OBJECTIVE To explore the improvement effect and potential mechanism of modified Yanghe decoction on bone destruction in rats with breast cancer bone metastasis based on the receptor-interacting serine/threonine-protein kinase 1 （RIPK1）/RIPK3 pathway. METHODS The rat model of breast cancer bone metastasis was established by injecting a suspension of breast cancer cells into the bone marrow cavity. The rats with successful modeling were randomly divided into a model group （intragastric administration of equal volume of normal saline）， modified Yanghe decoction low-， medium-， and high-dose groups （intragastric administration of corresponding decoction at 1.30， 2.60 and 5.20 g/kg， calculated by the dosage of crude drug）， high-dose modified Yanghe decoction+si-RIPK1 group （intragastric administration of corresponding decoction at 5.20 g/kg， calculated by the dosage of crude drug； simultaneous injection of small interfering RNA for RIPK1 via the tail vein）， and high-dose modified Yanghe decoction+si-NC group （intragastric administration of corresponding decoction at 5.20 g/kg， calculated by the dosage of crude drug； simultaneous injection of small interfering RNA for negative control via the tail vein）， with 12 rats in each group. Another 12 healthy rats were selected as the control group and were given the same volume of normal saline intragastrically， once a day， for 14 consecutive days. Body weight was measured before administration and at the end of the last administration. The mechanical pain threshold and thermal pain threshold were measured， and the bone destruction， pathological changes and osteoclast formation of the tibia were observed. The positive expression of receptor activator of nuclear factor-κB （RANK） and receptor activator of nuclear factor-κB ligand （RANKL） in the tibial tissue， as well as the phosphorylation levels of RIPK1， RIPK3 and mixed lineage kinase domain-like protein （MLKL） were detected. RESULTS Compared with the control group， the tumor cells of tibia tissues in rats of the model group showed significant proliferation and diffuse infiltration into the bone marrow cavity. Extensive areas of tumor necrosis of cells， severe bone destruction， thinning of the bone cortex， and damage to the bone trabeculae were observed. The body weight （before administration and at the end of the last administration）， mechanical pain threshold， thermal pain threshold， and the phosphorylation levels of RIPK1， RIPK3 and MLKL were decreased significantly； the tumor volume， the proportion of bone destruction area， the number of osteoclasts， and the positive expressions of RANK and RANKL were increased/up-regulated significantly （P＜0.05）. Compared with the model group， the above pathological changes in the tibial tissues of rats in modified Yanghe decoction low-， medium- and high-dose groups were all alleviated， and all quantitative indicators showed dose-dependent improvement （P＜0.05）. After silencing RIPK1， the aforementioned beneficial effects of high-dose modified Yanghe decoction were significantly weakened （P＜0.05）.CONCLUSIONSModified Yanghe decoction can alleviate bone destruction in rats with breast cancer bone metastasis. The above effect is related to the activation of the RIPK1/RIPK3 pathway.

ObjectiveTo establish an educational intervention framework of electronic picture books for children with autism spectrum disorder (ASD) based on Creative Problem Solving (CPS) model, and observe the effect on social function. MethodsElectronic picture books were designed using CPS model, including the program of reading, interactive animation design and associated artistic activities. From March to June, 2023, 24 children with mild to moderate ASD were recruited from Maanshan Institute of Special Education, and randomly assigned into experimental group 1 (CPS-based cognitive picture book interventions, n = 8), experimental group 2 (CPS-based social picture book interventions, n = 8) and control group (Bloom's Taxonomy-based picture book interventions, n = 8), and received the interventions for four weeks, with a total of twelve times. They were assessed with speech, social, perceptual and health behavior using Autism Treatment Evaluation Checklist (ATEC) before and after treatment, and the differences were calculated. ResultsThere was a significant difference among the groups in the social and perceptual scores differences (F > 4.344, P < 0.05) and a near-significant difference in the health behaviour score difference (F = 2.921, P = 0.076). Post Hoc test showed that the differences in social scores were higher in both experimental groups than in the control group (P < 0.05); the difference in perceptual scores was significantly higher in experimental group 1 than in experimental group 2 (P < 0.01), but there was no significant difference with the control group (P > 0.05); the difference in health behavior scores was higher in experimental group 2 than in the control (P < 0.05), and the difference in experimental group 1 was slightly higher than in the control group (P = 0.072). ConclusionElectronic picture book interventions based on the CPS model may be more effective in enhancing social, perceptual and health behavior in children with ASD, but there may be differences among models.

Objective: To investigate the clinical efficacy and safety of pudendal nerve modulation (PNM) in the treatment of female pudendal neuralgia (PN)，so as to promote the clinical application of this technique. Methods: A retrospective analysis was conducted on 20 female PN patients who failed conservative treatment at Gongli Hospital during Nov.2020 and Oct.2023.All patients underwent simultaneous PNM and sacral nerve modulation (SNM) with the assistance of 3D printing navigation.Dual-stage test electrodes for PNM and SNM were implanted，followed by alternate therapeutic trial for each modality.Secondary conversion rates and longitudinal outcomes，including visual analogue score (VAS)，patient health questionnaire-9 (PHQ-9)，and quality of life (QoL) scores were compared preoperatively，post-stage Ⅰ，and at 3，6，and 12 months post-stage Ⅱ. Results: All operations were successful.After the trial phase，the secondary conversion rate for PNM was significantly higher than that for SNM; 16 patients (16/20，80%) chose the second-phase PNM implantation surgery，3 (3/20，15%) chose second-phase SNM implantation，and 1 (1/20，5%) had electrodes removed due to ineffective results from both trials.Further assessment revealed that the improvements in VAS，PHQ-9，and QoL scores for PNM patients were significantly better than those for SNM patients after the first phase of surgery and at 3，6 and 12 months after the second-phase conversion (P<0.05).No complications such as electrode migration or infection were observed during the follow-up of 12-15 months. Conclusion: PNM provides more effective relief of pain symptoms and improvements in depressive states for female PN patients compared to SNM.With the assistance of 3D printing navigation，the operation is simple and safe，and offers stable therapeutic effects.It is worthy of clinical promotion and application.

BACKGROUND: Heavy metals are significant risk factors for kidney function. Numerous studies have shown that exposure to heavy metals negatively correlates with kidney function through oxidative stress pathways, and serum α-klotho is linked to oxidative stress. However, the role of α-klotho in the relationship between blood lead, mercury, and kidney function remains unclear. METHOD: This study evaluated the mediating role of alpha-klotho in the relationship between lead, mercury and renal function, using data from the 2007-2016 National Health and Nutrition Examination Survey (NHANES) in U.S. adults aged 40-79. The sample included 11,032 participants, with blood lead, mercury, α-klotho, and other relevant covariates measured. Inductively coupled plasma mass spectrometry was used to assess blood lead and mercury levels, and enzyme-linked immunosorbent assay (ELISA) was employed to measure serum α-klotho. Kidney function was evaluated using estimated glomerular filtration rate (eGFR) based on creatinine levels. Multivariable linear regression was conducted to analyze the relationships between blood lead, mercury, α-klotho, and eGFR. A mediation analysis model was used to assess whether α-klotho influenced these associations. RESULTS: We observed a significant association between blood lead and eGFR. Mediation analysis revealed that α-klotho accounted for 12.76% of the relationship between serum lead and eGFR in the NHANES population. Subgroup analysis showed that α-klotho mediated 12.43%, 6.87%, 21.50% and 5.44% of the relationship between blood lead and eGFR in women, middle-aged adults (40-59 years old), without cardiovascular disease and hypertension, respectively. However, α-klotho did not mediate the relationship between blood mercury and eGFR in terms of gender or age. This newly identified pathway may provide valuable insights for the prevention and treatment mechanisms related to kidney function impairment. CONCLUSION We found that blood lead was associated with renal function. According to the results of subgroup analysis, for blood lead, serum α-klotho mediated the association in females, middle aged 60-79 years. The relationship between blood mercury and renal function was not clinically significant, and serum α-Klotho mediated the relationship between blood mercury and renal function without significant clinical significance.
Humans ; Middle Aged ; Lead/blood* ; Female ; Klotho Proteins ; Male ; Aged ; Adult ; Mercury/blood* ; Glomerular Filtration Rate ; Nutrition Surveys ; United States ; Kidney/physiology* ; Glucuronidase/blood* ; Environmental Pollutants/blood*

OBJECTIVE: To investigate the role of telomerase reverse transcriptase (TERT) in alleviating doxorubicin (DOX)-induced cardiotoxicity. METHODS: (1) Cell experiments: rat H9c2 cardiomyocytes were divided into control group (CON group), null adenovirus transfection group (NC group), TERT overexpression adenovirus transfection group (TERT group), DOX group (treated with 1 μmol/L DOX for 12 hours), DOX+NC group, and DOX+TERT group (null adenovirus or TERT overexpression adenovirus were transfected for 24 hours and then treated with 1 μmol/L DOX for 12 hours). The mRNA expression of TERT in cardiomyocytes was detected by real-time fluorescence quantitative polymerase chain reaction (RT-qPCR). The level of mitochondrial membrane potential was detected by immunofluorescence. The expression levels of intracellular Bax, Bcl-2, microtubule-associated protein 1 light chain 3 (LC3) and p62 were detected by Western blotting. (2) Animal experiments: male C57BL/6 mice were randomly divided into a sham operation group (Sham group), DOX group (acute cardiotoxicity model was constructed by intraperitoneal injection of DOX 15 mg/kg), DOX+NC group and DOX+TERT group (modeled after transfection with airborne adenovirus or TERT overexpression adenovirus for 7 days). After 7 days of modeling, the area of myocardial fibrosis was detected by Sirius scarlet staining, and cardiac function was detected by echocardiography. RESULTS: (1) Cellular experiments: the mRNA expression level of TERT was significantly higher in the TERT group compared with the CON and NC groups. Compared with the CON group, the TERT mRNA expression level of cardiomyocytes in the DOX group and the DOX+NC group were significantly lower, the level of mitochondrial membrane potential was significantly lower, the protein expressions of Bax and LC3 were significantly increased, and the protein expressions of Bcl-2 and p62 were significantly decreased. No significant differences were found between the DOX group and DOX+NC group. Compared with the DOX group and DOX+NC group, the TERT mRNA expression level was increased in the DOX+TERT group (relative expression: 1.02±0.10 vs. 0.61±0.05, 0.54±0.03, both P < 0.05), the level of mitochondrial membrane potential was significantly increased (1.14±0.05 vs. 0.96±0.01, 0.96±0.01, both P < 0.05), the protein expressions of Bax and LC3 were significantly decreased, and the protein expressions of Bcl-2 and p62 were significantly increased (Bax/β-actin: 0.88±0.01 vs. 1.31±0.02, 1.26±0.01; LC3-II/I: 2.16±0.05 vs. 2.64±0.06, 2.58±0.02; Bcl-2/β-actin: 0.65±0.01 vs. 0.40±0.01, 0.41±0.01; p62/β-actin: 0.45±0.01 vs. 0.23±0.02, 0.29±0.01; all P < 0.05). (2) Animal experiments: compared with the Sham group, the percentage of myocardial fibrosis area was significantly increased and left ventricular ejection fraction (LVEF) and fractional shortening (FS) were significantly decreased in the DOX group and DOX+NC group. Compared with the DOX group and DOX+NC group, the percentage of myocardial fibrotic area was significantly decreased in the DOX+TERT group (%: 2.33±0.06 vs. 3.76±0.07, 3.87±0.06, both P < 0.05), and the LVEF and FS were significantly increased [LVEF (%): 67.00±1.14 vs. 54.60±1.57, 53.40±2.18; FS (%): 38.60±0.51 vs. 30.60±1.10, 30.00±0.71; all P < 0.05]. CONCLUSION Up-regulation of TERT expression can inhibit DOX-induced cardiomyocyte autophagy and apoptosis, attenuate DOX-induced myocardial fibrosis in mice, improve cardiac function, and thus alleviate DOX-induced cardiotoxicity.
Animals ; Doxorubicin/toxicity* ; Telomerase/metabolism* ; Myocytes, Cardiac/metabolism* ; Rats ; Male ; Cardiotoxicity ; Mice, Inbred C57BL ; Mice ; Membrane Potential, Mitochondrial ; Adenoviridae ; bcl-2-Associated X Protein/metabolism* ; Proto-Oncogene Proteins c-bcl-2/metabolism* ; Transfection ; Apoptosis

Objective To analyze the characteristics of influenza incidence and the changes of innate immune cells among children who visited the pediatric outpatient or emergency department of a hospital in Shanghai from Jan.2019 to Dec.2023,so as to provide references for the prevention of influenza in children.Methods Influenza-like illness(ILI)children who first visited the pediatric outpatient or emergency department of The First Affiliated Hospital of Naval Medical University from Jan.2019 to Dec.2023,and underwent influenza virus antigen or nucleic acid testing were enrolled.Their clinical and laboratory data were collected for retrospective analysis.With a month as the basic monitoring unit,a line chart was used to describe the changes in the number of influenza cases and the positive rate.Then,these cases were assigned to pre-coronavirus disease 2019(COVID-19)group(Jan.2019 to Dec.2019),mid-COVID-19 group(Jan.2020 to Dec.2022),or post-COVID-19 group(Jan.2023 to Dec.2023),and the influenza positive rates among these groups were compared.To further observe the changes of the innate immune cells of children with influenza A after non-pharmacological intervention(NPI)measures,considering the development characteristics of children's white blood cells,children with influenza A were assigned to 2 subgroups according to age:0-6 years or 7-16 years.Within each subgroup,they were assigned to pre-NPI group or post-NPI group according to time.A ratio of 1∶1 matching was carried out according to gender and age using propensity score matching,and the blood routine parameters were compared between the 2 groups.Results A total of 41 028 ILI children were enrolled.During the COVID-19 period from Jan.2020 to Dec.2022,the influenza positive rates decreased significantly(P＜0.001),and almost no influenza virus was detected.The peak of influenza reappeared in Mar.2023,with a lag in the peak period,but higher than previous years'peak,and the speed of reaching the peak was faster.In each subgroup,the white blood cell count and lymphocyte ratio of children with influenza A in the post-NPI group were lower than those in the pre-NPI group(all P＜0.001),and the monocyte ratio was higher than that in the pre-NPI group(both P＜0.001).Conclusion The implementation of NPI measures during COVID-19 leads to disruption of influenza transmission route and changes in the epidemic trend of influenza.The influenza virus causes serious public health problems after COVID-19 period,and children with influenza A experience more serious immune response.It is recommended to strengthen the vaccination of influenza vaccine before the flu season.

Objective:To explore the external treatment methods of hemorrhoids based on ancient books and documents; To guide clinical medication.Methods:The relevant articles on external treatment of hemorrhoids using Chinese materia medica included in Zhong Hua Yi Dian (5th edition) were retrieved. Excel 2021 was used to analyze the properties, tastes, meridian tropism, external treatment methods and drug efficacy of Chinese materia medica included in the prescriptions, and the relevant discussion contents were sorted out according to the classification of external treatment methods of hemorrhoids. Results:A total of 255 articles in ancient books were included, involving 165 prescriptions. 146 kinds of Chinese materia medica for external treatment of hemorrhoids were selected. The medicinal properties were mainly cold and warm, the main tastes were pungent, bitter and sweet, and the meridian tropism mainly involved the liver, spleen, stomach, heart, lung and large intestine meridians. Fumigation, application and application are the most widely used external treatment methods. Chinese materia medica efficacy mainly includes heat clearing drugs, surface relieving drugs, resuscitation drugs, astringent drugs, anti venom, anti insect and anti itching drugs, and tonic drugs.Conclusions:Ancient physicians treated hemorrhoids with both cold and heat, and paid equal attention to clearing heat and reducing fire, warming and activating blood circulation. They paid attention to the combination of local medication of lesions and the overall treatment of multiple meridians and multiple viscera, so as to achieve the simultaneous treatment of specimens. The treatment methods were rich, including fumigation and washing method to improve local microcirculation, application method using natural adhesive, coating method focusing on precise administration and ligation method of minimally invasive, forming a unique external treatment system, which can be used for modern clinical reference.

Objective To develop a machine learning(ML)-based prediction model for assessing the therapeutic effects of resveratrol(RES)on the pathological damage of acute pancreatitis(AP),and to optimize RES administration strategies for AP through validation using an animal model.Methods AAn ML-based prediction model was constructed using published data.Interpretability analysis was applied to identify high-efficacy zones within the parameter space of administration dose and frequency,which was followed by rigorous screening to select the optimal dosing strategy that balanced therapeutic efficacy and experimental feasibility.A total of 32 C57BL/6 mice were randomly assigned to 4 groups(n=8 per group),including a control group(Ctrl),an AP model group induced by caerulein(CER)and referred to as CER-AP,a treatment group receiving RES via intraperitoneal injection(RES i.p.),and a treatment group receiving RES via intragastric gavage(RES i.g.).The Ctrl group received intraperitoneal injection of normal saline.The CER-AP and the treatment groups were induced with 10 intraperitoneal injections of CER at 50 μg/kg.RES was administered to the RES i.p.and RES i.g.groups according to the optimal dose and timing predicted by the ML model.Blood and tissue samples were collected 12 hours after the experiment started.Results The gradient boosting decision tree model,optimized via Hyperopt,yielded the best performance,predicting that the optimal dose and administration frequency were 19.992 mg/kg and 3.828 times,respectively.Accordingly,a regimen of 20 mg/kg RES,administered four times,was used in the animal experiments.Compared with the Ctrl group,the CER-AP group exhibited higher pancreatic pathology scores and elevated levels of serum amylase,lipase,pancreatic myeloperoxidase,and trypsin,with all differences reaching statistical significance(all P<0.05).The administration of 20 mg/kg RES via both intraperitoneal injection and intragastric gavage mitigated pancreatic inflammatory cell infiltration and necrosis,improved the overall pathology score,and reduced serum amylase,lipase,and pancreatic myeloperoxidase levels to varying degrees(all P<0.05).Conclusion A regimen of 20 mg/kg RES administered four times effectively alleviates the severity of CER-induced AP.The therapeutic benefits appear to arise from a multi-target regulatory network that simultaneously suppresses inflammatory cascades,mitigates oxidative stress,and reduces apoptosis,thereby reducing pancreatic tissue damage and systemic inflammatory responses.

Objective:To investigate whether sivelestat sodium (SV) mitigates paraquat (PQ)-induced acute lung injury (ALI)/acute respiratory distress syndrome (ARDS)-associated pulmonary fibrosis in mice by suppressing the NLRP3 inflammasome signaling pathway.Methods:Male C57BL/6J mice were randomly divided into four groups ( n=8 per group): Control group, PQ group, PQ+SV group, and SV group. The PQ and PQ+SV groups received an intraperitoneal injection of PQ solution (20 mg/kg) to establish a PQ poisoning model, while the Control and SV groups received an equivalent volume of saline. One hour later, the PQ+SV and SV groups were administered SV solution (100 mg/kg) intraperitoneally, whereas the Control and PQ groups received saline. After 48 hours, the mice were euthanized, and lung tissues were collected. Pathological changes were assessed via hematoxylin-eosin (HE) and Masson staining, followed by Smith and Ashcroft scoring. Immunohistochemistry was performed to evaluate the expression of NLRP3 inflammasome, caspase-1, α-smooth muscle actin (α-SMA), and collagen I. Western blotting was used to measure NLRP3 protein levels. Intergroup comparisons were conducted using one-way ANOVA with LSD post-hoc correction. Results:The Control and SV groups exhibited normal lung morphology, whereas the PQ+SV group showed reduced hemorrhage, congestion, and edema compared to the PQ group. Both PQ and PQ+SV groups exhibited significant weight loss post-intervention compared to the Control group (both P<0.001). HE and Masson staining revealed thickened alveolar septa, congestive and edematous alveolar walls, extensive inflammatory cell infiltration, and collagen deposition in the PQ group. In contrast, the PQ+SV group demonstrated alleviated alveolar wall congestion, reduced inflammatory infiltration, and decreased collagen deposition, with significantly lower Smith and Ashcroft scores [(5.92±1.34) vs. (10.88±1.88), P<0.001; (3.42±1.35) vs. (5.75±0.79), P<0.001]. Immunohistochemistry indicated reduced expression percentages of NLRP3 and caspase-1 in the PQ+SV group compared to the PQ group [(12.79%±0.43%) vs. (16.59%±0.40%), P<0.001; (17.71%±0.92%) vs. (19.84%±0.71%), P<0.001]. Similarly, α-SMA and collagen I expression in lung interstitium was significantly lower in the PQ+SV group [(11.79%±0.58%) vs. (16.14%±0.74%), P<0.001; (16.43%±0.56%) vs. (18.86%±0.60%), P<0.001]. Western blotting confirmed decreased NLRP3 protein expression in the PQ+SV group [(0.54±0.12) vs. (0.81±0.24), P<0.05]. Conclusions:SV attenuates PQ-induced ALI/ARDS-associated pulmonary fibrosis progression by inhibiting the NLRP3 inflammasome, suggesting that NLRP3 may be a key therapeutic target for early intervention in PQ-induced pulmonary fibrosis.

Objective To evaluate the efficacy of transurethral resection of bladder tumor(TURBT)in treating cystitis glandularis(CG),and to explore the influencing factors.Methods A retrospective analysis was conducted on 243 CG patients treated with TURBT during Jan.2013 and Dec.2020 in our hospitals.Postoperative efficacy was assessed using global response assessment(GRA).The correlation between GRA score and the demographic characteristics,comorbidities,initial complaints,and postoperative recurrence was determined with logistic regression analysis.Results Among the 243 patients,3.70％(9/243)had dysplasia,2.47％(6/243)had exuberant hyperplasia of Brinell's nest,and 2.06％(5/243)had intestinal metaplasia.The mean GRA score was(2.02±0.72)after a follow-up of(47.10±28.53)months.Re-operation was performed in 10.29％(25/243)of the patients due to recurrence,and the improvement of hydronephrosis and dysuria was 70.59％(12/17)and 50.00％(15/30),respectively.Pelvic fat increase developed in 1 patient(0.41％)after surgery.Logistic regression analysis showed that postoperative GRA score was not significantly correlated with demographic characteristics,body mass index,comorbidities,alcoholism and postoperative recurrence(P＞0.05).Conclusion TURBT is an effective method in the treatment of CG,which can significantly improve patients'hydronephrosis and dysuria.However,approximately 10％of the patients experience recurrence,necessitating further surgery,which suggests the need for vigilance regarding potential recurrence during treatment.