ObjectiveTo make clear exercise combined with Shenghui Tang interferes in acetylcholine receptor （M1AChR） to improve mitochondrial autophagy and enhance cognition of Alzheimer's disease （AD） model rats through the adenylate activated protein kinase （AMPK）/mammalian target of rapamycin （mTOR） signaling pathway. MethodsForty-eight male SD rats of SPF grade were randomly divided into a blank group， a model group， a Shenghui Tang group （9.3 g·kg^-1）， an exercise group， an exercise + Shenghui Tang group （9.3 g·kg^-1）， and a rapamycin group （1.5 mg·kg^-1）. Except for the blank group， the rat model of AD was constructed by injecting amyloid beta （Aβ_1-42） into hippocampus stereotaxically. The exercise group received treadmill exercise for 4 weeks， while the Shenghui Tang group received intragastric administration for 4 weeks， and the exercise + Shenghui Tang group received treadmill exercise and intragastric administration of Shenghui Tang for 4 weeks simultaneously. After the intervention， the Morris water maze test was used to detect the learning and memory ability. Spontaneous behavior was observed in the open field test. The pathological structure of hippocampal neurons was observed by NISSl staining. The expression level of M1AChR in hippocampus was detected by immunohistochemistry （IHC）. The autophagy ultrastructure of hippocampal neurons was observed by transmission electron microscopy. The apoptosis rate was evaluated by terminal deoxynucleotidyl transferase dUTP nick end labeling （TUNEL）. The expression of Beclin1 and microtubule-associated protein light chain 3β （LC3β） was detected by immunofluorescence （IF）. The protein expression of M1AChR， AMPK， p-AMPK， mTOR， Beclin1， LC3β， and chelate 1 （SQSTM1/p62） in hippocampus was detected by Western blot. ResultsCompared with the blank group， the model group exhibited significantly increased platform escape latency on the fifth day （P<0.01） and significantly decreased activity distance in the target quadrant and times of crossing the platform （P<0.01）. The total movement distance in the open field， the time of movement in the central area， and the average speed obviously decreased （P<0.05）. The arrangement of nerve cells in hippocampus CA1 region was dispersed， and the numbers of Nissl bodies and M1AChR positive cells significantly decreased （P<0.01）. The expression of TUNEL positive cells was significantly increased （P<0.01）. The typical autophagic lysosomal structure decreased. The protein expression of M1AChR， p-AMPK/AMPK， p-mTOR/mTOR， Beclin1， LC3Ⅱ/Ⅰ in hippocampus was significantly decreased （P<0.01）， and the protein expression of p62 was significantly increased （P<0.01）. Compared with the model group， the exercise + Shenghui Tang group exhibited obviously improved space exploration and positioning navigation ability （P<0.05， P<0.01）. The total movement distance in the open field， the time of movement in the central area， and the average speed of movement significantly increased （P<0.01）. The number of Nissl bodies significantly increased （P<0.01）. The number of M1AChR positive cells in hippocampus was significantly increased （P<0.01）. The expression of TUNEL positive cells was significantly decreased （P<0.01）. The protein expression of M1AChR， p-AMPK/AMPK， p-mTOR/mTOR， Beclin1， LC3Ⅱ/Ⅰ in hippocampus was significantly increased （P<0.01）， while the protein expression of p62 was significantly decreased （P<0.01）. Compared with the exercise + Shenghui Tang group， the Shenghui Tang group and the exercise group showed significantly increased platform escape latency on the fifth day （P<0.01） and obviously decreased activity distance in the target quadrant and times of crossing the platform （P<0.05， P<0.01）. The total movement distance in the open field， the time of movement in the central area， and the average speed of movement significantly decreased （P<0.01）. The number of Nissl bodies and the number of M1AChR positive cells significantly decreased （P<0.01）. The expression of TUNEL positive cells was obviously increased （P<0.05）. Ultrastructure of the hippocampal region showed decreased autophagy level. The protein expression of M1AChR， p-AMPK/AMPK， p-mTOR/mTOR， LC3Ⅱ/Ⅰ in the hippocampus was obviously decreased in the Shenghui Tang group （P<0.05， P<0.01）， while the protein expression of p62 was significantly increased （P<0.01）. In the exercise group， the protein expression of M1AChR， p-AMPK/AMPK， Beclin1， and LC3Ⅱ/Ⅰ was obviously decreased （P<0.05， P<0.01）， while the protein expression of p-mTOR/mTOR and p62 was significantly increased （P<0.01）. ConclusionExercise combined with traditional Chinese medicine can enhance the expression of M1AChR in the hippocampus of AD model rats， induce autophagy through the AMPK/mTOR signaling pathway， and improve the learning and memory ability of AD rats.

Objective To investigate the regulatory mechanism of transforming growth factor-β1 (TGF-β1) in different types of mitral valvular disease (MVD) with atrial fibrillation (AF). Methods From August 2011 to August 2012, patients with moderate to severe MVD accompanied by AF who required mitral valve replacement at the Department of Cardiovascular Surgery, West China Hospital, Sichuan University, were included. Based on echocardiographic results, patients were divided into two groups: a mitral regurgitation (MR) with AF (MR-AF) group and a mitral stenosis (MS) with AF (MS-AF) group. Left atrial tissue samples were collected during surgery. Techniques such as enzyme-linked immunosorbent assay, real-time fluorescence quantitative polymerase chain reaction, immunohistochemistry, and Western blotting were used to detect key molecules in the TGF-β1/JNK pathway. Results Sixteen patients were enrolled. There were 8 patients in the MR-AF group, including 5 males and 3 females, with an average age of (41.38±11.19) years; and 8 patients in the MS-AF group, including 6 males and 2 females, with an average age of (43.12±5.30) years. The left atrial volume load was higher in MR-AF patients, while the left atrial pressure load was higher in MS-AF patients. In MS-AF patients, the relative expression levels of MAPK9, JUN, CASP3, BAX, and BCL2 mRNA in left atrial tissues were significantly upregulated. The serum TGF-β1 protein level and the relative expression levels of p-JNK, p-c-Jun, and Caspase-3 proteins in the left atrial tissues of the MR-AF group were higher. Myocardial cell damage was more severe in the MS-AF group, and the protein expression level of Bcl-2 was higher. Conclusion Different MVD have distinct hemodynamic characteristics. The myocardium of the left atrium in MR-AF patients is more prone to apoptosis, possibly through the activation of the TGF-β1/JNK signaling pathway.

Purpose: The aim of this study was to investigate the feasibility of an intelligent handheld ultrasound (US) device for assisting non-expert general practitioners (GPs) in detecting carotid plaques (CPs) in community populations. Methods: This prospective parallel controlled trial recruited 111 consecutive community residents. All of them underwent examinations by non-expert GPs and specialist doctors using handheld US devices (setting A, setting B, and setting C). The results of setting C with specialist doctors were considered the gold standard. Carotid intima-media thickness (CIMT) and the features of CPs were measured and recorded. The diagnostic performance of GPs in distinguishing CPs was evaluated using a receiver operating characteristic curve. Inter-observer agreement was compared using the intragroup correlation coefficient (ICC). Questionnaires were completed to evaluate clinical benefits. Results: Among the 111 community residents, 80, 96, and 112 CPs were detected in settings A, B, and C, respectively. Setting B exhibited better diagnostic performance than setting A for detecting CPs (area under the curve, 0.856 vs. 0.749; P<0.01). Setting B had better consistency with setting C than setting A in CIMT measurement and the assessment of CPs (ICC, 0.731 to 0.923). Moreover, measurements in setting B required less time than the other two settings (44.59 seconds vs. 108.87 seconds vs. 126.13 seconds, both P<0.01). Conclusion Using an intelligent handheld US device, GPs can perform CP screening and achieve a diagnostic capability comparable to that of specialist doctors.

Purpose: The aim of this study was to investigate the feasibility of an intelligent handheld ultrasound (US) device for assisting non-expert general practitioners (GPs) in detecting carotid plaques (CPs) in community populations. Methods: This prospective parallel controlled trial recruited 111 consecutive community residents. All of them underwent examinations by non-expert GPs and specialist doctors using handheld US devices (setting A, setting B, and setting C). The results of setting C with specialist doctors were considered the gold standard. Carotid intima-media thickness (CIMT) and the features of CPs were measured and recorded. The diagnostic performance of GPs in distinguishing CPs was evaluated using a receiver operating characteristic curve. Inter-observer agreement was compared using the intragroup correlation coefficient (ICC). Questionnaires were completed to evaluate clinical benefits. Results: Among the 111 community residents, 80, 96, and 112 CPs were detected in settings A, B, and C, respectively. Setting B exhibited better diagnostic performance than setting A for detecting CPs (area under the curve, 0.856 vs. 0.749; P<0.01). Setting B had better consistency with setting C than setting A in CIMT measurement and the assessment of CPs (ICC, 0.731 to 0.923). Moreover, measurements in setting B required less time than the other two settings (44.59 seconds vs. 108.87 seconds vs. 126.13 seconds, both P<0.01). Conclusion Using an intelligent handheld US device, GPs can perform CP screening and achieve a diagnostic capability comparable to that of specialist doctors.

OBJECTIVE: To analyze the clinical features and laboratory characteristics of patients with cold agglutinin disease (CAD)/cold agglutinin syndrome (CAS) who were positive for acidified-serum lysis test (Ham test), and to compare them with Ham test negative CAD/CAS patients and paroxysmal nocturnal hemoglobinuria (PNH) patients, in order to provide references for the differential diagnosis of these diseases. METHODS: 53 patients diagnosed with CAD/CAS and 67 patients diagnosed with classic PNH in our hospital from January 2015 to December 2020 were retrospectively analyzed. The patients were grouped according to clinical diagnosis and results of cold agglutinin test (CAT), direct antiglobulin test (DAT), Ham test and PNH clone detection. The clinical and laboratory characteristics of each group were compared. RESULTS: The patients were grouped as follows: Ham^- CAD/CAS group, CAD/CAS patients negative for Ham test (n=36); Ham⁺ CAD/CAS group, CAD/CAS patients positive for Ham test (n=17); classic PNH group (n=67). Compared with the classic PNH group, the Ham⁺ CAD/CAS group had a higher median age (P =0.024), weaker positivity of Ham test, higher positive rates of CAT and DAT, and lower positive rate of PNH clone detection (all P <0.001). The proportions of patients with splenomegaly and cyanosis in Ham⁺ CAD/CAS group were significantly higher than those in classic PNH group (P =0.002 and P <0.001). Ham⁺ CAD/CAS group displayed lower red blood cell count (RBC) and lactate dehydrogenase (LDH) level (P =0.007 and P <0.001), and higher mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), and indirect bilirubin (IBIL) level (P =0.003, P =0.004 and P =0.006) than those in classic PNH group. The levels of serum complement C3 and C4 in Ham⁺ CAD/CAS group were lower than those in classic PNH group (P =0.001 and P <0.001). The positive rate of urinary occult blood in Ham⁺ CAD/CAS group was lower than that in classic PNH group (P =0.010). The clinical and laboratory characteristics of Ham⁺ CAD/CAS group were similar to those of Ham^- CAD/CAS group, except for median age, hemoglobin (Hb), MCHC, mean corpuscular volume (MCV), reticulocyte ratio (Ret), Ham test results, DAT positive types, and proportion of splenomegaly. CONCLUSION Some clinical features and laboratory indicators of CAD/CAS patients with positive results of Ham test are different from those of classic PNH patients, but relatively similar to those of CAD/CAS patients with negative results of Ham test. These results may provide a reference for differential diagnosis of related diseases.
Humans ; Anemia, Hemolytic, Autoimmune/blood* ; Retrospective Studies ; Hemoglobinuria, Paroxysmal/diagnosis* ; Female ; Male ; Coombs Test ; Diagnosis, Differential ; Middle Aged ; Adult

OBJECTIVE: To screen anti-tumor drugs that improve antigen processing and presentation in acute myeloid leukemia (AML) cells. METHODS: A TCR-like or TCR mimic antibody that can specifically recognize HLA-A*0201:WT1_126-134 ( RMFPNAPYL) complex (hereafter referred to as HLA-A2:WT1) was synthesized to evaluate the function of antigen processing and presentation machinery (APM) in AML cells. AML cell line THP1 was incubated with increasing concentrations of IFN-γ, hypomethylating agents (HMA), immunomodulatory drugs (IMiD), proteasome inhibitors (PI) and γ-secretase inhibitors (GSI), followed by measuring of HLA-ABC, HLA-A2 and HLA-A2:WT1 levels by flow cytometry at consecutive time points. RESULTS: The TCR-like antibody we generated only binds to HLA-A*0201⁺WT1⁺ cells, indicating the specificity of the antibody. HLA-A2:WT1 level of THP-1 cells detected with the TCR-like antibody was increased significantly after co-incubation with IFN-γ, showing that the HLA-A2:WT1 TCR like antibody could evaluate the function of APM. Among the anti-tumor agents screened in this study, GSI (LY-411575) and HMA (decitabine and azacitidine) could significantly increase the HLA-A2:WT1 level. The IMiD lenalidomide and pomalidomide could aslo upregulate the expression of HLA-A2:WT1 complex under certain concentrations of the drugs and incubation time. As proteasome inhibitors, carfilzomib could significantly decreased the expression of HLA-A2:WT1, while bortezomib had no significant effect on HLA-A2:WT1 expression. CONCLUSION HLA-A2:WT1 TCR-like antibody can effectively reflect the APM function. Some of the anti-tumor drugs can affect the APM function and immunogenicity of tumor cells.
Humans ; Leukemia, Myeloid, Acute/immunology* ; Antineoplastic Agents/pharmacology* ; Antigen Presentation/drug effects* ; HLA-A2 Antigen/immunology* ; Receptors, Antigen, T-Cell/immunology* ; Cell Line, Tumor ; Interferon-gamma

OBJECTIVE: To evaluate the efficacy and safety of Shexiang Tongxin Dropping Pill (STDP) in treating stable angina patients with phlegm-heat and blood-stasis syndrome by exercise duration and metabolic equivalents. METHODS: This multicenter, randomized, double-blind, placebo-controlled clinical trial enrolled stable angina patients with phlegm-heat and blood-stasis syndrome from 22 hospitals. They were randomized 1:1 to STDP (35 mg/pill, 6 pills per day) or placebo for 56 days. The primary outcome was the exercise duration and metabolic equivalents (METs) assessed by the standard Bruce exercise treadmill test after 56 days of treatment. The secondary outcomes included the total angina symptom score, Chinese medicine (CM) symptom scores, Seattle Angina Questionnaire (SAQ) scores, changes in ST-T on electrocardiogram and adverse events (AEs). RESULTS: This trial enrolled 309 patients, including 155 and 154 in the STDP and placebo groups, respectively. STDP significantly prolonged exercise duration with an increase of 51.0 s, compared to a decrease of 12.0 s with placebo (change rate: -11.1% vs. 3.2%, P<0.01). The increase in METs was significantly greater in the STDP group than in the placebo group (change: -0.4 vs. 0.0, change rate: -5.0% vs. 0.0%, P<0.01). The improvement of total angina symptom scores (25.0% vs. 0.0%), CM symptom scores (38.7% vs. 11.8%), reduction of nitroglycerin consumption (100.0% vs. 11.3%), and all domains of SAQ, were significantly greater with STDP than placebo (all P<0.01). The changes in Q-T intervals at 28 and 56 days from baseline were similar between the two groups (both P>0.05). Twenty-five participants (16.3%) with STDP and 16 (10.5%) with placebo experienced AEs (P=0.131), with no serious AEs observed. CONCLUSION STDP could improve exercise tolerance in patients with stable angina and phlegm-heat and blood stasis syndrome, with a favorable safety profile. (Registration No. ChiCTR-IPR-15006020).
Humans ; Double-Blind Method ; Drugs, Chinese Herbal/adverse effects* ; Male ; Female ; Middle Aged ; Angina, Stable/physiopathology* ; Aged ; Syndrome ; Treatment Outcome ; Placebos ; Tablets

Global public health faces substantial challenges from malignant tumors and infectious diseases. Vaccination provides an approach for treating and preventing these diseases. Oral vaccinations are particularly advantageous in disease treatment and prevention due to their non-invasive nature, high patient compliance, convenience, cost-effectiveness, and capacity to stimulate comprehensive and adaptive immune responses. However, the overwhelming majority of oral vaccines remain in experimental development, struggling with clinical and commercial translation due to their suboptimal efficacy. Thus, enhancing scientists' understanding of the interaction between vaccines and gastrointestinal immune system, creating antigen delivery systems suitable for the gut mucosal environment, developing more potent antigenic epitopes, and using personalized combination therapies are critical for advancing the next generation of oral vaccines. This article explores the fundamental principles and applications of current oral anti-tumor and anti-infective vaccines and discusses considerations necessary for designing future oral vaccines.

Nitrogen narcosis is a neurological syndrome that manifests when humans or animals encounter hyperbaric nitrogen, resulting in a range of motor, emotional, and cognitive abnormalities. The anterior cingulate cortex (ACC) is known for its significant involvement in regulating motivation, cognition, and action. However, its specific contribution to nitrogen narcosis-induced hyperlocomotion and the underlying mechanisms remain poorly understood. Here we report that exposure to hyperbaric nitrogen notably increased the locomotor activity of mice in a pressure-dependent manner. Concurrently, this exposure induced heightened activation among neurons in both the ACC and dorsal medial striatum (DMS). Notably, chemogenetic inhibition of ACC neurons effectively suppressed hyperlocomotion. Conversely, chemogenetic excitation lowered the hyperbaric pressure threshold required to induce hyperlocomotion. Moreover, both chemogenetic inhibition and genetic ablation of activity-dependent neurons within the ACC reduced the hyperlocomotion. Further investigation revealed that ACC neurons project to the DMS, and chemogenetic inhibition of ACC-DMS projections resulted in a reduction in hyperlocomotion. Finally, nitrogen narcosis led to an increase in local field potentials in the theta frequency band and a decrease in the alpha frequency band in both the ACC and DMS. These results collectively suggest that excitatory neurons within the ACC, along with their projections to the DMS, play a pivotal role in regulating the hyperlocomotion induced by exposure to hyperbaric nitrogen.
Animals ; Gyrus Cinguli/drug effects* ; Male ; Mice, Inbred C57BL ; Locomotion/drug effects* ; Neurons/drug effects* ; Mice ; Nitrogen/toxicity* ; Inert Gas Narcosis/physiopathology* ; Corpus Striatum/physiopathology*

Purpose: The aim of this study was to investigate the feasibility of an intelligent handheld ultrasound (US) device for assisting non-expert general practitioners (GPs) in detecting carotid plaques (CPs) in community populations. Methods: This prospective parallel controlled trial recruited 111 consecutive community residents. All of them underwent examinations by non-expert GPs and specialist doctors using handheld US devices (setting A, setting B, and setting C). The results of setting C with specialist doctors were considered the gold standard. Carotid intima-media thickness (CIMT) and the features of CPs were measured and recorded. The diagnostic performance of GPs in distinguishing CPs was evaluated using a receiver operating characteristic curve. Inter-observer agreement was compared using the intragroup correlation coefficient (ICC). Questionnaires were completed to evaluate clinical benefits. Results: Among the 111 community residents, 80, 96, and 112 CPs were detected in settings A, B, and C, respectively. Setting B exhibited better diagnostic performance than setting A for detecting CPs (area under the curve, 0.856 vs. 0.749; P<0.01). Setting B had better consistency with setting C than setting A in CIMT measurement and the assessment of CPs (ICC, 0.731 to 0.923). Moreover, measurements in setting B required less time than the other two settings (44.59 seconds vs. 108.87 seconds vs. 126.13 seconds, both P<0.01). Conclusion Using an intelligent handheld US device, GPs can perform CP screening and achieve a diagnostic capability comparable to that of specialist doctors.