglycerin-mediated dilation （NMD） level between 2 groups [MD＝0.13， 95%CI（－0.74， 1.00）， P＝0.77]. Subgroup analyses based on the different medications and intervention time in the control group showed better improvement in FMD level of patients receiving ivabradine， compared with placebo （P＜0.05）； compared with placebo and β-blocker， the level of NO in patients receiving ivabradine was improved significantly （P＜0.05）， while ET-1 level was decreased significantly （P＜0.05）. Regardless of the duration of the intervention， the levels of FMD， NO， and ET-1 in the intervention group were significantly improved compared to the control group （P＜0.01）， while the difference in NMD was not statistically significant （P＞0.05）. CONCLUSIONS Ivabradine can improve vascular endothelial function in patients with coronary artery disease.

OBJECTIVE To develop a standard of hierarchical management for patients with chronic obstructive pulmonary disease （COPD） from the perspective of pharmacists. METHODS The triangle hierarchical management model was used as the framework. Through literature research， the indicators of the hierarchical management standard for COPD patients were preliminarily compiled. A questionnaire was designed and administered to 18 experts， and Delphi method was conducted in two rounds to determine the contents of the standard. RESULTS The response rates for both rounds of expert consultation were 100%， with both authority coefficients of experts of 0.903 and Kendall coordination coefficiens of 0.279 and 0.189 for each indicator. The final established standard of hierarchical management for COPD patients included 25 stratified indicators and 17 pharmaceutical hierarchical management indicators. There were 9， 8 and 8 indicators in the high-risk， medium-risk， and stable layers， respectively， considering three aspects： disease， medication， and self-management level. The corresponding first-level， second- level， and third-level pharmaceutical management included 6， 6 and 5 indicators， respectively， including inhalation technical guidance， medication adherence guidance， treatment monitoring， and follow-up， etc. CONCLUSIONS The standard of hierarchical management for COPD patients established by Delphi method is scientific and reliable， which can provide a reference for pharmacists to carry out hierarchical management of COPD patients in China.

Objective:Assisted traction technology is effective in increasing the rate of super minimally invasive surgery (SMIS) in patients with early gastric cancer (EGC), and shortening the operator′s learning curve. We adopt the variable angle traction technique of tissue clamp dental floss as a traction technique in this research.Methods:Patients with early gastric cancer who were treated with SMIS - non full layer resection of EGC were enrolled in the First Medical Center of Chinese PLA General Hospital from January 2022 to June 2023. This research was carried out by experts at the same level. It was divided into two groups: traction and non-traction. Submucosal detachment time (SDT), submucosal detachment rate (SDS), lamina propria exposure, muscularis propria defect (MPD), bleeding during operation, block resection, surgical resection, hand operation expenses, and surgical instruments were recorded.Results:Nine patients adopted variable angle traction, and 9 patients did not. The overall resection rate and curative resection rate of both groups were 100%. The mean SDT time was 28.00 (21.00, 34.00) min in traction group and 56.00 (40.00, 85.00) min in non traction group. And it had statistical significance ( P = 0.005). The SDS was (0.58 ± 0.21) cm 2/min in traction group and (0.23 ± 0.10) cm 2/min in non-traction group. And it had statistical significance ( P<0.05). Exposure of intrinsic muscle layer (IML): 8 cases in the traction group and 6 cases in the non-traction group. Intraoperative IML injury: in the traction group, 8 cases were MPD-0 and 1 case was MPD-Ft; in the non-traction group, 4 cases were MPD-0, 1 case was MPD-Pt, and 4 cases were MPD-Ft. There was no statistical difference between the two groups in terms of intraoperative bleeding, hospitalization expenses, surgical expenses, and the total hospitalization time. There were no serious adverse reactions or outcomes. Conclusions:The variable angle traction method accelerates SDT and SDS for SMIS-non full layer resection of EGC. It has the advantages of the sufficient separation of IML and mucosal layer, the deeper dissection depth, the low injury of IML, low intraoperative bleeding, and no additional medical costs. Therefore, this method can become an auxiliary treatment technology for SMIS.

Objectives:To assess the effectiveness and safety of ivabradine for the treatment of chronic heart failure in the context of the new quadruple combination. Methods:Clinical data of 656 chronic heart failure patients hospitalized in Nanjing Drum Tower Hospital from March 2021 to June 2022 were retrospectively collected,and the patients were divided into control group(n=361)and observation group(n=295)according to ivabradine use,and both groups were treated with the new quadruple drug therapy.Propensity score matching was performed,268 patients in the observation group and 268 patients in the control group were successfully matched.The effectiveness(primary endpoint was the composite endpoint of cardiovascular death and rehospitalisation for worsening heart failure within 1 year of discharge;secondary endpoints were rehospitalisation for worsening heart failure,all-cause rehospitalisation,cardiovascular death,and all-cause death)and safety outcome measures(including bradycardia,atrial fibrillation,blurred vision,renal impairment,and hypertension)were compared between the two groups at 1 year after treatment. Results:After matching,there were no statistically significant differences at baseline characteristics between the two groups.Kaplan-Meier survival curve showed that the occurrence rates of primary endpoints(P=0.031),readmission for worsening heart failure(P=0.020),and all-cause readmission(P=0.036)were lower in the observation group than in the control group.Multivariate Cox proportional hazard regression analysis showed that the occurrence rates of primary endpoint events(P=0.045)and readmission for heart failure worsening(P=0.028)were lower in the observation group than in the control group. Conclusions:The ivabradine use on top of the new quadruple therapy regimen in patients with chronic heart failure is beneficial to improve one-year prognosis with favorable safety profile.

Objective To investigate the relationship between the development of terminal rectal ganglion and spinal cord/sacral abnormalities in boys with complex anorectal malformations(ARMs)in order to improve the understanding of rectal ganglion development abnormalities in ARMs patients.Methods A retrospective trial was conducted on the male patients with complex ARMs admitted to our hospital from 2015 to 2021.The terminal rectal specimens were taken from them during anoplasty.According to the findings on development of terminal rectal ganglion after HE staining,the patients were classified into G1 group(ganglion cells observed)and G2 group(no ganglion cells observed).Imaging techniques were used to evaluate whether there were abnormalities in the spinal cord and sacrum,and their correlation with the terminal rectal ganglion development was analyzed.Results A total of 139 patients were enrolled,and their median age at anoplasty was 5.77(4.57,6.97)months.There were no significant differences between the G1(n=80,57.6％)and G2(n=59,42.4％)groups in ARMs pathological type(P=0.706)and age at surgery(P=0.140).Radiological findings showed there were 48 cases(34.5％)of spinal cord anomalies(SCA),25 cases(18.0％)of sacral abnormalities and 18 cases(12.9％)of coccyx abnormalities.No significant differences were observed in the incidences of SCA and sacral abnormalities between the G1 and G2 groups(P＜0.05).Moreover,the differences of fatty filum terminale and syrinx were statistically significant(P＜0.05).In addition,the ratio of sacrum to coccyx between the G1 and G2 groups were 0.72±0.10 vs 0.67±0.12(P＜0.05)of the anteroposterior position and 0.77±0.09 vs 0.72±0.09(P＜0.05)of the lateral position.Multivariate logistic regression analysis showed that sacral abnormalities,fatty filum terminale and syrinx were independent predictors of rectal terminal ganglion absence in male patients with complex ARMs.Conclusion The development of terminal rectal ganglia in male patients with ARMs is closely associated with the abnormalities of spinal cord and sacrum.Sacral abnormalities,fatty filum terminale and syrinx are independent predictors of rectal terminal ganglion absence in male patients with complex ARMs.