BACKGROUND:Ca2+expression in astrocytes has been found to be closely related to cognitive function,and the Ca2+signaling pathway regulated by inositol 1,4,5-trisphosphate receptors(IP3R2)and ryanodine receptor(RYR)2 receptors has become a hot spot in the study of cognitive disorder-related diseases. OBJECTIVE:To investigate the expression of Ca2+signals mediated by IP3R2 and RYR2 in hippocampal astrocytes in animal models of delayed encephalopathy after acute carbon monoxide poisoning,and to explore the possible pathogenesis of delayed encephalopathy after acute carbon monoxide poisoning. METHODS:C57BL mice with qualified cognitive function were selected by Morris water maze experiment and randomly divided into control group and experimental group.An animal model of delayed encephalopathy after acute carbon monoxide poisoning was established by static carbon monoxide inhalation in the experimental group,and the same amount of air was inhaled in the control group.Behavioral and neuronal changes,astrocyte specific marker glial fibrillary acidic protein,IP3R2,RYR2 receptor and Ca2+concentration in astrocytes of the two groups were detected using Morris water maze,hematoxylin-eosin staining,western blot,immunofluorescence double labeling and Ca2+fluorescence probe at 21 days after modeling. RESULTS AND CONCLUSION:In the Morris water maze,the escape latency of the experimental group was significantly longer than that of the control group(P<0.05).Hematoxylin-eosin staining results showed that in the experimental group,the number of hippocampal pyramidal cells decreased,the cell structure was disordered,and the nucleus was broken and dissolved.Immunofluorescence results showed that IP3R2 and RYR2 were co-expressed with glial fibrillary acidic protein in the hippocampus,and the expressions of IP3R2,RYR2 and glial fibrillary acidic protein were up-regulated in the hippocampus of the experimental group(P<0.05).Western blot analysis showed that the expressions of IP3R2,RYR2,and glial fibrillary acidic protein in the hippocampus of the experimental group were increased(P<0.05).Ca2+concentration in hippocampal astrocytes increased significantly in the experimental group(P<0.05).To conclude,astrocytes may affect Ca2+signals by mediating IP3R2 and RYR2 receptors,then impair the cognitive function of mice with carbon monoxide poisoning,and eventually lead to delayed encephalopathy after acute carbon monoxide poisoning.

Objective:To investigate the effects of the Epley and Semont procedures with varying lateral angles of the head on posterior semicircular canal benign paroxysmal positional vertigo （PC-BPPV）. Methods:A total of 115 patients with unilateral PC-BPPV were randomly divided into five groups: Epley group, Semont group, Semont+10° group, Semont+20° group, and Semont+30° group, with 23 patients in each group. Corresponding reduction treatments were performed. Results:The total effective rates for the Epley group, Semont group, Semont+10° group, Semont+20° group, and Semont+30° group were 95.7% （22/23）, 4.3% （1/23）, 30.4% （7/23）, 52.2% （12/23）, and 87.0% （20/23） respectively. The inefficiencies were 4.3% （1/23）, 95.7% （22/23）, 69.6% （16/23）, 47.8% （11/23）, and 13.0% （3/23）. Statistically significant differences were observed in the total effective rates among the five groups （χ²=54.11, P<0.01）. The total effective rates in the Semont group, Semont+10° group, and Semont+20° group were significantly different from that of the Epley group （P<0.01）, while no statistically significant difference was found between the Semont+30° group and the Epley group （P= 0.608>0.012 5）. Conclusion:Among the four Semont methods with different lateral lying angles, the total effective rate of reduction treatment increased with the elevation of the lateral lying angle on the affected side. The efficacy of the Semont+30° group in treating PC-BPPV was not significantly different from the Epley group's reduction effect, which was markedly superior to that of the other four Semont methods at different angles. Therefore, the Semont+30° reduction technique is recommended for the treatment of PC-BPPV.
Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; Benign Paroxysmal Positional Vertigo/therapy* ; Head ; Posture ; Semicircular Canals/physiopathology* ; Treatment Outcome

Poly(ADP-ribosyl)ation (PARylation) is a specific form of post-translational modification (PTM) predominantly triggered by the activation of poly-ADP-ribose polymerase 1 (PARP1). However, the role and mechanism of PARylation in the advancement of acute kidney injury (AKI) remain undetermined. Here, we demonstrated the significant upregulation of PARP1 and its associated PARylation in murine models of AKI, consistent with renal biopsy findings in patients with AKI. This elevation in PARP1 expression might be attributed to trimethylation of histone H3 lysine 4 (H3K4me3). Furthermore, a reduction in PARylation levels mitigated renal dysfunction in the AKI mouse models. Mechanistically, liquid chromatography-mass spectrometry indicated that PARylation mainly occurred in receptor for activated C kinase 1 (RACK1), thereby facilitating its subsequent phosphorylation. Moreover, the phosphorylation of RACK1 enhanced its dimerization and accelerated the ubiquitination-mediated hypoxia inducible factor-1α (HIF-1α) degradation, thereby exacerbating kidney injury. Additionally, we identified a PARP1 proteolysis-targeting chimera (PROTAC), A19, as a PARP1 degrader that demonstrated superior protective effects against renal injury compared with PJ34, a previously identified PARP1 inhibitor. Collectively, both genetic and drug-based inhibition of PARylation mitigated kidney injury, indicating that the PARylated RACK1/HIF-1α axis could be a promising therapeutic target for AKI treatment.

OBJECTIVE: To observe the effects of enhanced rehabilitation on the prognosis of critically ill patients in the intensive care unit (ICU). METHODS: A single-center retrospective historical controlled study was conducted, patients admitted to the ICU of Peking University First Hospital from May 1, 2020, to April 30, 2021, and from October 1, 2021, to September 30, 2022 were enrolled. According to the different rehabilitation treatment strategies during different periods, patients were divided into the conventional rehabilitation group (patients receiving conventional rehabilitation treatment from May 1, 2020, to April 30, 2021) and the enhanced rehabilitation group (patients receiving the therapy of multidisciplinary team, ie medical care-rehabilitation-nursing care from October 1, 2021, to September 30, 2022). General data, acute physiology and chronic health evaluation II (APACHE II), and study endpoints were collected. Primary endpoints included rehabilitation-therapy rate, intervention time for rehabilitation, rehabilitation-related adverse events, and prognostic indicators such as (length of stay in hospital, length of stay in the ICU, and duration of mechanical ventilation). Secondary endpoints included incidence of deep vein thrombosis and hospital mortality. Kaplan-Meier curves were used to analyze cumulative discharge rates within 50 days. RESULTS: A total of 539 ICU patients were enrolled, with 245 in the conventional rehabilitation group and 294 in the enhanced rehabilitation group; 322 patients had an APACHE II score ≤ 15, while 217 patients had an APACHE II score > 15. Compared to the conventional rehabilitation group, the enhanced rehabilitation group demonstrated significantly higher rehabilitation-therapy rate [51.70% (152/294) vs. 11.43% (28/245)], earlier intervention time for rehabilitation [days: 2.00 (1.00, 3.00) vs. 4.00 (3.00, 7.00)]; shorter length of stay in hospital [days: 18.00 (12.00, 30.00) vs. 21.00 (13.00, 36.00)] and lower incidence of DVT [17.01% (50/294) vs. 24.08% (59/245)]. The differences were all statistically significant (all P < 0.05). There were no rehabilitation-related adverse events occurred in either group. Kaplan-Meier analysis demonstrated a significantly higher cumulative discharge rate within 50 days in the enhanced rehabilitation group compared to the conventional rehabilitation group [86.7% (255/294) vs. 82.9% (203/245); Log-Rank test: χ² = 4.262, P = 0.039]. Subgroup analysis showed that for patients with APACHE II score ≤ 15, the enhanced rehabilitation subgroup had higher rehabilitation-therapy rate [44.32% (78/176) vs. 6.16% (9/146), P < 0.05]. For patients with APACHE II score > 15, compared to the conventional rehabilitation group, the enhanced subgroup demonstrated higher rehabilitation-therapy rate [62.71% (74/118) vs. 19.19% (19/99), P < 0.05] and shorter length of stay in hospital [days: 20.50 (12.00, 31.25) vs. 26.00 (16.00, 43.00), P < 0.05]. CONCLUSIONS Enhanced rehabilitation therapy with medical care, rehabilitation and nursing care, improved rehabilitation-therapy rate, advanced time of rehabilitation treatment, reduced length of stay in hospital and incidence of deep vein thrombosis in critically ill patients, particularly benefited those with APACHE II score > 15. The enhanced rehabilitation was beneficial to the patient in the intensive care unit with safety and worth more investigation.
Humans ; Retrospective Studies ; Critical Illness/rehabilitation* ; Intensive Care Units ; Prognosis ; Length of Stay ; APACHE ; Historically Controlled Study ; Male ; Female ; Middle Aged ; Aged

Ferroptosis is a form of programmed cell death,which plays a crucial driving role in the onset and progression of diabetic nephropathy(DN).Ferroptosis is closely related to the damage of renal intrinsic cells in patients with diabetes.Chinese materia medica can improve DN by regulating the ferroptosis of renal intrinsic cells,with a good research and application prospect.This article reviewed the key regulatory factors and regulatory pathways of ferroptosis in DN,explained the"imbalance between yin and yang"of ferroptosis in DN based on TCM theories,and combed the research status of targeted inhibition of ferroptosis by active components of Chinese materia medica.The regulation of active components of Chinese materia medica on ferroptosis in DN has the characteristics of multiple targets,multiple links and integrity,which can provide a reference for the mechanism research and drug development of Chinese materia medica in treating DN.

Chinese materia medica mainly prevents and treats diminished ovarian reserve by regulating PI3K/Akt, PI3K/Akt/mTOR, PI3K/Akt/FoxO3, PTEN/PI3K/Akt, TGF-β1/Smads, Nrf2/HO-1, AMPK and other signaling pathways. It also involves Hippo, Wnt / β-catenin, Notch and other signaling pathways, which can improve the ovarian environment, promote ovarian function repair, inhibit ovarian granulosa cell apoptosis, promote oocyte growth, regulate hormone levels, and play anti-inflammatory, anti-oxidation and anti-fibrosis roles.

Objective To retrospectively analyze multicenter data from domestic sources, aiming to explore the link between intrahepatic cholangiocarcinoma (ICC) tumor size and prognosis, establishing a classification system based on tumor size. Methods Between December 2011 and September 2018, 280 ICC patients from 13 hospitals were included. The tumor size prognosis cutoff was identified by the minimum P-value method, and the classification's overall survival related effectiveness was assessed by Kaplan-Meier analysis. Results All 280 patients were divided into the group of tumor maximum diameter ≤4 cm and >4 cm. Tumor size was confirmed as an independent prognosis factor by multivariate COX regression analysis (HR=2.110, 95% CI: 1.358-3.280). Conclusions The tumor size dichotomy classification system based on the Chinese patient group can expediently predict ICC prognosis and offers an important basis for selecting post-operative individualized adjuvant therapy and follow up plans.

Objective:To compare the differences in clinical characteristics among the patients at clinical high risk for bipolar disorder(CHR-BD),the patients with bipolar disorder(BD),and the healthy controls(HC)at low risk,and to provide the basis for the diognasis and treatment of CHR-BD.Methods:For the first time,the BD risk criteria and prospective structured assessment tools were jointly used in outpatients aged 16-30 years,and 43 CHR-BD patients were included to ensure the accuracy of the assessment.Meanwhile,33 BD patients and 32 HC subjects were also enrolled.The clinical symptoms,neurocognitive function,and global functional levels of the subjects in the three groups were evaluated using observer-rated and self-rated tools.The CHR-BD and BD groups were combined,and Logistic regression analysis was used to identify the independent influencing factors related to diagnostic status;Pearson or Spearman correlation analysis was used to analyze the correlations between the global functional levels and the symptoms or neurocognitive characteristics of the patients in CHR-BD and BD groups.Results:There were statistically significant differences in the scores of symptom and global functional level scales among HC,CHR-BD,and BD groups(P<0.05).Compared with HC group,the scores of mood symptoms(anxiety,depression,and mania/hypomania),psychotic symptoms,total affective temperament questionnaire scores,and some dimensions(cyclothymic,depressive,irritable,and anxious temperaments)in CHR-BD and BD groups were significantly increased(P<0.001),while the global functional levels were significantly decreased(P<0.001).Compared with BD group,the lowest global functional level score in the past year in CHR-BD group was significantly increased(P=0.022),while the current global functional level score was significantly decreased(P=0.005).No significant differences were observed in neurocognitive function scores among the three groups(P>0.05).The lowest global functional level score in the past year was an independent influencing factor for BD diagnosis[odds ratio(OR)=0.952,95%confidence interval(CI):0.917-0.988,P=0.010].In both CHR-BD and BD patients,the current global functional levels were negatively correlated with depressive(r=-0.417,P=0.005;r=-0.617,P<0.001)and anxiety symptoms(r=-0.360,P=0.018;r=-0.506,P=0.003).In BD patients,the current global functional level was negatively correlated with lifetime manic/hypomanic symptoms(r=-0.360,P=0.039),psychotic symptoms(r=-0.502,P=0.003),and affective temperament scores(r=-0.479,P=0.005),while the lowest global functional level in the past year was negatively correlated with lifetime manic/hypomanic symptoms(r=-0.391,P=0.024).Conclusion:CHR-BD patients share similar mood symptom characteristics with BD patients,and their global functional levels are negatively correlated with depressive and anxiety symptoms.BD patients exhibit worse lowest global functional levels in the past year,and their global functional levels are negatively correlated with manic/hypomanic symptoms.

Objective:To explore the clinical characteristics and identification of the independent risk factors for disease progression in patients with anti-gp210 antibody-positive primary biliary cholangitis (PBC).Methods:A retrospective cohort study was performed. A total of 323 cases with PBC diagnosed in Tianjin Medical University General Hospital from January 2013 to June 2023 (125 patients with anti-gp210 antibody-positive and 198 patients with anti-gp210 antibody-negative) were included. Baseline and follow-up data were collected. The independent sample t-test and Mann-Whitney U rank sum test were used for comparison between groups of continuous data. The χ2 test was used to compare the data between groups for the count data. The Pearson test was used for correlation analysis between continuous variables. The Kaplan-Meier method was used to analyze the disease progression-free survival rate. The Cox regression model was used to analyze the risk factors for disease progression. Results:The male proportion (11.2% vs. 5.1%, P=0.040) and IgM level [3.29(1.88, 4.80) g/L vs. 2.56(1.44, 3.87) g/L, P=0.019] were significantly higher in patients with PBC with positive anti-gp210 antibodies than those of the negative group. Histopathological analysis showed that the Scheuer score [1(0,3) vs. 0(0,2)], bile duct inflammation [(2(1,3) vs. 1(1,2)] and bile duct reaction score [(2(1,3) vs. 1(1,2)] were higher in the positive group than those of the negative group ( P<0.05), and the maturity of the tertiary lymphoid structure was higher ( P=0.011). Kaplan-Meier analysis showed that the 5-year disease-free survival rate was significantly lower in patients with positive anti-gp210 antibodies than that of the negative group (55.8% vs. 79.7%, P=0.006) at a median follow-up of 3(2,6) years. Multivariate Cox regression analysis showed that γ-glutamyl transferase [ HR=1.002 (95% CI: 1.000～1.003)] and platelet count [ HR=0.993 (95% CI: 0.988～0.999)] were the independent influencing factors for disease progression in patients with anti-gp210 antibody-positive PBC ( P=0.002, 0.017). Conclusion:Patients with anti-gp210 antibody-positive PBC have more severe clinical pathological manifestations and a higher risk of disease progression. Higher levels of γ-glutamyl transferase and lower platelet counts during the first visit are independent risk factors for disease progression in patients with anti-gp210 antibody-positive PBC, which can be used as dynamic monitoring indicators for this population, suggesting the need for early intensive intervention.

Objective To observe the effects of Bushen Antai Mixture on vascular recasting at the maternal-fetal interface in mice with recurrent spontaneous abortion(RSA)based on AMPK/ULK1/Beclin1 pathway.Methods CBA/J female mice and BALB/c male mice were caged at a ratio of 2:1 to establish normal pregnant mice(normal group),and CBA/J female mice and DBA/2 male mice were caged to establish RSA model.The RSA mice were randomly divided into model group,autophagy agonist group and TCM high-,medium-and low-dosage groups,with 10 mice in each group.From the first day of pregnancy,TCM high-,medium-and low-dosage groups were given Bushen Antai Mixture 35.1,11.7 and 3.9 g/kg by gavage respectively,and the normal group,model group and autophagy agonist group were given the same amount of normal saline by gavage for 15 days.The embryo development was observed and the embryo loss rate was calculated,the morphology of decidual tissue was observed by HE staining;the contents of vascular endothelial growth factor(VEGF)and vascular endothelial cadherin(VE-cadherin)in decidual tissue were detected by ELISA;the expressions of autophagy related proteins adenosine monophosphate-activated protein kinase(AMPK),UNC-51 like kinase 1(ULK1),Beclin1 and LC3B in decidual tissue were detected by Western blot.Results Compared with the normal group,the embryo loss rate of mice in the model group significant increased(P<0.01),the cells of the decidual tissue were disordered,the interstitium was edematous,the nuclei disappeared,there were a large number of inflammatory cells infiltration,the number of blood vessels was reduced,the contents of VEGF and VE-cadherin in decidual tissue significantly decreased(P<0.01),and the protein expressions of AMPK,ULK1,Beclin1,LC3BⅡ/LC3BⅠ significantly decreased(P<0.01).Compared with the model group,the embryo loss rate of mice in TCM high-,medium-and low-dosage groups and autophagy agonist group showed a significant downward trend(P<0.05),and the cells of decidual tissue were aligned,the interstitium edema was reduced,the nuclei of the cells increased,the inflammatory cells infiltration were reduced and the number of blood vessels increased,the contents of VEGF and VE-cadherin in decidual tissue significantly increased in TCM high-,medium-dosage groups and autophagy agonist group(P<0.05),and the protein expressions of AMPK,ULK1,Beclin1 and LC3BⅡ/LC3BⅠ significantly increased(P<0.01).Conclusion Bushen Antai Mixture may promote the recasting of blood vessels at the maternal-fetal interface by activating AMPK/ULK1/Beclin1 pathway,improve the pregnancy survival rate of RSA mice,and play a role in the treatment of RSA.