ObjectiveTo evaluate the clinical efficacy and safety of Qidan Tangshen Granules （芪丹糖肾颗粒， QTG） in the treatment of early diabetic kidney disease （DKD） with qi deficiency， blood stasis， and kidney deficiency syndrome， and to explore its mechanism. MethodsA double-blind， double-simulated method was used to enroll 200 patients with early DKD and qi deficiency， blood stasis， and kidney deficiency syndrome. Patients were randomly assigned in a 1∶1 ratio to the treatment group （100 cases） and the control group （100 cases）. The treatment group received QTG plus a valsartan capsule simulant， while the control group received valsartan capsules plus a QTG simulant， both for 12 weeks. The primary outcome was the urinary albumin-to-creatinine ratio （UACR）. Secondary outcomes included estimated glomerular filtration rate （eGFR）， fasting blood glucose （FBG）， 2-hour postprandial blood glucose （PBG）， glycated hemoglobin （HbA1c）， and traditional Chinese medicine （TCM） syndrome scores （including individual symptom scores for fatigue， dull complexion， soreness and weakness of the waist and knees， headache and chest pain， irritability， spontaneous sweating， thirst and polydipsia， polyphagia， polyuria， numbness of the limbs， and the total TCM syndrome score）. Oxidative stress markers including serum 8-hydroxy-2'-deoxyguanosine （8-OHDG）， 3-nitrotyrosine （3-NT）， and superoxide dismutase （SOD） were also assessed. Clinical efficacy and TCM syndrome efficacy were evaluated after treatment， and routine blood tests， urinalysis， and liver function tests were conducted and adverse reaction during the tria was recorded to assess safety. ResultsA total of 191 patients completed the study （95 in the treatment group and 96 in the control group）. The treatment group showed significant reductions in UACR， FBG， PBG， and HbA1c levels after treatment （P＜0.05 or P＜0.01）. The single TCM symptom scores except for polyphagia and total TCM syndrome scores significantly decreased （P＜0.05 or P＜0.01）. Compared to the control group， the treatment group had signi-ficantly lower UACR， FBG， PBG levels， and total TCM syndrome scores， sinlge symptoms scores except for polyphagia and limb numbness （P＜0.05 or P＜0.01）. Among 40 randomly selected patients （21 cases in the treatment group and 19 cases in the control group） for oxidative stress analysis， there were no significant differences in SOD， 3-NT， and 8-OHDG levels before and after treatment within or between groups （P＞0.05）. The overall effective rate in the treatment group was 64.2% （61/95） and 39.6% （38/96） in the control group， while the TCM syndrome efficacy rates were 80.0% （76/95） and 24.0% （23/96）， respectively， with the treatment group showing superior efficacy （P＜0.01）. No significant differences were observed in routine blood tests， urinalysis， or liver function indices before and after treatment in either group （P＞0.05）. The incidence of adverse reactions was 8.4% （8/95） in the treatment group and 9.4% （9/96） in the control group， with no statistically significant difference （P＞0.05）. ConclusionQTG can effectively reduce UACR and blood glucose levels， alleviate clinical symptoms， and improve clinical efficacy in patients with early DKD with qi deficiency， blood stasis， and kidney deficiency syndrome. The treatment is well-tolerated and safe， with no significant impact on oxidative stress markers.

Objective: To explore the influence of group psychological counseling on the mental health of children with mother s authoritarian parenting. Methods: From November 2022 to February 2023, 76 students from grades 4 to 6 whose mother showed authoritarian parenting style, while fathers adopted no authoritative, authoritarian or democratic parenting style and who scored ≥65 on the total MHT were selected using the Parenting Style Questionnaire (PBI) and the Mental Health Diagnostic Test (MHT). All the participants and their mothers were randomly assigned to the intervention and control groups. Before and after the intervention, participants filled out questionnaires on parental bonding instrument and mental health test. Control group: regular delivery of mental health education information, 2 times per week, for 8 weeks, without any other intervention. Intervention group: group counseling activities were conducted once a week. Each intervention lasted 1.5-2 hours and lasts for 8 weeks. Before and after the intervention, participants filled in the family parenting style and mental health screening questionnaires. Results: After the intervention, compared with the control group, students in the intervention group showed a significant decrease in the total scale score of the MHT, learning anxiety, social anxiety, allergic tendency, physical symptoms, fear tendency, and impulsive tendency ( t=-0.43, -1.04 , -0.81, P >0.05). After intervention, the intervention group students showed a significant decrease in psychological diagnosis test scores, learning anxiety, anxiety towards others, allergic tendencies, physical symptoms, phobic tendencies, and impulsive tendencies compared to the control group students ( t=-20.00, -5.06, -2.09, -3.36, -6.15, -4.76, -5.15, P <0.05). Conclusion Rregular group psychological counseling can effectively improve the academic anxiety, social anxiety, allergic tendencies, physical symptoms, fearful and impulsive tendencies of students whose mothers with authoritarian parenting style, and greatly improve their mental health.

Objective To investigate the correlation between brain injury and spleen damage in a rat model of acute ischemic stroke and stasis interaction,and its effect on the MCP-1/CCR2 axis,and to provide an experimental basis for the mechanism of brain-spleen inflammatory coupling in spleen lesions caused by acute ischemic stroke.Methods Forty male SD rats were randomly divided into a sham group,carrageenan/yeast stasis syndrome group(carrageenan/yeast,CA/Y),middle cerebral artery occlusion group(MCAO),and middle cerebral artery stasis syndrome group(MCAO CA/Y)with 10 rats in each group.CA/Y and MCAO CA/Y groups were injected with 10 mg/kg carrageenan and 10 mg/kg intraperitoneally on the first day of modeling.2 mg/kg of dry yeast suspension were injected subcutaneously on the second day.MCAO and MCAO CA/Y groups were established by wire embolism on the second day.At 24 h after cerebral infarction modeling,the neurological deficit score was calculated in each group,the percentage of the cerebral infarction area was determined by TTC staining,the spleen weight was measured,and the correlation between the percentage of the cerebral infarction area and spleen weight was analyzed by the Spearman correlation coefficient.Furthermore,the pathological morphology of brain and spleen tissues was observed by hematoxylin-eosin(HE)staining,and chemotactic protein 1(MCP-1)and interferon-γ(IFN-γ)contents were measured in rat plasma by enzyme-linked immunosorbent assays.Western blot was used to detect chemokine C-C-motif receptor 2(CCR2)protein expression in the ischemic side of brain tissue.Results Compared with the sham group,the neurological deficit score,cerebral infarction area,and MCP-1 and IFN-γ contents in plasma were significantly increased(P＜0.01),spleen weight was decreased significantly(P＜0.01),and CCR2 protein expression in brain tissue was significantly upregulated(P＜0.05)in MCAO and MCAO CA/Y groups.Moreover,the area of cerebral infarction was increased significantly(P＜0.01),the spleen weight was decreased significantly(P＜0.01),and CCR2 protein expression in brain and spleen tissues was significantly upregulated(P＜0.05)Compared with the MCAO group,the area of cerebral infarction in the MCAO CA/Y group was significantly increased(P＜0.01)and the spleen weight was decreased significantly(P＜0.05).Spearman correlation analysis showed that the spleen weight was negatively correlated to the percentage of the cerebral infarction area(P＜0.01,r=-0.9711).Pathological morphology observation revealed that the pathological changes in the MCAO CA/Y group were the most serious,cerebral liquefaction necrosis foci were seen in the brain tissue cortex,arrangement of neuronal cells in the lesions was sparse and disordered with volume atrophy and a small number of vacuoles and nuclear solidification,most neuronal cells were degenerated and necrotic,microglia hyperplasia was obvious,small blood vessels were significantly increased,and interstitial lipid degeneration was severe.The density of periarterial lymph sheath cells in some of the spleen tissue was reduced and the marginal area is widened.Conclusions A correlation between brain and spleen injury was found after acute ischemic stroke with stasis and toxin syndrome,and the chemokine signaling axis of MCP-1/CCR2 might be involved in the mechanism of brain-spleen inflammation coupling.

Objective To with analyzing the gene expression profile of idiopathic non-cirrhotic portal hypertension(INCPH)by bioinformatics methods,we may obtain its key genes and signaling pathways to explore the molecular mechanism of INCPH and predict the potential traditional Chinese medicine.Methods The gene microarray dataset GSE77627 on INCPH was downloaded from gene expression omnibus(GEO)database,the data were normalized and screened for differential genes(DEGs)of INCPH using R language,and all DEGs were analyzed for gene ontology(GO)and Kyoto encyclopedia of genes and genomes(KEGG)enrichment using Metascape database,and protein-protein interaction network was constructed by STRING database;meanwhile DEGs with the top 15 Degree values were screened as key genes using CytoHubba plugin.Subsequently,the key genes were mapped to each other with the medical ontology information retrieval platform(coremine medical)to screen potential Chinese herbal medicines for the treatment of INCPH with P<0.05,and the potent components that potential Chinese medicines have were screened from the TCMSP database,imported into Cytoscape software to construct a Chinese medicine correlation network map and predict the key targets.Results A total of 1880 DEGs were screened,including 1061 up-regulated and 819 down-regulated genes.DEGs were analyzed using the protein interaction database STRING and cytoHubba in Cytoscape software to obtain key genes,which were RPS27A,CDC42,EIF4E,MAPK1,PIK3R1,RPS6,RPS9,RPS8,RPL15,RPL27A,RPL24,RPL27,RPL26,RPL12 and MAPK14.The GO and KEGG analysis mainly involved gamete production and AGE-RAGE signaling pathway in INCPH.Conclusion The potential traditional Chinese medicines screened for INCPH are Ginseng Radix et Rhizoma,Salviae Miltiorrhizae Radix et Rhizoma,Scutellariae Radix,etc,which may be a potential source of molecular drugs for the treatment of INCPH.

Objective:To compare the efficacy of minimally invasive steel plate combined with percutaneous hollow nail fixation through the sinus tarsi incision versus "L"-shaped incision steel plate fixation in the treatment of calcaneal fractures.Methods:A retrospective analysis was conducted on 103 cases of Sanders type II-IV calcaneal fractures treated with minimally invasive steel plate combined with percutaneous hollow nail fixation through sinus tarsi incision from January 2017 to March 2024 at the orthopedic department of Hangzhou Sir Run Run Shaw Hospital (minimally invasive group). An additional 103 cases treated with "L"-shaped incision steel plate fixation during the same period were included as controls (open group). The preoperative hospital stay, surgical time, postoperative hidden blood loss, postoperative hospital stay, postoperative infection rate, postoperative Bohler angle, Gissane angle, calcaneal mid-width, sustentacular effective fixation rate, and American Orthopaedic Foot and Ankle Society (AOFAS) ankle-hindfoot score at 6 and 12 months postoperatively were compared between the two groups.Results:There were no statistically significant differences in age, gender, diabetes, smoking history, and body mass index between the minimally invasive group and the open group ( P>0.05). In the minimally invasive group, the preoperative hospital stay (3.1±1.5 days), postoperative hospital stay (3.5±1.5 days), hidden blood loss (293.3±71.4 ml), surgical time (64.4±13.2 min), and AOFAS score at 6 months postoperatively (79.9±3.9) were superior to those in the open group (7.1±0.7 days, 5.6±0.9 days, 408.3±101.7 ml, 91.5±24.3 min, and 70.5±6.1, respectively) ( P<0.05), with no significant difference in AOFAS score at 1 year postoperatively ( P>0.05). Additionally, the preoperative hospital stay (3.7±1.5 days), postoperative hospital stay (4.0±2.0 days), hidden blood loss (336.3±75.3 ml), and AOFAS score at 6 months postoperatively (77.4±3.8) in the minimally invasive group were superior to those in the open group (7.6±0.9 days, 8.2±2.6 days, 441.3±89.2 ml, and 64.6±8.4, respectively) ( P<0.05), with no significant difference in surgical time and AOFAS score at 1 year postoperatively ( P>0.05). Within-group comparisons indicated that as fracture severity increased, preoperative ( P<0.05) and postoperative hospital stays ( P<0.05) increased in the open group, while surgical time increased in the minimally invasive group ( P<0.05). AOFAS scores at 6 months postoperatively varied between complex and simple fractures in both groups ( P<0.05). There were no statistically significant differences in postoperative Bohler angle, Gissane angle, and calcaneal mid-width between the two groups ( P>0.05). The sustentacular effective fixation rate in the minimally invasive group was 85.4%, superior to 47.4% in the open group for simple fractures ( P<0.05), with no statistically significant difference for complex fractures ( P>0.05). The incision infection rate was 0 in the minimally invasive group compared to 3 cases (3%) in the open group, with no statistically significant difference ( P=0.246). Conclusion:Minimally invasive steel plate combined with percutaneous hollow nail fixation through sinus tarsi incision for calcaneal fractures offers the advantages of shorter hospital stay, reduced surgical trauma, lower incision infection rate, and better short-term efficacy compared to open incision. It is suitable for most Sanders type II-IV calcaneal fractures.

Both cholinergic dysfunction and protein citrullination are the hallmarks of rheumatoid arthritis (RA), but the relationship between the two phenomena remains unclear. We explored whether and how cholinergic dysfunction accelerates protein citrullination and consequently drives the development of RA. Cholinergic function and protein citrullination levels in patients with RA and collagen-induced arthritis (CIA) mice were collected. In both neuron-macrophage coculture system and CIA mice, the effect of cholinergic dysfunction on protein citrullination and expression of peptidylarginine deiminases (PADs) was assessed by immunofluorescence. The key transcription factors for PAD4 expression were predicted and validated. Cholinergic dysfunction in the patients with RA and CIA mice negatively correlated with the degree of protein citrullination in synovial tissues. The cholinergic or alpha7 nicotinic acetylcholine receptor (α7nAChR) deactivation and activation resulted in the promotion and reduction of protein citrullination in vitro and in vivo, respectively. Especially, the activation deficiency of α7nAChR induced the earlier onset and aggravation of CIA. Furthermore, deactivation of α7nAChR increased the expression of PAD4 and specificity protein-3 (SP3) in vitro and in vivo. Our results suggest that cholinergic dysfunction-induced deficient α7nAChR activation, which induces the expression of SP3 and its downstream molecule PAD4, accelerating protein citrullination and the development of RA.

OBJECTIVE: To screen for small molecular compounds with selective inhibitory activity against cutaneous melanoma cells with BAP1 deletion. METHODS: Cutaneous melanoma cells expressing wild-type BAP1 were selected to construct a BAP1 knockout cell model using CRISPR-Cas9 system, and small molecules with selective inhibitory activity against BAP1 knockout cells were screened from a compound library using MTT assay. Rescue experiment was carried out to determine whether the sensitivity of BAP1 knockout cells to the candidate compounds was directly related to BAP1 deletion. The effects of the candidate compounds on cell cycle and apoptosis were detected with flow cytometry, and the protein expressions in the cells were analyzed with Western blotting. RESULTS: The p53 activator RITA from the compound library was shown to selectively inhibit the viability of BAP1 knockout cells. Overexpression of wild-type BAP1 reversed the sensitivity of BAP1 knockout cells to RITA, while overexpression of the mutant BAP1 (C91S) with inactivated ubiquitinase did not produce any rescue effect. Compared with the control cells expressing wild-type BAP1, BAP1 knockout cells were more sensitive to RITA-induced cell cycle arrest and apoptosis (P < 0.0001) and showed an increased expression of p53 protein, which was further increased by RITA treatment (P < 0.0001). CONCLUSION Loss of BAP1 results in the sensitivity of cutaneous melanoma cells to p53 activator RITA. In melanoma cells, the activity of ubiquitinase in BAP1 is directly related to their sensitivity to RITA. An increased expression of p53 protein induced by BAP1 knockout is probably a key reason for RITA sensitivity of melanoma cells, suggesting the potential of RITA as a targeted therapeutic agent for cutaneous melanoma carrying BAP1-inactivating mutations.
Humans ; Melanoma ; Skin Neoplasms ; Tumor Suppressor Protein p53 ; Apoptosis ; Cell Division ; Tumor Suppressor Proteins/genetics* ; Ubiquitin Thiolesterase/genetics*

OBJECTIVE To investigate the efficacy and safety of aerosol inhalation of polycolistin B in the treatment of severe pneumonia combined with mechanical ventilation， and to provide a reference of real-world data for clinical drug therapy. METHODS A retrospective cohort study was conducted to analyze the clinical data of 87 patients with severe pneumonia combined with mechanical ventilation at the First Affiliated Hospital of Shandong First Medical University from January 2021 to February 2023. According to route of administration， all patients were divided into combined group （24 cases， receiving aerosol YXH2021ZX013） inhibition of polycolistin B combined with intravenous dripping） and routine group （63 cases， intravenous dripping of polycolistin B alone）. The differences in efficacy （mortality，clinical response rate and bacterial clearance rate）and safety （elevated serum creatinine， bronchospasm and skin pigmentation） were compared between two groups； the influential factors of primary outcome index as mortality were analyzed through univariate analysis and multivariate Logistic regression analysis. RESULTS In terms of efficacy， there were no statistical differences in mortality（37.50% vs. 41.27%， P＝0.749）， clinical response rate （54.17% vs. 55.56%， P＝0.907） and bacterial clearance rate （45.83% vs. 44.44%， P＝0.907） between the two groups. In terms of safety， the incidence of bronchospasm in the combined group was significantly higher than that of the routine group （12.50% vs. 0， P＝0.028）， but the differences in incidence of elevated serum creatinine and skin pigmentation between two groups were not statistically significant （P＞0.05）. Univariate analysis showed that the moralities were higher in the case of infected with Acinetobacter baumannii， Klebsiella pneumoniae and combined use of quinolones （P＜0.05）； multivariate Logistic regression analysis showed that infection with A. baumannii （OR＝3.36， P＝0.014） and combined use of quinolones （OR＝3.54， P＝0.013） were independently associated with mortality （P＜0.05）. CONCLUSIONS For severe pneumonia patients with mechanical ventilation， intravenous dripping of polycolistin B combined with aerosol inhalation does not show superior efficacy compared with intravenous dipping of polycolistin B alone， but significantly increases the incidence of bronchospasm. Infection with A. baumannii and combined use of quinolones are independent risk factors for the increase of mortality.

OBJECTIVE To analyze the dose-adjusted concentrations of Posaconazole oral suspension in patients undergoing hematopoietic stem cell transplantation （HSCT） and their influential factors. METHODS Data were collected from hospitalized HSCT patients admitted to the First Affiliated Hospital of Shandong First Medical University （Shandong Provincial Qianfoshan Hospital） from January 2021 to April whtwhm@yeah.net 2023 who took Posaconazole oral suspension for the prevention of invasive fungal disease （IFD） and received blood concentration of posaconazole. The rate of concentration attainment and clinical failure rate of posaconazole for the prevention of IFD were evaluated， and one-way and multiple linear regression analyses were performed for the influential factors of dose-adjusted concentrations （C0/D） of posaconazole. RESULTS A total of 44 patients were enrolled； the mean C0 of posaconazole in patients was （0.99±0.94） µg/mL， and 20 patients had a C0≥0.7 μg/mL， with a concentration attainment rate of 45.45% for the prevention of IFD； 13 cases were clinical failures， with a clinical failure rate of 29.55%. Of 24 patients who did not achieve C0/D of posaconazole for IFD prophylaxis， one patient was a clinical failure despite timely dose adjustment of posaconazole in seven patients； seven of the thirteen patients who did not undergo dose adjustment were clinical failures； and the remaining four patients were switched to other antifungal agents. The results of univariate analysis showed that gender， body mass index （BMI）， renal function， combined use of sodium phenytoin， omeprazole and metoclopramide had a significant effect on the C0/D of posaconazole （P＜0.05）； the results of multivariate linear regression analysis showed that gender， BMI and combined use of sodium phenytoin were the independent factors affecting the C0/D of posaconazole （P＜0.05）. CONCLUSIONS Significant individual differences are reflected in the blood concentration of Posaconazole oral suspension； gender， BMI and combined use of sodium phenytoin are independent factors affecting the C0/D of posaconazole.

Objective:To explore the mechanism of biliary fibrosis after end to end anastomosis of bile duct.Methods:12 Neijiang miniature pigs (6-8 months old, weight 30-40 kg) were divided into experimental group ( n=6) and control group ( n=6). The model of end to end anastomosis after transection of the common bile duct was established in experimental group. Control group was a sham operation group, and only T tube was placed. After 9 months, Masson staining, fluorescence quantitative PCR and immunohistochemistry were used to analyze the expressing changes of pro-fibrotic factor transforming growth factor-β1 (TGF-β1), connective tissue growth factor (CTGF) and epithelial-mesenchymal transition (EMT) markers, including cytokeratin-19 (CK19), E-cadherin (E-Cad) and fibroblast specific protein-1 (S100A4), α-smooth muscle actin (α-SMA) and collagen components Collagen I (COL-1), collagen III (COL-3) and fibronectin (FN) in the anastomotic bile duct tissues. Results:Masson staining showed that the submucosal collagen fibers increased significantly in the experimental group. Compared with the control group, the mRNA expression of TGF-β1 [(3.482±0.313) vs. (1.000±0.102), t=18.43, P<0.001], CTGF [(2.160±0.287) vs. (1.000±0.103), t=9.32, P<0.001] were increased, the difference was statistically significant. Compared with control group, the mRNA and protein expression of CK19 and E-Cad were decreased in the experimental group, while the mRNA and protein expression of S100A4 and α-SMA were increased in the experimental group (all P<0.01). Conclusion:It was feasible in the short term to perform an end-to-end anastomosis after transection of the common bile duct, but there was an obvious fibrosis in the anastomotic bile duct tissue at later time.