ObjectiveTo establish a mouse model of rheumatoid arthritis with interstitial lung disease （RA-ILD） in DBA/1 mice using Porphyromonas gingivalis （Pg） infection combined with collagen-induced arthritis （CIA）， and to comprehensively evaluate pathological characteristics in joints， lungs， and serum. MethodsForty DBA/1 mice were randomly divided into four groups， i.e.， Control， Pg infection （Pg）， CIA， and Pg infection combined with CIA （Pg+CIA）， with 10 mice in each group. Arthritis clinical symptoms were evaluated by recording arthritis incidence and clinical scores. Micro-CT scanning was used to assess knee joint pathology. Histopathological changes and collagen deposition in knee joints and lung tissues were analyzed using hematoxylin-eosin （HE） and Masson staining. Immunohistochemistry was performed to detect protein expression of α-smooth muscle actin （α-SMA）， typeⅠ collagen （ColⅠ）， and fibronectin （FN） in lung tissues. Real-time quantitative polymerase chain reaction（Real-time PCR）was used to measure mRNA expression levels of α-SMA， ColⅠ， FN， tumor necrosis factor-α （TNF-α）， interleukin-6 （IL-6）， and IL-1β in lung tissues. Enzyme-linked immunosorbent assay （ELISA） was used to detect serum levels of Pg， cyclic citrullinated peptide （CCP）， and immunoglobulin G （IgG）. ResultsJoint lesions： The CIA and Pg+CIA groups showed 100% arthritis incidence， with evident joint redness， swelling， and deformity. The number of affected limbs was 27 and 28， and clinical scores were 68 and 70， respectively. No obvious clinical symptoms were observed in the Pg group. Histopathological and imaging analyses showed severe joint lesions in the CIA and Pg+CIA groups， with significantly increased histopathological scores， bone mineral density， bone volume fraction， trabecular thickness， and trabecular number compared to the Control group （P<0.01）. No obvious joint pathology was observed in the Pg group. Lung lesions： The Pg+CIA group exhibited marked alveolar inflammation， interstitial inflammatory cell infiltration， and alveolar wall thickening， with pronounced blue staining of collagen fibers. Histopathological scores and collagen area ratios were significantly higher than those of the Control， Pg， and CIA groups （P<0.05）. Lung protein and mRNA expression levels of α-SMA， ColⅠ， and FN were markedly increased， and mRNA levels of IL-6， TNF-α， and IL-1β were significantly elevated compared to the Control group （P<0.05）. Serology： The Pg+CIA group showed significantly higher levels of CCP， Pg， and IgG compared with the Control， Pg， and CIA groups （P<0.05）. ConclusionDBA/1 mice subjected to Pg infection combined with CIA exhibited pronounced symptoms and pathological features of RA-ILD， along with elevated serum anti-CCP antibody levels. This model represents a novel RA-ILD mouse model， providing a valuable experimental tool for investigating RA-ILD pathogenesis and developing new therapeutics， and serves as a basis for establishing anti-cyclic citrullinated peptide antibody （ACPA）-positive RA-ILD animal models.

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.

Transcranial temporal interference stimulation (tTIS) is a novel non-invasive transcranial electrical stimulation technique that achieves deep brain stimulation through multiple electrodes applying electric fields of different frequencies. Current studies on the mechanism of tTIS effects are primarily based on rodents, but experimental outcomes are often significantly influenced by electrode configurations. To enhance the performance of tTIS within the limited cranial space of rodents, we proposed various electrode configurations for tTIS and conducted finite element simulations using a realistic mouse model. Results demonstrated that ventral-dorsal, four-channel bipolar, and two-channel configurations performed best in terms of focality, diffusion of activated brain regions, and scalp impact, respectively. Compared to traditional transcranial direct current stimulation (tDCS), these configurations improved by 94.83%, 50.59%, and 3 514.58% in the respective evaluation metrics. This study provides a reference for selecting electrode configurations in future tTIS research on rodents.
Animals ; Transcranial Direct Current Stimulation/instrumentation* ; Electrodes ; Mice ; Computer Simulation ; Finite Element Analysis ; Brain/physiology*

In recent years, the ongoing development of transcranial electrical stimulation (TES) and transcranial magnetic stimulation (TMS) has demonstrated significant potential in the treatment and rehabilitation of various brain diseases. In particular, the combined application of TES and TMS has shown considerable clinical value due to their potential synergistic effects. This paper first systematically reviews the mechanisms underlying TES and TMS, highlighting their respective advantages and limitations. Subsequently, the potential mechanisms of transcranial electromagnetic combined stimulation are explored, with a particular focus on three combined stimulation protocols: Repetitive TMS (rTMS) with transcranial direct current stimulation (tDCS), rTMS with transcranial alternating current stimulation (tACS), and theta burst TMS (TBS) with tACS, as well as their clinical applications in brain diseases. Finally, the paper analyzes the key challenges in transcranial electromagnetic combined stimulation research and outlines its future development directions. The aim of this paper is to provide a reference for the optimization and application of transcranial electromagnetic combined stimulation schemes in the treatment and rehabilitation of brain diseases.
Humans ; Transcranial Magnetic Stimulation/methods* ; Transcranial Direct Current Stimulation/methods* ; Brain Diseases/therapy*

Diabetic cardiomyopathy is a heart dysfunction disorder caused by diabetic hyperglycemia,which can induce heart failure and seriously threaten human health.Circular RNAs play an important role in the pathological regulation of many diseases such as atherosclerosis,myocardial infarction and diabetic cardiomyopathy.Myocardial cell death is an important factor in diabetic cardiomyopathy.It has been found that circRNAs are closely related to the common types of cell death in diabetic cardiomyopathy:apoptosis,pyroapoptosis,autophagy,necroptosis and ferroptosis.This paper reviews the mechanism of circular RNAs in myocardial cell death in diabetic cardiomyopathy.

Background and purpose:The Shanghai Municipal Center for Disease Control and Prevention provides annual updates on cancer statistics in Shanghai.Breast cancer is one of the common malignant tumors among women.In recent years,the incidence of female breast cancer was increasing,while its trend of mortality showed declining.This study aimed to investigate the survival rates of new female breast cancer cases in Shanghai from 2002 to 2017.Methods:Data of new cases and deaths of female breast cancer patients with follow-up information from 2002 to 2017 were obtained from the Population-based Cancer Registry and Vital Statistics System of Shanghai Municipal Center for Disease Control and Prevention.Numbers,proportions,and survival rates were stratified by year of diagnosis,age,histological type and stage at diagnosis for analysis.The 5-year observed survival rates were calculated based on the life table method.The probabilities of surviving from 0 to 99 years were estimated with the Elandt-Johnson model,and then cumulative expected survival rates were calculated using the Ederer Ⅱ method.Finally,the 5-year relative survival rates were calculated.The annual percent change(APC)of survival rates was estimated by Joinpoint Regression Program.Results:A total of 73 600 new female breast cancer cases were diagnosed from 2002 to 2017 in Shanghai.Among them,67 681 cases were morphological verification,accounting for 91.96%.By December 31,2022,23 745(32.26%)cases had died,and 19 466(26.45%)cases had died of cancer.A total of 68 332(92.84%)cases,who were either dead or followed for over 5 years,were considered to have complete follow-up.The remaining 5 268(7.16%)cases were lost to follow-up.73 538(99.92%)cases were included in the observed cohort for survival analysis.The number of observed cases nearly doubled from 3330 in 2002 to 6095 in 2017.The 5-year observed survival rate changed from 78.77%in 2002 to 84.55%in 2017 dynamically,showed a low increasing trend with an average rate of 0.50%per year(APC=0.50%,t=8.75,P＜0.001).The 5-year relative survival rate also increased from 83.46%to 89.24%slowly,with an average rate of 0.47%(APC=0.47%,t=9.80,P＜0.001).The overall 5-year observation survival rate of female cancer was 83.24%(82.96%-83.52%),and the 5-year relative survival rate was 87.58%(87.29%-87.87%)in Shanghai from 2002 to 2017.It was increasing over time,decreasing with aging and advanced stage at diagnosis continuously.There was no significant difference in the 5-year relative survival rates between the groups aged 15 to 64(P＞0.05).The group with an unknown stage had the highest number of cases,followed by the stage Ⅱ group,and then the stage Ⅰ group.The 5-year relative survival rate of cases with stage Ⅰ disease reached 99.10%(98.78%-99.42%),but these cases only accounted for 25.51%of the total.The 5-year relative survival rate of cases with stage Ⅳ disease was 52.54%(50.98%-54.11%),and these cases accounted for 6.13%of the total.The 5-year relative survival rate of cases with s unknown stage was 82.04%(81.42%-82.65%),and these cases accounted for 31.05%of the total.Conclusion:The diagnostic levels and survival rates of female breast cancer in Shanghai were relatively high and continue to improve.However,the proportions of cases with unknown histological type and unknown stage remain relatively high,and the proportion of stage Ⅰ cases is not very large.The survival rates of stage Ⅳ cases are relatively low.This study provides evidence for further research,prevention and control efforts for female breast cancer.

Objective:To compare the effect of transcranial magnetic stimulation (rTMS) of the contralesional hemisphere at different frequencies on the recovery of upper limb motor function after a moderate-to-severe ischemic stroke.Methods:The inter-hemisphere compensation model was applied along with electroencephalogram (EEG) power spectrum density measurements. Thirty stroke survivors were randomly assigned to a sham stimulation group ( n=9), a high-frequency stimulation group ( n=11) or a low-frequency stimulation group ( n=10). In addition to physical and pharmacological therapy, the low-frequency and high-frequency groups received 1Hz or 5Hz rTMS, while the sham group received sham stimulation. The rTMS was delivered over the contralesional (unaffected) hemisphere once daily for 20 minutes over 15 consecutive days. Before, as well as 7 and 15 days after the treatment, all of the subjects′ motor functioning was assessed using the Fugl-Meyer Assessment for the upper extremity (FMA-UE) and their ability in the activities of daily living was assessed using the modified Barthel Index (MBI). Resting-state EEGs with the eyes closed were also recorded, and absolute alpha power across the whole brain was calculated. Changes from baseline FMA-UE and MBI scores and absolute alpha power were analyzed using one-way and repeated-measures analysis of variance. Results:After the treatment, significant within-group improvements from baseline were observed in the FMA-UE scores, MBIs and absolute alpha power, except for absolute alpha power in the low-frequency and sham groups. The repeated-measures analysis of variance revealed significant time × group interactions for FMA-UE ( F=9.926, P≤0.001), MBI ( F=8.789, P≤0.001) and absolute alpha power ( F=4.511, P≤0.05). So the treatment effects varied among the groups. Post hoc Bonferroni-corrected comparisons showed that the high-frequency group exhibited significantly greater improvements from baseline in terms of all three indicators compared with the other two groups. Conclusions:High-frequency (5Hz) rTMS applied to the contralesional hemisphere produced greater improvement than low-frequency (1Hz) stimulation in the upper limb motor function of patients with moderate-to-severe stroke. These findings support the use of the interhemispheric compensation model to guide rTMS therapy, particularly for patients with FMA-UE scores below 43.

ObjectiveTo investigate the effect of the nitroglycerin-controlled low central venous pressure （CLCVP） technique on brain metabolic markers and cerebral blood oxygen saturation in patients undergoing laparoscopic hepatectomy for liver cancer， and to reduce the risk of neurological complications. MethodsA total of 105 patients who underwent elective laparoscopic hepatectomy for liver cancer in Haikou Hospital Affiliated to Xiangya Hospital of Central South University from April 2020 to May 2023 were enrolled and randomly divided into CLCVP group with 54 patients and non-CLCVP group with 51 patients. The patients in the CLCVP group were treated with the nitroglycerin CLCVP technique during surgery， while those in the non-CLCVP group were given conventional surgical treatment. The two groups were compared in terms of the following indicators： perioperative indicators； hemodynamic parameters and cerebral oxygen metabolism before anesthesia induction （T0）， at 5 minutes after anesthesia induction （T1）， at 5 minutes after the beginning of liver parenchyma dissection （T2）， at 5 minutes after the end of hepatectomy （T3）， and immediately after the end of surgery （T4）； the changes in liver function parameters after surgery； the incidence rate of adverse reactions. The independent-samples t test was used for comparison of continuous data between two groups， and the chi-square test was used for comparison of categorical data between two groups； the analysis of variance with repeated measures was used for comparison between multiple time points. ResultsCompared with the non-CLCVP group， the CLCVP group had significantly lower intraoperative blood loss and intraoperative fluid infusion volume （t=5.408 and 7.220， both P<0.05）， while there were no significant differences between the two groups in time of operation， anesthesia time， extubation time， resuscitation time and intraoperative urine volume （all P>0.05）. Compared with the data at T0， both groups had significant reductions in mean arterial pressure， heart rate， and central venous pressure during surgery （all P<0.05）， and compared with the non-CLCVP group， the CLCVP group had significantly lower mean arterial pressure and central venous pressure （P<0.05） and a significantly higher heart rate （P<0.05） at T2 and T3. Compared with the data at T0， both groups had a significant reduction in Ca-jvDO₂ at T2‍ ‍—‍ ‍T4 time points （all P<0.05）， while there was no significant difference in Ca-jvDO₂ between the two groups at each time point （all P>0.05）. Compared with the data at T0， the CLCVP group had a significant reduction in rSO₂ at T2‍ ‍—‍ ‍T4 time points （all P<0.05）， and the CLCVP group had a significantly lower level of rSO₂ than the non-CLCVP group at T2‍ ‍—‍ ‍T3 time points （both P<0.05）； there were no significant changes in CERO₂ and Djv-aBL in either group at each time point （all P>0.05）. At 3 and 7 days after surgery， both groups had significant increases in the liver function parameters of aspartate aminotransferase （AST）， alanine aminotransferase （ALT）， and total bilirubin （TBil） （all P<0.05）， and the CLCVP group had significantly lower levels of AST and ALT than the non-CLCVP group （all P<0.05）； there was no significant difference in TBil between the two groups at each time point （all P>0.05）. There was no significant difference in the incidence rate of perioperative complications between the two groups （χ²=0.729， P=0.394）. ConclusionThe application of the nitroglycerin CLCVP technique in laparoscopic hepatectomy for liver cancer can reduce the amount of intraoperative blood loss in patients， but it is necessary to further enhance the monitoring of cerebral blood oxygen saturation during surgery， so as to reduce the risk of neurological complications as much as possible.

ObjectiveTo unveil the mechanism of Jianpi Huogu prescription （JPHGP） in ameliorating the dyslipidemia of steroid-induced osteonecrosis of the femur head （SONFH） by oxylipidomics combined with transcriptomics. MethodsSixty SD rats were assigned into normal， model， low-， medium-， and high-dose （2.5， 5， 10 g·kg^-1， respectively） JPHGP， and Jiangushengwan （1.53 g·kg^-1） groups. Lipopolysaccharide was injected into the tail vein at a dose of 20 μg·kg^-1 on days 1 and 2， and methylprednisolone sodium succinate was injected at a dose of 40 mg·kg^-1 into the buttock muscle on days 3 to 5. The normal group received an equal volume of normal saline. Drug administration by gavage began 4 weeks after the last injection， and samples were taken after administration for 8 weeks. Hematoxylin-eosin staining was conducted to reveal the histopathological changes of the femoral head， and the number of adipocytes， the rate of empty bone lacunae， and the trabecular area were calculated. Micro-computed tomography was used for revealing the histological and histomorphometrical changes of the femoral head. Enzyme-linked immunosorbent assay was employed to measure the serum levels of triglyceride （TG）， total cholesterol （TC）， low-density lipoprotein （LDL）， high-density lipoprotein （HDL）， apolipoprotein A1 （ApoA1）， and apolipoprotein B （ApoB）. At the same time， the femoral head was collected for oxylipidomic and transcriptomic detection. The differential metabolites and differential genes were enriched and analyzed， and the target genes regulating lipid metabolism were predicted. The predicted target proteins were further verified by molecular docking， immunohistochemistry， and Western blot. ResultsCompared with the normal group， the model group showcased thinning of the femoral head， trabecular fracture， karyopyknosis， subchondral cystic degeneration， increases in the number of adipocytes and the rate of empty bone lacunae （P<0.01）， a reduction in the trabecular area （P<0.01）， decreases in BMD， Tb.Th， Tb.N， and BV/TV， and increases in Tb.Sp and BS/BV （P<0.01）. Compared with the model group， the JPHGP groups showed no obvious thinning of the femoral head or subchondroidal cystic degeneration. The high- and medium-dose JPHGP groups presented declines in the number of adipocytes and the rate of empty bone lacunae， an increase in the trabecular area （P<0.05， P<0.01）， rises in BMD， Tb.Th， Tb.N， and BV/TV， and decreases in Tb.Sp and BS/BV （P<0.05， P<0.01）. Compared with the normal group， the model group showcased raised serum levels of TG， TC， LDL， and ApoB and lowered serum levels of HDL and ApoA1 （P<0.01）. Compared with the model group， the JPHGP groups had lowered serum levels of TG， TC， LDL， and ApoB （P<0.05， P<0.01） and a risen serum level of ApoA1 （P<0.05， P<0.01）. Moreover， the serum level of HDL in the high-dose JPHGP group increased （P<0.01）. A total of 19 different metabolites of disease set and drug set were screened out by oxylipidomics of the femoral head， and 119 core genes with restored expression were detected by transcriptomics. The enriched pathways were mainly concentrated in inflammation， lipids， apoptosis， and osteoclast differentiation. Molecular docking， immunohistochemistry， and Western blot results showed that compared with the normal group， the model group displayed increased content of 5-lipoxygenase （5-LO） and peroxisome proliferator-activated receptor γ （PPARγ） in the femoral head （P<0.01）. Compared with the model group， medium- and high-dose JPHGP reduced the content of 5-LO and PPARγ （P<0.05， P<0.01）. ConclusionJPHGP can restore the levels of oxidized lipid metabolites by regulating the 5-LO-PPARγ axis to treat SONFH in rats. Relevant studies provide experimental evidence for the efficacy mechanism of JPHGP in the treatment of SONFH.