BACKGROUND: Liver biopsy for the diagnosis of non-alcoholic steatohepatitis (NASH) is limited by its inherent invasiveness and possible sampling errors. Some studies have shown that cytokeratin-18 (CK-18) concentrations may be useful in diagnosing NASH, but results across studies have been inconsistent. We aimed to identify the utility of CK-18 M30 concentrations as an alternative to liver biopsy for non-invasive identification of NASH. METHODS: Individual data were collected from 14 registry centers on patients with biopsy-proven non-alcoholic fatty liver disease (NAFLD), and in all patients, circulating CK-18 M30 levels were measured. Individuals with a NAFLD activity score (NAS) ≥5 with a score of ≥1 for each of steatosis, ballooning, and lobular inflammation were diagnosed as having definite NASH; individuals with a NAS ≤2 and no fibrosis were diagnosed as having non-alcoholic fatty liver (NAFL). RESULTS: A total of 2571 participants were screened, and 1008 (153 with NAFL and 855 with NASH) were finally enrolled. Median CK-18 M30 levels were higher in patients with NASH than in those with NAFL (mean difference 177 U/L; standardized mean difference [SMD]: 0.87 [0.69-1.04]). There was an interaction between CK-18 M30 levels and serum alanine aminotransferase, body mass index (BMI), and hypertension ( P  < 0.001, P  = 0.026 and P  = 0.049, respectively). CK-18 M30 levels were positively associated with histological NAS in most centers. The area under the receiver operating characteristics (AUROC) for NASH was 0.750 (95% confidence intervals: 0.714-0.787), and CK-18 M30 at Youden's index maximum was 275.7 U/L. Both sensitivity (55% [52%-59%]) and positive predictive value (59%) were not ideal. CONCLUSION This large multicenter registry study shows that CK-18 M30 measurement in isolation is of limited value for non-invasively diagnosing NASH.
Humans ; Non-alcoholic Fatty Liver Disease/diagnosis* ; Keratin-18 ; Biomarkers ; Biopsy ; Hepatocytes/pathology* ; Apoptosis ; Liver/pathology*

OBJECTIVE Amyotrophic lateral sclerosis(ALS)is a fetal neurodegenerative disease characterized by the progressive loss of upper and lower motor neu-rons,leading to skeletal muscle atrophy,weakness,and paralysis.Oxidative stress plays a crucial role in ALS pathogenesis,including the familial forms of the disease arising from mutations in the gene coding for superox-ide dismutase(SOD1).Additionally,the abnormal accu-mulation of TAR DNA-binding protein of 43 ku(TDP-43)is a pathological feature present in almost all patients,even though the pathogenesis of ALS is unclear.Current-ly,there is no drug that can cure ALS/FTLD.Tetramethyl-pyrazine nitrone(TBN)is a derivative of tetramethylapyr-azine,derived from traditional Chinese medicine Ligusti-cum chuanxiong,which has been extensively proven to have therapeutic effects on various models of neurode-generative diseases.METHODS We investigated the therapeutic effect of TBN in the SOD1G93A and TDP-43M337V ALS mouse models.In the SOD1G93A trans-genic mouse model,TBN was administered to mice via intraperitoneal or intragastric injection after the onset of motor deficits.We injected the TDP-43M337V virus into the striatum of mice unilaterally and bilaterally,and then administered TBN 30 mg·kg-1 intragastrically to observe changes in behavior and survival rate of mice.RESULTS TBN slowed the progression of motor neuron disease,as evidenced by improved motor performance,reduced spi-nal motor neuron loss and associated glial response,and decreased skeletal muscle fiber denervation and fibrosis.TBN treatment activated mitochondrial antioxidant activity through the PGC-1α/Nrf2/HO-1 pathway and decreased the expression of human SOD1.In the mice with unilateral injection of TDP-43M337V into the striatum,TBN improved motor deficits and cognitive impairment in the early stages of disease progression.In mice with bilateral injection of TDP-43M337V into the striatum,TBN not only improved motor function but also prolonged survival.Moreover,we demonstrate that its therapeutic effect may be through activation of the Akt/mTOR/GSK-3β and AMPK/PGC-1α/Nrf2 signaling pathways.CONCLUSION TBN shows promise as an agent for the treatment of ALS/FTLD.TBN is currently undergoing clinical investigation for several indications,including a Phase Ⅱ trial for ALS.

Objective:To explore the safety and feasibility of bilateral axillo-breast approach （BABA） robot in the operation of thyroid cancer in obese women. Methods:The clinical data of 81 obese female patients who underwent da Vinci robotic thyroid cancer surgery（robotic group） at the Department of Thyroid and Breast Surgery, PLA 960 Hospital from May 2018 to December 2021 were retrospectively analyzed and compared with the clinical data of 106 obese female thyroid cancer patients who underwent open surgery（open group） during the same period. The age, body mass index（BMI）, mean time of surgery, mean postoperative drainage, tumor diameter, postoperative tumor stage, number of lymph node dissection in the central and lateral cervical regions, number of positive lymph nodes in the central and lateral cervical regions, postoperative cosmetic outcome satisfaction score, mean postoperative hospital stay and postoperative complications of all patients were counted. The results were analyzed using SPSS 26.0 statistical software, and the count data were compared using the χ² test, and the measurement data were compared using the t test. Results:All patients completed the operation successfully, and there was no conversion in the robot group, postoperative pathological results were all composed of papillary thyroid carcinoma. The operation time in the robot group was（144.62±36.38） min, which was longer than that in the open group（117.06±18.72） min（P<0.05）. The average age of the robot group was（40.25±9.27） years, which was lower than that of the open group（49.59±8.70） years（P<0.05）. The satisfactory score of cosmetic effect in the robot group（9.44±0.65） was higher than that in the open group（5.23±1.07）（P<0.05）. There was no significant difference in tumor diameter, BMI, average postoperative drainage, temporary hypoparathyroidism and recurrent laryngeal nerve injury, number of central and lateral cervical lymph node dissection, number of positive lymph nodes in the central and lateral cervical regions, and average postoperative hospital stay between the two groups. There was no permanent hypoparathyroidism and recurrent laryngeal nerve injury in both groups. Conclusion:The application of BABA pathway robot in thyroid cancer surgery in obese women is safe and feasible, and the cosmetic effect is better after operation.
Humans ; Female ; Adult ; Middle Aged ; Robotics/methods* ; Retrospective Studies ; Recurrent Laryngeal Nerve Injuries ; Thyroidectomy/methods* ; Carcinoma, Papillary/surgery* ; Thyroid Neoplasms/pathology* ; Neck Dissection ; Treatment Outcome

Objective: To understand the mental sub-health status of Chinese adolescents and its correlation with muscle strength index, and to provide information for relevant research in mental health and muscle strength development of Chinese adolescents. Methods: A total of 16 545 adolescents aged 13-22 year-old in six administrative regions of China were administered with the Adolescent Sub-Health Multidimensional Assessment Questionnaire (MSQA). Muscle strength indicatros were tested and its relations with mental sub-health were analyzed. Results: The detection rates of Chinese adolescents emotional problems, character problems, social adjustment difficulties, and mental sub-health status were 25.5%, 25.0%, 16.0%, and 19.7%, respectively. The detection rates of mental sub-health status of adolescents in the group of muscle index P75 were 30.3%, 19.0%, and 10.4%, respectively, and the difference was statistically significant(χ2=522.03, P<0.01). Logistic regression analysis showed that junior high school(OR=2.55), high school(OR=2.27), male students(OR=1.15), muscle index Conclusion There is a correlation between the mental sub-health of Chinese adolescents and the muscle strength index. The higher the muscle strength index, the lower detection rate of mental sub-health.

Liver fibrosis, liver cirrhosis and hepatocellular carcinoma caused by chronic hepatitis B are still the main diseases that seriously affect the health of Chinese population. Notably, even if serum HBV-DNA cannot be detected after treatment, many patients will still develop liver disease. Therefore, in addition to the quantitative analysis of HBV-DNA and HBsAg, other new serological markers should be sought to facilitate the selection of CHB antiviral drugs and methods, monitoring efficacy and follow-up, efficacy prediction, and the risks of viral rebound after drug withdrawal. This article focuses on three new serological markers, namely HBcrAg, HBV-RNA and anti-HBc, with a view to applying them in clinical practice.

Objective: To analyze and compare the correlation between body mass index (BMI) and cardiopulmonary fitness of children and adolescents aged 7 to 18 years in China and Japan, and to provide important reference for healthy development promotion of children and adolescents in China. Methods: A total of 9 594 children and adolescents aged 7-18 years in China and Japan were selected and examined for height, weight and 20 meters shuttle run test (20mSRT), 4 800 of whom were randomly selected and included for analysis. Independent sample t test was used to compare the differences of BMI and 20mSRT between Chinese and Japanese children and adolescents of different sex and age. Logistic regression was used to compare the odds ratio of high cardiopulmonary fitness among children and adolescents of different nutritional status. Pearson correlation and linear regression were used to analyze the correlation between BMI and 20mSRT. Results: Odds ratios of high cardiopulmonary fitness were 0.57, 0.52 and 0.33 in wasting, overweight and obese children and adolescents in China, and 0.49, 0.36 and 0.16 in Japan, respectively, with significant differences(P<0.05). The BMI-Z scores of Chinese and Japanese children and adolescents ranged from - 2.72 to 8.76. There were significant differences in 20mSRT-z between different BMI-Z groups(P<0.05). The 20mSRT-z score of Chinese and Japanese children and adolescents initially increased with BMI-Z score and then decreased with the increase of BMI-z score. With the decrease of BMI-Z score, 20mSRT performance in Chinese boys decreased significantly. Conclusion Compared with the normal weight peers in China and Japan, the proportion of wasting, overweight and obese children and adolescents with high cardiopulmonary fitness is lower. The BMI-Z score and 20mSRT-z score shows a general inverted "U-shaped" trend. The effect of wasting on cardiopulmonary fitness is greater in Chinese boys.

Memantine is a non-competitive N-methyl-D-aspartate receptor (NMDAR) antagonist clinically approved for moderate-to-severe Alzheimer's disease (AD) to improve cognitive functions. There is no report about the proteomic alterations induced by memantine in AD mouse model yet. In this study, we investigated the protein profiles in the hippocampus and the cerebral cortex of AD-related transgenic mouse model (3×Tg-AD) treated with memantine. Mice (8-month) were treated with memantine (5 mg/kg/bid) for 4 months followed by behavioral and molecular evaluation. Using step-down passive avoidance (SDA) test, novel object recognition (NOR) test and Morris water maze (MWM) test, it was observed that memantine significantly improved learning and memory retention in 3xTg-AD mice. By using quantitative proteomic analysis, 3301 and 3140 proteins in the hippocampus and the cerebral cortex respectively were identified to be associated with AD abnormalities. In the hippocampus, memantine significantly altered the expression levels of 233 proteins, among which PCNT, ATAXIN2, TNIK, and NOL3 were up-regulated, and FLNA, MARK 2 and BRAF were down-regulated. In the cerebral cortex, memantine significantly altered the expression levels of 342 proteins, among which PCNT, PMPCB, CRK, and MBP were up-regulated, and DNM2, BRAF, TAGLN 2 and FRY1 were down-regulated. Further analysis with bioinformatics showed that memantine modulated biological pathways associated with cytoskeleton and ErbB signaling in the hippocampus, and modulated biological pathways associated with axon guidance, ribosome, cytoskeleton, calcium and MAPK signaling in the cerebral cortex. Our data indicate that memantine induces higher levels of proteomic alterations in the cerebral cortex than in the hippocampus, suggesting memantine affects various brain regions in different manners. Our study provides a novel view on the complexity of protein responses induced by memantine in the brain of AD.
Alzheimer Disease ; Animals ; Axons ; Brain ; Calcium ; Cerebral Cortex ; Cognition ; Computational Biology ; Cytoskeleton ; Hippocampus ; Learning ; Memantine ; Memory ; Mice ; Mice, Transgenic ; N-Methylaspartate ; Proteome ; Ribosomes ; Water

Objective To investigate the promoting repair effects of chitosan/gelatin electrospinning membrane implantation on conjunctival injury.Methods Chitosan/gelatin electrospinning membrane was prepared using electrospinning technique,and the general characteristics of the membrane was examined under the scanning electron microscope.Conjunctival injury models were established in the right eyes of 30 New Zealand white rabbits by surgical resection of 6 mm×8 mm bulbar conjunctiva,bums of weak acid at injury site and then randomized into model group,human amniotic membrane (AM) implanted group and electrospinning membrane implanted group.AM or electrospinning membrane was interlayerly implanted between conjunctiva and sclera during operation according to grouping.The inflammatory response and histopathological change at injury site were examined by slit lamp microscope and optical microscope in 4,8,14 and 28 days after surgery.The use and care of the animals followed by code of ethics for animal experiments at the animal experiment center of He University.Results Chitosan/gelatin electrospinning membrane presented with a crosslinked network structure like AM,with the nano-microstructure of 0.1-0.5 μm fibre.No obvious inflammatory symptom was seen in the experimental eyes of various groups in 4 days after operation.In 8 days after operation,conjunctival edema and erosion were found in the model group,and slight conjunctival congestion was exhibited in the eyes of AM implanted group and electrospinning membrane implanted group.In 14 to 28 days after operation,conjunctival edema and new blood vessels were seen in the model group,and the conjunctivas were well recovered in the AM implanted group and electrospinning membrane implanted group.Histopathological examination showed dissociation,attaching,thickening and epithelization of injuried conjunctivas gradually in the model group from 4 to 28 days after operation.In the AM implanted group,attaching of AM was in 4 days,melting of AM was in 8 days,epithelization of injuried conjunctivas was in 14 days and renovation of conjunctivas was in 24 days after operation,and a rapid repairing procedure was found in the electrospinning membrane implanted group under the optical microscope.Conclusions Compared with the self-repairing process of conjunctival injury,implantion of chitosan/gelatin electrospinning membrane or AM can speed up the renovation of injuried conjunctivas,and the effects of chitosan/gelatin electrospinning membrane are better than those of AM in promoting conjunctiva repair and inhibiting scarring.

Objective To study the therapeutic effect of anti-CD80 bivalent antibody on mouse lu-pus nephritis and to explore the possible molecular mechanism. Methods A mouse model of lupus nephritis was established through intraperitoneal injection of 0. 5 ml of pristine in female C57BL/6J mice. Appearance of urinary protein and significantly increased levels of peripheral antinuclear antibody ( ANA) and anti-doub-le-stranded DNA ( anti-dsDNA) antibody in the fourth month after injection indicated that the mouse model was established successfully. Then the mice were divided into two groups including anti-CD80 bivalent anti-body intervention group (injected with 200μg of anti-CD80 bivalent antibody at day 1, 3, 5, 8 and 15, fol-lowed by three times of injection with an interval of one month) and model group ( injected with the same protein using the same strategy). A normal control group was set up accordingly. Albustix test paper was used to monitor the dynamic changes in mouse urinary protein. Flow cytometry was used to analyze the acti-vation of immune-related cells in spleen. Levels of autoantibodies ( ANA and anti-dsDNA) and levels of IFN-γ and IL-4 in serum were detected by indirect immunofluorescence assay. Renal tissue samples were an-alyzed with hematoxylin and eosin ( HE) staining and immunocomplex ( IC) assay. Results Urinary pro-tein level of the anti-CD80 bivalent antibody intervention group was significantly lower than that of the model group (P<0. 05). Activated macrophages, dendritic cells, neutrophils and B cells in spleen tissues of the anti-CD80 bivalent antibody intervention group were significantly less than those of the model group ( P<0. 05), and the numbers of CD4+ and CD154+ T cells were significantly less than those of the model group (P<0. 05). Positive rates and titers of ANA and dsDNA in serum samples of the intervention group were lower than those of the model group (P<0. 05). Levels of IFN-γand IL-4 in serum samples of the interven-tion group were decreased as compared with those of the model group (P<0. 05). HE staining and immuno-fluorescence assay showed that glomerular inflammatory injury and necrosis were alleviated and kidney im-mune complex deposition was reduced after anti-CD80 bivalent antibody intervention. Conclusion Anti-CD80 bivalent antibody specifically binds to the CD80 molecule on antigen presenting cell surface, blocks the CD80/CD28 co-stimulatory signaling pathway and down-regulates the body′s immune response, which al-leviates and reverses the lupus-like nephritis-induced pathological damages in mice.

Objectvi e To investigate whether promoting gap junctions may contribute to the radiosensi-tivity in triple negative breast cancer( TNBC)cells.Methods HCC70(triple-negative),MCF-7(ER-posi-tive)or SK-BR3(HER2-positive )cells were transfected with pcDNA/5 -Cx43 expression plasmid using liposome 2000.The transfected cells were treated with various doses of radiation(0,5,10,15 Gy),and the level of Cx43 protein was determined by Western blot and the cell connectivity was determined by fluorescent tracer technique. Cell proliferation inhibition,clone formation ability and apoptosis were detected using MTT,clone formation assay, AnnexinV-FITC/PI double staining and flow cytometer,respectively.Results The level of Cx43 protein signifi-cantly increased in HCC 70 -Cx43 ,MCF-7 -Cx43 and SK-BR3 -Cx43 cells.After transfection the cells were treated with various doses of radiation,level of Cx43protein was gradually enhanced in dose dependent fashion .The re-sults form fluorescent tracer technique showed that fluorescence intensity was gradually elevated with increase of radiation doses.Cell viability and clone formation ability were decreased gradually in dose dependent manner in HCC70-Cx43 ,MCF-7 -Cx43 and SK-BR3-Cx 43 cells.Unexpectedly,the inhibitive effect of proliferation ability and clone formation ability in HCC70 -Cx43 cell was higher than in MCF-7 -Cx43 and SK-BR3 -Cx43 cells under same conditions.The results from AnnexinV-FITC/PI and flow cytometer showed that apoptosis rate was enhanced gradually accompanying with increase of radiation doses.Conclu sion Enhancing the function of cell gap junc-tions promoted radiosensitivity of breast cancer cells,particularly in TNBC cells.Radiation can strengthen cell gap junctions in breast cancer cell and cytotoxicity of TNBC cell can be enhanced by both synergistic effects.