BACKGROUND:Rheumatoid arthritis is influenced by complex genetic and environmental factors.Although observational studies have found some correlation between plasma proteins and rheumatoid arthritis,the susceptibility to confounding and reverse causation makes it difficult to clarify whether these proteins are pathogenic factors of rheumatoid arthritis.OBJECTIVE:To explore the potential of plasma proteins as biomarkers and therapeutic targets in rheumatoid arthritis through Mendelian randomization analysis of plasma proteins in the onset and progression of rheumatoid arthritis.METHODS:A large-scale two-sample Mendelian randomization analysis was conducted to comprehensively assess the causal relationships between 1 553 circulating proteins and rheumatoid arthritis based on the Decode database(developed by Decode Genetics in Iceland,which contains genomic data from the Icelandic population),the MR-Base platform(developed by a team of researchers at the University of Oxford in the United Kingdom,specifically designed to provide genetic and phenotypic data for Mendelian randomization analyses),and the GWAS Catalog platform(developed by the European Institute of Bioinformatics,which provides data for genome wide association studies worldwide).The causal effects were estimated using the Wald ratio and inverse variance weighting methods,with Bonferroni correction applied to control for false positives caused by multiple testing.To ensure the robustness of the results,sensitivity analyses were performed to validate the positive causal relationship between circulating proteins and rheumatoid arthritis,and Bayesian colocalization and phenome scanning were used to exclude confounding effects and horizontal pleiotropy.Additionally,external validation was carried out using new plasma protein datasets to reduce the likelihood of false discoveries.Finally,small-molecule compounds associated with candidate proteins were identified using the Drug Signatures Database(DsigDB),and molecular docking was performed to predict the binding patterns and energies between proteins and compounds,identifying the most stable and likely binding molecules and mechanisms.RESULTS AND CONCLUSION:(1)Sensitivity analyses,including Bayesian colocalization and phenome scanning,identified four plasma proteins with reliable causal relationships with rheumatoid arthritis:FCRL3,IL6R,ICOSLG,and TNFAIP3.Their genetic effects were estimated as follows:FCRL3[odds ratio(OR)=1.12,95％confidence interval(CI):1.07-1.17],IL6R(OR=0.94,95％CI:0.91-0.96),ICOSLG(OR=2.42,95％CI:1.67-3.52),and TNFAIP3(OR=2.19,95％CI:1.88-2.56).Furthermore,molecular docking analysis revealed that the small-molecule compound benzo[a]pyrene exhibited favorable binding with these candidate proteins,suggesting its potential as a therapeutic agent for rheumatoid arthritis.(2)This study provides a comprehensive analysis of the genetic causal relationships of FCRL3,IL6R,ICOSLG,and TNFAIP3 in rheumatoid arthritis.These proteins not only serve as potential molecular biomarkers for rheumatoid arthritis risk screening and disease prevention,but also offer key candidate targets for further understanding the pathogenic mechanisms of rheumatoid arthritis and developing targeted therapies.Although the study is based on European populations,its findings offer important insights for biomedical research in China.By incorporating Mendelian randomization methods to analyze genetic causality,future research on rheumatoid arthritis in the Chinese population could provide more accurate causal inferences,offering theoretical support for localized risk assessment and treatment strategies.

BACKGROUND:Rheumatoid arthritis is influenced by complex genetic and environmental factors.Although observational studies have found some correlation between plasma proteins and rheumatoid arthritis,the susceptibility to confounding and reverse causation makes it difficult to clarify whether these proteins are pathogenic factors of rheumatoid arthritis.OBJECTIVE:To explore the potential of plasma proteins as biomarkers and therapeutic targets in rheumatoid arthritis through Mendelian randomization analysis of plasma proteins in the onset and progression of rheumatoid arthritis.METHODS:A large-scale two-sample Mendelian randomization analysis was conducted to comprehensively assess the causal relationships between 1 553 circulating proteins and rheumatoid arthritis based on the Decode database(developed by Decode Genetics in Iceland,which contains genomic data from the Icelandic population),the MR-Base platform(developed by a team of researchers at the University of Oxford in the United Kingdom,specifically designed to provide genetic and phenotypic data for Mendelian randomization analyses),and the GWAS Catalog platform(developed by the European Institute of Bioinformatics,which provides data for genome wide association studies worldwide).The causal effects were estimated using the Wald ratio and inverse variance weighting methods,with Bonferroni correction applied to control for false positives caused by multiple testing.To ensure the robustness of the results,sensitivity analyses were performed to validate the positive causal relationship between circulating proteins and rheumatoid arthritis,and Bayesian colocalization and phenome scanning were used to exclude confounding effects and horizontal pleiotropy.Additionally,external validation was carried out using new plasma protein datasets to reduce the likelihood of false discoveries.Finally,small-molecule compounds associated with candidate proteins were identified using the Drug Signatures Database(DsigDB),and molecular docking was performed to predict the binding patterns and energies between proteins and compounds,identifying the most stable and likely binding molecules and mechanisms.RESULTS AND CONCLUSION:(1)Sensitivity analyses,including Bayesian colocalization and phenome scanning,identified four plasma proteins with reliable causal relationships with rheumatoid arthritis:FCRL3,IL6R,ICOSLG,and TNFAIP3.Their genetic effects were estimated as follows:FCRL3[odds ratio(OR)=1.12,95％confidence interval(CI):1.07-1.17],IL6R(OR=0.94,95％CI:0.91-0.96),ICOSLG(OR=2.42,95％CI:1.67-3.52),and TNFAIP3(OR=2.19,95％CI:1.88-2.56).Furthermore,molecular docking analysis revealed that the small-molecule compound benzo[a]pyrene exhibited favorable binding with these candidate proteins,suggesting its potential as a therapeutic agent for rheumatoid arthritis.(2)This study provides a comprehensive analysis of the genetic causal relationships of FCRL3,IL6R,ICOSLG,and TNFAIP3 in rheumatoid arthritis.These proteins not only serve as potential molecular biomarkers for rheumatoid arthritis risk screening and disease prevention,but also offer key candidate targets for further understanding the pathogenic mechanisms of rheumatoid arthritis and developing targeted therapies.Although the study is based on European populations,its findings offer important insights for biomedical research in China.By incorporating Mendelian randomization methods to analyze genetic causality,future research on rheumatoid arthritis in the Chinese population could provide more accurate causal inferences,offering theoretical support for localized risk assessment and treatment strategies.

OBJECTIVE: To investigate the distribution characteristics of polymorphonuclear neutrophil (PMN) in the lungs during the early stage of severe burns and the mechanism of neutrophil elastase (NE) promoting lung injury. METHODS: 6-8-week-old male C57BL/6J mice were selected for the experiments. A 30% total body surface area (TBSA) III degree burn mouse model was established (severe burn group); the Sham-injury group was treated with 37 centigrade water. In the sodium sivelestat intervention group (SV intervention group), NE competitive inhibitor, sivelestat, 100 mg/kg, was injected via tail vein immediately after injury, while other groups received an equal volume of saline. Ten mice were harvested from each group to observe survival for 72 hours. Respiratory function tests were tested at 0 (immediate), 3, 6, 12, and 24 hours after molding. hematoxylin-eosin (HE) and immunohistochemical staining were used to observe lung tissue structure, inflammatory changes and PMN infiltration. The PMN absolute count in mice lung tissue was detected buy flow cytometry. At 6, 12, and 24 hours after molding, PMN counts and the concentration of NE [enzyme linked immunosorbent assay (ELISA)] in peripheral blood plasma, lung tissue, and bronchoalveolar lavage fluid (BALF) were detected. RESULTS: (1) HE staining results showed that compared with the Sham-injury group, the lungs of mice in the severe burn group showed inflammatory changes and PMN infiltration, with more significant changes at 6 hours. Immunohistochemistry results also confirmed that the expression of NE protein released from PMN significantly increased after 6 hours of severe burn injury [(3.79±0.62)% vs. (0.18±0.05)%, t = 11.56, P < 0.01]. (2) Compared with the Sham-injury group, the number of PMN and the concentration of NE in the peripheral blood and lung tissues in the severe burn group were significantly increased (F values were 13.709, 55.350 and 29.890, 13.286, respectively, all P < 0.01), peaking at 6 hours [plasma PMN count (×10⁹/L): 2.92±1.01 vs. 0.92±0.29, lung tissue PMN absolute count (cells): 48 788.03±11 833.91 vs. 1 516.72±415.35, plasma NE (ng/L): 24 522.71±3 842.92 vs. 7 009.34±4 067.86, lung tissue NE (ng/L): 262 189.04±9 695.13 vs. 65 026.03± 16 016.31, all P < 0.01]. The number of PMN in the lung of severely burned mice was highly correlated with NE concentration (r = 0.892, P < 0.001). There was no significantly difference in the PMN absolute count in the BALF of mice between the Sham-injury group and severe burn group (F = 1.403, P > 0.05). The Sham-injury group and severe burn group contained a small amount of NE in the BALF, and the concentration of NE in the BALF of the severely burned 6 hours and 12 hours groups were significantly higher than those of the Sham-injury group (ng/L: 328.58±158.10, 415.30±240.89 vs. 61.95±15.80, both P < 0.05). (3) Kaplan-Meier survival curve showed that the 72-hour survival rate of mice in the SV intervention group was significantly higher than that in the severe burn group (100% vs. 10%, Log-Rank test: χ² = 19.12, P < 0.001). (4) Compared with the Sham-injury group, all lung function indices of the severe burn group decreased significantly. All lung function indices of SV intervention group improved gradually over time, which were significantly better than those of the severe burn group. (5) Compared with the Sham-injury group, the PMN absolute count in lung tissue and the concentration of NE in plasma and lung tissue were significantly higher in the SV intervention group (F values were 46.709, 3.535, 32.701, respectively, all P < 0.05), with a peak at 6 hours. Compared with the severe burn group, the SV intervention group had a higher PMN absolute count in lung tissue (cells: 8 870.80±7 013.89 vs. 25 974.92±22 240.8, P < 0.05), and higher plasma and lung tissue NE concentrations (ng/L: 14 955.94±3 944.41 vs. 21 972.75±4 573.05, 81 956.87±38 658.35 vs. 168 182.30±83 513.91, both P < 0.01) were significantly decreased. CONCLUSIONS In the early stage of severe burns, there is a significant infiltration of PMN into the lungs. The NE promotes lung injury in the early stage of severe burn, and improve lung injury by inhibiting the action of NE.
Animals ; Burns/metabolism* ; Leukocyte Elastase/metabolism* ; Male ; Mice, Inbred C57BL ; Mice ; Neutrophils/metabolism* ; Lung/metabolism* ; Disease Models, Animal ; Neutrophil Infiltration ; Lung Injury/metabolism* ; Glycine/analogs & derivatives* ; Sulfonamides

Radiation enteritis(RE)is an inflammatory reaction caused by radiation exposure,commonly observed following radiotherapy for malignancies in the abdominal,pelvic and retroperitoneal regions.The authors believe that the pathogenesis of RE is complex,involving factors such as deficiency and excess,cold and heat,as well as qi and blood.The general pathogenesis can be summarized as"instability of the Zhongzhou,depletion of essence and blood,dysregulation of ascending and descending,and accumulation of heat-toxins".And"the instability of the Zhongzhou and subsequent malnutrition of the intestines"are the key drivers of disease progression.Based on theoretical exploration and clinical observations,this article proposed a comprehensive diagnostic and therapeutic approach centered on"stabilizing the Zhongzhou,replenishing essence and blood,regulating ascending and descending functions,and clearing heat-toxins".These four methods are often applied simultaneously,with"stabilizing the Zhongzhou and regulating the intestines"serving as the core of treatment.The approach is tailored according to the individual patient's condition of blood,qi and body fluids.A medical case was attached as evidence for verification.

Cancer cachexia is a complex syndrome caused by multiple factors,which seriously affects the quality of life and prognosis of patients.Its overall pathogenesis is related to the deficiency of spleen qi,insufficiency of kidney essence,internal generation of turbid toxins,and the obstruction of the production of qi,blood and essential qi,which cannot nourish the muscles and bones.Under the guidance of the dynamic diagnosis and treatment system of"spleen and kidney exhaustion as the root cause and internal accumulation of turbid toxins as the manifestation",the overall regulation is carried out from four dimensions:opening and closing the spleen and stomach,nourishing the kidney and promoting transportation,transforming turbid toxins and detoxification,and tonifying qi and nourishing yin.It has shown unique value in the intervention of cancer cachexia and can provide ideas and references for the clinical practice of TCM in treating cancer cachexia.

Tumor-related insomnia is one of the common complications of tumor patients,which is secondary to tumor disease and related to tumor disease itself or tumor treatment.Combined with the unique pathogenesis of"heat-toxicity internal stagnation"of tumor-related insomnia,the important treatment methods are to clear away heat,attack toxicity,regulate qi and supplement healthy qi.This article explained the research status,etiology and pathogenesis,treatment principles of the disease,in order to provide new ideas and methods for the differentiation and treatment of tumor-related insomnia in TCM.

Radiation enteritis(RE)is an inflammatory reaction caused by radiation exposure,commonly observed following radiotherapy for malignancies in the abdominal,pelvic and retroperitoneal regions.The authors believe that the pathogenesis of RE is complex,involving factors such as deficiency and excess,cold and heat,as well as qi and blood.The general pathogenesis can be summarized as"instability of the Zhongzhou,depletion of essence and blood,dysregulation of ascending and descending,and accumulation of heat-toxins".And"the instability of the Zhongzhou and subsequent malnutrition of the intestines"are the key drivers of disease progression.Based on theoretical exploration and clinical observations,this article proposed a comprehensive diagnostic and therapeutic approach centered on"stabilizing the Zhongzhou,replenishing essence and blood,regulating ascending and descending functions,and clearing heat-toxins".These four methods are often applied simultaneously,with"stabilizing the Zhongzhou and regulating the intestines"serving as the core of treatment.The approach is tailored according to the individual patient's condition of blood,qi and body fluids.A medical case was attached as evidence for verification.

Tumor-related insomnia is one of the common complications of tumor patients,which is secondary to tumor disease and related to tumor disease itself or tumor treatment.Combined with the unique pathogenesis of"heat-toxicity internal stagnation"of tumor-related insomnia,the important treatment methods are to clear away heat,attack toxicity,regulate qi and supplement healthy qi.This article explained the research status,etiology and pathogenesis,treatment principles of the disease,in order to provide new ideas and methods for the differentiation and treatment of tumor-related insomnia in TCM.

Cancer cachexia is a complex syndrome caused by multiple factors,which seriously affects the quality of life and prognosis of patients.Its overall pathogenesis is related to the deficiency of spleen qi,insufficiency of kidney essence,internal generation of turbid toxins,and the obstruction of the production of qi,blood and essential qi,which cannot nourish the muscles and bones.Under the guidance of the dynamic diagnosis and treatment system of"spleen and kidney exhaustion as the root cause and internal accumulation of turbid toxins as the manifestation",the overall regulation is carried out from four dimensions:opening and closing the spleen and stomach,nourishing the kidney and promoting transportation,transforming turbid toxins and detoxification,and tonifying qi and nourishing yin.It has shown unique value in the intervention of cancer cachexia and can provide ideas and references for the clinical practice of TCM in treating cancer cachexia.

Objective In order to explore the influence and effect of case teaching method based on real patients in oto-rhinolaryngology on clinical practice ability of general practice.Methods 96 trainees of general practice in otolaryngology de-partment from January 2018 to January 2021 were randomly divided into two groups:a CBL group and a control group.In the CBL group,CBL teaching method was adopted based on real patients in Otorhinolaryngology.Conventional teaching method was used in the control group.Results The theoretical scores of written test and the examination of clinical skill operation scores of the CBL group and the control group were analyzed.There was significant difference between the two groups(P＜0.05).The students in CBL group were more satisfied with clinical thinking ability,analysis and problem solving ability,active learning abil-ity,learning efficiency,teacher-student interaction,doctor-patient communication ability and consultation skills than the control group.There was significant difference between the two groups(P＜0.05).Conclusion The CBL teaching method can obvi-ously improve the learning enthusiasm and clinical practice ability of general resident training doctors.The teaching quality has been significantly improved.It is of great value to cultivate excellent general practitioners.