OBJECTIVES: To determine the pharmacological impact of hesperidin, the main component of Citri Reticulatae Pericarpium, on depressive behavior and elucidate the mechanism by which hesperidin treats depression, focusing on the gut-brain axis. METHODS: Fifty-four Sprague Dawley male rats were randomly allocated to 6 groups using a random number table, including control, model, hesperidin, probiotics, fluoxetine, and Citri Reticulatae Pericarpium groups. Except for the control group, rats in the remaining 5 groups were challenged with chronic unpredictable mild stress (CUMS) for 21 days and housed in single cages. The sucrose preference test (SPT), immobility time in the forced swim test (FST), and number in the open field test (OFT) were performed to measure the behavioral changes in the rats. Enzyme-linked immunosorbent assay was used to determine the levels of 5-hydroxytryptamine (5-HT) and brain-derived neurotrophic factor (BDNF) in brain tissue, and the histopathology was performed to evaluate the changes of colon tissue, together with sequencing of the V3-V4 regions of 16S rRNA gene on feces to explore the changes of intestinal flora in the rats. RESULTS: Compared to the control group, the rats in the model group showed notable reductions in body weight, SPF, and number in OFT (P<0.01). Hesperidin was found to ameliorate depression induced by CUMS, as seen by improvements in body weight, SPT, immobility time in FST, and number in OFT (P<0.05 or P<0.01). Regarding neurotransmitters, it was found that at a dose of 50 mg/kg hesperidin treatment upregulated the levels of 5-HT and BDNF in depressed rats (P<0.05). Compared to the control group, the colon tissue of the model group exhibited greater inflammatory cell infiltration, with markedly reduced numbers of goblet cells and crypts and were significantly improved following treatment with hesperidin. Simultaneously, the administration of hesperidin demonstrated a positive impact on the gut microbiome of rats treated with CUMS, such as Shannon index increased and Simpson index decreased (P<0.01), while the abundance of Pseudomonadota and Bacteroidota increased in the hesperidin-treated group (P<0.05). CONCLUSION The mechanism responsible for the beneficial effects of hesperidin on depressive behavior in rats may be related to inhibition of the expressions of BDNF and 5-HT and preservation of the gut microbiota.
Animals ; Hesperidin/therapeutic use* ; Rats, Sprague-Dawley ; Depression/drug therapy* ; Male ; Stress, Psychological/drug therapy* ; Brain/metabolism* ; Brain-Derived Neurotrophic Factor/metabolism* ; Serotonin/metabolism* ; Gastrointestinal Microbiome/drug effects* ; Behavior, Animal/drug effects* ; Rats ; Brain-Gut Axis/drug effects* ; Chronic Disease ; Colon/drug effects*

ObjectiveTo investigate the effect of mucin 1 (MUC1) on the proliferation and apoptosis of nasopharyngeal carcinoma (NPC) and its regulatory mechanism. MethodsThe 60 NPC and paired para-cancer normal tissues were collected from October 2020 to July 2021 in Quanzhou First Hospital. The expression of MUC1 was measured by real-time quantitative PCR (qPCR) in the patients with PNC. The 5-8F and HNE1 cells were transfected with siRNA control (si-control) or siRNA targeting MUC1 (si-MUC1). Cell proliferation was analyzed by cell counting kit-8 and colony formation assay, and apoptosis was analyzed by flow cytometry analysis in the 5-8F and HNE1 cells. The qPCR and ELISA were executed to analyze the levels of TNF-α and IL-6. Western blot was performed to measure the expression of MUC1, NF-кB and apoptosis-related proteins (Bax and Bcl-2). ResultsThe expression of MUC1 was up-regulated in the NPC tissues, and NPC patients with the high MUC1 expression were inclined to EBV infection, growth and metastasis of NPC. Loss of MUC1 restrained malignant features, including the proliferation and apoptosis, downregulated the expression of p-IкB、p-P65 and Bcl-2 and upregulated the expression of Bax in the NPC cells. ConclusionDownregulation of MUC1 restrained biological characteristics of malignancy, including cell proliferation and apoptosis, by inactivating NF-κB signaling pathway in NPC.

Objective To evaluate the bioequivalence of test product and reference product in a single dose of amoxicillin clavulanate potassium tablet under fasting and fed conditions in healthy volunteers.Methods An open label,randomized,single dose,four-period,crossover bioequivalence study was designed.Fasting and postprandial tests were randomly divided into 2 administration sequence groups according to 1:1 ratio,amoxicillin clavulanate potassium tablet test product or reference product 375 mg,oral administration separately,liquid chromatography tanden mass spectrometry was applied to determine the concentration of amoxicillin and clavulanate potassium in plasma of healthy subjects after fasting or fed administration,while Phoenix WinNonlin 8.2 software were used for pharmacokinetics(PK)parameters calculation and bioequivalence analysis.Results Healthy subjects took the test product and the reference product under fasting condition,the main PK parameters of amoxicillin are as follows:Cmax were(5 075.57±1 483.37)and(5 119.86±1 466.73)ng·mL-1,AUC0_twere(1.32 × 104±2 163.76)and(1.30 × 104±1 925.11)ng·mL-1,AUC0-∞were(1.32 × 104±2 175.40)and(1.31 ×104±1 935.86)ng·mL-1;the main PK parameters of clavulanic acid are as follows:Cmax were(3 298.27±1 315.23)and(3 264.06±1 492.82)ng·mL-1,AUC0-twere(7 690.06±3 053.40)and(7 538.39±3 155.89)ng·mL-1,AUC0-∞were(7 834.81±3 082.61)and(7 671.67±3 189.31)ng·mL-1;the 90％confidence intervals of Cmax,AUC0-tand AUC0-∞ after logarithmic conversion of amoxicillin and clavulanate potassium of the two products were all within 80.00％-125.00％.Healthy subjects took the test and reference product under fed condition,the main PK parameters of amoxicillin are as follows:Cmax were(4 514.08±1 324.18)and(4 602.82±1 366.48)ng·mL-1,AUC0-twere(1.15 × 104±1 637.95)and(1.15 × 104±1 665.69)ng·mL-1,AUC0-∞ were(1.16 × 104±1 646.26)and(1.15 × 104±1 607.20)ng·mL-1;the main PK parameters of clavulanic acid are as follows:Cmax were(2 654.75±1 358.29)and(2 850.51±1 526.31)ng·mL-1,AUC0-twere(5 882.82±2 930.06)and(6 161.28±3 263.20)ng·mL-1,AUC0-∞ were(6 022.70±2 965.05)and(6 298.31±3 287.63)ng·mL-1;the 90％confidence intervals of Cmax,AUC0-t and AUC0-∞ after logarithmic conversion of amoxicillin and clavulanate potassium of the two products were all within 80.00％-125.00％.Conclusion The two formulations were bioequivalent to healthy adult volunteers under fasting and fed conditions.

Objective:To analyze the level and clinical significance of IL-18 and IL-18-binding protein (BP) in the bone marrow of patients with myelodysplastic syndrome (MDS) .Methods:A total of 43 newly diagnosed patients with MDS who were admitted to the Department of Hematology, Tianjin Medical University General Hospital, from July 2020 to February 2021 were randomly selected. The control group consisted of 14 patients with acute myeloid leukemia (AML) and 25 patients with iron-deficiency anemia (IDA). The levels of IL-18 and IL-18 BP in the bone marrow supernatant were measured, and their correlations with MDS severity, as well as the functionality of CD8 + T cells and natural killer cells, was analyzed. Results:The levels of IL-18, IL-18 BP, and free IL-18 (fIL-18) in the bone marrow supernatant of patients with MDS were higher than in the IDA group. The level of fIL-18 was linearly and negatively correlated with the MDS-International Prognostic Scoring System (IPSS) score. IL-18 receptor (IL-18Rα) expression on CD8 + T cells in the MDS group was lower than in the IDA group, and the levels of fIL-18 and IL-18Rα were positively correlated with CD8 + T-cell function in the MDS group. Conclusion:IL-18 BP antagonizes IL-18, leading to a decrease in fIL-18 in the bone marrow microenvironment of patients with MDS, affecting CD8 + T-cell function, which is closely related to MDS severity; therefore, it may become a new target for MDS treatment.

Objective:To investigate the clinical features of nontuberculous mycobacteria (NTM) disease patients with positive anti-interferon γ (IFN-γ) autoantibody.Methods:Forty-three adult human immunodeficiency virus-uninfected patients with NTM disease hospitalized in Huashan Hospital, Fudan University and Jing′an Branch, Huashan Hospital, Fudan University from July 2021 to August 2023 were included. Clinical data and NTM strain information of the patients were collected. The plasma levels of anti-IFN-γ autoantibodies were detected by enzyme-linked immunosorbent assay, and the patients were divided into antibody positive group and antibody negative group. The clinical characteristics and laboratory examination results between the two groups were compared. The independent sample t test, Mann-Whitney U test and chi-square test were used for statistical analysis. Multivariate logistic regression analysis was used to determine the correlation factors of positive anti-IFN-γ autoantibodies. Results:Among the 43 patients, 13 cases (30.2%) were positive for anti-IFN-γ autoantibodies and 30 cases (69.8%) were negative. The proportions of patients with NTM disseminated infection (9/13 vs 30.0%(9/30))and combined bacterial infection (5/13 vs 6.7%(2/30)) in antibody positive group were both higher than those in antibody negative group, and the differences were both statistically significant ( χ2=5.74 and 6.73, respectively, both P<0.05). The white blood cell count, platelet count, the proportion of platelet count >350×10 9/L of antibody positive patients were all higher than those of antibody negative group, while the white sphere ratio was lower than that of antibody negative group, with statistical significance ( t=2.42, 3.02, χ2=9.77 and t=3.66, respectively, all P<0.05). Erythrocyte sedimentation rate, C-reactive protein, procalcitonin, globulin, immunoglobulin G, immunoglobulin A and immunoglobulin M in antibody positive patients were all higher than those in antibody negative group, and the differences were all statistically significant ( U=99.50, 112.00, 115.50, 61.50, 76.50, 99.00 and 83.00, respectively, all P<0.05). Mycobacterium abscessus complex (seven cases and 11 cases, respectively) and Mycobacterium avium complex (five cases and 13 cases, respectively) were the main isolated strains in antibody positive and antibody negative patients. Multivariate logistic regression analysis showed that combined with bacterial infection (odds ratio ( OR)=21.83, 95% confidence interval ( CI) 1.94 to 245.71), NTM disseminated infection ( OR=7.64, 95% CI 1.10 to 53.26), platelet count>350×10 9/L ( OR=14.31, 95% CI 1.91 to 107.04) were risk factors for anti-IFN-γ autoantibodies positive (all P<0.05). Conclusions:Patients with positive anti-IFN-γ autoantibodies have higher probability of having elevated levels of systemic inflammation. Anti-IFN-γ autoantibody test is recommended for patients with NTM disease who present with co-bacterial infection, NTM disseminated infection, or elevated platelet count (>350×10 9/L).

The Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) (American Psychiatric Association, 2013) defines autism spectrum disorder (ASD) as a complex neurodevelopmental disorder that begins in early childhood and is accompanied by social communication deficits and repetitive stereotyped behaviors. According to the monitoring data released in 2021 in the United States, the prevalence of ASD in children was as high as 2.27%; that is, one in 44 children had autism (Maenneret al., 2021). China publicly reported this figure to be around 0.7% (Zhou et al., 2020). The current view is that children with ASD are generally impaired in their adaptation ability (McDonaldet al., 2016; Hodgeet al., 2021; Opertoet al., 2021). Adaptive behaviors comprise the conceptual, social, and practical skills that enable individuals to adapt to the environment, which play an important role in daily life (McDonald et al., 2019). "Adaptive behavior" was first described by Doll (1936). Subsequently, abnormalities in adaptive behavior were included in the criteria for intellectual disability for the first time (Heber, 1961). The American Association on Mental Retardation (AAMR) has refined and specified this term several times. Researchers hold different opinions on the structure of social adaptive capability. Greenspan and Granfield (1992) divided social adaptive capability into social understanding and social interaction. However, an increasing number of scholars considered that the concept of adaptive behaviors in children was constructed via multiple dimensions. The most representative one among them was the Vineland Adaptive Behavior Scales (VABS) proposed by Sparrow et al. (1984). This scale illustrates that adaptive behavior includes communication, daily living skills, socialization, and motor skills. Harrison and Oakland (2003) developed an Adaptive Behavior Assessment System (ABAS), by applying the theory of adaptive behavior proposed by AAMR and the American Association on Intellectual and Developmental Disabilities (AAIDD). This system shows that adaptive behavior has three adaptive composites, namely, conceptual composite (including communication, learning function, and self-management), social composite (including leisure and social skills), and practical composite (including community application, home living, health and safety, and self-care). As there are different requirements for the social adaptive capability of children from different cultural backgrounds and various regions, Chinese scholars have translated the Normal Development of Social Skills from Infant to Junior High School Children (S-M) scale compiled by Japanese scholars into Chinese, which is now widely used in China (Zhang et al., 1995). The impairment of adaptive function in children with ASD includes multiple dimensions, such as socialization, communication, and daily living skills (Kanne et al., 2011), and the degree of impairment can predict the prognosis and outcome in real life, including education acquisition and independent living ability (Farley et al., 2009). Therefore, adaptive behavioral capacity is considered to be a key intervention point that directly affects the individual and social outcomes of autistic children (Veenstra-VanderWeele et al., 2017; Bölte et al., 2019).
Humans ; Autism Spectrum Disorder/psychology* ; Male ; Adaptation, Psychological ; Child, Preschool ; Female ; Child ; Retrospective Studies ; China/epidemiology*

ObjectiveTo assess the prognostic value of ¹⁸F-FDG PET/CT parameters for predicting therapeutic response in diffuse large B-cell lymphoma （DLBCL）. MethodsWe retrospectively analyzed the clinical data and ¹⁸F-FDG PET/CT radiomics features of 81 DLBCL patients enrolled between June 2015 and October 2020. Multivariate logistic regression analysis was used to identify the predictive factors for therapeutic response of DLBCL， based on which a predictive model was developed accordingly. The performance of the model was evaluated by receiver operating characteristic （ROC） curves and calibration plots. ResultsDuring the two years after first chemotherapy， 23 patients （28.3%） developed relapse and 58 patients （71.7%） had progression-free survival （PFS）. The analysis for the predictive capability of the binary logistic regression model incorporating the PET/CT features revealed that the imaging features of ¹⁸F-FDG PET/CT after chemotherapy were independent prognostic factors for PFS. Among them， SUV_THR-mean2 was the most important factor for predicting therapeutic response in DLBCL patients after chemotherapy， with a cutoff value of 2.00 （AUC=0.81）. Conclusions¹⁸F-FDG PET/CT showed a valuable prognostic performance for PFS in DLBCL patients after chemotherapy， with the imaging feature after chemotherapy SUV_TLR-mean2 being the optimal independent predictor. Our predictive model of imaging features might have an important prognostic value in assessing the risk of disease progression， guiding the treatment and follow-up protocol， improving therapeutic efficiency and cutting down the medical cost.

Abstract: Objective To investigate the impact of SARS-CoV-2 virus infection on the risk of thrombosis in COVID-19 outpatient patients with mild and regular symptoms. Methods Outpatient patients during the SARS-CoV-2 large-scale infection period after the policy adjustment for COVID-19 in Beijing in 2022 were selected as the observation group, and the dynamic zero-clearing period before the policy adjustment and outpatient patients during the 2022/2021/2020 period were taken as the three control groups. The patients with physiological factors that may increase the risk of coagulation, such as thrombotic diseases, malignant tumors, female pregnancy and other physiological factors, were excluded. Pediatric patients under 14 years old were also excluded. Age was expressed as median (interquartile). The changes in blood routine, fibrin/fibrinogen degradation products, and D-Dimer in Beijing outpatient patients were studied with statistical method and data analysis techniques. Results Compared with the control groups, the observation group showed a statistically significant decrease in red blood cells (RBC), hemoglobin (Hb), and hematocrit (HCT) levels, and an increase in monocytes (MONO) and platelet (PLT) counts, all showed statistically significant differences (P<0.0001). The proportion of fibrinogen degradation product (FDP) and D-Dimer of observation group exceeding the range increased significantly. Compared with the three control groups, the number of outpatient fibrinogen degradation products (FDP) in the observation group of patients aged 50 years and verage number of patients under 50 years old in the observation group with D-Dimer exceeding the threshold increased by more than 48.98%, and the monthly average number of patients with D-Dimer exceeding the threshold in patients aged 50 or older increased by 346%-998%. Conclusions The results of this study suggest that outpatient patients with mild or regular SARS-CoV-2 infection are also at risk for thrombotic events, and monitoring blood coagulation indicators such as D-dimer is recommended to avoid the sudden onset of thrombosis-related fatal complications .

Abstract OBJECTIVE To establish an efficient and simple HPLC-MS/MS method for determination of flucloxacillin in newborn plasma, and to investigate the interaction between ambroxol and flucloxacillin in newborns. METHODS The samples were analyzed by API4000 HPLC-MS/MS. Ultimate XB-C18 column(2.1 mm×100 mm, 5 μm) were carried out. The mobile phase was composed of water-0.1% formic acid(A) and acetonitrile-0.1% formic acid(B). The quantitative analysis of the ion transitions were monitored at m/z 452.6→284.2 for flucloxacillin and m/z 821.4→397.3 for rifampicin(internal standard). RESULTS The linear range of flucloxacillin under this analysis method was 0.20-80 ng·mL-1, and the lower limit of quantification was 0.20 ng·mL-1; The intra-day and inter-day precision of flucloxacillin were both less than 8.23%; The extraction recovery was in the range of 85.3%-89.2%, and the matrix effect was between 89.3%-92.3%; The stability of plasma samples was good under conditions of 12 h at room temperature, 4 h at room temperature after treatment, repeated freeze-thaw for 3 times, and -20 ℃ freezing for 30 d. The results of clinical samples indicated that the combination of ambroxol could significantly increase the blood concentration of flucloxacillin. CONCLUSION The established HPLC-MS/MS method is accurate, sensitive and can be used for the determination of flucloxacillin concentration in neonatal plasma. The results of clinical samples indicate that ambroxol can significantly increase the blood concentration of flucloxacillin. There are drug interactions between ambroxol and flucloxacillin.