Although symptomatic treatment is widely applied in clinical practice， it is often regarded as a relatively low-level therapeutic method. Based on Traditional Chinese Medicine （TCM） state theory， the macroscopic， mesoscopic， and microscopic characterization parameters of TCM symptomatology are horizontally integrated， the full life cycle of states （pre-disease， incipient disease， manifest disease， post-disease） is vertically covered， and the cognitive system of "symptoms" is reconstructed from multiple dimensions. Accordingly， the application approach of symptomatic treatment at different state stages is proposed： implementing preventive intervention in the pre-disease state， strengthening the interception of disease progression in the incipient disease state， regulating dynamic development and treatment in the manifest disease state， and formulating a staged diagnosis and treatment strategy which focuses on functional rehabilitation in the post-disease state.

OBJECTIVES: The purinergic receptor P2X2 (P2RX2) encodes an ATP-gated ion channel permeable to Na⁺, K⁺, and especially Ca²⁺. Loss-of-function mutations in P2RX2 are known to cause autosomal dominant nonsyndromic deafness 41 (DFNA41), which manifests as high-frequency hearing loss, accelerated presbycusis, and increased susceptibility to noise-induced damage. Zebrafish, owing to their small size, rapid development, high fecundity, transparent embryos, and high gene conservation with humans, provide an ideal model for studying human diseases and developmental mechanisms. This study aims to generate a p2rx2 knockout zebrafish model using CRISPR/Cas9 gene editing system to investigate the effect of p2rx2 deficiency on the auditory system, providing a basis for understanding P2RX2-related hearing loss and developing gene therapy strategies. METHODS: Two CRISPR targets (sgRNA1 and sgRNA2) spaced 47 bp apart were designed within the zebrafish p2rx2 gene. Synthesized sgRNAs and Cas9 protein were microinjected into single-cell stage Tübingen (TU)-strain zebrafish embryos. PCR and gel electrophoresis verified editing efficiency at 36 hours post-fertilization (hpf). Surviving embryos were raised to adulthood (F0), tail-clipped, genotyped, and screened for positive mosaics. F1 heterozygotes were generated by outcrossing, and F2 homozygous mutants were obtained by intercrossing. Polymerase chain reaction (PCR) combined with sequencing verified mutation type and heritability. At 5 days post-fertilization (dpf), YO-PRO-1 staining was used to examine hair cell morphology and count in lateral line neuromasts and the otolith region. Auditory evoked potential (AEP) thresholds at 600, 800, 1 000, and 2 000 Hz were measured in nine 4-month-old wild type and mutant zebrafish per group. RESULTS: A stable p2rx2 knockout zebrafish line was successfully established. Sequencing revealed a 66 bp insertion at the first target site introducing a premature stop codon (TAA), leading to early termination of protein translation and loss of function. Embryos developed normally with no gross malformations. At 5 dpf, mutants exhibited significantly reduced hair cell density in the otolith region compared with wild type, although lateral line neuromasts were unaffected. AEP testing showed significantly elevated auditory thresholds at all 4 frequencies in homozygous mutants compared with wild type (all P<0.001), indicating reduced hearing sensitivity. CONCLUSIONS We successfully generated a p2rx2 loss-of-function zebrafish model using CRISPR/Cas9 technology. p2rx2 deficiency caused hair cell defects in the otolith region and increased auditory thresholds across frequencies, indicating its key role in maintaining zebrafish auditory hair cell function and hearing perception. The phenotype's restriction to the otolith region suggests tissue-specific roles of p2rx2 in sensory organs. This model provides a valuable tool for elucidating the molecular mechanisms of P2RX2-related hearing loss and for screening otoprotective drugs and developing gene therapies.
Animals ; Zebrafish/genetics* ; Receptors, Purinergic P2X2/deficiency* ; CRISPR-Cas Systems/genetics* ; Gene Knockout Techniques ; Phenotype ; Zebrafish Proteins/genetics* ; Disease Models, Animal

Objective:To investigate the clinical diagnosis and treatment of IgG4-related disease（IgG4-RD） primarily involving the nasal cavity and skull base. Methods:A retrospective analysis was conducted on the clinical data of 8 patients with IgG4-RD primarily involving the nasal cavity and skull base who visited the Nasal and Skull Base Surgery Department at Xiangya Hospital from October 2017 to January 2024. The cohort comprised 4 males and 4 females, aged 8 to 69 years. Clinical data, laboratory examination results, imaging findings, histopathological results, and treatment plans were collected. The clinical manifestations, diagnosis, treatment and follow-up results of IgG4-RD primarily involving nasal cavity and skull base were summarized and previous literature were also reviewed. Results:The initial symptoms in the 8 patients included nasal congestion, headache, sensory function decline, and facial deformities. Three patients also had parotid and pulmonary involvement. Among the 8 patients, 4 underwent partial surgical resection combined with glucocorticoid therapy; 1 underwent partial surgical resection combined with glucocorticoid and immunosuppressant therapy; 1 received glucocorticoid therapy alone; and 2 received glucocorticoid combined with immunosuppressant therapy. Follow-up was conducted one month after treatment, lasting from 5 to 79 months. During the follow-up period, recurrence was observed in 1 patient treated with glucocorticoid combined with immunosuppressants and in 1 patient treated with glucocorticoid alone, while the other 6 patients achieved significant remission. Conclusion:The diagnosis of nasal cavity and skull base IgG4-RD requires the combination of histopathology, laboratory tests, and imaging results. Treatment primarily includes glucocorticoids or combined immunosuppressants. For patients with significant compression symptoms, sensory function impairment, or facial deformities, surgical resection is an important treatment option. Given the high risk of recurrence, early intervention, active treatment, and long-term follow-up are crucial.
Humans ; Male ; Skull Base/pathology* ; Female ; Middle Aged ; Retrospective Studies ; Aged ; Nasal Cavity/pathology* ; Adult ; Immunoglobulin G4-Related Disease/therapy* ; Immunoglobulin G ; Child ; Young Adult ; Adolescent

Drug resistance is one of the key factors affecting the effectiveness of cancer treatment methods, including chemotherapy, radiotherapy, and immunotherapy. Its occurrence is related to factors such as mRNA expression and methylation within cancer cells. If drug resistance in patients can be accurately identified early, doctors can devise more effective treatment plans, which is of great significance for improving patients' survival rates and quality of life. Cancer drug resistance prediction based on artificial intelligence (AI) technology has emerged as a current research hotspot, demonstrating promising application prospects in guiding clinical individualized and precise medication for cancer patients. This review aims to comprehensively summarize the research progress in utilizing AI algorithms to analyze multi-omics data including genomics, transcriptomics, epigenomics, proteomics, metabolomics, radiomics, and histopathology, for predicting cancer drug resistance. It provides a detailed exposition of the processes involved in data processing and model construction, examines the current challenges faced in this field and future development directions, with the aim of better advancing the progress of precision medicine.

Acute lung injury (ALI) has been a kind of acute and severe disease that is mainly characterized by systemic uncontrolled inflammatory response to the production of huge amounts of reactive oxygen species (ROS) in the lung tissue. Given the critical role of ROS in ALI, a Fe₃O₄ loaded bovine serum albumin (BSA) nanocluster (BF) was developed to act as a nanomedicine for the treatment of ALI. Combining with NIR irradiation, it exhibited excellent ROS scavenging capacity. Significantly, it also displayed the excellent antioxidant and anti-inflammatory functions for lipopolysaccharides (LPS) induced macrophages (RAW264.7), and Sprague Dawley rats via lowering intracellular ROS levels, reducing inflammatory factors expression levels, inducing macrophage M2 polarization, inhibiting NF-κB signaling pathway, increasing CD4⁺/CD8⁺ T cell ratios, as well as upregulating HSP70 and CD31 expression levels to reprogram redox homeostasis, reduce systemic inflammation, activate immunoregulation, and accelerate lung tissue repair, finally achieving the synergistic enhancement of ALI immunotherapy. It finally provides an effective therapeutic strategy of BF + NIR for the management of inflammation related diseases.

OBJECTIVES: Diabetes mellitus is closely associated with sudden sensorineural hearing loss (SSNHL), but no definitive evidence has established a causal relationship between type 1 diabetes mellitus (T1DM) and SSNHL. This study aims to investigate the impact of T1DM on SSNHL from a genetic perspective, providing insights for risk prediction and treatment strategies. METHODS: Genetic data related to exposure (T1DM) and outcome (SSNHL) were obtained from publicly available genome-wide association studies (GWAS). Instrumental variables were selected, and Mendelian randomization (MR) analysis was conducted to explore the causal association between T1DM and SSNHL. Inverse variance weighted (IVW) analysis was used as the primary method, with random-effects IVW serving as the main analytical approach. MR-Egger, weighted median, simple mode, and weighted mode analyses were utilized as supplementary methods. Cochran's Q test was applied to evaluate the heterogeneity of the selected instrumental variables, MR-PRESSO was applied to detect outliers, MR-Egger regression was used to assess horizontal pleiotropy and leave-one-out analysis was conducted to examine the robustness of individual single nucleotide polymorphisms (SNPs) on the overall results. RESULTS: A total of 127 SNPs were selected as instrumental variables for the MR analysis. IVW analysis demonstrated a genetically determined association between T1DM and SSNHL (OR=1.036, 95% CI 1.002 to 1.071, P=0.038). Forest plots and scatter plots indicated a causal relationship, suggesting that T1DM increases the risk of SSNHL. Cochran's Q test demonstrated no significant heterogeneity among SNPs (MR-Egger: Q=126.030, P=0.356; IVW: Q=126.450, P=0.373). The funnel plot appeared symmetrical, indicating that the selected instrumental variables were primarily related to exposure rather than potential confounding factors. The MR-Egger intercept was not significantly different from zero (P=0.527), indicating no evidence of horizontal pleiotropy among the SNPs. MR-PRESSO analysis did not identify any outlier SNPs (P=0.356). Leave-one-out analysis confirmed the robustness of the findings, as the results remained stable after removing individual SNPs. CONCLUSIONS Two-sample MR analysis supports the conclusion that T1DM patients have an increased risk of developing SSNHL.
Humans ; Mendelian Randomization Analysis ; Hearing Loss, Sensorineural/etiology* ; Diabetes Mellitus, Type 1/genetics* ; Genome-Wide Association Study ; Hearing Loss, Sudden/etiology* ; Polymorphism, Single Nucleotide ; Risk Factors ; Genetic Predisposition to Disease

OBJECTIVES: This study investigated the seasonal impact of diurnal temperature range (DTR) on hospitalization rates for intracerebral hemorrhage (ICH) in middle-aged and elderly adults. METHODS: We collected data on the DTR and hospitalization records of ≥45-year-old patients with ICH in 2019 in Hunan Province, central China. Time-series analyses were performed using a distributed lag non-linear model. RESULTS: Overall, 54,690 hospitalizations for ICH were recorded. DTR showed a non-linear relationship with ICH hospitalization in both middle-aged and elderly populations (45-59 and ≥60 years, respectively). During spring, a low DTR coupled with persistently low temperatures increased ICH risk in both age groups, while a high DTR was associated with an increased risk in the middle-aged group only (relative risk [RR], 1.24; 95% confidence interval [CI], 1.21 to 1.27). In the summer, a low DTR combined with persistently high temperatures was linked to a higher risk exclusively in the middle-aged group. A high DTR in the autumn was correlated with increased risk in both age groups. In winter, either a low DTR with a continuously low temperature or a high DTR elevated the risk solely in the elderly population (RR, 1.37; 95% CI, 1.00 to 1.69). In the elderly group, the impact of DTR on hospitalization risk manifested within a 5-day period. CONCLUSIONS The impact of DTR on ICH hospitalization risk differed significantly across seasons and between age groups. Elderly individuals demonstrated greater sensitivity to the impact of DTR. Weather forecasting services should emphasize DTR values, and interventions targeting sensitive populations are needed.

Humans ; Nutrition Assessment ; Prognosis ; Silicosis/prevention & control* ; Occupational Diseases ; China/epidemiology* ; Occupational Exposure ; Silicon Dioxide

Mitral valve replacement is one of the most common heart valve surgeries in China. In recent years, with the increase in degenerative valve diseases, older patients, and the progress of anti-calcification technology of biological valves, the proportion of mitral valve biological valve replacement has been increasing year by year. After the damage of traditional mitral valve biological valves, re-operation of valve replacement with thoracotomy is required. However, the adhesion between the heart and sternum, as well as the damage caused by cardiopulmonary bypass and cardiac arrest, can cause significant trauma to elderly patients and those with multiple organ dysfunction, leading to increased mortality and complication rates. In recent years, interventional valve surgery, especially transcatheter valve-in-valve surgery, has developed rapidly. This procedure can correct the damaged mitral valve function without stopping the heart, but there are still many differences between its technical process and conventional aortic valve replacement surgery. Therefore, organizing and writing multicenter expert recommendations on the technical process of transcatheter valve-in-valve surgery for damaged mitral valve biological valves is of great significance for the training and promotion of this technology.

ObjectiveTo explore the possible mechanism of moxibustion at "Feishu （BL13）" and "Tianshu （ST25）" in treatment of bronchial asthma. MethodsA total of 48 SD rats were randomly divided into normal group （n=12） and modeling group （n=36）. The bronchial asthma rat model was established by sensitization with ovalbumin （OVA） injection and aerosol provocation. Thirty-two successfully modeled rats were further randomly divided into four groups including model group， Feishu group， Tianshu group， and Feishu-Tianshu group， with 8 rats in each group. Rats in the normal group and the model group were tied and fixed without intervention， while those in the Feishu group received moxibustion at bilateral of "Feishu （BL13）" for 30 minutes； rats in the Tianshu group received moxibustion at bilateral "Tianshu （ST25）" for 30 minutes， and those in the Feishu-Tianshu group received moxibustion at both "Feishu （BL13）" and "Tianshu （ST25）" bilaterally for 15 minutes each. One hour after the intervention， 1% OVA solution was aerosolized for 20 minutes in all groups except the normal group， which was given the same volume of 0.9% sodium chloride solution instead of OVA solution for aerosol stimulation. The above interventions were performed once daily for 14 days. Behavioral observations were performed after modeling and during the interventions. The samples were collected 24h after the last intervention. HE and Masson staining were used to observe pathological morphological changes of lung tissues， and the percentage of collagen fiber deposition area was counted. The levels of leukocyte differentiation antigen11b （CD11b）， leukocyte differentiation antigen 40 （CD40）， leukocyte differentiation antigen 86 （CD86）， and programmed death ligand 2 （PD-L2） in serum， as well as the expression of interleukin-8 （IL-8）， interleukin-11 （IL-11）， interleukin-27 （IL-27） in lung tissue， were detected by enzyme-linked immunosorbent assay （ELISA）. Western blot was used to detect the expression of matrix metalloproteinase-9 （MMP-9）， matrix metalloproteinase inhibitor 1 （TIMP-1） and transforming growth factor β （TGF-β） proteins in lung tissue. The content of six short-chain fatty acids （SCFAs） including acetic acid， propionic acid， isobutyric acid， butyric acid， valeric acid， and hexanoic acid in feces was detected by gas chromatography-mass spectrometry. ResultsCompared to the normal group， the rats in the model group gradually showed mental depression or restlessness， dull hair， slow activity， reduced food intake， unformed stool， accompanied by symptoms of shortness of breath and wheezing. The pathological results showed severe abnormalities in lung tissue structure in the model group， including extensive infiltration of inflammatory cells around the bronchi， thickening of the airway smooth muscle layer， and substantial deposition of collagen fibers. Significant increases were observed in the levels of serum CD11b， CD40， CD86， and PD-L2， levels of IL-8， IL-11， and IL-27 in the lung tissue， as well as protein expression levels of MMP-9， TGF-β， and TIMP-1 in lung tissue， while the fecal levels of acetic acid， propionic acid， isobutyric acid， butyric acid， valeric acid， and n-caproic acid significantly decreased （P＜0.05 or P＜0.01）. Compared to those in the model group， the spirit， hair， activity， drinking and eating condition， shortness of breath， and wheezing symptoms of rats in the Feishu group， Tianshu group， and Feishu-Tianshu group were improved； the stool was basically formed， and the pathological morphology of lung tissue were improved； the levels of serum CD11b， CD40， CD86 and PD-L2， the levels of IL-8 and IL-27 in the lung tissue， the percentage of collagen fiber deposition area， and the TGF-β protein expression notably decreased； content of IL-11 and MMP-9 in the lung tissue and protein expression of T1MP-1 in Feishu group and Feishu-tianshu group significantly decreased； content of six SCFAs in the Feishu-Tianshu group increased （P＜0.05 or P＜0.01）. Compared to those in the Feishu group， the percentage of collagen fiber deposition area and TIMP-1 protein expression in lung tissue in the Feishu-Tianshu group significantly decreased， while the fecal levels of acetic acid and butyric acid notably increased （P＜0.05 or P＜0.01）. Compared to those in the Tianshu group， the serum level of CD40 in the Feishu-Tianshu group was significantly reduced， and the percentage of collagen fiber deposition area， the content of IL-11， and the protein expressions of MMP-9， TGF-β and TIMP-1 in the lung tissue notably decreased， while the fecal levels of acetic acid， propionic acid， and butyric acid significantly increased （P＜0.05 or P＜0.01）. ConclusionMoxibustion at "Feishu （BL13）" and "Tianshu （ST25）" exhibits a favorable therapeutic effect on airway remodeling in bronchial asthma rats， and the combined application of "Feishu （BL13）" and "Tianshu （ST25）" acupoints demonstrates a synergistic effect. The mechanism may be related to the regulation of intestinal SCFAs content， influencing the differentiation of immune cells， and reducing airway inflammation.