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

Objective To observe the value of ultrasound microvascular flow imaging(MV-Flow)combined with maternal serum vascular endothelial growth factor(VEGF)expression level for diagnosis of fetal growth restriction(FGR).Methods Totally 87 pregnant women with FGR(FGR group,including 43 cases of gestational week＜28 weeks[＜28 weeks subgroup]and 44 cases of ≥28 weeks[≥28 weeks subgroup])and 112 normal pregnant women with normal fetuses(normal control group,55 with gestational week＜28 weeks[NC 1 subgroup]and 57 with ≥28 weeks[NC 2 subgroup])were prospectively enrolled.MV-Flow technology was used to measure placental microvascular index(MVI),and the placental microvascular circulation was evaluated.The expression level of maternal serum VEGF was detected simultaneously,also of placental maternal surface immediately after delivery.The receiver operating characteristic curves were drawn to explore the value of placental MVI,maternal serum VEGF and the combination of placental MVI,maternal serum VEGF for diagnosing FGR.Results The levels of placental MVI and maternal serum VEGF in 2 subgroups of FGR group were both lower than those in control group(all P＜0.01).Placental VEGF expression level in FGR group was significantly lower than that in control group(P＜0.01).The area under the curve(AUC)of placental MVI,maternal serum VEGF and their combination for diagnosing FGR＜28 weeks was 0.981,0.870 and 0.997,respectively,while for diagnosing FGR≥28 weeks was 0.991,0.867 and 0.993,respectively.AUC of maternal serum VEGF alone for diagnosing in 2 subgroups of FGR were both lower than that of placental MVI and combination of placental MVI and maternal serum VEGF(all P＜0.05),while no significant difference of AUC was found between placental MVI and combination of maternal serum VEGF and placental MVI(both P＞0.05).Conclusion Both placental MVI and maternal serum VEGF level could be used to screen FGR,and the former was more valuable.

Objective To perform structural analysis on the homogeneous polysaccharide SP800301 isolated from Saposhnikoviae Radix to determine its chemical structure.Methods Polysaccharides were separated and purified from Saposhnikoviae Radix using column chromatography,such as DEAE-cellulose and Sephadex G-75.The molecular weight distribution,monosaccharide composition,oligosaccharide fragments,sugar residue types,and glycosidic bond connection of the isolated homogeneous polysaccharide SP800301 from Saposhnikoviae Radix were analyzed using electrospray ionization multistage mass spectrometry,gas chromatography-mass spectrometry,and nuclear magnetic resonance to determine its structure.The appearance characteristics of the Saposhnikoviae Radix polysaccharide were characterized using electron and atomic force microscopy.Results Polysaccharide SP800301 extracted from Saposhnikoviae Radix had good homogeneity with a molecular weight of 9.1×104 g/mol.The uronic acid content was 52.72%.The monosaccharide group comprised rhamnose,galacturonic acid,glucose,galactose,and arabinose,with a molar ratio of 4.3:58.1:25.4:5.0:7.3.The polysaccharide was mainly composed of polygalacturonic acid as the primary chain.The branched chain was comprised of rhamnose,galacturonic acid,galactose,glucose,and arabinose,with arabinose at the end of the branched chain and part of the galacturonic acid in the sugar chain forming a methyl ester.Conclusion This study clarified the chemical structure of the homogeneous polysaccharide SP800301 from Saposhnikoviae Radix,enriched the chemical composition of Saposhnikoviae Radix polysaccharides,laid the foundation for further research on the immune regulatory mechanism of Saposhnikoviae Radix polysaccharides,and provided a scientific basis for clinically using Saposhnikoviae Radix.

Objective To evaluate the ability of the ratio of peripheral blood white blood cell(WBC)counts to platelet counts to predict the onset of radiation-induced thymic lymphoma(TL)in a mouse model.Methods Mice were subjected to fractionated total-body irradiation(TBI)to established a TL model before the changes of the WBC-to-platelet ratio during the development and progression of TL were investigated.Four-week-old male C57BL/6J mice were randomized into the normal(non-irradiation)group and radiation exposure group that was subjected to 1.8 Gy TBI once weekly for four consecutive weeks.The survival and TL-incidence of those two groups were compared within 370 days of TBI.Histomorphology and hematoxylin & eosin(H&E)staining of the thymus were used for definite diagnosis of TL while flow cytometry was adopted to detect the frequency changes of T cells in the thymus,bone marrow and spleen.Peripheral blood(PB)cell counts were measured to analyze the changes of peripheral hemogram during TL pathogenesis.Results No mice in the normal group were diagnosed with TL while 83％of the irradiated mic suffered from TL within 370 days of fractionated TBI(P＜0.0001).Using histopathologic technology,medium-sized tumor cells were observed in the thymus of irradiated mice diagnosed with TL.Cytometric analysis showed decreased frequencies of CD4 mono-positive cells and increased frequencies of CD8 mono-positive cells in the thymus,bone marrow and spleen of mice diagnosed with TL.PB analysis displayed a significant increase in the WBC-to-platelet ratio one week prior to the TL-caused death in the irradiated mice(P＜0.01).Conclusion Elevation of the peripheral blood WBC-to-platelet ratio can help predict the onset of IR-induced TL of mice.

Objective:To evaluate the safety of patients with hepatic adenoma undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) .Methods:A retrospective analysis of the clinical characteristics and prognosis of eight patients with hepatic adenoma who underwent allo-HSCT in the Hematology Department of Peking University People’s Hospital from January 2010 to March 2024 was conducted.Results:Of the eight patients who underwent allo-HSCT with hepatic adenoma, one patient was considered MDS-h transfusion-dependent and seven had aplastic anemia. The median age of the patients was 23 years (13-48 years). The median time from the diagnosis of AA or MDS to transplantation was 14 years (6-24 years), whereas the median time from taking androgens to diagnosing hepatic adenoma was 9 years (5-13 years). Six cases underwent haplo-HSCT, one case underwent matched unrelated donor HSCT, and one case underwent matched related donor HSCT. All patients achieved neutrophil engraftment at a median time of 11.5 days (11-20 days) and PLT engraftment within 60 days at a median of 19 days (10-37 days) after haplo-HSCT. Moreover, seven patients developed CMV anemia after transplantation, three patients had hemorrhagic cystitis, and two patients developed acute GVHD. During and after transplantation, eight patients did not show severe liver function damage or rupture of hepatic adenoma. In relation to imaging size, four patients showed varying degrees of reduction in hepatic adenoma size after transplantation, whereas four patients did not show significant changes in hepatic adenoma size after transplantation. The median follow-up time was 540.5 (30-2 989) days. Of the eight patients, six survived and two died. Furthermore, no direct correlation was observed between death and hepatic adenoma.Conclusion:Patients with hepatic adenomas undergoing allo-HSCT are not contraindications for transplantation, which will not increase transplant-related mortality.

Objective:To systematically summarize and comparatively analyze the development, establishment and usage of oncology drugs speedy review approaches in China and in the United States between 2012 and 2021.Methods:Based on National Medical Products Administration (NMPA) and Food and Drug Administration (FDA) websites, the development and current status of the speedy review approaches were consulted and summarized. Approved oncology drugs in China and in the United States (87 in China, 118 in the United States) over the past decade were analyzed using chi-square test for group comparison.Results:Five speedy approaches have been established in China and in the United States, three of which are the same, priority review, conditional approval or accelerated approval and breakthrough therapy. The rest two are special review and approval, special examination and approval in China, and fast track and real-time oncology review in the United States. Compared to the United States, speedy review approaches in China set up late (1992 vs. 2005). The overall utilization rates of the oncology drugs speedy review approaches were similar between the China and United States (90.8% vs. 92.4%, P=0.800) in the previous 10 years, and priority review have highest utilization rates in both China and the United States without significant group difference (77.0% vs. 82.2%, P=0.381); relatively low utilization rates of conditional approval (31.0% vs. 44.9%, P=0.041) and breakthrough therapy (2.3% vs. 50.0%, P＜0.001) were seen in China. 52.9% of new drugs applied for special examination and approval in China and 40.7% of new drugs applied for fast track in the United States. Overall, the priority review both in China and the United States are stable, with a similar average annual utilization rate (84.8% vs. 83.7%); accelerated approval and breakthrough therapies in the United States fluctuate wildly, but the situation is tending towards stability in the last 3 years. Conclusions:Both China and the United States have established a relatively complete accelerated review system, with an overall utilization rate over 90%; China's accelerated review started late, although the overall utilization rate is close to that of the United States. The utilization rates of conditional approval and breakthrough therapy are still relatively low. Flexible usage of speedy review approaches, gaining regulatory recognition to use alternative endpoints, achieving real-time review and guidance are keys to accelerate new drug development in China.

Objective:To systematically summarize and comparatively analyze the development, establishment and usage of oncology drugs speedy review approaches in China and in the United States between 2012 and 2021.Methods:Based on National Medical Products Administration (NMPA) and Food and Drug Administration (FDA) websites, the development and current status of the speedy review approaches were consulted and summarized. Approved oncology drugs in China and in the United States (87 in China, 118 in the United States) over the past decade were analyzed using chi-square test for group comparison.Results:Five speedy approaches have been established in China and in the United States, three of which are the same, priority review, conditional approval or accelerated approval and breakthrough therapy. The rest two are special review and approval, special examination and approval in China, and fast track and real-time oncology review in the United States. Compared to the United States, speedy review approaches in China set up late (1992 vs. 2005). The overall utilization rates of the oncology drugs speedy review approaches were similar between the China and United States (90.8% vs. 92.4%, P=0.800) in the previous 10 years, and priority review have highest utilization rates in both China and the United States without significant group difference (77.0% vs. 82.2%, P=0.381); relatively low utilization rates of conditional approval (31.0% vs. 44.9%, P=0.041) and breakthrough therapy (2.3% vs. 50.0%, P＜0.001) were seen in China. 52.9% of new drugs applied for special examination and approval in China and 40.7% of new drugs applied for fast track in the United States. Overall, the priority review both in China and the United States are stable, with a similar average annual utilization rate (84.8% vs. 83.7%); accelerated approval and breakthrough therapies in the United States fluctuate wildly, but the situation is tending towards stability in the last 3 years. Conclusions:Both China and the United States have established a relatively complete accelerated review system, with an overall utilization rate over 90%; China's accelerated review started late, although the overall utilization rate is close to that of the United States. The utilization rates of conditional approval and breakthrough therapy are still relatively low. Flexible usage of speedy review approaches, gaining regulatory recognition to use alternative endpoints, achieving real-time review and guidance are keys to accelerate new drug development in China.