Body mass index’s effect on CRSwNP extends to pathological endotype and recurrence.

BACKGROUND: Elevated body mass index (BMI) has been recognized as an important contributor to corticosteroid insensitivity in chronic rhinosinusitis with nasal polyps (CRSwNP). We aimed to delineate the effects of elevated BMI on immunological endotype and recurrence in CRSwNP individuals. METHODOLOGY: A total of 325 patients with CRSwNP undergoing FESS were recruited and stratified by BMI. H&E staining was employed for histological evaluation. Characteristics of inflammatory patterns were identified by immunohistochemical staining. The predictive factors for recurrence were determined and evaluated by multivariable logistic regression analysis and the receiver operating characteristic (ROC) curves across all subjects and by weight group. RESULTS: In all patients with CRSwNP, 26.15% subjects were classified as overweight/obese group across BMI categories and exhibited a higher symptom burden. The upregulated eosinophil/neutrophil-dominant cellular endotype and amplified type 2/ type 3 coexisting inflammation was present in overweight/obese compared to underweight/normal weight controls. Additionally, a higher recurrent proportion was shown in overweight/obese patients than that in underweight/normal weight cohorts. Multivariable logistic regression analysis identified BMI as an independent predictor for recurrence. The predictive capacity of each conventional parameter (tissue eosinophil and CLCs count, and blood eosinophil percentage) alone or in combination was poor in overweight/obese subjects. CONCLUSIONS: Overweight/obese CRSwNP stands for a unique phenotype and endotype. Conventional parameters predicting recurrence are compromised in overweight/obese CRSwNP, and there is an urgent need for novel biomarkers that predict recurrence for these patients.

Small extracellular vesicles facilitate epithelial-mesenchymal transition in chronic rhinosinusitis with nasal polyps via the miR-375-3p/QKI axis.

BACKGROUND: Epithelial-mesenchymal transition (EMT) plays a crucial role in the pathogenesis of chronic rhinosinusitis with nasal polyps (CRSwNP). However, the involvement of small extracellular vesicles (sEVs) in EMT and their contributions to CRSwNP has not been extensively investigated. METHODS: SEVs were isolated from nasal mucosa through ultracentrifugation. MicroRNA sequencing and reverse-transcription quantitative polymerase chain reaction were employed to analyze the differential expression of microRNAs carried by sEVs. Human nasal epithelial cells (hNECs) were used to assess the EMT-inducing effect of sEVs/microRNAs. EMT-associated markers were detected by western blotting and immunofluorescence. Dual-luciferase reporter assay was performed to determine the target gene of miR-375-3p. MicroRNA mimic, lentiviral, and plasmid transduction were used for functional experiments. RESULTS: In line with the greater EMT status in eosinophilic CRSwNP (ENP), sEVs derived from ENP (ENP-sEVs) could induce EMT in hNECs. MiR-375-3p was elevated in ENP-sEVs compared to that in control and nonENP. MiR-375-3p carried by ENP-sEVs facilitated EMT by directly targeting KH domain containing RNA binding (QKI) at seed sequences of 913-919, 1025-1033, and 2438-2444 in 3’-untranslated region. Inhibition of QKI by miR-375-3p overexpression promoted EMT, which could be reversed by restoration of QKI. Furthermore, the abundance of miR-375-3p in sEVs was closely correlated with the clinical symptom score and disease severity. CONCLUSIONS: MiR-375-3p-enriched sEVs facilitated EMT by suppressing QKI in hNECs. The association of miR-375-3p with disease severity underscores its potential as both a diagnostic marker and a therapeutic target for the innovative management of CRSwNP.

[Study on novel inflammatory indicators in marathon exercise monitoring].

To analyze the changes in lactate dehydrogenase, creatine kinase, creatine kinase isoenzyme, high-sensitivity troponin T, N-terminal B-type natriuretic peptide precursor, homocysteine, and novel inflammatory indices (neutrophil-lymphocyte ratio, platelet-lymphocyte ratio, systemic immune-inflammation index) before and after competitions in amateur marathon runners, and to assess the effects of myocardial injury due to acute exercise and the value of novel inflammatory indices in marathon exercise monitoring. This paper is an analytical study. Amateur athletes recruited by Beijing Hospital to participate in the 2022 Beijing Marathon and the 2023 Tianjin Marathon, and those who underwent health checkups at the Beijing Hospital Medical Checkup Center from January to June 2023 were selected as the study subjects, and 65 amateur marathon runners (41 males and 24 females) and 130 healthy controls (82 males and 48 females) were enrolled in the study according to the inclusion criteria. Peripheral blood was collected one week before, immediately after, and one week after running, and routine blood tests, cardiac enzymes, infarction markers, N-terminal B-type natriuretic peptide precursor, and homocysteine were performed to calculate the values of novel inflammatory indexes. Wilcoxon signed-rank test and Spearman's rank correlation analysis were used to compare the differences in the levels of each index between the amateur marathon population and the health checkup population, and to compare the changes and correlations of each index at the three time points in the amateur marathoners.The results showed that the neutrophil-lymphocyte ratios of the healthy physical examination population and 65 amateur marathoners 1 week before running were 1.73 (1.33, 2.16) and 1.67 (1.21, 2.16), the platelet-lymphocyte ratios were 122.75 (96.69, 155.89) and 120.86 (100.74, 154.63), and the systemic immune inflammation index was 398.62 (274.50, 538.69) and 338.41 (258.62, 485.38), etc.; on 1 week before running, immediately after running and 1 week after running, lactate dehydrogenase of 65 amateur marathon runners was 173.00(159.00, 196.50)U/L,284.00(237.50, 310.50)U/L, 183.00(165.50, 206.50)U/L, creatine kinase was 131.00(94.30, 188.20)U/L,318.00(212.00, 573.15)U/L,139.00(90.55, 202.40)U/L, creatine kinase isoenzyme was 2.50(1.76, 3.43)µg/L,6.24(4.87, 10.30)µg/L,2.73(1.57, 4.40)µg/L.In 65 amateur marathon runners, lactate dehydrogenase, creatine kinase, creatine kinase isoenzyme, high sensitivity troponin T, N-terminal B-type natriuretic peptide precursor, homocysteine, and novel inflammation markers were significantly elevated in the immediate post-run period compared with 1 week before the run, and the differences were statistically significant (Z=-7.009, Z=-6.813, Z=-6.885, Z=-7.009, Z=-7.009, Z=-6.656; P<0.05 for the above indicators).Neutrophil-lymphocyte ratio, platelet-lymphocyte ratio, and systemic immune-inflammatory index all showed significant positive correlation with the pre-and post-run rates of change of high-sensitivity troponin T (ρ=0.28, P=0.03;ρ=0.31, P=0.01;ρ=0.27, P=0.03); these 3 markers were also significantly and positively correlated with the pre-and post-run rates of change in a collection of myocardial-related markers such as lactate dehydrogenase, creatine kinase, creatine kinase isozymes, high-sensitivity troponin T, N-terminal B-type natriuretic peptide precursor, and homocysteine, respectively(r=0.446, P=0.039; r=0.452, P=0.033; r=0.449, P=0.036).In addition, the platelet-lymphocyte ratio was positively correlated with the pre-and post-run rates of change in creatine kinase and creatine kinase isoenzymes(ρ=0.27, P=0.03;ρ=0.28, P=0.02).In conclusion, acute myocardial injury may be triggered during marathon exercise. Changes in novel inflammatory markers were significantly associated with changes in myocardial enzymes, infarction markers, N-terminal B-type natriuretic peptide precursors, and homocysteine, which may be of value for the prediction of myocardial injury during exercise.

[Comparative study of ultra-high field diffusion-weighted MRI imaging between hepatocellular carcinoma and paracancerous, distant cancerous, and background liver tissues].

Objective: To investigate the differences in multi-b-value apparent diffusion coefficient (ADC) and exponential apparent diffusion coefficient (eADC) between hepatocellular carcinoma (HCC) and paracancerous liver tissue, distant cancerous liver tissue, and background liver tissues by ultra-high field 3.0T diffusion-weighted (DWI) MRI imaging. Methods: Sixty-eight consecutive HCC cases confirmed by surgical pathology from January 2018 to October 2021 were enrolled and divided into a cirrhosis (n=39) and a non-cirrhosis group (n=29) according to the presence or absence of cirrhosis.The average ADC and eADC of liver tissues of paracancerous (including proximal and distal), distant cancerous, and background were measured by DWI images with diffusion sensitivity factors (b) of 50, 100, 400, 600 s/mm2, and 1 000 s/mm2, respectively. The Kruskal-Wallis H test and Bonferroni method were used to test the differences between the measured values of the five tissues. The statistical differences were used to evaluate the diagnostic efficacy of the five tissues by parametric receiver operating characteristic (ROC) curve and area under the curve (AUC). Results: The comparison of average ADC and eADC among five types of tissues in the liver cirrhosis group showed that the average ADC and eADC measured at b values of 50, 100, 400, and 600 s/mm2 had statistically significant differences (adjusted P<0.005) between cancerous and proximal paracancerous, distal paracancerous, distant cancerous, and background liver tissue, as well as the average ADC measured at b=1 000 s/mm2 between cancerous and proximal paracancerous tissue. The average ADC and eADC in the non-cirrhosis group had statistically significant differences (adjusted P<0.005) between cancerous and proximal paracancerous, distant paracancerous, distant cancerous, and background liver tissue measured at b values of 50, 100, and 400 s/mm2, respectively. The average ADC and eADC measured at b=600 s/mm2 showed statistically significant differences (adjusted P<0.005) between cancerous and proximal paracancerous, distal paracancerous, and distant cancerous liver tissue, as well as the average ADC measured at b=1 000 s/mm2 between cancerous and distal paracancerous, and distant cancerous liver tissue. The average ADC and eADC in the cirrhosis group had no statistically significant difference between the proximal paracancerous and the distant cancerous, as well as the background liver tissue measured at b-values of 50, 100, 400, 600, and 1 000 s/mm2, respectively (adjusted P>0.005), while there were statistically significant differences (adjusted P<0.005) in the average ADC values in the non-cirrhosis group between the proximal paracancerous and the distant paracancerous and background liver tissues at b=50 s/mm2, as well as the average ADC and eADC values between the proximal paracancerous and the distant liver tissues at b=100 s/mm2. The average ADC and eADC values measured in the cirrhosis group and non-cirrhosis group had no statistically significant difference between the distant paracancerous, distant cancerous, and background liver tissue (adjusted P>0.005). The efficacy of average ADC and eADC in distinguishing five types of tissues (cancerous and proximal paracancerous, distant paracancerous, distant cancerous, and background liver tissue) showed that in the cirrhosis group, the diagnostic efficacy was best at b=50 s/mm2. The area under the ROC curve (AUC) of average ADC was 0.815, 0.828, 0.855, and 0.855, respectively, and the AUC of average eADC was 0.815, 0.830, 0.856, and 0.855, respectively. The diagnostic efficacy was best in the non cirrhosis group at b=100 s/mm2, with average ADC AUCs of 0.787, 0.823, 0.841, and 0.821, and average eADC AUCs of 0.836, 0.874, 0.893, and 0.873, respectively. The AUC of the average ADC in the non-cirrhosis group for distinguishing between proximal paracancerous and distant cancerous liver tissues, as well as proximal paracancerous and background liver tissues, with b=50 s/mm2, were 0.605 and 0.604, respectively. The average AUC of ADC and eADC for distinguishing between proximal paracancerous and distant liver tissues with b=100 s/mm2 were 0.619 and 0.620, respectively. Conclusion: The average ADC and eADC measured by multiple b-values are helpful in distinguishing HCC from proximal paracancerous, distal paracancerous, distant-cancerous, and background liver tissues in patients with cirrhosis and non-cirrhosis, while the average ADC and eADC at b=50 s/mm2 and 100 s/mm2 exhibit differences between the proximal paracancerous from the distant cancerous liver tissue and background liver tissue in patients with non-cirrhosis.

[Correlation between contrast-enhanced ultrasound parameters and Crohn's disease activity].

Objective: By investigating the correlation between quantitative parameters of contrast enhanced ultrasound (CEUS) and commonly used activity assessment indicators of Crohn's disease (CD), and comparing the predictive power of laboratory inflammatory indicators with CEUS on Crohn's disease (CD), the significance of CEUS was evaluated. Methods: A case-control study. From October 2019 to December 2021, the clinical data of 67 patients with CD who were diagnosed by endoscopy and underwent contrast-enhanced ultrasonography were retrospectively analyzed in the First Affiliated Hospital with Nanjing Medical University, and their routine ultrasound and CEUS parameters, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), fecal calprotectin (FC), Crohn's disease activity index (CDAI) and simplified endoscopic score for Crohn's disease (SES-CD) were collected. Using SES-CD as the standard, the patients were divided into a remission group and an active group, and the correlation of laboratory inflammatory indexes and contrast-enhanced ultrasound parameters with CDAI and SES-CD were evaluated. Besides, the ROC curve was used to analyze the predictive efficacy of each index on CD endoscopic activity. Results: A total of 67 patients were included in this study. According to the SES-CD score, there were 17 patients in the remission group and 50 patients in the active group. Except for the coefficient of the enhancement wash in slope and time to peak (TTP), the peak intensity (PI), area under the angiography curve, and laboratory inflammatory indexes were significantly different between the two groups (P<0.05), which also showed a moderate positive correlation with CDAI and SES-CD (P<0.05). ROC analysis showed that among the non-invasive indicators, PI and area under the angiography curve had the highest AUCs for predicting CD endoscopic activity, which were 0.912 and 0.891, respectively; with SES-CD taking >3 as the cut-off value, the corresponding sensitivities were 78.0% and 72.0%, with specificities of 100.0% and 94.1%, respectively. Conclusion: CEUS can objectively and repeatedly evaluate the disease activity of CD patients, and has great clinical application value, which can be used as a reliable imaging method for diagnosis and follow-up of patients with Crohn's disease.

[Establishment and behavioral evaluation of a mouse model of long-term free-choice alcohol drinking].

OBJECTIVE: To establish a model of long-term free drinking mouse by feeding mice with alcohol to simulate the state of human voluntary long-term drinking, and on this basis, to further discuss the evaluation criteria of long-term free drinking mice model in sports, anxiety and cognitive behavior. METHODS: Forty six-week-old SPF C57BL/6 male mouse were randomly divided into two groups: Long-term free drinking group (n=20) and normal control group (n=20). The two groups were given solid feed normally. The long-term free drinking group was free to take 10% alcohol and water every day, while the normal drinking group only took water every day. The mice were fed for 7 months, and were evaluated by a series of behavioral methods, including Rota-rod test, balance beam test, open filed test, the elevated plus maze, two-box social behavior, new object recognition, Y maze and water maze. RESULTS: With the increase of drinking days, the mice showed significant alcohol addiction in the alcohol preference test. With the increase of alcohol intake, the mice in the long-term free choice drinking group had slightly shiny fur and reduced diet. Compared with the control group, the weight gain began to slow down from the third month, and the weight decreased significantly by the sixth and seventh months (P=0.006, P < 0.001). The mice showed reduced balance locomotion ability (P=0.003, P=0.001) in the rotary bar and balance beam test. In the open field and elevated cross test, the mice had obvious anxiety-like behavior (P < 0.001). The mice showed decreased social ability in the two boxes of social behavior (P < 0.016). In the experiment of new object recognition and Y maze, the exploration of new object decreased (P=0.018, P=0.040). In the water maze, cognitive functions, such as learning and spatial memory were reduced (P < 0.001). CONCLUSION: The successful establishment of the long-term free drinking mouse model is more convenient for us to carry out further research on the neural mechanism of alcohol addiction, and lays an experimental foundation for exploring the neural mechanism of alcohol addiction and related new targets.

Nanocomposite of Ag nanoparticles and deep eutectic solvent-derived carbon dots with oxidase mimicking activity as synergistic bactericidal agent.

A new type of nitrogen and chloride co-doped carbon dots (N/Cl-CDs) based on choline chloride-urea-glycine ternary deep eutectic solvents (DESs) was synthesized using a one-step hydrothermal method. The prepared N/Cl-CDs exhibited oxidase-like activity and excellent antibacterial activity against Escherichia coli, Staphylococcus aureus and methicillin-resistant Staphylococcus aureus (MRSA). The addition of silver nanoparticles (Ag NPs) (i.e. N/Cl-CDs + Ag NPs) to the N/Cl-CDs also significantly enhanced the oxidase and antibacterial activities. The nanocomposite (1·8 mg ml-1 ) completely inactivated 105 CFU per ml of MRSA in 90 min. E. coli and S. aureus were labelled with the N/Cl-CDs, enabling multicolour fluorescence imaging at different excitation wavelengths. The nanocomposites have high antibacterial efficiency as a new bactericidal agent, as well as application potential with good biocompatibility and low toxicity.

The cross-sectional study of depressive symptoms and associated factors among adolescents by backpropagation neural network.

OBJECTIVES: This study aimed to investigate the association between depressive symptoms and diet- and lifestyle-related behaviors among adolescents. STUDY DESIGN: Cross-sectional study. METHODS: Our study used stratified random cluster sampling method to recruit 6,251 adolescents aged 11-19 years as samples for research and analysis. The Center for Epidemiological Studies Depression Scale was used to assess depressive symptoms. Chi-squared test, t test, and logistic regression were used to explore the diet and lifestyle factors of depressive symptoms. Backpropagation (BP) neural network model was used to investigate the ranking of diet and lifestyle behaviors factors of depressive symptoms. RESULTS: The prevalence of depressive symptoms among adolescents was 32.1%. Multivariable logistic regression was used to determine 10 important variables of depressive symptoms. After ranking the importance by BP neural network, the top three important variables were found, which were sleep duration (100%), screen time (49.1%), and breakfast (23.6%). CONCLUSION: Sleep duration, screen time, and breakfast were associated factors with the most significant impacts on depressive symptoms.

[Pathological characteristics and clinical prognosis of nodular sclerosis grade 2 of classic Hodgkin's lymphoma].

Objective: To investigate the pathological characteristics and clinical prognosis of nodular sclerosis grade 2 of classic Hodgkin's lymphoma (cHL-NS2) in our cancer center. Methods: A retrospective collection of 23 cases of cHL-NS2 admitted in Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College from July 2008 to April 2019 was performed. Fifty-five cases of nodular sclerosis grade 1 of classical Hodgkin's lymphoma (cHL-NS1) during the same period were selected as control group. Survival curves were plotted using the Kaplan-Meier method, and Cox regression model was used to analyze the influencing factors for survival. Results: The median age of 23 cases of cHL-NS2 was 30 years old. Five cases had extra nodal invasion, and 19 cases were Ⅰ-Ⅱ stage based on Ann Arbor system. The pathological morphology of cHL-NS2 showed that the lymph node structure was completely destroyed and was divided into nodules by thick collagen. The tumor cells in the nodules were abundant and proliferated in sheets. The boundaries between the tumor cells were not clear. The incidence of tumor necrosis in cHL-NS2 was 43.5% (10/23), which was significantly higher than 18.2% (10/55) in cHL-NS1 (P=0.040). The 3-year progression-free survival (PFS) rate of patients in the cHL-NS2 group was 58.1%, which was significantly lower than 89.7% in the cHL-NS1 group (P=0.002). In all of 78 cases, the 3-year PFS rate of patients who did not obtain complete response (CR) was 67.1%, which was significantly lower than 92.2% in patients who achieved CR (P=0.030). Multivariate Cox regression analysis demonstrated that both cHL-NS2 and failure to obtain CR by first-line treatment were independent indicators for short PFS time (P<0.05). Conclusions: In cHL-NS2, the morphology of tumor cells are diverse, and tumor necrosis can be easily found. Under the current first-line treatments of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) or bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP), cHL-NS2 is an independent indicator for worse PFS.

Differentially expressed proteins identified by TMT proteomics analysis in children with verrucous epidermal naevi.

BACKGROUND: Verrucous epidermal naevi (VEN) are benign skin tumours, considered keratinocytic epidermal naevi, that appear at birth or early childhood. VEN may display a range of appearances, depending on patient age. Although the number of studies regarding VEN is increasing, the exact mechanism of VEN is still unknown. OBJECTIVES: The aim of this study was to analyse the changes in the expression of protein factors in lesions of VEN children by TMT labelling-based quantitative proteomics. METHODS: A total of 8 children with VEN (5 for experiment and 3 for validation) and 8 healthy children (5 for experiment and 3 for validation) presented to the Department of Dermatology, the First Affiliated Hospital of Anhui Medical University, Boao Super Hospital, between January 2019 and November 2019. The lesions and lesion-adjacent tissues from children with VEN and naevus-adjacent normal skin tissues from children with pigmented naevi were defined as the VEN group, VENC group and C group, respectively. We performed a proteomics analysis to screen for differentially expressed proteins in the lesions of these individuals. We further performed Western blotting to validate the relative expression levels of nine targeted proteins in the validation group. RESULTS: According to the proteomics results, a total of 4970 proteins were identified, and 4770 proteins were quantified. Among these proteins, 586 proteins were up- or downregulated at least 1.3-fold with a P-value < 0.05 (upregulated: 399, downregulated: 187) in lesions between the VEN group and the C group. These proteins played important roles in multiple biological functions, such as cornification, epidermal cell differentiation and neutrophil activation, and formed a complicated protein-protein interaction network. Of the 586 up- or downregulated proteins, nine were selected for further validation. According to Western blotting analysis results, the relative expression levels of Involucrin, NDUFA4, Loricrin, Keratin type II cytoskeletal 6A (Cytokeratin 6A), BRAF, Filaggrin, S100A7 and Desmocollin-3 were significantly upregulated in VEN children and may be associated with skin barrier dysfunction, epidermal cell overgrowth and differentiation, inflammation and immune and oxidative phosphorylation, which are involved in the pathogenesis of VEN. CONCLUSIONS: According to TMT-based proteomics and Western blotting results, we identified eight noteworthy proteins, Involucrin, NDUFA4, Loricrin, Keratin type II cytoskeletal 6A, BRAF, Filaggrin, S100A7 and Desmocollin-3, that were upregulated in the lesions of VEN children and may be associated with the pathogenesis of VEN. Our findings provide new starting points for identifying precise pathogenic mechanisms or therapeutic targets for VEN.

[Activity comparison of humanized CD19 CAR-T cells with murine CD19 CAR-T on Nalm-6 cells and xenograft tumor model].

Objective: To compare the activity difference of the high affinity humanized CD19 chimeric antigen receptor (CAR)-T cells and murine CD19 CAR-T cells. Methods: Peripheral venous blood T cells from 8 healthy volunteers were collected and infected with humanized and murine CD19 CAR lentivirus. Human and murine CD19 CAR-T cells were prepared and cell proliferation was detected by cell counting kit-8 (CCK-8) method. The cytotoxicity of CD3(+) T cells, humanized and murine CD19 CAR-T cells to NALM-6 cells was detected by lactate dehydrogenase assay. Thirty BAL B/c nude mice transplanted with NALM-6 cells were randomly divided into 3 groups with 10 mice in each group and injected humanized CD19 CAR-T cells, mouse CD19 CAR-T cells and control CD3(+) T cell via tail vein, respectively. The proportion of NALM-6 cells in peripheral blood and the proportion of CD19 CAR-T cells in T cells from the vein of the inner canthus were detected by flow cytometry. The overall survival of BAL B/c nude mice was observed. Results: The proliferation of mouse and humanized CD19 CAR-T cells were (68.50±0.93)% and (80.63±1.41)%, respectively (t=20.353, P<0.001) after cultured in vitro for 24 hours, and were (91.38±1.41)% and (148.13±1.25)%, respectively (t=85.364, P<0.001) after cultured for 48 hours. When the effect to target ratio was 1∶1, there was no difference between the humanized and murine CD19 CAR-T cell group after co-culture for 24 hours (P=0.169), while the killing activity of humanized CD19 CAR-T cells against NALM-6 cells was higher than that of murine CD19 CAR-T cells (P<0.01) after 48 hours of co-culture. When the effect to target ratio was 4∶1, the cytotoxicity of humanized CD19 CAR-T cells against NALM-6 cells was higher than that of murine CD19 CAR-T cells in co-culture for 24 and 48 hours (P<0.01). On the seventh day of CD19 CAR-T cell therapy, the proportion of NALM-6 cells in the peripheral blood of BAL B/c nude mice decreased to the lowest level in the humanized CD19 CAR-T cell group and the murine CD19 CAR-T cell group. After 21 days, the proportion of NALM-6 cells in the murine CD19 CAR-T cell group was higher than that in the humanized CD19 CAR-T cell group (P(21 d)=0.001, P(28 d)<0.001, P(35 d)<0.001). The proportion of humanized and murine CD19 CAR-T cells in the peripheral blood reached the peaks after 7 days of therapy, and the proportion of humanized CD19 CAR-T cells was higher than that of murine CAR-T cells (P(7 d)=0.002). The CD19 CAR-T cells disappeared in the peripheral blood in the murine CD19 CAR-T cell group after 14 days of therapy, while in the humanized CD19 CAR-T cell group it disappeared after 21 days of therapy. The median survival of BAL B/c nude mice in the murine CD19 CAR-T cell group and the humanized CD19 CAR-T cell group was 42 days and 63 days, respectively (χ(2)=15.382, P<0.001). Conclusions: High affinity humanized CD19 CAR-T cells have stronger proliferation, higher cytotoxicity and longer survival time compared with those of murine CD19 CAR-T cells. The results indicate that the clinical efficacy of humanized CD19 CAR-T cells would be better than that of murine CD19 CAR-T cells.

Insufficient left ventricular unloading after extracorporeal membrane oxygenation : A case-series observational study.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) is a method widely used to support circulation in patients with fulminant myocarditis (FM). However, a common complication associated with ECMO is left ventricular (LV) overload. METHODS: This case series observed the effects of intra-aortic balloon pump (IABP) and beta-blockers for the treatment of LV overload after ECMO. The cases of eight patients with FM who underwent ECMO from September 2009 to July 2016 were reviewed. RESULTS: Six of the eight patients survived. After ECMO treatment, insufficient LV unloading occurred in six patients. Among these six patients, three experienced electrical storm but spontaneous circulation returned after interventions with beta-blockers and IABP. The survivors demonstrated full recovery of cardiac function. CONCLUSION: Beta-blockers may prevent the occurrence of electrical storm, and IABP is feasible for the treatment of LV overload after ECMO application.

[Clinical study of percutaneous vertebroplasty combined with (125)I seeds implantation in the treatment of patients with thoracic metastatic tumor complicated with posterior vertebral defect].

Objective: To analyze the safety and efficacy of percutaneous vertebroplasty combined with interstitial implantation (125)I of seeds (PVPI) in the treatment of thoracic vertebroplasty with posterior vertebra defect. Methods: A retrospective analysis of the clinical data of 64 patients with thoracic spine metastases admitted to Yunnan Cancer Hospital from November 2017 to May 2019 was conducted, including 32 patients with posterior vertebra defect (experimental group) and 32 cases without (control group). Forty-two vertebral bodies of 32 patients in the experimental group were treated with improved PVPI surgery, which performed with the secondary sealing method and inclined puncture needle injection bone cement rotary filling technology, to reduce leakage. The 54 vertebral bodies of 32 patients in control group underwent PVPI. The two groups of patients were followed up on the second day, one month, three months and six months after the operation, and the short-term efficacy, long-term efficacy and safety indicators of the two groups were compared. Results: All 64 patients successfully completed the surgical treatment. The visual analogue scores and Karnofsky scores of the experimental group and the control group were improved to varying degrees on the second day, 1 month, 3 months and 6 months after the operation. There was no statistically significant difference between the two groups (P>0.05). The amount of bone cement in the experimental group and control group was (2.36±0.20) ml and (2.39±0.17) ml, and the difference was not statistically significant (P=0.482). The amount of (125)I seed implantation was (30.63±0.91) and (32.56±0.68), respectively, the difference was not statistically significant (P=0.925). The partial response rates of the study group and the control group were 81.3% and 87.5%, the stable disease rates were 12.5% and 9.4%, the differences were not statistically significant (P>0.05). The median overall survival (mOS) of the study group was 13 months, and the median progression-free survival (mPFS) was 8 months. The mOS of the control group was 14 months, and the mPFS was 8 months. The differences were not statistically significant (P>0.05). In the experimental group, 6 (14.3%) vertebral bodies had cement leakage, of which 2 (4.8%) were cement leakage at posterior vertebra, 4 (9.5%) were paravertebral cement leakage. Seven (13.0%) paravertebral cement leakage occurred in the control group. There was no significant difference in bone cement leakage between the two groups (P=0.097). Bone cement leakage in both groups did not cause serious complications such as spinal cord injury and paraplegia. Conclusion: The application of PVPI in the treatment of thoracic metastatic tumor patients with posterior vertebra defect can acquire better clinical efficacy and safety through conduction of the improved intraoperative technology and paying more attention to the control of bone cement distribution and other issues.

[Analysis on poor efficacy factors in the treatment of recurrent/refractory B-cell lymphoma with CD19 CAR-T cells].

Objective: To investigate the factors influencing the efficacy of CD19 chimeric antigen receptor T (CAR-T) cells in the treatment of patients with relapsed refractory B cell lymphoma and to provide evidence for further improvement of CAR-T efficacy. Methods: A total of 34 patients with relapsed and refractory B-cell lymphoma were recruited from the Department of Hematology of Tianjin First Central Hospital from February 2017 to January 2019. All patients received CD19 CAR-T cell therapy. These patients were evaluated for efficacy, factors with poor efficacyand adverse effects. Results: The overall response rate was 58.8% (20/34) and the complete remission rate was 41.2% (14/34) after infusion of CD19 CAR-T cells in 34 patients with relapsed refractory B cell lymphoma. According to the efficacy of CAR-T cells, patients were divided into two groups, 20 in the effective group and 14 in the poorly effective group. The median am ount of CD19 CAR-T cell infusions in these two groups were 8.6 (5.0-12.7)×10(6)/kg and 9.7 (5.8-15.0) × 10(6)/kg, respectively, and the difference was not statistically significant (P=0.654). The percentage of CD19 CAR-T cells in the effective group and the poorly treated group was 10.28% (3.92%-44.16%) and 4.05% (0.92%-28.63%), respectively.The effective group had a higher proportion of CAR-T cells than the poorly treated group, but the difference was not statistically significant (P=0.371).The presence of massive mass was an unfavorable factor affecting the efficacy of CD19 CAR-T cells and the difference was statistically significant (P=0.001). Logistic regression multivariate analysis showed that the characteristics of massive tumors were still independent prognostic factors for poor efficacy of CD19 CAR-T cells (P=0.005, OR=0.039). Of all 34 patients, there were 70.6% (24/34) who showed varying degrees of adverse reactions after the infusion of CD19 CAR-T cells, mainly cytokines release syndrome (CRS). The median time of occurrence of fever was on the third day after infusion (0-11th) day. 16 patients were with grade 1 CRS, 7 with grade 2, and 1 with grade 3. After glucocorticoids and support treatment, they all showed improvements. Conclusions: CD19 CAR-T cell therapy has achieved a certain effect in CD19(+)B cell lymphoma, but has poor efficacy on some patients. Large mass tumors may be an adverse factors to CAR-T cell treatment.

[Etiology and clinical features of primary adrenal insufficiency].

Objective: To summarize the etiology of primary adrenal insufficiency (PAI) and analyze its clinical features. Methods: A retrospective analysis was performed in the Department of Endocrinology, Peking Union Medical College Hospital from October 1981 to June 2019. Patients with PAI as the first symptom were enrolled. The etiology of PAI was analyzed and the clinical characteristics was also summarized. Results: A total of 131 patients with PAI were enrolled, including 87 males and 44 females (57 adolescents, and 74 adults). The age ranged from 0 to 73 years. The primary cause of PAI in adolescents was genetic defects (52.6%, 30/57), in which congenital adrenal dysplasia caused by DAX1 gene deficiency accounted for 50.0% (15/30), followed by autoimmunity (22.8%, 13/57). The primary cause of adult PAI was infection (58.1%, 43/74), of which tuberculosis accounted for the majority (93.0%, 40/43), and autoimmune adrenalitis accounted for 19.0% (14/74). Compared with the tuberculosis group, female patients were more common, and the onset age was younger, the plasma cortisol, serum sodium, fasting blood glucose, creatinine and aldosterone were lower (all P<0.05), and serum potassium and renin levels were higher in the autoimmune adrenalitis group (both P<0.05). Conclusions: In the current study, the proportion of PAI caused by infection in the adult group was higher than that in the adolescent group. The most common cause of adult PAI was tuberculosis infection. The most common cause of childhood PAI was genetic defects. Autoimmune damage to the adrenal glands may be more severe than tuberculosis infection.

[Analysis of prognosis factors for reintervention after endovascular aneurysm repair in patients with abdominal aortic aneurysm].

Objectives: To examine the prognosis factors for readmission after endovascular aneurysm repair (EVAR) for abdominal aortic aneurysm (AAA) patients in the Chinese population. Methods: A total of 1 129 AAA patients who underwent EVAR at Department of Vascular Surgery, Zhongshan Hospital, Fudan University, from January 2010 to December 2017 were enrolled. There were 948 males and 181 females, with an age of (71.2±9.6) years (range: 18 to 93 years). Comorbidities included primary hypertension found in 630 patients, diabetes mellitus in 129 patients and coronary heart disease in 163 patients. A total of 214 patients had a history of smoking, and 11 patients had a history of previous aortic intervention.Clinical data including baseline information, laboratory examinations and follow-up data before December 31, 2019 were retrospectively collected. The primary end point was readmission. Cox regression analysis was used to analyze the prognosis factors for the end point. Results: All patients completed at least one follow-up with a follow-up time of 22.7(42.6) months (range: 1 to 120 months). The readmission rate of 1 year post-operation was 4.52% (51/1 129). The overall readmission rate was 11.34% (128/1 129) during the whole follow-up duration. The main reasons of readmission included endoleak in 60 patients with readmission, iliac limb occlusion in 25 patients and distal iliac aneurysm in 12 patients. Age (HR=0.972, 95%CI: 0.956 to 0.987, P<0.01) and elevated pre-operative fibrinogen level (HR=2.213, 95%CI: 1.185 to 4.134, P=0.013) were found to be the prognosis factors for the survival time free from aortic-related readmission in univariate Cox regression analysis. Elevated pre-operative fibrinogen level (HR=2.542, 95%CI: 1.353 to 4.776, P=0.004) was found to be the prognosis factor for the survival time free from aortic-related readmission in multivariate Cox regression analysis. Conclusions: The most common reason for readmission was endoleak, followed by iliac limb occlusion and distal iliac aneurysm. Elevated pre-operative fibri nogen level was the risk factor for the survival time free from aortic-related readmission, though further researches were warranted for exploring the underlying mechanism.

The cAMP responsive element-binding (CREB)-1 gene increases risk of major psychiatric disorders.

Bipolar disorder (BPD), schizophrenia (SCZ) and unipolar major depressive disorder (MDD) are primary psychiatric disorders sharing substantial genetic risk factors. We previously reported that two single-nucleotide polymorphisms (SNPs) rs2709370 and rs6785 in the cAMP responsive element-binding (CREB)-1 gene (CREB1) were associated with the risk of BPD and abnormal hippocampal function in populations of European ancestry. In the present study, we further expanded our analyses of rs2709370 and rs6785 in multiple BPD, SCZ and MDD data sets, including the published Psychiatric Genomics Consortium (PGC) genome-wide association study, the samples used in our previous CREB1 study, and six additional cohorts (three new BPD samples, two new SCZ samples and one new MDD sample). Although the associations of both CREB1 SNPs with each illness were not replicated in the new cohorts (BPD analysis in 871 cases and 1089 controls (rs2709370, P=0.0611; rs6785, P=0.0544); SCZ analysis in 1273 cases and 1072 controls (rs2709370, P=0.230; rs6785, P=0.661); and MDD analysis in 129 cases and 100 controls (rs2709370, P=0.114; rs6785, P=0.188)), an overall meta-analysis of all included samples suggested that both SNPs were significantly associated with increased risk of BPD (11 105 cases and 51 331 controls; rs2709370, P=2.33 × 10-4; rs6785, P=6.33 × 10-5), SCZ (34 913 cases and 44 528 controls; rs2709370, P=3.96 × 10-5; rs6785, P=2.44 × 10-5) and MDD (9369 cases and 9619 controls; rs2709370, P=0.0144; rs6785, P=0.0314), with the same direction of allelic effects across diagnostic categories. We then examined the impact of diagnostic status on CREB1 mRNA expression using data obtained from independent brain tissue samples, and observed that the mRNA expression of CREB1 was significantly downregulated in psychiatric patients compared with healthy controls. The protein-protein interaction analyses showed that the protein encoded by CREB1 directly interacted with several risk genes of psychiatric disorders identified by GWAS. In conclusion, the current study suggests that CREB1 might be a common risk gene for major psychiatric disorders, and further investigations are necessary.

[Relationship between periodontitis and osteoporosis in postmenopausal women].

OBJECTIVE: To explore the relationships of periodontal parameters, cortical width on mental foramen and osteoporotic condition in postmenopausal women. METHODS: Ninetyeight postmenopausal women between 50 to 65 years old were recruited. General conditions, such as age, menopausal age, duration of menopause, and body mass index (BMI) were recorded. Periodontal parameters were examined, including oral hygiene index simplified (OHI-S), probing depth (PD), clinical attachment loss (CAL), gingival recession (GR) and bleeding on probing (BOP). Panoramic radiograph was taken and the cortical width (CW) of mental foramen was measured on images. The examiner was celebrated. Bone mass density (BMD) of left hip and lumbar spine was assessed using standardized dual energy X-ray absorptiometry. According to World Health Organization, based on the T-score of BMD (difference of the measured BMD and the mean value of young white women in terms of standard deviations), the subjects were divided into osteoporotic group (T-score<-2.5) and non-osteoporotic group (T-score≥-2.5). These parameters were compared between the groups. RESULTS: The number of osteoporotic group was 47 (47.96%). Ages and duration of menopause were significantly different between the groups. Osteoporotic group presented older ages [(59.64±4.58) years vs. (56.94 ± 4.26) years, P<0.05], and longer duration of menopause [(10.17± 5.37) years vs. (6.02 ±4.48) years, P<0.05]. There was no significant difference in menopausal age and BMI between the groups. BOP% was statistically significantly higher in osteoporotic group (29.43±21.12) than in non-osteoporotic group (21.43±17.09), with a P-value of 0.046. The other periodontal parameters, including OHI-S, PD, CAL, and GR were not statistically significantly different in the groups. The CWs were statistically significantly lower in osteoporotic group compared with non-osteoporotic group, with a P-value of 0.001. The mean values of CWs were (3.61±1.04) mm (osteoporotic group) and (4.25±0.77) mm (non-osteoporotic group), respectively. CONCLUSION: The study demonstrated absence of a significant association between periodontal parameters and BMD. However, the CWs were found to be related with the BMD, which may be used to detect BMD abnormal in maxillofacial imaging. The dentists should pay attention not only to the oral health, but also to the general bone mass density, which may be detected on panoramic images.

[Serum status and their changes of some vitamin substances and homocysteine in healthy subjects in Beijing].

Objective: To investigate serum status of folate, vitamin B(12), homocysteine (Hcy) and hydroxyvitamin D (25OHD) and their trends in different gender and age groups. Methods: This was a cross-sectional study. The enrolled subjects were those received medical examination in Beijing Hospital from September to November 2018 and were identified as appeared healthy persons. 1220 subjects were recruited and were divided into groups of young and middle age group (30-49 years, 50-59 years) and the elderly group (60-69 years, 70-79 years and ≥80 years). We measured folate, vitamin B(12), and 25OHD using electrochemiluminescence by chemiluminescence immunoassay. Hcy was measured by autobiochemical analyzer. Results: Total folate levels in male and female subjects were 7.16 (4.74-10.75) and 9.17 (6.49-13.55) µg/L respectively. Total vitamin B(12) levels in the male and female were 505.60 (386.80-700.90) and 582.60 (430.70-846.98) ng/L respectively. Hcy levels were 14.68 (12.25-18.58) and 11.29 (9.65-13.58) µmol/L. 25OHD levels were 21.60 (16.40-28.70) and 16.80 (12.30-24.15) µg/L respectively. Total folate and vitamin B(12) levels in female were higher than that in male subjects (Z=-7.796, -4.772, P<0.001). However, total Hcy and 25OHD levels in male were higher than that in female subjects (Z=-15.230, -8.447, P<0.001). Comparing with the substances in the above age groups, folate level in the elderly was lower than that in the younger age and middle age groups.However, vitamin B(12), 25OHD and Hcy levels were higher in the elderly groups. Furthermore, the levels of folate, vitamin B(12) and 25OHD were getting higher in the group of ≥80 years female compared with the rest of the age groups, but it turned lower in the male group of ≥80 years. Conclusions: There are some differences in the serum values of folate, vitamin B(12), Hcy and 25OHD among various age groups as well as between males and females. These should be considered in the development of national reference ranges.

Methamphetamine abuse impairs motor cortical plasticity and function.

Exposure to addictive drugs triggers synaptic plasticity in reward-related brain regions, such as the midbrain, nucleus accumbens and the prefrontal cortex. Effects of chronic drug exposure on other brain areas have not been fully investigated. Here, we characterize synaptic plasticity in motor cortex after methamphetamine self-administration in rats. We show that this causes a loss of corticostriatal plasticity in rat brain slices and impaired motor learning in the rotarod task. These findings are paralleled by the observation of a lack of transcranial magnetic stimulation-induced potentiation or depression of motor evoked potentials in human patients with addiction, along with poor performance in rotary pursuit task. Taken together, our results suggest that chronic methamphetamine use can affect behavioral performance via drug-evoked synaptic plasticity occluding physiological motor learning.