Macrophages are innate immune cells connected with the development of inflammation. Retinoic acid has previously been proved to have anti-inflammatory and anti-arthritic properties. However, the exact mechanism through which retinoic acid modulates arthritis remains unclear. This study aimed to investigate whether retinoic acid ameliorates rheumatoid arthritis by modulating macrophage polarization. This study used retinoic acid to treat mice with adjuvant arthritis and evaluated anti-inflammatory effects by arthritis score, thermal nociceptive sensitization test, histopathologic examination and immunofluorescence assays. In addition, its specific anti-arthritic mechanism was investigated by flow cytometry, cell transfection and inflammatory signaling pathway assays in RAW264.7 macrophages in vitro. Retinoic acid significantly relieved joint pain and attenuated inflammatory cell infiltration in mice. Furthermore, this treatment modulated peritoneal macrophage polarization, increased levels of arginase 1, as well as decreased inducible nitric oxide synthase expression. In vitro, we verified that retinoic acid promotes macrophage transition from the M1 to M2 type by upregulating mitogen-activated protein kinase (MAPK) phosphatase 1 (MKP-1) expression and inhibiting P38, JNK and ERK phosphorylation in lipopolysaccharide-stimulated RAW264.7 cells. Notably, the therapeutic effects of retinoic acid were inhibited by MKP-1 knockdown. Retinoic acid exerts a significant therapeutic effect on adjuvant arthritis in mice by regulating macrophage polarization through the MKP-1/MAPK pathway, and play an important role in the treatment of rheumatic diseases.

Objective To analyze the clinical characteristics,treatment,and prognosis of immune checkpoint inhibitor-related diabetes mellitus(ICI-DM).Methods The clinical characteristics,laboratory examinations,treatment regimens,and follow-up outcomes of 10 ICI-DM patients who were diagnosed and treated in the First Medical Center of Chinese PLA General Hospital between July 2019 and December 2024 were retrospectively analyzed.Relevant literatures were retrieved from domestic and foreign databases such as PubMed,CNKI,and VIP.The clinical characteristics of ICI-DM were summarized based on the literature results.Results All 10 patients were PD-1 inhibitor users,including 5 males and 5 females,with a median age of 54.5(51.3,64.0)years and a body mass index(BMI)of(22.0±2.15)kg/m2.Among them,9 cases(90.0%)were fulminant type 1 diabetes mellitus(FT1DM);9 cases(90.0%)had a severity of adverse events reaching grade 3-4 according to the Common Terminology Criteria for adverse events(CTCAE).The median time from PD-1 inhibitor treatment to the occurrence of the classic diabetes symptoms referred to as"three more and one less"(polyuria,polydipsia,polyphagia,and weight loss)in all patients was 145.5(110.5,204.8)days,and the medication duration was 6.0(4.3,7.8)cycles.The average blood glucose level of the 10 patients at the time of consultation was 25.3(10.0-41.4)mmol/L,and the glycated hemoglobin(HbA1c)level was 8.0%(6.6%-10.9%).Eight patients had fasting and 2-hour C-peptide levels<0.1 ng/ml(fasting C-peptide from<0.010 to 0.067 ng/ml,2-hour C-peptide from<0.010 to 0.077 ng/ml).Nine of the 10 patients were negative for diabetes autoantibodies,while 1 was not tested.All 10 patients were successfully treated with insulin and other therapies.During the follow-up after discharge,all patients still relied on insulin treatment,and no significant recovery of pancreatic islet β cell function was observed compared with that at discharge.Literature review revealed that ICI-DM was more common in PD-1 inhibitor users,with clinical mainly manifested as diabetic ketoacidosis(DKA)(65.4%)and diabetic ketosis(13.1%).Patients had severely impaired pancreatic islet function and required long-term insulin treatment,and some cases were complicated by thyroid or pituitary dysfunction.Conclusions ICI-DM typically presents as FT1DM,often manifesting with DKA or diabetic ketosis at onset.It is characterized by severe and irreversible loss of pancreatic islet function,necessitating lifelong insulin therapy.To enable early detection and prompt treatment,close monitoring of blood glucose is essential during ICI treatment.

Objective: To analyze the association between alcohol consumption and lumbar disc herniation (LDH), so as to provide a reference for the development of prevention and treatment strategies for LDH. Methods: From May to July 2022, permanent residents aged ≥18 years from eight counties (cities/districts) in Gansu Province were selected using a multistage stratified random sampling method. Data on basic characteristics, alcohol consumption in the past 30 days, hypertension, and diabetes mellitus were collected through questionnaire surveys. LDH was determined based on imaging findings, combined with disease history or clinical symptoms. Multivariable logistic regression model was used to analyze the association between alcohol consumption and LDH, with subgroup analyses conducted by gender, age, ethnicity, and altitude of residence. Propensity score matching (PSM) was utilized for sensitivity analysis. Results: A total of 4 545 individuals were surveyed. There were 2 026 (44.58%) males and 2 519 (55.42%) females. The mean age was (44.82±15.33) years. The study participants were predominantly of Han ethnicity, with 2 598 persons accounting for 57.17%. The altitude of residence was mainly above 3 500 m, with 1 941 persons accounting for 42.71%. There were 574 alcohol drinkers, accounting for 12.63%. LDH was detected in 1 035 cases, with a detection rate of 22.77%. Multivariable logistic regression analysis showed that after adjusting for gender, age, physical activity, and hypertension, compared to non-drinking residents, alcohol-consuming residents exhibited a 27.6% reduction in the risk of LDH (OR=0.724, 95%CI: 0.544-0.963). No significant interaction effects on LDH risk were observed between alcohol consumption and gender, age, ethnicity, or altitude of residence (all Pfor interaction >0.05). The results of the sensitivity analysis indicated that compared to non-drinking residents, alcohol-consuming residents exhibited a 38.8% reduction in the risk of LDH (OR=0.612, 95%CI: 0.382-0.976). Conclusion Alcohol consumption was statistically associated with a lower risk of LDH.

Macrophages are innate immune cells connected with the development of inflammation. Retinoic acid has previously been proved to have anti-inflammatory and anti-arthritic properties. However, the exact mechanism through which retinoic acid modulates arthritis remains unclear. This study aimed to investigate whether retinoic acid ameliorates rheumatoid arthritis by modulating macrophage polarization. This study used retinoic acid to treat mice with adjuvant arthritis and evaluated anti-inflammatory effects by arthritis score, thermal nociceptive sensitization test, histopathologic examination and immunofluorescence assays. In addition, its specific anti-arthritic mechanism was investigated by flow cytometry, cell transfection and inflammatory signaling pathway assays in RAW264.7 macrophages in vitro. Retinoic acid significantly relieved joint pain and attenuated inflammatory cell infiltration in mice. Furthermore, this treatment modulated peritoneal macrophage polarization, increased levels of arginase 1, as well as decreased inducible nitric oxide synthase expression. In vitro, we verified that retinoic acid promotes macrophage transition from the M1 to M2 type by upregulating mitogen-activated protein kinase (MAPK) phosphatase 1 (MKP-1) expression and inhibiting P38, JNK and ERK phosphorylation in lipopolysaccharide-stimulated RAW264.7 cells. Notably, the therapeutic effects of retinoic acid were inhibited by MKP-1 knockdown. Retinoic acid exerts a significant therapeutic effect on adjuvant arthritis in mice by regulating macrophage polarization through the MKP-1/MAPK pathway, and play an important role in the treatment of rheumatic diseases.

Objective To explore the functional mechanism of spinal cord fragile X mental retardation protein(FMRP)involved in neuropathic pain(NP)by using the sciatic nerve model of chronic compression injury(CCI).Methods First,to investigate the changes of spinal cord FMRP and β-catenin following the development of NP,this study compared the 50%mechanical withdrawal threshold(MWT)and thermal withdrawal latency(TWL)in CCI rats,as well as changes of FMRP and β-catenin in the spinal dorsal horn post-surgery,through random grouping.Immunofluorescence staining was performed on spinal cord tissue sections from CCI rats.Second,to further validate the alterations in pain behavior when the FMRP function was lost,we measured the 50%MWT,TWL,and FMRP and β-catenin in the spinal dorsal horn after FMRP knockdown in CCI rats.Finally,we measured the 50%MWT,TWL,and FMRP and β-catenin in the case of FMRP hyperfunction for validation.Results Compared with the baseline CCI group and the naive and sham groups after modeling,the CCI group after modeling showed decreases in 50%MWT and TWL(all P<0.001).After modeling,compared with the naive group and the sham group,the CCI group presented up-regulated expression of FMRP(P=0.027,P=0.022)and β-catenin(P<0.001,P=0.001)in the spinal dorsal horn.No co-localization of FMRP with astrocytes and microglia was observed in the spinal cord,while the co-localization with neurons was observed.Compared with the baseline,the CCI+FMRP knockdown group showed decreases in 50%MWT(P=0.015)and TWL(P=0.001)after modeling.After intrathecal injection of small interfering RNA(siRNA),the 50%MWT(P=0.020)and TWL(P=0.009)of the CCI+FMRP knockdown group were increased.Moreover,compared with the CCI group and the CCI+solvent group,the CCI+FMRP knockdown group showed increases in 50%MWT(both P<0.001)and TWL(P=0.005,P=0.006).After intrathecal injection of siRNA,the expression levels of FMRP(P=0.012,P=0.007)and β-catenin(both P<0.001)in the spinal dorsal horn of the CCI+FMRP knockdown group were lower than those of the CCI group and the CCI+solvent group.Compared with the baseline FMRP overexpression group and the naive and negative control groups after adeno-associated virus(AAV)injection,the FMRP overexpression group after AAV injection showed decreases in 50%MWT and TWL(all P<0.001).After AAV injection,compared with the naive group and the negative control group,the FMRP overexpression group demonstrated up-regulated expression of FMRP(both P<0.001)and β-catenin(P=0.006,P=0.008)in the spinal cord.Conclusions This study confirms that spinal cord FMRP and β-catenin are involved in NP induced by CCI.Spinal cord FMRP may be one of the potential therapeutic targets for NP.
Animals ; beta Catenin/metabolism* ; Neuralgia/metabolism* ; Fragile X Mental Retardation Protein/physiology* ; Spinal Cord/metabolism* ; Rats ; Rats, Sprague-Dawley ; Male

Objective:To evaluate the relationship between transverse sinus stenosis (TSS) and cerebral blood flow in normal adults based on four-dimensional flow (4D Flow) MRI.Methods:The study was a cross-sectional study. Totally 81 normal volunteers who underwent magnetic resonance venography (MRV) and 4D Flow MRI were prospectively enrolled at Beijing Friendship Hospital, Capital Medical University from January 2020 to December 2022. Based on MRV evaluation of transverse sinus dysplasia, the volunteers were divided into a dysplasia group (26 cases) and a non-dysplasia group (55 cases); The area of the stenosis and the normal transverse sinus at the distal end were measured. The degree of TSS and the bilateral average transverse sinus stenosis (BA-TSS) were calculated. TSS was determined using TSS levels of 1/3, 1/2, and 2/3 as thresholds, and was divided into three groups: no TSS group, unilateral TSS group, and bilateral TSS group, with 28, 39, and 14 cases, 37, 37, and 7 cases, and 43, 36, and 2 cases, respectively. Based on 4D Flow MRI, the blood flow of the internal carotid artery, vertebral artery, superior sagittal sinus, straight sinus, and transverse sinus distal and proximal ends were measured. The cerebral blood flow (bilateral internal carotid artery blood flow+bilateral vertebral artery blood flow), venous sinus return blood flow 1 (superior sagittal sinus blood flow+straight sinus blood flow), return blood flow 2 (sum of bilateral transverse sinus distal end blood flow), return blood flow 3 (sum of bilateral transverse sinus proximal end blood flow), and the ratio of return blood flow to cerebral blood flow were calculated. Independent sample t-test was used to compare the differences between the group with and without transverse sinus dysplasia; Single factor analysis of variance was used to compare the differences between the TSS free group, unilateral TSS group, and bilateral TSS group. Based on single factor linear regression, the relationships between BA-TSS and blood flow parameters were analyzed.Results:There was no statistically significant difference in various blood flow parameters between the group with and without transverse sinus dysplasia (all P>0.05). When using 1/3, 1/2, and 2/3 as thresholds, there was no statistically significant difference in various blood flow parameters between the non TSS group, unilateral TSS group, and bilateral TSS group (all P>0.05). BA-TSS was linearly positively correlated with cerebral blood flow (β=0.986, 95% CI 0.108-1.865, P=0.028), but not linearly correlated with return blood flow 1, 2, and 3 (all P>0.05). The degree of BA-TSS was linearly negatively correlated with return blood flow 1/cerebral blood flow (β=-0.001, 95% CI -0.002-0, P=0.009) and return blood flow 2/cerebral blood flow (β=-0.001, 95% CI -0.002-0, P=0.018), but not with return blood flow 3/cerebral blood flow ( P=0.076). Conclusion:The BA-TSS degree in normal adults is positively correlated with cerebral blood inflow and negatively correlated with the proportion of venous sinus outflow.

Objective·To investigate the causal relationship between plasma zinc-alpha-2-glycoprotein 1(AZGP1)and heart failure(HF)by using Mendelian randomization(MR)analysis and experimental validation.Methods·A two-sample MR analysis was performed to assess the causal relationship between AZGP1 and HF by integrating large-scale genome-wide association study(GWAS)data on plasma proteins and HF.The inverse-variance weighted(IVW)method was employed as the primary analytical approach,supplemented by MR-Egger regression,weighted median,and simple median methods.Horizontal pleiotropy was tested by using MR-PRESSO global test and MR-Egger intercept analysis.Colocalization analysis was conducted to validate genetic locus overlap.Additionally,a clinical cohort(84 HF patients and 68 healthy controls)was analyzed,with plasma AZGP1 levels quantified by enzyme-linked immunosorbent assay(ELISA).Results·MR analysis showed that elevated plasma AZGP1 levels were significantly associated with reduced HF risk(OR=0.82,95%CI 0.75?0.90,P=1.70×10-5).Colocalization analysis confirmed that AZGP1 expression and HF shared causal genetic variants(posterior probability for H4=0.69).Sensitivity and reverse MR analyses supported the robustness of the results.ELISA confirmed that plasma AZGP1 levels were significantly lower in HF patients compared to healthy controls,reinforcing its protective role in HF.Conclusion·This study demonstrates AZGP1 exerts a protective causal effect on HF and may serve as a potential biomarker for HF treatment.

Body weight abnormalities, including overweight, obesity, and underweight, have become a dual public health challenge in Chinese adults: overweight and obesity lead to a variety of chronic complications, while underweight increases the risks of malnutrition, sarcopenia, and organ dysfunction. To systematically address these issues, multidisciplinary experts in endocrinology, sports science, nutrition, and psychiatry from various regions have held multiple weight management seminars. Based on the latest epidemiological data and clinical evidence, they expanded the guideline to include assessment and intervention strategies for underweight, in addition to the core content of obesity management. This guideline outlines the etiological mechanisms, evaluation methods, and multidimensional management strategies for overweight and obesity, covering key areas such as diagnosis and assessment, medical nutrition therapy, exercise prescription, pharmacological intervention, and psychological support. It is intended to provide a scientific and standardized approach to weight management across the adult population, aiming to curb the rising prevalence of obesity, mitigate complications associated with abnormal body weight, and improve nutritional status and overall quality of life.

Objective To investigate the status of hearing impaired children's hearing device independence skills,and to explore the ways to improve their self-use of hearing equipment.Methods This study surveyed 64 re-habilitation teachers and 411 parents of children with hearing impairment aged 0-12 years.Through face-to-face or remote telephone interview,3 good habits(A asking parents for advice before removing the HA,B putting the de-vice into a moisture-proof box after removing it,C bringing batteries to school and knowing where are them)and 3 key abilities[D wearing the device independently,E replacing the battery independently,and F independently handle foreign bodies in the ear mold(Fa)and water vapor(Fb)]was investigated.The age when mastering skills or de-veloping habits difference of hearing impaired children in different groups were compared.Results ① The ratio of ability D in the bilateral CI group and the bilateral HA group of preschool children was 30.97％and 18.57％respec-tively.Among elementary school children,85.29％and 90.70％had this ability respectively.② The ratio of ability E in the bilateral CI group,the bilateral HA group and the bimodel group were 11.50％,15.71％and 16.49％,re-spectively.Among elementary school children,64.71％,53.49％and 68.52％had this ability,respectively.③Among preschool children,there was no statistical difference in age when different equipment groups developed the three good habits and acquired ability D and E(P＞0.05).④ Among primary school children,there was a statisti-cal difference in the age when different equipment groups formed habit A(P＜0.05),and the age when double CI group had this ability was slightly earlier than the double HA group.There was no significant difference in other abilities among age groups(P＞0.05).Conclusion The age at which hearing impaired children develop the three good habits precedes the age at which they master the key skills,which accords with the law of skill acquisition and development of ordinary children.Corresponding teaching process should be based on the age and ability of hearing-impaired children without considering the type of equipment.