Alzheimer's disease (AD) is a neurodegenerative disease with clinical hallmarks of progressive cognitive impairment. Synergistic effects of the Aβ-Tau cascade reaction are tightly implicated in AD pathology, and microglial NLRP3 inflammasome activation drives neuronal tauopathy. However, the underlying mechanism of how Aβ mediates NLRP3 inflammasome remains unclear. Herein, we determined that oligomeric Aβ (o-Aβ) bound to microglial Kv2.1 and promoted Kv2.1-dependent potassium efflux to activate NLRP3 inflammasome resulting in neuronal tauopathy by using Kv2.1 inhibitor drofenine (Dfe) as a probe. The underlying mechanism has been intensively investigated by assays with Kv2.1 knockdown in vitro (si-Kv2.1) and in vivo (AAV-ePHP-si-Kv2.1). Dfe deprived o-Aβ of its capability to promote microglial NLRP3 inflammasome activation and neuronal Tau hyperphosphorylation by inhibiting the Kv2.1/JNK/NF-κB pathway while improving the cognitive impairment of 5×FAD-AD model mice. Our results have highly addressed that the Kv2.1 channel is required for o-Aβ-driven microglial NLRP3 inflammasome activation and neuronal tauopathy in AD model mice and highlighted that Dfe as a Kv2.1 inhibitor shows potential in the treatment of AD.

Dendritic cells (DCs) serve as the primary antigen-presenting cells in autoimmune diseases, like rheumatoid arthritis (RA), and exhibit distinct signaling profiles due to antigenic diversity. Type II collagen (CII) has been recognized as an RA-specific antigen; however, little is known about CII-stimulated DCs, limiting the development of RA-specific therapeutic interventions. In this study, we show that CII-stimulated DCs display a preferential gene expression profile associated with migration, offering a new perspective for targeting DC migration in RA treatment. Then, saikosaponin D (SSD) was identified as a compound capable of blocking CII-induced DC migration and effectively ameliorating arthritis. Optineurin (OPTN) is further revealed as a potential SSD target, with Optn deletion impairing CII-pulsed DC migration without affecting maturation. Function analyses uncover that OPTN prevents the proteasomal transport and ubiquitin-dependent degradation of C-C chemokine receptor 7 (CCR7), a pivotal chemokine receptor in DC migration. Optn-deficient DCs exhibit reduced CCR7 expression, leading to slower migration in CII-surrounded environment, thus alleviating arthritis progression. Our findings underscore the significance of antigen-specific DC activation in RA and suggest OPTN is a crucial regulator of CII-specific DC migration. OPTN emerges as a promising drug target for RA, potentially offering significant value for the therapeutic management of RA.

Vascular damage plays a significant role in the onset and progression of Alzheimer's disease (AD). However, the precise molecular mechanisms underlying the induction of neuronal injury by vascular damage remain unclear. The present study aimed to examine the impact of fibrinogen (Fg) on tau pathology. The results showed that Fg deposits in the brains of tau P301S transgenic mice interact with tau, enhancing the cytotoxicity of pathological tau aggregates and promoting tau phosphorylation and aggregation. Notably, Fg-modified tau fibrils caused enhanced neuronal apoptosis and synaptic damage compared to unmodified fibrils. Furthermore, intrahippocampal injection of Fg-modified tau fibrils worsened the tau pathology, neuroinflammation, synaptic damage, neuronal apoptosis, and cognitive dysfunction in tau P301S mice compared to controls. The present study provides compelling evidence linking Fg and tau, thereby connecting cerebrovascular damage to tau pathology in AD. Consequently, inhibiting Fg-mediated tau pathology could potentially impede the progression of AD.
Animals ; tau Proteins/metabolism* ; Alzheimer Disease/metabolism* ; Fibrinogen/metabolism* ; Mice, Transgenic ; Mice ; Disease Models, Animal ; Memory Disorders/metabolism* ; Male ; Mice, Inbred C57BL ; Brain/metabolism* ; Hippocampus/metabolism* ; Protein Aggregation, Pathological/metabolism* ; Apoptosis ; Phosphorylation

OBJECTIVE To preliminarily assess the horizontal sound localization and its influencing factors in patients with unilateral sudden sensorineural hearing loss during the acute phase.METHODS The azimuth discrimination test and azimuth identification test were completed,with the speech sound(65 dB SPL)as the stimulus.The minimum audible angle(MAA)and root-mean-square error(RMSE)were obtained,and the RMSE of the affected side and the healthy side were calculated respectively.According to the WHO(2021)hearing loss classification criteria,the data were analyzed based on the pure-tone average(PTA)of the affected ear.And the best resident hearing at each frequency of the affected ear was recorded.RESULTS The performance of the unilateral sudden sensorineural hearing loss patients in the sound localization varied greatly.Some performed close to the normal level,while others completely lost the ability to localize sound.The RMSE of the moderate hearing loss group(≥35 dB HL)was significantly higher than that of the normal hearing group(P<0.01),the MAA of the moderate to severe hearing loss group(≥50 dB HL)showed statistically significant differencescompared with normal hearing group(P<0.001).The RMSE of the affected side of patients in the severe and above hearing loss group was significantly larger than that of the healthy side.Regression analysis showed that the best resident hearing at each frequency of the affected ear was the most significant factor affecting MAA(R2=0.572,P<0.001)and RMSE(R2=0.768,P<0.001).CONCLUSION The horizontal sound localization of unilateral sudden sensorineural hearing loss patients in the acute phase varies greatly.When the PTA of the affected side reaches moderate hearing loss,the localization ability is significantly lower than that of normal-hearing individuals.The best resident hearing at each frequency of the affected ear is the key factor affecting the localization ability.

An analysis was conducted on the clinical manifestations, auxiliary examinations, diagnosis and treatment process, treatment, and prognosis of a child with neurobrucellosis. 408 relevant literature on neurobrucellosis from January 2012 to December 2022 were searched through Chinese and English databases such as CNKI, Wanfang Data, and Biomedical Literature Database (PubMed). Literature was screened based on inclusion and exclusion criteria, A total of 14 children with neurobrucellosis were selected for analysis, with an average age of onset of 10 years old. Among the patients, there were 3 cases of middle cranial nerve injury, 2 cases of ataxia, 1 case of myelitis, 2 cases of mental symptoms, 1 case of optic disc edema, 1 case of sagittal sinus thrombosis, and the rest were manifested as meningitis and encephalitis. The imaging results suggested that there was often no specific area of invasion, with magnetic resonance imaging (MRI) commonly involving the cortex, central half oval, and basal ganglia. Extensive white matter changes were also frequently observed, which is consistent with the findings of this case report. Neurobrucellosis has diverse clinical manifestations and lacks specificity. It is mainly diagnosed based on comprehensive analysis of neuropsychiatric symptoms, cerebrospinal fluid and serological results, imaging characteristics, etc. Early diagnosis and treatment are of great significance in preventing complications of neurobrucellosis.

BACKGROUND:The content of serum thrombin in patients with osteoarthritis is significantly higher than that in normal individuals,and thrombin can induce inflammatory degeneration of rat chondrocytes,suggesting that inhibiting the function of thrombin may become a method for treating osteoarthritis.Celecoxib is a common therapeutic drug for the clinical treatment of osteoarthritis.It is not yet known whether it improves chondrocyte degeneration by inhibiting the activity of thrombin. OBJECTIVE:To investigate the effect of celecoxib on thrombin-induced degeneration of rat chondrocytes. METHODS:Thrombin levels in the serum of osteoarthritis patients and normal individuals were detected by an ELISA kit.Primary chondrocytes of neonatal Sprague-Dawley rats were isolated,and all experiments were performed with cells from passage one.Chondrocytes were randomly divided into three groups:control group,thrombin group,and celecoxib group.The cell morphology of the three groups was observed under an inverted microscope,and an Edu kit was used to detect the cell proliferation.qRT-PCR was used to detect the expression of extracellular matrix components(aggrecan,elastin,cartilage oligomeric matrix proteins),inflammatory factors(interleukin-1,interleukin-6,and tumor necrosis factor-α),and chemokines(monocyte chemotactic protein 2,monocyte chemotactic protein 7,granulocyte chemotactic protein 6).The expression of type 2 collagen α1 was detected by immunofluorescence.Western blot method was used to detect the expression of catabolic metabolism genes,such as matrix metalloproteinase 9,matrix metalloproteinase 13,and cyclooxygenase 2. RESULTS AND CONCLUSION:Patients with osteoarthritis had higher levels of thrombin in the serum compared with normal individuals.Under the microscope,celecoxib was found to significantly inhibit fibroid changes in chondrocytes.Compared with the thrombin group,celecoxib inhibited the proliferation of chondrocytes.The downregulation of extracellular matrix gene expression,such as type II collagen α1,in the thrombin group was inhibited by celecoxib(P<0.05).Thrombin promoted the expression of inflammatory factors(interleukin-1,interleukin-6,and tumor necrosis factor-α),chemokines(monocyte chemotactic protein 2,monocyte chemotactic protein 7,granulocyte chemotactic protein 6),as well as catabolic genes(matrix metalloproteinase 9,matrix metalloproteinase 13,and cyclooxygenase 2),and under the intervention of celecoxib,the expression of these genes could be downregulated(P<0.05).Overall,these findings indicate that celecoxib inhibits the pro-inflammatory effects of thrombin and thereby ameliorates chondrocyte degeneration in rats.

Objective:To investigate the association of total sleep time (TST) and oxygen desaturation index (ODI) with hypertension in patients with obstructive sleep apnea/hypopnea syndrome (OSA).Methods:A total of 440 OSA patients admitted to Yixing Hospital from January 2017 to December 2022 were consecutively enrolled, including 236 patients with hypertension (OSA+hypertension group) and 204 patients without hypertension (OSA group). The clinical data and polysomnograpic parameters were collected. Univariate and multivariate logistic regression was used to analyze the related factors of OSA complicated with hypertension. The multiplicative interaction between TST and ODI on OSA with hypertension was analyzed. A two-factor cross-over analysis of TST and ODI was performed and the additive interaction model was used to analyze the additive interaction between TST and ODI on OSA with hypertension.Results:Univariate logistic regression showed that male sex, smoking, diabetes, coronary heart disease, TST <7 h, age, body mass index, neck circumference, waist circumference, Epworth Sleepiness Scale (ESS) score, TST, AHI, ODI>16 times/h, triglyceride, high density lipoprotein cholesterol and fasting blood glucose were positively correlated with hypertension in OSA patients (all P<0.05). Multivariate logistic regression analysis showed that smoking ( OR=4.327, 95% CI: 2.499-2.499, P<0.001), TST<7 h ( OR=1.748, 95% CI: 1.079-2.832, P=0.023) and ODI>16 times/h ( OR=3.482, 95% CI: 2.016-6.014, P<0.001) were independently associated with hypertension in OSA patients. After introducing a multiplicative term and adjusting for confounding factors, there was a positive multiplication interaction between TST <7 h and ODI>16 times/h ( OR=2.958, 95% CI: 1.079-8.113, P<0.050). Multivariate logistic regression analysis showed that the risk of hypertension in OSA patients with TST<7 h and ODI>16 times/h was 7.196 times (95% CI: 3.421-15.137) higher than that in patients with TST≥7 h and ODI≤16 times/h. The additive interaction model showed a synergistic effect between TST<7 h and ODI>16 times/h, with S value of 4.302 (95% CI: 1.566-11.815), RERI value of 4.756 (95% CI: 0.642-8.869) and API value of 66.10% (95% CI: 43.10%-89.10%). Conclusion:Shortened sleep duration and increased ODI are independent risk factors for hypertension in OSA patients, and when they coexist, the risk of hypertension in OSA patients is further increased.

Objective:To perform harmonization based on the ComBat method for PET brain imaging scanned by different types of scanners from the same manufacturer and explored its effect on center effect.Methods:The three-dimensional (3D) Hoffman brain model was scanned by two different PET/CT instruments (Siemens Biograph64 TruePoint and Biograph128 mCT). Fourteen healthy subjects (8 males, 6 females, age: (57.7±9.5) years) underwent 18F-FDG PET/CT on Siemens Biograph64 TruePoint and 12 healthy subjects (9 males, 3 females, age: (55.8±10.5) years) underwent 18F-FDG PET/CT on Siemens Biograph128 mCT (all from Huashan Hospital, Fudan University; from November 2020 to March 2023). The whole brain was divided into 116 brain regions based on the anatomical automatic labeling (AAL) brain template. The ComBat method was applied to harmonized the PET data from brain model and healthy subjects. Mann-Whitney U test was performed on the radioactive counts and SUV ratios (SUVR) before and after homogenization acquired by both PET/CT instruments. Voxel-based statistical parametric mapping (SPM) independent-sample t test was also performed on data of healthy subjects. Results:In 3D Hoffman brain model, radioactivity counts (5 590.33(4 961.67, 6 102.95) vs 6 116.03(5 420.97, 6 660.66); z=-9.35, P<0.001) and SUVR (1.35(1.19, 1.47) vs 1.37(1.21, 1.49); z=-3.63, P<0.001) were significantly different between the two PET/CT scanners before harmonization and not after harmonization (radioactivity counts: 5 845.95(5 192.68, 6 378.63) vs 5 859.17(5 193.84, 6 380.52); SUVR: 1.35(1.20, 1.48) vs 1.36(1.20, 1.49); both z=-0.68, both P=0.498). In the healthy subjects, radioactive counts in 19 brain regions (12 422.78(11 181.60, 13 424.28)-18 166.40(15 882.80, 18 666.27); z values: from -3.24 to -2.06, all P<0.05) and SUVR in 40 brain regions (1.46(1.41, 1.52)-2.28(2.16, 2.36); z values: from -3.65 to -1.70, all P<0.05) were significantly different between the two scanners before harmonization, while after homogenization there were no statistical differences for all 116 brain regions (radioactivity counts: 9 243.55(8 502.38, 9 854.87)-20 419.60(19 931.51, 21 179.43); z values: from -0.72 to 0, all P>0.05; SUVR: 1.04(1.01, 1.09)-2.32(2.24, 2.40); z values: from -0.82 to 0, all P>0.05). SPM showed that significant differences of glucose metabolism in the cerebral cortex, basal ganglia, midbrain and cerebellum were found in healthy subjects between the two PET/CT scanners before homogenization, and brain regions with obvious differences reduced after homogenization. Conclusion:ComBat harmonization method is efficient at removing the center effect among different types of PET/CT scanners from the same manufacturer and may provide a simple and easy-to-implement homogenization for multicenter brain imaging studies.

ObjectiveTo compare the annual and age trends of the age-standard incidence rate （ASIR） and the age-standard mortality rate （ASMR） of lung cancer in countries with different human development index （HDI） from 1990 to 2019. MethodsThe data were collected from the global burden of disease study and GLOBOCAN 2020. The average annual percentage change （AAPC） and age trends of ASIR and ASMR in lung cancer were analyzed by the Joinpoint regression model， and the comparison between the four groups was analyzed by Kruskale-Wallis analysis. ResultsIn 2020， the incidence and mortality of lung cancer gradually increased with age and HDI grade. From 1990 to 2019， the global ASIR and ASMR of lung cancer decreased， and the ASIR of lung cancer among male decreased， while the ASIR of lung cancer among female increased. The results showed that ASIR of lung cancer in female residents in countries with very high HDI increased significantly from 1996 to 2011， resulting in an overall upward trend in female ASIR， while the other groups showed a downward trend. It was found that ASIR and ASMR of lung cancer in China and India were on the rise， while ASIR and ASMR of lung cancer in Russia and the United States were on the decline. ConclusionAlthough very high/high HDI countries face a higher burden of lung cancer occurrence and death， the accumulation of lung cancer burden is completed in the transitioning period. Therefore， lung cancer prevention measures in countries in transition are critical for global lung cancer control.

Objective:To establish a modified controlled abciximab and device investigation to lower late angioplasty complication (CADILLAC) score, and to compare the predictive value of modified CADILLAC score, the global registry of acute coronary event (GRACE) score and the thrombolysis in myocardial infarction (TIMI) score in predicting the risk of short-term death after percutaneous coronary intervention (PCI) in patients with acute ST segment elevation myocardial infarction (STEMI).Methods:A retrospective study was conducted. The clinical data of 169 STEMI patients under going PCI admitted to the department of cardiology of Guizhou Provincial People's Hospital from September 2019 to December 2020 through emergency chest pain fast track were enrolled. A multivariate Logistic regression analysis was used to screen the factors closely related to the mortality risk within 30 days of STEMI, and a modified CADILLAC scoring system was established by referring to CADILLAC scoring settings. The score of modified CADILLAC, GRACE and TIMI scores of patients were calculated after admission, and the number of deaths due to cardiovascular disease (CVD) within 30 days after onset was recorded. The receiver operating characteristic curve (ROC curve) was used to evaluate the predictive value of three scoring systems on the risk of death within 30 days after PCI in patients with STEMI.Results:In 169 STEMI patients, 16 patients died of CVD within 30 days after PCI, and the actual case mortality was 9.47%. Multivariate Logistic regression analysis showed that age > 75 years old, cardiac function Killip ≥ Grade Ⅲ, ventricular arrhythmia, ST segment elevation ≥ 0.2 mV, cardiac troponin I (cTnI) increase, systolic blood pressure (SBP) < 90 mmHg (1 mmHg ≈ 0.133 kPa) were all independent predictors of death after PCI in STEMI patients. The improved CADILLAC scoring system was constructed based on the above predictive factors combined with left ventricular ejection fraction (LVEF) less than 0.40. The GRACE, TIMI and modified CADILLAC scores of dead patients were significantly higher than those of survival patients (GRACE score: 197.60±31.83 vs. 149.81±36.72, TIMI score: 11.21±2.13 vs. 7.27±1.97, modified CADILLAC score: 12.60±2.52 vs. 6.96±2.17, all P < 0.05). The higher the risk stratification of the three scores, the higher the mortality of patients with CVD within 30 days after PCI [the mortality of patients with low, medium and high risk in GRACE score were 2.41% (2/83), 9.61% (5/52) and 26.47% (9/34); the mortality of patients with low, medium and high risk in TIMI score were 3.12% (3/96), 12.82% (5/39) and 23.53% (8/34); and the mortality of patients with low, medium and high risk in modified CADILLAC score were 3.19% (3/94), 7.69% (4/52) and 39.13% (9/23), respectively, all P < 0.01]. The area under the ROC curve (AUC) of the GRACE, TIMI and the modified CADILLAC scores predicting the risk of death 30 days after PCI in STEMI patients were 0.855 [95% confidence interval (95% CI) was 0.702-0.923], 0.725 (95% CI was 0.666-0.812) and 0.882 (95% CI was 0.732-0.936), respectively, all P = 0.000; the sensitivity of its prediction accuracy were 81.59%, 78.65% and 89.26%, and the specificity were 78.62%, 57.12% and 75.54%, respectively. Conclusions:The GRACE and the modified CADILLAC scores have predictive value for the short-term mortality risk of STEMI patients after PCI, and the modified CADILLAC score is more accurate. But the TIMI score has a poor predictive effect on the short-term mortality risk of STEMI patients after PCI.