Hypoxic-ischemic brain damage (HIBD) is one of the main causes of disability in middle-aged and elderly people, as well as high mortality rates and long-term physical impairments in newborns. The pathological manifestations of HIBD include neuronal damage and loss of myelin sheaths. Tau protein is an important microtubule-associated protein in brain, exists in neurons and oligodendrocytes, and regulates various cellular activities such as cell differentiation and maturation, axonal transport, and maintenance of cellular cytoskeleton structure. Phosphorylation is a common chemical modification of Tau. In physiological condition, it maintains normal cell cytoskeleton and biological functions by regulating Tau structure and function. In pathological conditions, it leads to abnormal Tau phosphorylation and influences its structure and functions, resulting in Tauopathies. Studies have shown that brain hypoxia-ischemia could cause abnormal alteration in Tau phosphorylation, then participating in the pathological process of HIBD. Meanwhile, brain hypoxia-ischemia can induce oxidative stress and inflammation, and multiple Tau protein kinases are activated and involved in Tau abnormal phosphorylation. Therefore, exploring specific molecular mechanisms by which HIBD activates Tau protein kinases, and elucidating their relationship with abnormal Tau phosphorylation are crucial for future researches on HIBD related treatments. This review aims to focus on the mechanisms of the role of Tau phosphorylation in HIBD, and the potential relationships between Tau protein kinases and Tau phosphorylation, providing a basis for intervention and treatment of HIBD.
Humans ; tau Proteins/physiology* ; Phosphorylation ; Hypoxia-Ischemia, Brain/physiopathology* ; Animals ; Oxidative Stress

OBJECTIVE: To explore clinical effect of bone cement-strengthened pedicle screw technique in the correction of stage Ⅲ asymptomatic Kümmell disease with kyphosis. METHODS: A retrospective analysis was conducted on clinical data of 40 asymptomatic stage Ⅲ Kümmell disease patients admitted between March 2019 and December 2021, including 15 males and 25 females, aged from 61 to 81 years old with an average of (67.4±5.2) years old;according to different surgical methods, they were divided into percutaneous kyphoplasty group (PKP) and reinforced screw group. There were 18 patients in PKP group, including 7 males and 11 females, aged from 61 to 78 years old with an average of (66.2±5.5) years old;the courses of disease ranged from 5 to 12 months with an average of (7.33±1.78) months;bone mineral density(BMD) T values ranged from -2.45 to -4.00 with an average of (-3.08±0.46);2 patients with T₈-T₉, 10 patients with T₁₀-T₁₂, and 6 patients with L₁-L₂;treated with PKP. There were 22 patients in reinforced screw group, including 8 males and 14 females, aged from 65 to 81 years old with an average of (68.5±3.8) years old;the courses of disease ranged from 4 to 15 months with an average of (7.86±2.73)months;bone mineral density(BMD) T values ranged from -2.40 to -4.50 with an average of (-3.18±0.54);3 patients with T₈-T₉, 12 patients with T₁₀-T₁₂, and 7 patients with L₁-L₂;treated with bone cement reinforced pedicle screw internal fixation combined with kyphoplasty. Cobb angle and anterior margin height of the injured vertebra were compared before operation, 3 d and 12 months after operation. Visual analogue scale (VAS) and Oswestry disability index (ODI) were compared between two groups before operation and 12 months after operation. The incidence of postoperative complications was compared between two groups. RESULTS: All patients were followed up, PKP group followed up for 11 to 14 months with an average of (11.97±0.96) months and 10 to 14 months with an average of (12.05±1.09) months in reinforced screw group;there was no significant difference between two groups (P>0.05). Postoperative Cobb angle at 3 days and 12 months in reinforced screw group were (7.34±2.26) ° and (18.86±1.96) °, while in PKP group were (18.88±1.89) ° and (23.28±1.90) °;there were statistical difference between two groups (P<0.05). The anterior margin height of the injured vertebra in reinforced screw group were (25.28±1.33) mm and (19.62±2.22) mm at 3 days and 12 months after operation, while in PKP group were (18.61±2.16) mm and(15.93±1.34) mm;there were statistical difference between two groups (P<0.05). Cobb angle and the anterior margin height of the injured vertebra were significantly improved at 3 days and 12 months after operation between two groups (P<0.05). Postoperative VAS and ODI at 12 months in PKP group were (2.00±0.69) score and (13.44±4.02)%, while in reinforced screw group were(1.91±0.61) score and (10.18±4.26)%;which were significantly lower than (6.89±0.76) score and (36.33±3.40)% in PKP group, (7.23±0.75) score and (37.09±3.73) % in reinforced screw group before operation. There were no difference in postoperative VAS between two groups at 12 months (P>0.05);postoperative ODI in reinforced screw group at 12 months was lower than that in PKP group(P<0.05). There was no significant difference in complications between two groups (χ²=0.071, P>0.05). CONCLUSION PKP and bone cement reinforced nail combined with PKP could improve kyphotic deformity and postoperative function, and relieve pain. The application of bone cement-reinforced nail fixation technology could provide a more stable support, more obvious functional recovery, lower the risk of re-collapse of the injured vertebra, and maintain the long-term stability of spine.
Humans ; Male ; Female ; Aged, 80 and over ; Kyphosis/surgery* ; Aged ; Bone Cements ; Middle Aged ; Retrospective Studies ; Pedicle Screws ; Spinal Fractures/surgery* ; Fracture Fixation, Internal/methods* ; Bone Screws ; Kyphoplasty

OBJECTIVES: To investigate the clinical features of children with STAT gene mutations, and to explore corresponding immunotherapy strategies. METHODS: A retrospective analysis was performed for the clinical data of 10 children with STAT gene mutations who were admitted to the Department of Pediatrics of the First Affiliated Hospital of Guangzhou Medical University, from October 2015 to October 2024. Exploratory immunotherapy was implemented in some refractory cases, and the changes in symptoms, imaging manifestations, and cytokine levels were assessed after treatment. RESULTS: For the 10 children, the main clinical manifestations were recurrent rash since birth (7/10), cough (8/10), wheezing (5/10), expectoration (4/10), and purulent nasal discharge (4/10). Genotyping results showed that there was one child with heterozygous loss-of-function (LOF) mutation in the STAT1 gene, four children with heterozygous LOF mutation in the STAT3 gene, and five children with heterozygous gain-of-function (GOF) mutation in the STAT3 gene. Two children with LOF mutation in the STAT3 gene showed decreased interleukin-6 levels and improved clinical symptoms and imaging findings after omalizumab treatment. Three children with GOF mutation in the STAT3 gene achieved effective disease control after treatment with methylprednisolone (0.5 mg/kg per day). Two children with GOF mutation in the STAT3 gene received treatment with JAK inhibitor and then showed some improvement in symptoms. CONCLUSIONS STAT gene mutation screening should be considered for children with recurrent rash and purulent respiratory tract infections. Targeted immunotherapy may improve prognosis in patients with no response to conventional treatment.
Humans ; Male ; Immunotherapy ; Female ; Child, Preschool ; Child ; Gain of Function Mutation ; Retrospective Studies ; Infant ; Loss of Function Mutation ; STAT Transcription Factors/genetics*

OBJECTIVE: To identify the underlying mechanism by which quercetin (Que) alleviates sepsis-related acute respiratory distress syndrome (ARDS). METHODS: In vivo, C57BL/6 mice were assigned to sham, cecal ligation and puncture (CLP), and CLP+Que (50 mg/kg) groups (n=15 per group) by using a random number table. The sepsisrelated ARDS mouse model was established using the CLP method. In vitro, the murine alveolar macrophages (MH-S) cells were classified into control, lipopolysaccharide (LPS), LPS+Que (10 μmol/L), and LPS+Que+acetylcysteine (NAC, 5 mmol/L) groups. The effect of Que on oxidative stress, inflammation, and apoptosis in mice lungs and MH-S cells was determined, and the mechanism with reactive oxygen species (ROS)/p38 mitogen-activated protein kinase (MAPK) pathway was also explored both in vivo and in vitro. RESULTS: Que alleviated lung injury in mice, as reflected by a reversal of pulmonary histopathologic changes as well as a reduction in lung wet/dry weight ratio and neutrophil infiltration (P<0.05 or P<0.01). Additionally, Que improved the survival rate and relieved gas exchange impairment in mice (P<0.01). Que treatment also remarkedly reduced malondialdehyde formation, superoxide dismutase and catalase depletion, and cell apoptosis both in vivo and in vitro (P<0.05 or P<0.01). Moreover, Que treatment diminished the release of inflammatory factors interleukin (IL)-1β, tumor necrosis factor-α, and IL-6 both in vivo and in vitro (P<0.05 or P<0.01). Mechanistic investigation clarifified that Que administration led to a decline in the phosphorylation of p38 MAPK in addition to the suppression of ROS expression (P<0.01). Furthermore, in LPS-induced MH-S cells, ROS inhibitor NAC further inhibited ROS/p38 MAPK pathway, as well as oxidative stress, inflammation, and cell apoptosis on the basis of Que treatment (P<0.05 or P<0.01). CONCLUSION Que was found to exert anti-oxidative, anti-inflammatory, and anti-apoptotic effects by suppressing the ROS/p38 MAPK pathway, thereby conferring protection for mice against sepsis-related ARDS.
Animals ; Sepsis/drug therapy* ; Quercetin/therapeutic use* ; Respiratory Distress Syndrome/enzymology* ; p38 Mitogen-Activated Protein Kinases/metabolism* ; Mice, Inbred C57BL ; Reactive Oxygen Species/metabolism* ; Apoptosis/drug effects* ; Male ; Oxidative Stress/drug effects* ; MAP Kinase Signaling System/drug effects* ; Lung/drug effects* ; Mice ; Lipopolysaccharides ; Macrophages, Alveolar/pathology* ; Inflammation/pathology* ; Protective Agents/therapeutic use*

Ischemic stroke (IS) is a globally life-threatening disease. Presently, few therapeutic medicines are available for treating IS, and rt-PA is the only drug approved by the US Food and Drug Administration (FDA) in the US. In fact, many agents showing excellent neuroprotection but no blood flow-improving activity in animals have not achieved ideal clinical efficacy, while thrombolytic drugs only improving blood flow without neuroprotection have limited their wider application. To address these challenges and meet the huge unmet clinical need, we have designed and identified a novel compound AAPB with dual effects of neuroprotection and cerebral blood flow improvement. AAPB significantly reduced cerebral infarction and neural function deficit in tMCAO rats, pMCAO rats, and IS rhesus monkeys, as well as displayed exceptional safety profiles and excellent pharmacokinetic properties in rats and dogs. AAPB has now entered phase I of clinical trials fighting IS in China.

The tumor microenvironment is a crucial factor in tumor occurrence and progression. The hypoxic microenvironment is widely present in tumor tissue and is a key endogenous factor accelerating tumor deterioration. The "blood stasis toxin" theory, as an emerging perspective in tumor research, is regarded as the unique "soil" in tumor progression from the perspective of traditional Chinese medicine(TCM) due to its dynamic evolution mechanism, which closely resembles the formation of the hypoxic microenvironment. Scientifically integrating TCM theories with the biological characteristics of tumors and exploring precise syndrome differentiation and treatment strategies are key to achieving comprehensive tumor prevention and control. This article focused on the hypoxic microenvironment of the tumor, elucidating its formation mechanisms and evolutionary processes and carefully analyzing the internal relationship between the "blood stasis toxin" theory and the hypoxic microenvironment. Additionally, it explored the interaction among blood stasis, toxic pathogens, and hypoxic environment and proposed micro-level prevention and treatment strategies targeting the hypoxic microenvironment based on the "blood stasis toxin" theory, aiming to provide TCM-based theoretical support and therapeutic approaches for precise regulation of the hypoxic microenvironment.
Humans ; Tumor Microenvironment/drug effects* ; Neoplasms/therapy* ; Animals ; Medicine, Chinese Traditional ; Disease Progression ; Drugs, Chinese Herbal

Cardiotocography (CTG) is a non-invasive and important tool for diagnosing fetal distress during pregnancy. To meet the needs of intelligent fetal heart monitoring based on deep learning, this paper proposes a TWD-MOAL deep active learning algorithm based on the three-way decision (TWD) theory and multi-objective optimization Active Learning (MOAL). During the training process of a convolutional neural network (CNN) classification model, the algorithm incorporates the TWD theory to select high-confidence samples as pseudo-labeled samples in a fine-grained batch processing mode, meanwhile low-confidence samples annotated by obstetrics experts were also considered. The TWD-MOAL algorithm proposed in this paper was validated on a dataset of 16 355 prenatal CTG records collected by our group. Experimental results showed that the algorithm proposed in this paper achieved an accuracy of 80.63% using only 40% of the labeled samples, and in terms of various indicators, it performed better than the existing active learning algorithms under other frameworks. The study has shown that the intelligent fetal heart monitoring model based on TWD-MOAL proposed in this paper is reasonable and feasible. The algorithm significantly reduces the time and cost of labeling by obstetric experts and effectively solves the problem of data imbalance in CTG signal data in clinic, which is of great significance for assisting obstetrician in interpretations CTG signals and realizing intelligence fetal monitoring.
Humans ; Pregnancy ; Female ; Cardiotocography/methods* ; Deep Learning ; Neural Networks, Computer ; Algorithms ; Fetal Monitoring/methods* ; Heart Rate, Fetal ; Fetal Distress/diagnosis* ; Fetal Heart/physiology*

Objective::Pulmonary hypertension secondary to left heart failure is associated with an abnormal response to exercise and poor prognosis. The objective of this study is to develop an algorithm by using data from cardiopulmonary exercise testing (CPET) to assess the severity of pulmonary hemodynamics and predict clinical worsening and mortality in patients with heart failure.Methods::From April 2017 to December 2018, a total of 102 patients with heart failure who underwent CPET and invasive right heart catheterization participated in this prospective study. All enrolled patients had their clinical characteristics, hemodynamic parameters, and CPET results. Based on the CPET data namely peak oxygen uptake, the minute ventilation/carbon dioxide production slope, resting end-tidal carbon dioxide, oxygen uptake/work rate flattening, exercise oscillatory ventilation, and oxygen uptake efficiency slope, a Heart Failure Cardiopulmonary Exercise (HFCE) score was developed. The total score was then calculated to categorize patients into 3 groups: low score (0-3) ( n = 31), intermediate score (4-7) ( n = 45), and high score (8-14) ( n = 26). Clinical events were defined as all-cause death and rehospitalization for heart failure, which were recorded and tracked for at least 12 months. Pearson’s correlation coefficients were calculated to assess the relationship between the HFCE score and hemodynamic parameters, 6-minute walk distance, and N-terminal-pro hormone brain natriuretic peptide. Cox proportional hazards regression analysis was used to identify independent predictors of clinical events. Survival curves for clinical events were generated using the Kaplan-Meier method and compared among the 3 groups with different HFCE scores with a log-rank test. Results::The high HFCE score group had a higher prevalence of New York Heart Association class Ⅲ-Ⅳ (high score vs. intermediate score vs. low score: 85% (22/26) vs. 56% (25/45) vs. 45% (14/31), P = 0.008), higher N-terminal-pro hormone brain natriuretic peptide levels (high score vs. intermediate score vs. low score: (3,039 ± 2,171) ng/L vs. (2,039 ± 2,353) ng/L vs. (1,438 ± 947) ng/L, P = 0.035), lower 6-minute walk distance (high score vs. intermediate score vs. low score: (312 ± 79) m vs. (362 ± 84) m vs. (363 ± 76) m, P = 0.042) compared to intermediate score or low score. The high HFCE score correlated well with high levels of pulmonary vascular resistance ( r = 0.539, P < 0.01), pulmonary artery wedge pressure ( r = 0.292, P < 0.01), and mean pulmonary artery pressure ( r = 0.474, P < 0.01), as well as low levels of cardiac output ( r = -0.357, P < 0.01). Moreover, 46 patients developed composed clinical events at 12 months. In the multivariate model, the HFCE score was an independent predictor of composed clinical events (hazard ratio = 1.142, 95% confidence interval: 1.041-1.253, P = 0.005). Kaplan-Meier analysis showed a significantly higher probability of composed clinical events in patients with a higher HFCE score ( P log-rank = 0.004). Conclusion::The HFCE score—obtained through CPET—provides valuable prognostic information by indicating the severity of hemodynamics in patients with pulmonary hypertension secondary to left heart failure. It can likely serve as a reliable predictor for clinical worsening and mortality.

Objective::Pulmonary hypertension secondary to left heart failure is associated with an abnormal response to exercise and poor prognosis. The objective of this study is to develop an algorithm by using data from cardiopulmonary exercise testing (CPET) to assess the severity of pulmonary hemodynamics and predict clinical worsening and mortality in patients with heart failure.Methods::From April 2017 to December 2018, a total of 102 patients with heart failure who underwent CPET and invasive right heart catheterization participated in this prospective study. All enrolled patients had their clinical characteristics, hemodynamic parameters, and CPET results. Based on the CPET data namely peak oxygen uptake, the minute ventilation/carbon dioxide production slope, resting end-tidal carbon dioxide, oxygen uptake/work rate flattening, exercise oscillatory ventilation, and oxygen uptake efficiency slope, a Heart Failure Cardiopulmonary Exercise (HFCE) score was developed. The total score was then calculated to categorize patients into 3 groups: low score (0-3) ( n = 31), intermediate score (4-7) ( n = 45), and high score (8-14) ( n = 26). Clinical events were defined as all-cause death and rehospitalization for heart failure, which were recorded and tracked for at least 12 months. Pearson’s correlation coefficients were calculated to assess the relationship between the HFCE score and hemodynamic parameters, 6-minute walk distance, and N-terminal-pro hormone brain natriuretic peptide. Cox proportional hazards regression analysis was used to identify independent predictors of clinical events. Survival curves for clinical events were generated using the Kaplan-Meier method and compared among the 3 groups with different HFCE scores with a log-rank test. Results::The high HFCE score group had a higher prevalence of New York Heart Association class Ⅲ-Ⅳ (high score vs. intermediate score vs. low score: 85% (22/26) vs. 56% (25/45) vs. 45% (14/31), P = 0.008), higher N-terminal-pro hormone brain natriuretic peptide levels (high score vs. intermediate score vs. low score: (3,039 ± 2,171) ng/L vs. (2,039 ± 2,353) ng/L vs. (1,438 ± 947) ng/L, P = 0.035), lower 6-minute walk distance (high score vs. intermediate score vs. low score: (312 ± 79) m vs. (362 ± 84) m vs. (363 ± 76) m, P = 0.042) compared to intermediate score or low score. The high HFCE score correlated well with high levels of pulmonary vascular resistance ( r = 0.539, P < 0.01), pulmonary artery wedge pressure ( r = 0.292, P < 0.01), and mean pulmonary artery pressure ( r = 0.474, P < 0.01), as well as low levels of cardiac output ( r = -0.357, P < 0.01). Moreover, 46 patients developed composed clinical events at 12 months. In the multivariate model, the HFCE score was an independent predictor of composed clinical events (hazard ratio = 1.142, 95% confidence interval: 1.041-1.253, P = 0.005). Kaplan-Meier analysis showed a significantly higher probability of composed clinical events in patients with a higher HFCE score ( P log-rank = 0.004). Conclusion::The HFCE score—obtained through CPET—provides valuable prognostic information by indicating the severity of hemodynamics in patients with pulmonary hypertension secondary to left heart failure. It can likely serve as a reliable predictor for clinical worsening and mortality.

In-depth study of the components of polymyxins is the key to controlling the quality of this class of antibiotics. Similarities and variations of components present significant analytical challenges. A two-dimensional (2D) liquid chromatography-mass spectrometr (LC-MS) method was established for screening and comprehensive profiling of compositions of the antibiotic colistimethate sodium (CMS). A high concentration of phosphate buffer mobile phase was used in the first-dimensional LC system to get the components well separated. For efficient and high-accuracy screening of CMS, a targeted method based on a self-constructed high resolution (HR) mass spectrum database of CMS components was established. The database was built based on the commercial MassHunter Personal Compound Database and Library (PCDL) software and its accuracy of the compound matching result was verified with six known components before being applied to genuine sample screening. On this basis, the unknown peaks in the CMS chromatograms were deduced and assigned. The molecular formula, group composition, and origins of a total of 99 compounds, of which the combined area percentage accounted for more than 95% of CMS components, were deduced by this 2D-LC-MS method combined with the MassHunter PCDL. This profiling method was highly efficient and could distinguish hundreds of components within 3 h, providing reliable results for quality control of this kind of complex drugs.