OBJECTIVE To investigate the intervention effect and potential mechanism of breviscapine on hepatic fibrosis （HF） in rats based on the transforming growth factor-β（1 TGF-β1）/Smad2/extracellular signal-regulated protein kinase 1（ERK1） and Kelch-like epichlorohydrin-associated protein 1（Keap1）/nuclear factor-erythroid 2-related factor 2（Nrf2）/heme oxygenase-1（HO-1） pathways. METHODS Totally 60 rats were randomly divided into normal control group， model group， breviscapine low-dose， medium-dose and high-dose groups （5.4， 10.8， 21.6 mg/kg）， and colchicine group （positive control， 0.45 mg/kg）， with 10 rats in each group， half male and half female. Except for the normal control group， HF model of the other groups was induced by carbon tetrachloride. Subsequently， each drug group was given corresponding medicine by gavage once a day for 28 days. The liver appearance of rats in each group was observed and their liver coefficients were calculated. The levels of alanineaminotransferase （ALT） and aspartate aminotransferase （AST）in serum， those of ALT， AST， superoxide dismutase （SOD），malondialdehyde （MDA） and glutathione peroxidase （GSH- Px） in liver tissue were detected. The liver tissue inflammatory and fibrotic changes were observed. The protein and mRNA expressions of TGF-β1， Smad2， ERK1， Nrf2， Keap1 and HO-in liver tissue were detected. RESULTS Compared with the normal control group， the model group showed large areas of white nodular lesions in the liver， obvious inflammatory cell infiltration and collagen fiber deposition. The body weight， the levels of SOD and GSH-Px in liver tissue， the protein and mRNA expressions of Nrf2 and HO-1 were significantly lowered in the model group （P＜0.05）； the liver coefficient， the percentage of Masson staining positive area， ALT and AST levels of serum and liver tissue， MDA level of liver tissue， the protein and mRNA expressions of TGF-β1， Smad2， ERK1 and Keap1 were significantly increased （P＜0.05）. Compared with the model group， the liver lesions of rats in each drug group were improved， and the above quantitative indexes were generally reversed （P＜0.05）. CONCLUSIONS Breviscapine has a good intervention effect on HF rats， which may be related to inhibiting TGF-β1/Smad2/ERK1 pathway for anti-fibrosis and regulating Keap1/Nrf2/HO-1 pathway to inhibit oxidative stress.

Ketamine,an antagonist of the glutamate N-methyl-D-aspartate(NMDA)receptor,is cur-rently one of the most widely abused psychoactive substances.Prolonged abuse can result in damages to various systems in the body,making it crucial to investigate the regulatory mechanism of ketamine addic-tion and screening related biomarkers.In this study,zebrafish embryos/larvae were initially exposed a-cutely to ketamine.Then,a ketamine addiction model was established in 6-month-old zebrafish through conditioned place preference(CPP)experiments.The zebrafish brain transcriptome was analyzed using RNA-seq,while qPCR and Western blotting were employed to detect the expression of key genes.Results revealed significant reductions in the spontaneous tail coiling,embryo hatching rate,and survival rate of zebrafish embryos in the ketamine-treated group compared to the control group.The distance moved also decreased significantly,from 1904.2 mm in the control group to 319.0 mm in the high dose of ketamine group(300 μmol/L).Conditional positional preference experiments demonstrated that the control ze-brafish did not exhibit significant changes in activity in the CPP tank.In contrast,the ketamine-treated group increased their activity time in the light zone of the tank from 385.2 s before training to 706.4 s af-ter training,representing a 26.8％increase(***P＜0.001).This suggests a preference for ketamine stimulation in zebrafish.KEGG analysis indicated enrichment of differentially expressed genes in the neu-roactive ligand-receptor interaction pathway in the ketamine-treated samples.GSEA analysis further re-veals a significant upregulation of the glutamatergic synapse pathway(NES=1.5).In addition,compared with the control group,the mRNA levels of Grin2b and Gria2 in the ketamine group increased by 4.6 and 1.4 times,respectively,while the protein levels increased by 2.0 and 1.4 times,respectively.These findings suggest that ketamine can induce addiction in zebrafish,potentially through upregulation of the glutamatergic synaptic pathway.

We wished to establish an expert consensus on late stage of critical care (CC) management. The panel comprised 13 experts in CC medicine. Each statement was assessed based on the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) principle. Then, the Delphi method was adopted by 17 experts to reassess the following 28 statements. (1) ESCAPE has evolved from a strategy of delirium management to a strategy of late stage of CC management. (2) The new version of ESCAPE is a strategy for optimizing treatment and comprehensive care of critically ill patients (CIPs) after the rescue period, including early mobilization, early rehabilitation, nutritional support, sleep management, mental assessment, cognitive-function training, emotional support, and optimizing sedation and analgesia. (3) Disease assessment to determine the starting point of early mobilization, early rehabilitation, and early enteral nutrition. (4) Early mobilization has synergistic effects upon the recovery of organ function. (5) Early functional exercise and rehabilitation are important means to promote CIP recovery, and gives them a sense of future prospects. (6) Timely start of enteral nutrition is conducive to early mobilization and early rehabilitation. (7) The spontaneous breathing test should be started as soon as possible, and a weaning plan should be selected step-by-step. (8) The waking process of CIPs should be realized in a planned and purposeful way. (9) Establishment of a sleep-wake rhythm is the key to sleep management in post-CC management. (10) The spontaneous awakening trial, spontaneous breathing trial, and sleep management should be carried out together. (11) The depth of sedation should be adjusted dynamically in the late stage of CC period. (12) Standardized sedation assessment is the premise of rational sedation. (13) Appropriate sedative drugs should be selected according to the objectives of sedation and drug characteristics. (14) A goal-directed minimization strategy for sedation should be implemented. (15) The principle of analgesia must be mastered first. (16) Subjective assessment is preferred for analgesia assessment. (17) Opioid-based analgesic strategies should be selected step-by-step according to the characteristics of different drugs. (18) There must be rational use of non-opioid analgesics and non-drug-based analgesic measures. (19) Pay attention to evaluation of the psychological status of CIPs. (20) Cognitive function in CIPs cannot be ignored. (21) Delirium management should be based on non-drug-based measures and rational use of drugs. (22) Reset treatment can be considered for severe delirium. (23) Psychological assessment should be conducted as early as possible to screen-out high-risk groups with post-traumatic stress disorder. (24) Emotional support, flexible visiting, and environment management are important components of humanistic management in the intensive care unit (ICU). (25) Emotional support from medical teams and families should be promoted through"ICU diaries"and other forms. (26) Environmental management should be carried out by enriching environmental content, limiting environmental interference, and optimizing the environmental atmosphere. (27) Reasonable promotion of flexible visitation should be done on the basis of prevention of nosocomial infection. (28) ESCAPE is an excellent project for late stage of CC management.
Humans ; Consensus ; Critical Care/methods* ; Intensive Care Units ; Pain/drug therapy* ; Analgesics/therapeutic use* ; Delirium/therapy* ; Critical Illness

OBJECTIVE: To explore the effects of prognostic nutritional index (PNI) combined with D-dimer on the prognosis of patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL). METHODS: The clinical data of 73 DLBCL patients at initial diagnosis were retrospectively evaluated, and the optimal cut-off point of PNI and D-dimer were determined by ROC curve. The overall survival (OS) rate and progression-free survival (PFS) rate in different subgroups were compared using Kaplan-Meier survival curves. Univariate and multivariate Cox regression analysis was performed to identify the factors associated with OS. RESULTS: Compared with the low PNI group (PNI<44.775), the high PNI group (PNI≥44.775) had better OS (P =0.022) and PFS (P =0.029), the 2-year OS rates of the two groups were 55.6% and 78.3% respectively (P =0.041). Compared with the high D-dimer group (D-dimer≥0.835), the low D-dimer group (D-dimer<0.835) had better OS (P <0.001) and PFS (P <0.001), the 2-year OS rates of the two groups were 51.4% and 86.8% respectively (P =0.001). Meanwhile, patients in the high PNI+ low D-dimer group had better OS (P =0.003) and PFS (P <0.001) than the other three groups, the 2-year OS rate was statistically different from the other three groups (P <0.05). The multivariate analysis revealed that NCCN-IPI (HR =2.083, 95%CI : 1.034-4.196, P =0.040), PNI (HR =0.267, 95%CI : 0.076-0.940, P =0.040) and PNI+D-dimer (HR =9.082, 95%CI : 1.329-62.079, P =0.024) were the independent risk factors affecting OS in patients with DLBCL. Subgroup analysis showed that PNI, D-dimer, and PNI combined with D-dimer could improve the prognostic stratification in low and low-intermediate risk DLBCL patients. CONCLUSION High PNI, low D-dimer and combination of high PNI and low D-dimer at initial diagnosis suggest a better prognosis in DLBCL patients.
Humans ; Prognosis ; Nutrition Assessment ; Retrospective Studies ; Lymphoma, Large B-Cell, Diffuse/pathology*

Enterotoxigenic Escherichia coli（ETEC）infection can induce watery diarrhea，leading to dehydration，electrolyte disturbance，and even death in severe cases. Recombinant B subunit/inactivated whole-cell cholera（rBS/WC）vaccine is effective in preventing ETEC infectious diarrhea. On the basis of the latest evidence on etiology and epidemiology of ETEC，as well as the effectiveness，safety，and health economics of rBS/WC vaccine，National Clinical Research Center for Child Health（The Children’s Hospital，Zhejiang University School of Medicine）and Zhejiang Provincial Center for Disease Control and Prevention invited experts to develop expert consensus on rBS/WC vaccine in prevention of ETEC infectious diarrhea. It aims to provide the clinicians and vaccination professionals with guidelines on using rBS/WC vaccine to reduce the incidence of ETEC infectious diarrhea.

Objective:To improve the understanding of the diagnosis and treatment of early T-cell precursor acute lymphoblastic leukemia (ETP-ALL).Methods:The clinical data of a patient with ETP-ALL who was misdiagnosed as peripheral T-cell lymphoma-not otherwise specified (PTCL-NOS) admitted to the Second Hospital of Lanzhou University in October 2020 were retrospectively analyzed, and the relevant literature was reviewed.Results:The patient who presented "inguinal lymphadenopathy" as the first symptom underwent lymph node biopsy and pathological examination at local hospital, and he was diagnosed as PTCL-NOS according to the consultation of another 2 hospitals. After 2 courses of chemotherapy (CHOPE regimen, GLD regimen, unknown specific medication and dosage), the therapeutic efficacy was poor. For further diagnosis and treatment, this patient came to Lanzhou University Second Hospital. Flow cytometry found blast cells in the bone marrow, and then other related examinations were completed, he was finally diagnosed as ETP-ALL. The chemotherapy regimens of Hyper-CVAD and EA were alternatively used, progressive disease (PD) occurred after 3 courses of treatment, and chidamide was added in the 4th and 5th courses of treatment, the disease still progressed, and the patient died after follow-up. The disease course of the patient was about 12 months.Conclusions:ETP-ALL has unique immunophenotypic characteristics. ETP-ALL patients have a low remission rate after conventional induction therapy, high recurrence rate and poor prognosis. Currently, there is no effective standard treatment regimen, and allogeneic hematopoietic stem cell transplantation or timely addition of new drugs may improve the prognosis.

OBJECTIVE: To investigate the significance of a new risk stratification model (R2-ISS) in evaluating the prognosis of newly diagnosed multiple myeloma (MM). METHODS: Clinical data of 116 newly diagnosed MM patients admitted to Lanzhou University Second Hospital from June 2012 to March 2021 were retrospectively analyzed. According to R2-ISS, these patients were divided into four groups: low risk, low-intermediate risk, intermediate-high risk, and high risk. The significance of R2-ISS on prognosis of the patients was analyzed. RESULTS: Survival analysis showed that R2-ISS was associated with progression-free survival (PFS) (P=0.042) and overall survival (OS) (P=0.014). Cox univariate analysis showed that lactate dehydrogenase, serum calcium, serum creatinine, β₂-microglobulin, ISS, R-ISS, R2-ISS, t(4;14), and autologous hematopoietic stem cell transplantation (ASCT) were the influencing factors of OS in newly diagnosed MM patients (all P<0.05). Cox multivariate analysis showed that R-ISS, R2-ISS, and ASCT were independent risk factors affecting OS (all P<0.05). In addition, survival analysis of patients with different R2-ISS showed that ASCT improved PFS and OS. CONCLUSION R2-ISS has prognostic value for newly diagnosed MM patients, while ASCT can improve the prognosis of patients with different R2-ISS.
Humans ; Prognosis ; Multiple Myeloma/diagnosis* ; Retrospective Studies ; Social Group ; Risk Assessment

This article summarizes and analyzes the reported synthetic routes of brivudine in patent and literature.2′-Deoxyuridine was employed as starting material, affording brivudine through iodization, heck coupling, hydrolysis, decarboxylation, bromination and recrystallization.After optimization of reaction conditions of each step, a synthetic route suitable for industrial production was achieved with simple synthetic process, high yield and excellent purity.

OBJECTIVE: To explore the influence of controlling nutritional status (CONUT) score on the prognosis of newly diagnosed patients with multiple myeloma (MM). METHODS: The clinical data 119 patients with MM who were diagnosed according to the international myeloma diagnostic criteria in Lanzhou University Second Hospital from April 2010 to October 2018 were collected and retrospectively analyzed. The relationship between clinical indexes, including age, sex, MM type, absolute lymphocyte count (ALC), absolute neutrophil count (ANC), absolute monocyte count (AMC), hemoglobin (Hb), platelet (PLT), β RESULTS: Compared with high-scoring group, low-scoring group had a better OS ［median OS was 43.3 months and 127.67 months, respectively, 95% confidence interval (CI): 57.065-78.345, P=0.038］. At the same time, the low-scoring group also had higher level of ALC, ANC, AMC, Hb, PLT, ALB, and CHO but lower of GLO. Multivariate survival analysis showed that age (HR=1.027, 95%CI: 1.000-1.054, P=0.048), AMC (HR=11.284, 95%CI: 22.968-42.897, P<0.001), CONUT score (HR=1.198, 95%CI: 1.036-1.385, P=0.015), M protein (non-IgG/IgG type) type (HR=0.503, 95%CI: 0.259-0.977, P=0.043) were independent factors affecting the prognosis of MM patients. CONCLUSION The CONUT score as an immune-nutrition score is a convenient and easy-to-obtain index to effectively predict the prognosis of MM patients.
Humans ; Lymphocyte Count ; Multiple Myeloma/diagnosis* ; Nutritional Status ; Prognosis ; Retrospective Studies

OBJECTIVE: To explore the effects of serum free light chain (sFLC) and monoclonal protein (MP) on the efficacy and prognosis of patients with multiple myeloma relapse, and investigate the clinical value of light chain escape (LCE). METHODS: The relationship between sFLC/MP levels and clinical features and outcomes in 71 patients with multiple myeloma after relapse were retrospective analyzed. The patients were divided into MO group, MLC group and LCE group according to different levels of sFLC/MP after relapse. Then the clinical indicators, efficacy, survival after relapse (SAR) and overall survival (OS) of the patients in each group were compared. Meanwhile a paired sample t test was used to analyze the relevant indicators of the patients before and after relapse in LCE group. RESULTS: There were significant differences in ISS stage, the levels of Hb, PLT, ALB, SFLC/MP and the proportion of myeloplasma cells afte relapse (P<0.05). The initial treatment effect of the patients in MO group was better than those in the other groups, and the LCE group was the worst (P<0.05). Comparison of relevant indicators between the patients before and after relapse in LCE group showed that the levels of MP, Hb and PLT decreased significantly, while sFLC, LDH and Cr increased significantly (P<0.05). Multivariate analysis showed that MO was the independent risk factor affecting SAR, while MO and LCE were the independent risk factors affecting OS (P<0.05) of the patients.The average SAR of the patients in MO, MLC and LCE group was 41, 28.6 and 23.5 months (P=0.002), and the average OS was 79.6, 57.9 and 41 months (P<0.001), respectively. The patients in MO group showed longer SAR and OS, while the LCE group was the shortest. CONCLUSION After relapse, patients only with elevated MP levels have a better curative effect and prognosis, while only with elevated sFLC levels have poor curative effects and prognosis, which suggesting that sFLC/MP levels can be used as a good indicator for predicting the prognosis of multiple myeloma patients.The appearance of LCE indicates disease progression, poor prognosis and early relapse.
Humans ; Immunoglobulin Light Chains ; Multiple Myeloma ; Prognosis ; Recurrence ; Retrospective Studies