Sepsis-associated encephalopathy (SAE) is a complex disease with high mortality, an urgent clinical problem to be solved. The mechanism of SAE has not been fully elucidated and there is no effective treatment. Recent study found that high mobility group box 1 (HMGB1) is a late-stage pro-inflammatory mediator with the effect of activating inflammation, besides, HMGB1 plays important role in tissue repair, as well as in sepsis-induced brain injury. Therefore, In-depth research on the relationship between HMGB1 and SAE is expected to provide a new direction for the diagnosis and treatment of SAE. This review focuses on current status of SAE, HMGB1 and the four aspects of HMGB1, including impairment of blood-brain barrier, dysregulation of immune response, oxidative stress and neuronal apoptosis that involved in brain function impairment and SAE.

Objective To explore the effect of versican (VCAN) gene on immunocyte infiltration and prognosis of bladder urothelial carcinoma (BUC). Methods The high-throughput sequencing data and clinical data of BUC were downloaded from TCGA database. The correlation between the expression level of VCAN and clinical characteristics of BUC patients was analyzed using the Limma R package; univariate and multivariate Cox regression analysis were performed to analyze the effect of VCAN expression and clinical characteristics (including gender, age, tumor grade, tumor stage, lymph node metastasis and distant metastasis) on the prognosis of BUC patients; TIMER database was used to analyze the correlation between VCAN expression level and immunocyte infiltration. T24 cells were divided into three groups: control group (cells transfected without any siRNA), NC siRNA group (cells transfected with negative control siRNA), and VCAN siRNA group (cells transfected with VCAN siRNA). After transfection, the proliferation, invasion and cell cycle proportion of T24 cells were determined by MTT assay, Transwell assay and flow cytometry, respectively. The protein expression levels of Cyclin E, Cyclin D1, E-cadherin and matrix metalloproteinase-9 (MMP-9) were determined by Western blotting. Results Compared with normal bladder tissues, the expression level of VCAN mRNA in BUC tissues was significantly up-regulated, and was positively correlated with tumor grade, tumor stage and distant metastasis (P<0.01). High VCAN expression was an independent risk factor for poor prognosis in BUC patients (P<0.05). The results of TIMER database analysis showed that the expression level of VCAN was significantly positively correlated with the infiltration degree of macrophages and regulatory T cells in BUC (P<0.001). Compared with control group, the proliferation and invasion ability of T24 cells in VCAN siRNA group decreased significantly and the cell proportion of G₀/G₁ phase increased significantly (P<0.05), the protein expression levels of Cyclin E, Cyclin D1 and MMP-9 were down-regulated significantly, and of E-cadherin was up-regulated significantly (P<0.05). Conclusions VCAN is highly expressed in BUC and correlated with immune infiltration and prognosis of BUC. Silencing the expression of VCAN may significantly inhibit the proliferation and invasion of T24 cells by regulating the protein expression levels of Cyclin E, Cyclin D1, E-cadherin and MMP-9.

Objective To examine the differences between mouse models of classic heat stroke (CHS) with multiple organ dysfunction via two different rising strategies. Methods A total of 66 male C57BL/6J mice were divided into direct heat stroke (DHS) group (n=28), a stepwise heat stroke (SHS) group (n=28), and control group (n=10) using the random number table method. In the first two groups, animals received direct warming at 41 ℃ and stepwise warming from 25.0 ℃ to 39.5 ℃, using a simulated climate chamber, respectively. While the animals were in the climate chamber before reaching the endpoint, we constantly monitored the animal activity, animal consciousness, and rectal temperature. We randomly selected 4 animals from each group and collected the blood samples and organ tissues (liver, kidney, intestine, lung, and spleen) after 24 hours of recovery since the end of heat exposure. We used the automatic biochemical analyzer to measure the levels of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine (CREA), blood urea nitrogen (BUN), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), and creatine kinase isoenzyme MB (CK-MB). We employed multifactorial test kits to detect the levels of interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, monocyte chemoattractant protein (MCP)-1 and transforming growth factor (TGF)-β. We analyzed the histological sections from each organ and then calculated the pathological injury scores. We saved the remaining mice for the 72 h survival analysis. Results Both heat stroke strategies can establish a stable CHS model of the mouse. In contrast with mice in DHS group, mice in SHS group exposed to heat for a longer time [(181.61±41.88) min vs. (104.72±18.68) min, P<0.001], had a higher percentage of dehydration [(11.59±1.52)% vs. (7.07±1.84)%, P<0.001] and higher 72 h mortality (73.68% vs. 22.22%, P<0.05). After 24 hours' recovery, biochemical indicators (ALT, AST, CREA, BUN) of SHS group were higher than those of DHS group [(875.63±241.24) U/L vs. (139.38±188.22) U/L, P<0.01; (2406.75±1008.69) U/L vs. (208.13±149.23) U/L, P<0.01; (79.88±41.39) U/L vs. (18.75±10.51) U/L, P<0.05; (134.33±52.54) U/L vs. (17.75±7.31) U/L, P<0.01]. The pathological injury scores of each organ tissue of the SHS group were higher than those of the DHS group (P<0.05). The levels of MCP-1 of the SHS group were higher than that of the DHS group [(22.89±1.97) pg/ml vs. (15.97±3.91) pg/ml, P<0.05], and TGF-β of SHS group was lower than that of DHS group [(936.46±30.17) pg/ml vs. (1453.50±129.81) pg/ml, P<0.001]. Conclusions The stepwise warming method had a higher success rate in developing the model, a higher mortality rate within 72 h, and more severe organ damage than the direct warming method. Thus it was a more stable and reliable modeling method that was more consistent with the pathophysiological state of CHS patients at the actual onset of illness.

Objective To investigate the protective function and mechanism of rapamycin on the hypothalamus injury of rats with exertional heat stroke. Methods Eighty male Wistar rats were randomly divided into four groups: control group, rapamycin group (Rapa group), exertional heat stroke group (EHS group), and exertional heat stroke + rapamycin group (EHS+Rapa group), with 20 rats in each group. The rats in Rapa group and EHS+Rapa group were injected intraperitoneally with Rapa (1 mg/kg, once a day) for four consecutive days before modeling. The rats in control and EHS groups were treated with the same dose of 0.9% normal saline. In EHS group and EHS+Rapa group, the rats ran in a climate chamber with a temperature range of (39.5±0.3) ℃ and a humidity range of (55%±5%). After successful modeling, the rats were removed from the climate chamber for cooling at room temperature. The animals in control and Rapa groups ran at the same intensity and room temperature as EHS group. During the establishment of the model, we monitored the general state, measured core temperature, and profiled the survival curve of the rats in each group (11 rats randomly selected from each group). The rats in EHS group and EHS+Rapa group were removed from the chamber after modeling of 80 min, and after 300 min observation, each group of rats was anesthetized. Then we collected the abdominal aorta blood and hypothalamus. The histopathological changes in the hypothalamus were analyzed by HE and Nissl staining. Immunofluorescence was used to determine the apoptosis of hypothalamus. Western blotting was used to detect the expression of mammalian target of rapamycin (mTOR) and phosphorylated mTOR (pmTOR), autophagy effector protein (Beclin-1), ubiquitin-binding protein (p62) and autophagy marker microtubule-associated protein 1 light chain 3(LC3) in the hypothalamus of rats. We calculated the ratios of pmTOR/mTOR and LC3-Ⅱ/LC3-Ⅰ. We measured the expression levels of neuron-specific enolase (NSE), brain active peptide 100β protein (S100β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) in arterial serum by ELISA. Results When rats were entered into the climate chamber at 80 min, compared with control group, the core temperature of EHS group was significantly increased (P<0.001); compared with Rapa group, the core temperature of EHS+Rapa group was significantly increased (P<0.001). Compared with the EHS group, the survival rate of EHS+Rapa group was increased (P<0.01). HE and Nissl staining showed severe pathological damage in hypothalamic nerve cells in EHS group. We observed significantly less pathological damage in hypothalamic nerve cells in EHS+Rapa group than EHS group (P<0.001). Immunofluorescence analysis showed substantial cell apoptosis in the hypothalamus of EHS rats compared with control group (P<0.05). EHS+Rapa group had significantly less apoptosis in the hypothalamus than EHS group (P<0.05). Western blotting results showed that compared with control group, the ratio of pmTOR/mTOR, Beclin-1 expression, LC3-Ⅱ/LC3-Ⅰ ratio in the hypothalamus tissue of EHS group increased and p62 expression decreased (P<0.01); compared with EHS group, the ratio of pmTOR/mTOR in the hypothalamus of EHS+Rapa group decreased, Beclin-1 expression increased, LC3-Ⅱ/LC3-Ⅰ ratio increased and p62 expression decreased (P<0.05). ELISA results showed that the expression levels of NSE, S100β protein, and TNF-α in the serum of EHS group were significantly increased (P<0.05), while the expression of IL-6 in EHS group showed no significant difference (P>0.05). Compared with EHS group, the expression levels of NSE, S100β protein, IL-6, and TNF-α in the serum of EHS+Rapa group were significantly decreased (P<0.05). Conclusion Rapa can alleviate the hypothalamus tissue damage caused by exertional heat stroke, improve the function of brain cells, reduce the levels of inflammatory factors and the apoptosis of tissue cells, which is related to the inhibition of mTOR signaling pathway and the enhancement of hypothalamus autophagy level.

Objective To explore the clinical application value of transvaginal ultrasound combined with the micro-vascular flow (MV-Flow) imaging in analyzing the ultrasound characteristics of endometrium during ovulation in women of childbearing age. Methods A total of 74 women of childbearing age who underwent transvaginal gynecological ultrasound examination in the First Medical Center of Chinese PLA General Hospital from May 2022 to July 2022 were selected. Among them, aged 22-48 (34.4±5.0) years, including 35 women ≥35 years old in the elderly group and 39 women <35 years old in the younger group. All patients with clinically diagnosed of infertility were divided into infertility group (27 cases) and healthy control group (47 cases). On the day of ovulation, the endometrial thickness, peristalsis score, volume of endometrium, pulsatility index (PI) and resistance index (RI) of uterine spiral artery, PI and RI of bilateral uterine arteries, three-dimensional energy doppler flow parameters [blood flow index (FI), vascularization index (VI), vascular blood flow index (VFI)] and endometrial microvascular bleeding vascularization index (VI_MV) were measured by the transvaginal ultrasound. The above ultrasonic indexes were compared and analyzed between the two groups. Results There was no significant difference in the history of infertility between the younger group and the older group (P>0.05). The RI of uterine spiral artery in the younger group was lower than that in the older group, while the three-dimensional energy doppler flow parameters (VI, FI, VFI) and the VI_MV of endometrium in the younger group were significantly higher than those in the older group. There was no significant difference in age stratification between infertility group and healthy control group (P>0.05). The endometrial thickness, endometrial peristalsis score, endometrial volume, endometrial three-dimensional energy doppler flow parameters (VI, FI, VFI) and the VI_MV in inferbility group were significantly lower than those in healthy control group (P<0.05). Conclusion Transvaginal ultrasound indicators can evaluate the endometrium characteristics of women of childbearing age during ovulation to some extent, especially, VI_MV can quantitatively analyze the microblood perfusion of endometrium.

Gut microflora (GM) or intestinal microecology (IM) is of great importance in maintaining human homeostasis and health. Cardiovascular disease (CVD) is a global health burden nowadays with high morbidity and mortality, the existing research confirmed that GM/IM metabolic imbalance is closely related to the occurrence and development of CVD, and some GM/IM metabolites can also be used as biomarkers of CVD disease, and their detection or intervention becomes a possible means of diagnosis, prevention or treatment of CVD. Clinical drug metabolism and efficacy evaluation, and superior effect screening from the GM/IM level is also a research direction of clinical pharmacology. With the implementation of the concept of precision medicine and a wide health, GM/IM whole-genome sequencing and metabolomics continue to be researched, the basic research and clinical application of GM/IM and CVD will be a hot topic in the future. The research status of the relationship between GM/IM and CVD has been reviewed in present paper for providing diagnosis and treatment ideas and related references for the prevention and treatment of CVD.

Objective To analyze the clinical features and gene phenotype of sideroblastic anemia, B-cell immunodeficiency, periodic fevers, and developmental delay (SIFD) due to TRNT1 mutation in two siblings from non-consanguineous parents. Methods The clinical data of the siblings with SIFD that were diagnosed in the department of allergy, immunology and rheumatology of Guangzhou Women and Children's Medical Center were collected. Then we detected the whole genome sequencing analysis with the peripheral blood samples of the patients and their parent. We summarize the clinical characteristics and gene analysis of 55 patients with SIFD that were concluded from the PubMed, China national knowledge internet and Wanfang databases. Results The proband was a 15-year-old girl, she presented with recurrent fever and elevated inflammatory markers since she was 8 months of age. After 1 year-old of age, she gradually developed swelling and arthralgia of the right knee, flexion deformity of arthritis, bilateral cataract, developmental delay and growth retardation. She can't talk with others, can't walk by herself and had no menstruation until now. The proband's sibling brother was 7 years old, presented with hypoimmunoglobulinemia and normal B cell counts at 3 months, which showed low immunoglobulin A but with normal immunoglobulin G and M and normal B cell counts at 2 years old. Diarrhea appeared at 4 months of age. He was hospitalized with fever, bronchopneumonia and diarrhea at 8 months of age. Since then, he was prone to recurrent fever and diarrhea. At 19 months, he developed arthritis of both knees and presented bilateral cataract at the age of 2 years. Irregular infusion of immunoglobulin was performed, swelling and pain of the knee gradually improved and the frequency of fever decreased. Now, he still presents with developmental delay and growth retardation. He can talk with people by 3-7 words short sentences, but the pronunciation is not clear. He can understand and carry out the orders of his parent. He can walk alone but with poor stability. Whole genome sequencing of the blood revealed biallelic TRNT1 heterozygous mutations, c.1056+1G>A/c.1246A>G (p.K416E). A total of 55 cases were reported in the literatures, including 21 males and 30 females, and 4 cases were not mentioned in the references. The clinical manifestations presented with repeated fever, different levels of sideroblastic anemia and immunologic abnormalities, arthritis, growth retardation, hearing abnormalities, cataracts, repeated infections, skin rashes and so on. Intravenous infusion of immunoglobulin and tumor necrosis factor-α antagonists, hematopoietic stem cell transplantation and positive symptomatic treatments may improve the prognosis. Conclusions SIFD caused by TRNT1 gene mutation is an autosomal recessive inherited disease with diverse clinical manifestations. Genetic testing of TRNT1 gene mutationis is the basis of clinical diagnosis. Clinicians should recognize the complex disease, early diagnosis and intervention can improve the quality of life for patients.

Objective To evaluate the clinical effect of non-invasive prenatal testing (NIPT) by analyzing the efficiency of fetal chromosomal aneuploidy screening in Beijing. Methods The clinical data of 133 899 pregnant women, who underwent NIPT in eight prenatal diagnosis institutions of Beijing from January 2019 to December 2020, were collected and retrospectively analyzed. The test indications, results and prenatal diagnosis results were recorded. The positive rate of all pregnant women was calculated according to the test indications; According to the test results, it can be divided into trisomy 21 syndrome, trisomy 18 syndrome, trisomy 13 syndrome, sex chromosome abnormality, and other chromosome abnormalities. The prenatal diagnosis rate, positive rate, positive predictive value (PPV), sensitivity and specificity were calculated. Results Among the NIPT screening indicators, the detection rate of elderly pregnant women was the highest, accounting for 34.0% (45 509/133 899), followed by voluntary requirements, accounting for 32.7% (43 860/133 899). There were 1647 cases with high risk of NIPT, the positive rate was 1.2% (1647/133 899), and the positive rate of NT thickening and ultrasound structure abnormal were the highest in pregnant women. One thousand three hundred and forty-eight cases received prenatal diagnosis. The highest prenatal diagnostic rate was trisomy 18 reached to 91.5% (130/142), the lowest was the rate of sex chromosome abnormality reached to 76.4% (488/639). The overall prenatal diagnostic rate was 81.8% (1348/1647). The positive rates of trisomy 21, trisomy 18, trisomy 13, sex chromosome abnormality and other chromosomes abnormality were 0.2% (318/133 899), 0.1% (142/133 899), 0.1% (77/133 899), 0.5%(639/133 899) and 0.4% (471/133 899), respectively. The positive predictive values were 71.1% (226/318), 38.0% (54/142), 18.2%(14/77), 31.3% (200/639) and 17.8% (84/471), respectively. The sensitivity of trisomy 21, trisomy 18 and trisomy 13 was 98.7%, 96.4% and 100.0%, and all the specificity of was 99.9%. Conclusions The NIPT had high sensitivity and specificity but also still had the limitations of false positive and false negative. Therefore, prenatal diagnosis should be carried out for NIPT high-risk pregnant women, and it is important to strengthen the genetic counseling before and after testing.

Objective To investigate the changes of posterior chamber intraocular lens (ICL-V4c) implantation on retinal and choroid thickness, retinal blood flow density in the macular area, and optic disc in ultra-high myopia using optical coherence tomography angiography (OCTA). Methods From April 2020 to May 2021, 15 patients (30 eyes) with binocular equivalent spherical lens (SE) ≥–10.00 D in Beijing Tongren Hospital Affiliated to Capital Medical University were enrolled. All eyes had undergone the ICL-V4c treatment. We observed the visual acuity and intraocular pressure at the following time points: before the operation, 2-hour, 1-week, 1-month, and 9-month post-operation. OCTA was used to monitor the changes in retinal and choroid thickness in the macular area as well as retinal blood flow density around the macular area and optic disc. Results There was no statistically significant difference between uncorrected viusal acuity postoperative and best corrected viusal acuity preoperative at each time point after surgery (P>0.05). The postoperative intraocular pressure showed a downward trend, but the difference was not statistically significant. The vault at 9-month post-surgery was significantly lower than that at 1-week post-surgery, the difference was statistically significant (P=0.002). There were no statistically significant differences in deep retinal blood flow density, retinal thickness or choroid thickness in the macular area, blood flow density in the radial capillary network around the optic disc, and nerve fiber layer thickness at each postoperative time point (P>0.05). The superficial retinal blood flow density in the four directions of upper, lower, nasal, and temporal decreased significantly 2-hour after surgery, with statistical significance (P<0.05). With the extension of time, the blood flow density in each area increased significantly, and there was no statistical difference compared with that before surgery (P>0.05). Conclusion OCTA observation showed that ICL-V4c implantation had an effect on the superficial retinal blood flow density in the early stage of ultra-high myopia but would restored to the preoperative level during the time, and had no effect on the retinal choroid thickness in the remnant macular area, the blood flow density of the capillary network around the optic disc and the thickness of the nerve fiber layer.

Immunotherapy has become one of the hopes to ultimately defeat cancer after radiotherapy, chemotherapy and targeted therapy, and tumor-associated antigen is an important target in immunotherapy. As an important member of the melanoma associated antigen-A (MAGE-A) subfamily, MAGE-A4 is highly expressed in various tumor tissues and low expressed in normal tissues except testis and placenta. It is involved in the regulation of cell functions and has important roles in regulating cell cycle, inducing cell differentiation and growth, and participating in epithelial-mesenchymal transformation, which is closely related to the tumorigenesis, progression, metastasis and prognosis. The latest study shows that the phase Ⅱ clinical study of T cell receptor-transgenic T (TCR-T) immunotherapy based on MAGE-A4 target is being carried out. The results of phase Ⅰ study showed that the overall response rate (ORR) was 23.7% and the disease stability was 47.4%, suggesting that TCR-T immunotherapy based on MAGE-A4 target has good clinical application value. This paper summarizes the structure and biological function of MAGE-A4, the latest research progress of various solid tumors and its clinical application, aiming to provide theoretical basis for clinical transformation and immune-targeted therapy of MAGE-A4.