ObjectiveTo observe the effects of Xiaoyaosan on glucagon-like peptide-1 （GLP-1）/GLP-1 receptor （GLP-1r） and protein kinase A （PKA）/cAMP response element binding protein （CREB）/brain-derived neurotrophic factor （BDNF） signaling pathways in the hippocampal CA1 region of rats under chronic restraint stress （CRS），and to explore the mechanism of this formula to alleviate anxiety and depression-like behaviors. Methods40 specific pathogen-free male Sprague-Dawley （SD） rats were randomly divided into normal，model，Xiaoyaosan，and fluoxetine groups，with 10 rats in each group. CRS was used to induce anxiety and depression-like behaviors. The rats in the Xiaoyaosan group were gavaged with aqueous solution of traditional Chinese medicine formula granules （7.36 g·kg^-1·d^-1），while those in the fluoxetine group were gavaged with aqueous solution of fluoxetine （2 mg·kg^-1·d^-1）. Body weight was measured on days 0，7，14，and 21 of the experiment. On days 0 and 22 of the experiment，the sucrose preference test （SPT），forced swimming test （FST），and open field test （OFT） were performed. The pathological morphology of the hippocampal CA1 region was observed by Nissl staining. The relative mRNA expression of post-synaptic density protein-95 （PSD95） and synapsin （SYP） was detected by reverse transcription quantitative real-time polymerase chain reaction. Immunohistochemistry and Western blot were used to detect expression of proteins in the GLP-1/GLP-1r and PKA/CREB/BDNF pathways in the hippocampal CA1 region. ResultsAfter CRS modeling，compared with the normal group，the rats of the model group had anxiety and depression-like behavioral manifestations，neuronal damage in the hippocampal CA1 region，significantly downregulated expression of synaptic plasticity markers PSD95 and SYP genes （P<0.01），and inhibition of GLP-1/GLP-1r and PKA/CREB/BDNF signaling pathways （P<0.05，P<0.01）. Compared with the model group，the Xiaoyaosan group exhibited alleviated anxiety and depression-like behaviors，reduced neuronal damage in the hippocampal CA1 region， significantly increased expression of PSD95 and SYP genes （P<0.01），and the activation of the GLP-1/GLP-1r and PKA/CREB/BDNF signaling pathways （P<0.05，P<0.01）. ConclusionXiaoyaosan can alleviate anxiety and depression-like behaviors in CRS rats by improving synaptic plasticity in the hippocampal CA1 region. The mechanisms may be related to the activation of the GLP-1/GLP-1r pathway and its mediated PKA/CREB/BDNF signaling pathway by the formula.

OBJECTIVE To analyze the occurrence characteristics and risk factors of adverse drug reactions （ADR） of gemcitabine for injection in national centralized volume-based procurement （hereinafter referred to as “centralized procurement”）， and provide reference for clinical safe drug use. METHODS A retrospective study was conducted to collect the relevant case reports of gemcitabine for injection reported to the National Adverse Drug Reaction Monitoring System by Inner Mongolia Autonomous Region from January 2022 to December 2023； basic information of patients， drug use status， patient outcomes， rational drug use and other information were collected， and the occurrence characteristics of ADRs with leukopenia， myelosuppression， neutropenia， thrombocytopenia and liver dysfunction were analyzed. Univariate analysis and multivariate Logistic regression were used to analyze the correlation of gender， age， combination of antitumor drugs， original malignant tumor and drug dose with ADR. RESULTS A total of 315 cases reports （315 patients） of gemcitabine-induced ADR were included in this study， with a male-to-female ratio of 1.42∶1 and age of （61.17±9.13） years. The primary malignant tumor was pancreatic cancer （73 cases， 23.17%）. Leukopenia， myelosuppression and nausea were the most common ADR， followed by neutropenia， thrombocytopenia， liver dysfunction and so on. The severity grade of ADR was mainly 1-2， and the outcome of most ADR was good. Multivariate Logistic regression analysis showed that combination of antitumor drugs was a risk factor for myelosuppression and neutropenia （RR＝2.154， 95%CI： 1.218- 3.807， P＝0.008； RR＝3.099， 95%CI： 1.240-7.744， P＝0.016）； gender （female） was a risk factor for leukopenia and liver dysfunction （RR＝0.508， 95%CI： 0.302-0.853， P＝0.010； RR＝0.301， 95%CI： 0.102-0.887， P＝0.029）. In terms of drug use rationality， there were 143 cases （45.40%） of drug 126.com use in accordance with the indications of the label， and 172 cases （54.60%） of off-label drug use. Among them， the primary malignant tumors were bladder cancer， bile duct cancer and ovarian cancer， which ranked the top three off-label drug use. CONCLUSIONS The ADR caused by gemcitabine in Inner Mongolia is mainly in the blood and digestive systems. The severity of ADRs is mainly classified as 1-2 levels， and most ADRs have good outcomes. Gender （female） and combination medication are risk factors for gemcitabine-induced ADR. Appropriate chemotherapy regimen should be selected according to the patient’s condition and physical condition， and ADR monitoring in blood and digestive systems should be strengthened during medication of gemcitabine.

OBJECTIVE To investigate the effects of alirocumab combined with atorvastatin on clinical efficacy and safety of patients with acute coronary syndrome （ACS） who underwent percutaneous coronary intervention （PCI）. METHODS A total of 207 patients with ACS who underwent PCI in our hospital from January 2021 to December 2023 were randomly divided into alirocumab group， ezetimibe group and control group， with 69 cases in each group. All patients received routine thrombosis prevention and antihypertensive treatment after PCI. On this basis， patients in the control group were treated with atorvastatin （20 mg/time， once a day）； patients in the ezetimibe group were treated with ezetimibe （10 mg/time， once a day） + atorvastatin （20 mg/time， once a day）； patients in the alirocumab group were treated with alirocumab （75 mg/time， once every 2 weeks） + atorvastatin （20 mg/time， once a day）. All patients in the three groups were treated for 8 weeks and followed up for another 6 months after treatment. The levels of cardiac function and lipid metabolism indices before and after treatment， as well as the occurrence of major adverse cardiovascular event （MACE） and other adverse drug reaction （ADR） during the follow-up period were compared among the three groups. RESULTS After treatment for 8 weeks， the levels of cardiac function and lipid metabolism indices in the three groups were significantly improved compared with those before treatment （P＜0.05）. Compared with the control group and ezetimibe group， the left ventricular ejection fraction in the alirocumab group was significantly increased， and the left ventricular end-diastolic diameter （LVEDD） was significantly shortened （P＜0.05）. Compared with control group， LVEDD of ezetimibe group was significantly shortened （P＜0.05）， the levels of total cholesterol， triglyceride and low-density lipoprotein cholesterol in the alirocumab group and ezetimibe group were significantly decreased （P＜0.05）. During the follow-up period， there was no significant difference in the total incidence of MACE and the total incidence of other ADR such as headache and abdominal pain among the three groups （P＞0.05）. CONCLUSIONS Alirocumab combined with atorvastatin can significantly improve cardiac function and regulate lipid metabolism indices in patients with ACS after PCI without increasing the risk of MACE or other ADR.

Objective: To evaluate the effects of dietary intervention on blood pressure and renal function in patients with hypertensive nephropathy, so as to provide dietary and nutritional guidances for this population. Methods: Hypertensive nephropathy patients who were treated at Zhucheng People's Hospital from March 2023 to February 2024 were selected as the study subjects and randomly divided into the intervention group and the control group. The control group received routine antihypertensive treatment and health lifestyle guidance. On the basis of the treatment and guidance received by the control group, the intervention group implemented dietary intervention in accordance with the Clinical Practice Guidelines for Nutritional Therapy of Chronic Kidney Disease in China (2021 edition) for a period of 3 months. Systolic blood pressure (SBP), diastolic blood pressure (DBP) were measured before and after the intervention, and serum creatinine (Scr), blood urea nitrogen (BUN), uric acid (UA), cystatin and β2-microglobulin were detected. Differences of indicators before and after intervention between the two groups were compared using generalized estimation equation. Results: A total of 83 patients with hypertensive nephropathy were followed up, including 43 cases in the intervention group and 40 cases in the control group. There were no statistically significant differences in gender, age, body mass index, duration of hypertension, family history of hypertension, hypertension grade, physical activity index, or smoking status between the two groups (all P>0.05). The differences in SBP, DBP, Scr, BUN, and UA between the two groups, as well as the differences before and after the intervention, were statistically significant, and there was an interaction between the groups and the intervention time (all P<0.05). After intervention, the levels of SBP, DBP, Scr, BUN, and UA in the intervention group were lower than those in the control group (all P<0.05). The differences in cystatin and β2-microglobulin between the two groups and before and after the intervention were not statistically significant, and there was no interaction between the groups and the intervention time (all P>0.05). Conclusion Dietary intervention has a certain effect on reducing blood pressure and improving renal function indicators in patients with hypertensive nephropathy.

BACKGROUND: Severe stroke has high rates of mortality and morbidity. This study aimed to investigate the clinical course, causes of worsening, and outcomes of severe ischemic stroke. METHODS: This prospective, multicenter cohort study enrolled adult patients admitted ≤30 days after ischemic stroke from nine hospitals in China between September 2017 and December 2019. Severe stroke was defined as a score of ≥15 on the National Institutes of Health Stroke Scale (NIHSS). Clinical worsening was defined as an increase of 4 in the NIHSS score from baseline. Unfavorable functional outcome was defined as a modified Rankin scale score ≥3 at 3 months and 1 year after stroke onset, respectively. We performed Logistic regression to explore baseline features and reperfusion therapies associated with clinical worsening and functional outcomes. RESULTS: Among 4201 patients enrolled, 854 patients (20.33%) had severe stroke on admission. Of 3347 patients without severe stroke on admission, 142 (4.24%) patients developed severe stroke in hospital. Of 854 patients with severe stroke on admission, 33.95% (290/854) experienced clinical worsening (median time from stroke onset: 43 h, Q1-Q3: 20-88 h), with brain edema (54.83% [159/290]) as the leading cause; 24.59% (210/854) of these patients died by 30 days, and 81.47% (677/831) and 78.44% (633/807) had unfavorable functional outcomes at 3 months and 1 year respectively. Reperfusion reduced the risk of worsening (adjusted odds ratio [OR]: 0.24, 95% confidence interval [CI]: 0.12-0.49, P  <0.01), 30-day death (adjusted OR: 0.22, 95% CI: 0.11-0.41, P  <0.01), and unfavorable functional outcomes at 3 months (adjusted OR: 0.24, 95% CI: 0.08-0.68, P <0.01) and 1 year (adjusted OR: 0.17, 95% CI: 0.06-0.50, P  <0.01). CONCLUSIONS: Approximately one-fifth of patients with ischemic stroke had severe neurological deficits on admission. Clinical worsening mainly occurred in the first 3 to 4 days after stroke onset, with brain edema as the leading cause of worsening. Reperfusion reduced the risk of clinical worsening and improved functional outcomes. REGISTRATION ClinicalTrials.gov , NCT03222024.
Humans ; Male ; Female ; Prospective Studies ; Ischemic Stroke/mortality* ; Aged ; Middle Aged ; Aged, 80 and over ; Stroke ; Brain Ischemia

The prefrontal cortex (PFC) plays a pivotal role in orchestrating higher-order emotional and cognitive processes, a function that depends on the precise modulation of synaptic activity. Although pharmacological studies have demonstrated that dopamine signaling through dopamine D1 receptor (DRD1) in the PFC is essential for these functions, the cell-type-specific and molecular mechanisms underlying the neuromodulatory effects remain elusive. Using cell-type-specific knockout mice and patch-clamp recordings, we investigated the regulatory role of DRD1 on neurons and astrocytes in synaptic transmission and plasticity. Furthermore, we explored the mechanisms by which DRD1 on astrocytes regulate synaptic transmission and plasticity at the cellular level, as well as emotional and cognitive functions at the behavioral level, through two-photon imaging, microdialysis, high-performance liquid chromatography, transcriptome sequencing, and behavioral testing. We found that conditional knockout of the Drd1 in astrocytes (CKO^AST) increased glutamatergic synaptic transmission and long-term potentiation (LTP) in the medial prefrontal cortex (mPFC), whereas Drd1 deletion in pyramidal neurons did not affect synaptic transmission. The elevated level of d-serine in the mPFC of CKO^AST mice increased glutamatergic transmission and LTP through NMDA receptors. In addition, CKO^AST mice exhibited abnormal emotional and cognitive function. Notably, these behavioral changes in CKO^AST mice could be reversed through the administration of d-serine degrease to the mPFC. These results highlight the critical role of the astrocytic DRD1 in modulating mPFC synaptic transmission and plasticity, as well as higher brain functions through d-serine, and may shed light on the treatment of mental disorders.

Cerebral edema is characterized by fluid accumulation, and the glymphatic system (GS) plays a pivotal role in regulating fluid transport. Using the Tenecteplase system, magnesium salt of salvianolic acid B/ginsenoside Rg1 (SalB/Rg1) was injected intravenously into mice 4.5 h after middle cerebral artery occlusion and once every 24 h for the following 72 h. GS function was assessed by Evans blue imaging, near-infrared fluorescence region II (NIR-II) imaging, and magnetic resonance imaging (MRI). SalB/Rg1 had significant effects on reducing the infarct volume and hemorrhagic transformation score, improving neurobehavioral function, and protecting tissue structure, especially inhibiting cerebral edema. Meanwhile, the influx/efflux drainage of GS was enhanced by SalB/Rg1 according to NIR-II imaging and MRI. SalB/Rg1 inhibited matrix metalloproteinase-9 (MMP-9) activity, reduced cleaved β-dystroglycan (β-DG), and stabilized aquaporin-4 (AQP4) polarity, which was verified by colocalization with CD31. Our findings indicated that SalB/Rg1 treatment enhances GS function and attenuates cerebral edema, accompanying the regulation of the MMP9/β-DG/AQP4 pathway.
Animals ; Ginsenosides/administration & dosage* ; Brain Edema/etiology* ; Male ; Benzofurans/administration & dosage* ; Glymphatic System/diagnostic imaging* ; Mice ; Infarction, Middle Cerebral Artery/drug therapy* ; Aquaporin 4/metabolism* ; Disease Models, Animal ; Mice, Inbred C57BL ; Matrix Metalloproteinase 9/metabolism* ; Neuroprotective Agents/pharmacology* ; Depsides

Objective To investigate the application of equivalent uniform dose(EUD)in intensity-modulated rotational radiotherapy and to explore optimization methods for improving the quality of modulated treatment plans.Methods The impact of the parameter a in the EUD formula on the characteristics of the EUD curve was analyzed using Python.Thirty cases of head and neck tumors,thoracic tumors,and pelvic tumors were randomly selected for treatment planning.Dose optimization for the target area and organs at risk were performed using a physics-based optimization approach or an optimization approach that combines physical constraints with the EUD function.The dose distribution and compliance with constraints of the two groups of plans were compared,while also observing the effect of different values of a on the planning outcomes.Results The impact of the value of a on the changes in EUD curve characteristics was consistent with its impact on the results of EUD plan optimization.When -15≤a≤-5,the dose distribution in the target area was more uniform;when 1≤a≤7,the effect on the uniform dose and low-dose regions in organs at risk was more noticeable;when 10≤a≤30,the effect of constraining the high-dose regions in organs at risk was more pronounced,with the EUD for the target area and organs at risk exhibiting different expressions under different a values.The study also found that the target dose distribution and the protection of organs at risk in the EUD optimization group were better than those in the physical optimization group only.Conclusion The a-value has a significant impact on the,the dose distribution in the target area and the organ at risk,providing a reference for the setting of a-value while using EUD to optimize the intensity modulation plan.The using of EUD optimization method can not only achieve excellent dose distribution in the target area,but also significantly reduce the normal tissue dose and the probability of complications,which has certain clinical application value.

AIM:To investigate the expression of lipolysis-stimulated lipoprotein receptor(LSR)in dextran sodium sulfate(DSS)-induced colitis mice,and the effects of Lsr-specific knockout and overexpression in intestinal epithe-lium on intestinal inflammation in colitis mice.METHODS:C57BL/6J mice were administered 3%(w/v)DSS in drink-ing water for 6 days to induce colitis.Following the experiment,RNA-seq was employed to screen differentially expressed genes between the control group and experimental group.Changes in LSR expression were assessed using RT-qPCR,Western blot,and immunofluorescence staining.Intestinal epithelial Lsr-specific knockout mice were generated using the Cre-loxP system and subjected to DSS-induced colitis.Colitis severity was evaluated through changes in body weight,dis-ease activity index(DAI)score,colon length,and hematoxylin-eosin(HE)staining.Additionally,serum levels of tumor necrosis factor-α(TNF-α),interleukin-1β(IL-1β),IL-6,and IL-18 were measured via ELISA.Immunofluorescence staining was utilized to detect neutrophil and macrophage infiltration in colon tissues,while periodic acid-Schiff(PAS)staining was used to observe goblet cell numbers.Furthermore,adeno-associated virus(AAV-Lsr)was intraperitoneally injected to achieve LSR overexpression.Successful LSR overexpression was confirmed,and a DSS-induced colitis model was established using similar methods to observe intestinal inflammation.RESULTS:Results showed decreased LSR ex-pression in DSS-induced colitis mice.Intestinal epithelial Lsr-specific knockout mice exhibited increased susceptibility to DSS-induced colitis,evidenced by significantly reduced body weight(P<0.05),increased DAI(P<0.01),shortened co-lon length(P<0.05),and exacerbated pathological injury.Levels of pro-inflammatory cytokines TNF-α(P<0.05),IL-1β(P<0.01),IL-6(P<0.05),and IL-18(P<0.01)were significantly elevated,along with increased inflammatory cell infiltration and reduced goblet cell numbers in the colon.Conversely,LSR overexpression via AAV significantly alleviated intestinal inflammation in DSS-induced colitis mice.CONCLUSION:In conclusion,LSR expression decreased in DSS-induced colitis mice,and its loss exacerbated intestinal inflammation in this model.AAV-mediated LSR overexpression provided therapeutic relief from intestinal inflammation in DSS-induced colitis mice.

Objective:To construct a prediction model for ventilator-associated pneumonia (VAP) in mechanically ventilated preterm infants in the neonatal intensive care unit (NICU) and to test its clinical effect.Methods:This was a cross-sectional study. A total of 740 preterm infants admitted to the NICU for mechanical ventilation from July 2018 to June 2023 were retrospectively selected as the study subjects, and were divided into the modeling set (518 cases) and the validation set (222 cases) according to the ratio of 7∶3 using the computer-generated random number method. The modeling set was divided into the VAP group (181 cases) and the non-VAP group (337 cases) according to whether VAP occured, and 21 clinical characteristics were analyzed, using single factor difference analysis to screen predictive factors, the independent risk factors of VAP in mechanically ventilated preterm infants were determined by multivariate Logistic regression analysis, and the nomogram model was made by R software. Then, the nomogram model was tested by validating the data of the validation set. The receiver operating characteristic (ROC) curve, Hosmer-Lemeshow goodness-of-fit test, calibration curve and clinical decision curve were used to evaluate the efficacy and practical value of the model.Results:There were 88 males and 93 females in the VAP group, with 156 cases of gestational age<34 weeks and 25 cases of gestational age≥34 weeks. There were 155 males and 182 females in the non-VAP group, with 196 cases of gestational age<34 weeks and 141 cases of gestational age≥34 weeks. Birth weight ( OR=0.114, 95% CI 0.044-0.268, P<0.05) and oral care of breast milk ( OR=0.124, 95% CI 0.0.057-0.249, P<0.05) were protective factors for VAP in mechanically ventilated preterm infants, and Apgar score at 5 min after birth ( OR=2.895, 95% CI 1.318-6.419, P<0.05), serum prealbumin at 72 h of mechanical ventilation ( OR=4.837, 95% CI 2.643-9.063, P<0.05), gastric contents reflux ( OR=6.754, 95% CI 3.156-15.240, P<0.05), and time of mechanical ventilation ( OR=7.784, 95% CI 3.491-18.160, P<0.05) were independent risk factors for VAP in mechanically ventilated preterm infants. The area under the curve (AUC) of the ROC curve of the modeling set was 0.929 (95% CI 0.907-0.950, P<0.01), and the validation set (AUC) was 0.917 (95% CI 0.882-0.952, P<0.01), the model has good discrimination. The C indices of the modeling set and the validation set were 0.93 and 0.92 respectively by sampling 500 times by the Bootstrap method, indicating that the model had good consistency, and the decision curve suggested that the prediction model was far from the extreme curve and the net return value was high, indicating that the nomogram prediction model constructed this time had high prediction value. Conclusions:Birth weight, Apgar score at 5 min after birth, time of mechanical ventilation, oral care of breast milk, serum prealbumin at 72 h of mechanical ventilation, and gastric contents reflux are independent influencing factors for VAP in mechanically ventilated preterm infants. The nomogram prediction model constructed can provide a visual and simple evaluation tool for early identification of high-risk children and reducing the occurrence of VAP.