OBJECTIVE: To investigate whether meranzin hydrate (MH) can alleviate depression-like behavior and hypomotility similar to Chaihu Shugan Powder (CSP), and further explore the potential common mechanisms. METHODS: Totally 120 Spraque-Dawley rats were randomly divided into 5-8 groups including sham, vehicle, fluoxetine (20 mg/kg), mosapride (10 mg/kg), CSP (30 g/kg), MH (9.18 mg/kg), [D-Lys3]-GHRP-6 (Dlys, 0.5 mg/kg), and MH+Dlys groups by a random number table, 8 rats in each group. And 32 mice were randomly divided into wild-type, MH (18 mg/kg), growth hormone secretagogue receptor-knockout (GHSR-KO), and GHSR+MH groups, 8 mice in each group. The forced swimming test (FST), open field test (OFT), tail suspension test (TST), gastric emptying (GE) test, and intestinal transit (IT) test were used to assess antidepressant and prokinetic (AP) effects after drug single administration for 30 min with absorbable identification in rats and mice, respectively. The protein expression levels of brain-derived neurotrophic factor (BDNF) and phosphorylated mammalian target of rapamycin (p-mTOR) in the hippocampus of rats were evaluated by Western blot. The differences in functional brain changes were determined via 7.0 T functional magnetic resonance imaging-blood oxygen level-dependent (fMRI-BOLD). RESULTS: MH treatment improved depression-like behavior (FST, OFT) and hypomotility (GE, IT) in the acute forced swimming (FS) rats (all P<0.05), and the effects are similar to the parent formula CSP. The ghrelin antagonist [D-Lys3]-GHRP-6 inhibited the effect of MH on FST and GE (P<0.05). Similarly, MH treatment also alleviated depression-like behavior (FST, TST) in the wild-type mice, however, no effects were found in the GHSR KO mice. Additionally, administration of MH significantly stimulated BDNF and p-mTOR protein expressions in the hippocampus (both P<0.01), which were also prevented by [D-Lys3]-GHRP-6 (P<0.01). Besides, 3 main BOLD foci following acute FS rats implicated activity in hippocampus-thalamus-basal ganglia (HTB) circuits. The [D-Lys3]-GHRP-6 synchronously inhibited BOLD HTB foci. As expected, prokinetic mosapride only had effects on the thalamus and basal ganglia, but not on the hippocampus. Within the HTB, the hippocampus is implicated in depression and FD. CONCLUSIONS MH accounts for part of AP effects of parent formula CSP in acute FS rats, mainly via ghrelin-related shared regulation coupled to BOLD signals in brain areas. This novel functionally connection of HTB following acute stress, treatment, and regulation highlights anti-depression unified theory.
Rats ; Mice ; Animals ; Brain-Derived Neurotrophic Factor/metabolism* ; Ghrelin/metabolism* ; Antidepressive Agents/therapeutic use* ; Hippocampus ; Stress, Psychological ; Mammals/metabolism*

Objective: To investigate dose-response associations between fluid overload (FO) and hospital mortality in patients with sepsis. Methods: The current cohort study was prospective and multicenter. Data were derived from the China Critical Care Sepsis Trial, which was conducted from January 2013 to August 2014. Patients aged≥18 years who were admitted to intensive care units (ICUs) for at least 3 days were included. Fluid input/output, fluid balance, fluid overload (FO), and maximum FO (MFO) were calculated during the first 3 days of ICU admission. The patients were divided into three groups based on MFO values: MFO<5%L/kg, MFO 5%-10%L/kg, and MFO≥10% L/kg. Kaplan-Meier analysis was used to predict time to death in hospital in the three groups. Associations between MFO and in-hospital mortality were evaluated via multivariable Cox regression models with restricted cubic splines. Results: A total of 2 070 patients were included in the study, of which 1 339 were male and 731 were female, and the mean age was (62.6±17.9) years. Of 696 (33.6%) who died in hospital, 968 (46.8%) were in the MFO<5%L/kg group, 530 (25.6%) were in the MFO 5%-10%L/kg group, and 572 (27.6%) were in the MFO≥10%L/kg group. Deceased patients had significantly higher fluid input than surviving patients during the first 3 days [7 642.0 (2 874.3, 13 639.5) ml vs. 5 738.0 (1 489.0, 7 153.5)ml], and lower fluid output [4 086.0 (1 367.0, 6 354.5) ml vs. 6 130.0 (2 046.0, 11 762.0) ml]. The cumulative survival rates in the three groups gradually decreased with length of ICU stay, and they were 74.9% (725/968) in the MFO<5% L/kg group, 67.7% (359/530) in the MFO 5%-10%L/kg group, and 51.6% (295/572) in the MFO≥10%L/kg group. Compared with the MFO<5%L/kg group, the MFO≥10%L/kg group had a 49% increased risk of inhospital mortality (HR=1.49, 95%CI 1.28-1.73). For each 1% L/kg increase in MFO, the risk of in-hospital mortality increased by 7% (HR=1.07, 95% CI 1.05-1.09). There was a"J-shaped"non-linear association between MFO and in-hospital mortality with a nadir of 4.1% L/kg. Conclusion: Higher and lower optimum fluid balance levels were associated with an increased risk of in-hospital mortality, as reflected by the observed J-shaped non-linear association between fluid overload and inhospital mortality.
Humans ; Male ; Female ; Adult ; Middle Aged ; Aged ; Aged, 80 and over ; Hospital Mortality ; Cohort Studies ; Prospective Studies ; Water-Electrolyte Imbalance ; Sepsis ; Intensive Care Units ; Retrospective Studies

Objective: To analyze the epidemiological characteristics of norovirus-caused acute gastroenteritis outbreaks in China, identify the factors influencing the scale of outbreaks, and provide scientific evidences for early control of norovirus infection outbreaks. Methods: The descriptive epidemiological analysis approach was applied to analyze the incidence of national norovirus infection outbreaks by using the data from the Public Health Emergency Event Surveillance System in China from January 1, 2007 to December 31, 2021. The unconditional logistic regression model was applied to analyze the risk factors that affected the outbreaks' scale. Results: A total of 1 725 norovirus infection outbreaks were recorded in China from 2007 to 2021, with an upward trend in the number of the reported outbreaks. The southern provinces had their annual outbreak peaks from October to March; the northern provinces had two outbreak peaks from October to December and from March to June annually. The outbreaks occurred mainly in southeastern coastal provinces with a trend of gradual spread to central, northeastern and western provinces. The outbreaks mainly occurred in schools and childcare setting (1 539 cases, 89.22%), followed by enterprises and institutions (67 cases, 3.88%) and community households (55 cases, 3.19%). Human to human transmission was the main infection route (73.16%), and norovirus GⅡ genotype was the predominate pathogen causing the outbreaks (899 cases, 81.58%). The time interval between the onset of the primary case and the outbreak reporting M (Q₁, Q₃) was 3 (2, 6) days and the case number of the outbreak M (Q₁, Q₃) was 38 (28, 62). The timeliness of outbreak reporting was improved in recent years and the scale of the outbreaks showed a decreasing trend over the years, the differences in reporting timeliness and outbreak scale among different settings were significant (P<0.001). The factors that affected outbreaks' scale included the outbreak setting, transmission route, outbreak reporting timeliness and type of living areas (P<0.05). Conclusions: From 2007 to 2021, the number of the norovirus-caused acute gastroenteritis outbreaks increased in China and the more areas were affected. However, the outbreak scale showed a decreasing trend and the outbreak reporting timeliness was improved. It is important to further improve the surveillance sensitivity and reporting timeliness for the effective control of the outbreak scale.
Humans ; Child ; Norovirus ; Disease Outbreaks ; China ; Child Care ; Gastroenteritis

Objective: To evaluate the incidence of immune checkpoint inhibitor-based combination therapy-induced liver damage in patients with primary liver cancer. Methods: Clinical data of 65 hospitalized cases of primary liver cancer treated with programmed cell death-1 its ligand programmed death-ligand 1 (PD-1/PD-L1) antibody in the Department of Infectious Diseases of the Second Affiliated Hospital of Chongqing Medical University from January 1, 2018 to March 31, 2021 were retrospectively analyzed. The degree of liver injury before and after treatment was assessed according to CTCAE v5.0. Patients were grouped according to gender, age, presence or absence of cirrhosis, baseline Child-Pugh score, BCLC stage, and treatment regimen to compare the incidence of liver injury under different conditions. The χ (2) test or rank-sum test was used for comparison among multiple groups. Results: 46 cases (70.77%) had liver damage of any grade according to the CTCAE V5.0 criteria during the treatment and observation period. All 6 cases who received standardized anti-hepatitis B virus (HBV) treatment developed liver damage. 10 (15.38%), 15 (23.08%), 19 (29.23%), and 2 (3.08%) cases had grade 1, 2, 3, and 4 liver damage respectively. There was no statistically significant difference in the incidence of liver damage between male and female patients (68.33% and 100%, P = 0.180). There was no statistically significant difference in the incidence of liver damage among different age groups (P = 0.245). The incidence of liver damage in cirrhotic and non-cirrhotic group was 72.22%, and 63.64% (P = 0.370), respectively. The incidence of liver damage in patients with baseline Child-Pugh class A, B, and C were 71.43%, 61.11% and 100%, respectively, and the difference was not statistically significant (P = 0.878). The incidence of liver damage was not statistically significantly different under different BCLC stages (P = 1.000). The incidence of liver damage in the PD-1/PD-L1 antibody monotherapy, PD-1/PD-L1 antibody combined with targeted drug therapy, and PD-1/PD-L1 antibody combined with TACE/radiofrequency ablation treatment group were 60.00%, 67.85%, and 86.67%, respectively. There was no statistically significant difference in the incidence of liver damage between the treatment regimen (P = 0.480). Conclusion: Immune checkpoint inhibitor therapy-induced liver damage is common in patients with primary liver cancer; however, it rarely severely endangers the patient's life. Additionally, patient's gender, age, presence or absence of cirrhosis, baseline liver function, BCLC stage and the immunotherapy regimen has no effect on the incidence of immune-related liver damage.
Female ; Humans ; Immune Checkpoint Inhibitors ; Incidence ; Liver Neoplasms/epidemiology* ; Male ; Retrospective Studies

Aim To explore the mechanism of Fluspirilene inhibiting HCC through decreasing the expression of Akt.Methods The difference of mRNA was verified by the test of protein expression between Fluspirilenc treatment group and control group by HCC experiment in vivo and vitro, including Western blot, IHC after mRNA array.Results Akt expression was lower in Fluspirilene treatment group than that in control group by mRNA array.Protein expression of Akt, phosphorylate-CDK2 and phos- phorylate-Rb decreased massively in Fluspirilene treatment group in a concentration-dependent manner in HepG2 and Huh7 cells by Western blotting compared with those in control group.Declined expression of phosphorylate-Akt was proved in a concen- tration-dependent manner in xenograft tumor tissues in Fluspirilene treatment group compared with that in control group in IHC test.Conclusions Fluspirilene inhibits HCC by decreasing significantly the protein expression of Akt, phosphorylat-Akt, phos- phorylate-CDK2 and phosphorylate-Rb.

OBJECTIVE: To investigate the effects and mechanisms of intermittent and persistent noise exposure-induced anxiety and depression-like behavior in rats. METHODS: The specific pathogen free male SD rats were randomly divided into control group, four times/day intermittent noise exposure group, two times/day intermittent noise exposure group and persistent noise exposure group, with 15 rats in each group. The rats in the control group were housed in natural environment(background noise ≤50 dB), and the rats in other three exposure groups were exposed to noise with intensity of(95±2) dB of 20 to 20 000 Hz noise for four hours per day for 14 days; rats in the four times/day intermittent noise exposure group entered a five-hour quiet period every one hours of noise exposure, four times/day; rats in the two times/day intermittent noise exposure group entered a 10-hour quiet period every two hours of noise exposure, two times/day; rats in the persistent noise exposure group entered a 20-hour quiet period every four hours of noise exposure. After exposure, anxiety like behavior was evaluated by open field test and elevated cross maze test. The depression like behavior was evaluated by sugar preference test and forced swimming test. The pathological changes of neurons in the hippocampus were observed by hematoxylin-eosin(HE) staining, and the ultrastructural changes of hippocampal tissues were observed by transmission electron microscope. Chemiluminescence and colorimetry were used to detect the levels of reactive oxygen species(ROS), malondialdehyde, glutathione(GSH) and the activity of superoxide dismutase(SOD). RESULTS: In the behavioral experiment, the percentage of exercise time in the central area decreased in the three noise exposure groups(all P<0.01). The exercise distance in the central area and sugar preference index decreased in the persistent noise exposure group(both P<0.01). The percentage of open arm exercise time and open arm exercise distance decreased in the two times/day intermittent noise exposure group and persistent noise exposure group compared with the control group(all P<0.01). The open arm distance of rats in the persistent noise exposure group were lower than those in the four times/day intermittent noise exposure group(P<0.05), while the immobility time was longer than in control group and the four times/day intermittent noise exposure group(both P<0.05). The HE staining showed that the neuronal spacing in CA1 area of the hippocampus of rats was significantly widened, and the pyramidal cells showed degeneration and necrosis in the persistent noise exposure group. There was no obvious necrosis found in the neurons of the other three groups. The ultrastructure of neurons showed that most mitochondria of cells in the hippocampus of rats in the two times/day intermittent noise exposure group were swollen. In the persistent noise exposure group, some neurons of the hippocampus of rats were necrotic, the cell membrane was discontinuous, the mitochondria were swollen, and the cristae were broken, dissolved or even disappeared. The mitochondrial structure of the hippocampus of rats in the other two groups was normal. The activity of SOD in the hippocampus of rats decreased in the four times/day intermittent noise exposure group(P<0.05), and the activity of SOD and the level of GSH in the hippocampus of rats decreased in the two times/day intermittent noise exposure group(both P<0.05), compared with the control group. The level of ROS and malondialdehyde in the hippocampus of rats in the persistent noise exposure group increased(all P<0.05), while the SOD activity and GSH level decreased(all P<0.05), compared with the other three groups. CONCLUSION: Intermittent noise exposure causes less anxiety and depression-like changes in rats than persistent noise exposure. Noise may cause anxiety and depression in rats through oxidative stress pathways.

This study aimed to further validate the prognostic role of fibrinogen in upper tract urothelial carcinoma (UTUC) in a large Chinese cohort. A total of 703 patients who underwent radical nephroureterectomy were retrospectively identified. Fibrinogen levels of ≥4.025 g l^-1 were defined as elevated. Logistic regression analysis was performed to determine the association between fibrinogen and adverse pathological features. Kaplan-Meier analysis and Cox regression models were used to assess the associations of fibrinogen with cancer-specific survival (CSS), disease recurrence-free survival (RFS), and overall survival (OS). Harrell c-index and decision curve analysis were used to assess the clinical utility of multivariate models. The median follow-up duration was 42 (range: 1-168) months. Logistic regression analysis revealed that elevated fibrinogen was associated with higher tumor stage and grade, lymph node involvement, lymphovascular invasion, sessile carcinoma, concomitant variant histology, and positive surgical margins (all P < 0.05). Multivariate Cox regression analysis demonstrated that elevated fibrinogen was independently associated with decreased CSS (hazard ratio [HR]: 2.33; P < 0.001), RFS (HR: 2.09; P < 0.001), and OS (HR: 2.09; P < 0.001). The predictive accuracies of the multivariate models were improved by 3.2%, 2.0%, and 2.8% for CSS, RFS, and OS, respectively, when fibrinogen was added. Decision curve analysis showed an added benefit for CSS prediction when fibrinogen was added to the model. Preoperative fibrinogen may be a strong independent predictor of worse oncologic outcomes in UTUC; therefore, it may be valuable to apply this marker to the current risk stratification in UTUC.
Aged ; Biomarkers, Tumor ; Carcinoma, Transitional Cell/surgery* ; China ; Disease-Free Survival ; Female ; Fibrinogen/analysis* ; Humans ; Male ; Middle Aged ; Nephroureterectomy ; Prognosis ; Retrospective Studies ; Survival Rate ; Urologic Neoplasms/surgery*

OBJECTIVE: To explore the effectiveness and safety of golimumab in the treatment of severe/refractory cardiovascular Behcet syndrome (BS). METHODS: We retrospectively analyzed the clinical data of nine patients diagnosed with severe/refractory cardiovascular BS and treated with golimumab from February 2018 to July 2020 in Peking Union Medical College Hospital. We analyzed levels of erythrocyte sedimentation rate (ESR) and high-sensitivity C-reactive protein (hsCRP), imaging findings, and the doses of glucocorticoids and immunosuppressive agents during the period of combined treatment with golimumab. RESULTS: Nine patients were enrolled, including 8 males and 1 female, with a mean age and median course of (37.0±8.6) years and 120 (60, 132) months, respectively. Seven patients presented with severe aortic regurgitation combined with other cardiovascular involvement secondary to BS. Two patients presented with large vessel involvement, including multiple aneurysms and vein thrombosis. Prior to golimumab treatment, seven patients were treated with glucocorticoids and multiple immunosuppres-sants [with a median number of 3 (1, 3) types] while still experienced disease progression or elevated inflammation biomarkers during postoperative period. Eight patients with disease progression, uncontrolled inflammation and history of severe postoperative complications required effective and fast control of inflammation during perioperative period. One patient had adverse reaction with tocilizumab and switched to golimumab during perioperative period. The patients were treated with golimumab 50 mg every 4 weeks, along with concomitant treatment of glucocorticoid and immunosuppressants. After a median follow-up of (16.3±5.6) months, all the patients achieved clinical improvement. Vascular lesions were radiologically stable and no vascular progressive or newly-onset of vascular lesions was observed. The eight patients who experienced cardiac or vascular operations showed no evidence of postoperative complications. The ESR and hsCRP levels decreased significantly [16.5 (6.8, 52.5) mm/h vs. 4 (2, 7) mm/h, and 21.24 (0.93, 32.51) mg/L vs. 0.58 (0.37, 1.79) mg/L (P < 0.05), respectively]. The dose of prednisone was tapered from 35 (15, 60) mg/d to 10.0 (10.0, 12.5) mg/d. No prominent adverse reactions were observed. CONCLUSION Our study suggests that golimumab is effective in the treatment of severe/refractory cardiovascular BS. Combination immunosuppression therapy with golimumab contributes to control of inflammation, reduction of postoperative complications and tapering the dose of glucocorticoids or immunosuppressants.
Adult ; Antibodies, Monoclonal/therapeutic use* ; Behcet Syndrome/drug therapy* ; Drug Therapy, Combination ; Female ; Humans ; Male ; Middle Aged ; Retrospective Studies ; Treatment Outcome

OBJECTIVE: To investigate the status of vaccination in children with human immunodeficiency virus (HIV) infection. METHODS: A questionnaire survey was performed in 148 children in Hunan province, China who were registered in China's Acquired Immune Deficiency Syndrome Comprehensive Response Information Management System up to December 31, 2016 and were aged <15 years at the time of confirmed diagnosis of HIV infection. The information on vaccination, diagnosis of HIV infection, and diagnosis and treatment of related diseases was collected. RESULTS: Of the 148 children with HIV infection, there were 70 boys (47.3%) and 78 girls (52.7%); 140 children had an age of 3.8 (0.2-14.8) years at the time of confirmed diagnosis, and 8 children refused to answer this question. Mother-to-child transmission was found in 133 children (91.7%), blood transmission in 1 child (0.7%), and unknown in 14 children (9.5%). Of the 148 children, 129 (87.2%) received antiviral therapy and 19 (12.8%) did not receive such treatment. The vaccination rates of hepatitis B vaccine, bacille Calmette-Guérin vaccine, poliomyelitis live attenuated vaccine and diphtheria-pertussis-tetanus vaccine ranged from 70.9% to 77.7%, which was significantly lower than the national level (≥97%); the vaccination rates of the other vaccines in the National Immunization Program gradually decreased with age. No severe adverse effects were reported after vaccination. CONCLUSIONS Mother-to-child transmission is the main route of HIV infection in Chinese children. The diagnosis of children with HIV infection is significantly delayed, with low vaccination rates. Efforts should be made to strengthen early diagnosis, early treatment and vaccination in children with HIV infection, in order to improve their quality of life.
Adolescent ; Child ; Child, Preschool ; China ; Diphtheria-Tetanus-Pertussis Vaccine ; Female ; HIV ; HIV Infections ; Humans ; Infant ; Male ; Quality of Life ; Vaccination

Aim To determine the effect of exosomes from lipopolysaccharide-treated human bone marrow mesenchymal stem cells on proportion of Ly6Chigh and Ly6Clow monocytes/macrophages in inflammatory micro- environment. Methods BMSCs were obtained by gra-dient centrifugation, identified and then treated with li-popolysaccharide for 48 h. The exosomes were purified from conditional medium with or without LPS treatment and identified by CD63 protein using Western blot and transmission electron microscope. The diameters and concentration were detected by Nanoparticle Trafficking Analysis ( NTA ) . The monocytes/macrophages were sorted from bone marrow of the mice by magnetic beads. Cells were co-cultured with exosomes for 24 hours, and then treated with LPS for 48 hours. The proportion of Ly6C monocytes/macrophages was detec-ted by flow cytometry. Inflammatory cytokines in cell supernatant were investigated using ELISA. Results BMSCs surface markers CD44, CD90 were positively detected, but CD34, CD45 were not expressed. BM-SCs presented adipogenic differentiation ability. Exo-somes were positively expressing CD63 protein, and NTA showed that the diameters of exosomes were up to (82.4 ± 3.7 ) nm. BMSCs stimulated by LPS pro- duced more exosomes ( P < 0.01 ) . Exosomes from BMSCs with or without LPS treatment could increase the ratio of Ly6Chigh monocytes (P<0.01) and down-regulate the ratio of Ly6Chigh macrophages (P<0.05), and the effect of LPS treated-exosomes was more signif-icant than untreated-exosomes (P<0.05). Moreover, the concentration of IL-6 was also elevated under exo-somes treatment ( P <0.05 ) . Conclusions Human bone marrow mesenchymal stem cells-derived exosomes contribute to the regulation of Ly6Chigh monocytes/mac-rophages, indicating that they could be involved in the therapeutic treatment of inflammatory diseases.