ObjectiveThis paper aims to conduct a secondary analysis of a randomized controlled trial on the treatment of myelodysplastic syndrome （MDS） with deficiency of both the spleen and kidney and blockage of toxin and blood stasis with an arsenic-containing traditional Chinese medicine compound， by applying the mixed model for repeated measure （MMRM） and the method of stratified composite outcome with win ratio. The analysis includes the assessment of hematological efficacy and the composite outcome evaluation of adverse reactions， so as to more comprehensively assess the therapy of this regimen. MethodsThe MMRM and win ratio methods were used to evaluate the efficacy of a prospective，multi-center，double-blind，randomized controlled study. The blood routine （hemoglobin concentration，neutrophil count， and platelet count） and biochemical indexes （aspartate aminotransferase，alanine aminotransferase，serum creatinine，and serum ferritin） of the patients were detected at the time of enrollment and at the end of each course of treatment in the laboratory department of Xiyuan Hospital. The patients' syndromes at the time of enrollment and after treatment were recorded and scored according to the therapy standard of traditional Chinese medicine for diseases and syndromes. MMRM was used to analyze the blood routine indexes of the experimental group and the control group. This method has the advantages of high data reliability and dynamic efficacy under intervention and time. The win ratio method was used to evaluate the composite outcome of traditional Chinese medicine syndrome scores and biochemical indexes according to the priority and to verify the clinical safety of arsenic-containing traditional Chinese medicine compound. ResultsThe results of MMRM analysis showed that the hemoglobin concentration of patients in the group with arsenic-containing traditional Chinese medicine compound increased significantly compared with that before treatment in the group，while that in the placebo group decreased significantly （P<0.01）. When compared with that after treatment in the placebo group，the hemoglobin concentration of patients in the group with arsenic-containing traditional Chinese medicine compound increased significantly，and the mean difference of least squares （LS） was statistically significant （P<0.01）. When compared with those before treatment in the group，there were no statistically significant differences in the neutrophil count and platelet count in both groups. After treatment，there were no statistically significant differences in the neutrophil count， platelet count， and the mean difference of LS between the two groups. The analysis results of win ratio showed that the group with arsenic-containing traditional Chinese medicine compound had a significant advantage in the comparison of composite outcomes，with a win ratio （95% CI） of 2.01 （1.24-3.27） （P<0.01），and that the possibility of "winning" in terms of safety was 2.01 times that of the placebo group. The safety advantage of the group with arsenic-containing traditional Chinese medicine compound mainly came from the traditional Chinese medicine syndrome scores，renal function indexes， and iron reserve capacity indexes，and the number of winning times was less than that of losing times in the comparison of liver function outcomes. ConclusionThe MMRM analysis proves that the arsenic-containing traditional Chinese medicine compound can significantly improve the hemoglobin concentration of patients with myelodysplastic syndrome with refractory cytopenia and multilineage dysplasia （MDS-RCMD） of the type of deficiency of both the spleen and kidney and blockage of toxin and blood stasis. This conclusion is not interfered with by time trends and individual relationships and methodologically improves the credibility of the therapy of the arsenic-containing traditional Chinese medicine compound in treating MDS. Four outcomes are evaluated by the win ratio method，namely traditional Chinese medicine syndromes，liver function，renal function， and iron reserve capacity，proving that the arsenic-containing traditional Chinese medicine compound has the comprehensive advantages of improving the survival quality of the patients and reducing adverse reactions. The win ratio outcome provides clear comparative indexes for the evaluation of adverse reactions，making it easier for regulatory authorities，medical staff， and patients to understand the safety of the arsenic-containing traditional Chinese medicine compound in clinical application.

The aim of this study was to investigate whether β-hydroxybutyric acid(BHB)inhibits the phagocytic function of CD14+monocytes in dairy cows through the ROS(reactive oxygen spe-cies)-NLRP3(NOD-like receptor thermal protein domain associated protein 3)pathway.CD14+monocytes in the blood of postpartum healthy cows were extracted,and 3 mmol/L BHB was added after transfection of small interfering RNA targeting NLRP3(si-NLRP3).Monocytes were pre-treated with 10 nmol/L NLRP3 inhibitor MCC950(CP-456773)or 10 mmol/L ROS scavenger N-acetyl cysteine(NAC),and then was treated with 3 mmol/L BHB for 24 h.The protein abundance of NLRP3 was detected by Western blot and the phagocytosis of monocytes was determined by flow cytometry and immunofluorescence.The results showed that compared with the si-Control+BHB group,the phagocytic function of monocytes in the si-NLRP3+BHB treatment group was significantly increased,while the protein abundance of NLRP3 was significantly decreased.Com-pared with DMSO+BHB group,the phagocytic function of monocytes in MCC950+BHB group was significantly increased.In addition,compared with DMSO+BHB group,the protein abundance of NLRP3 in monocytes was significantly decreased in MCC950+BHB group.Compared with the PBS+BHB group,the phagocytosis of monocytes was significantly increased after the addition of ROS scavenger NAC,while the protein abundance of NLRP3 was significantly decreased.These results indicated that BHB inhibited the phagocytosis of CD14+monocytes in cows via the ROS-NLRP3 pathway.Therefore,regulating the activation of NLRP3 inflammasome may be an effective method to improve the decrease of monocyte phagocytosis in perinatal dairy cows.

Signaling lymphocyte activation molecule family 6(SLAMF6)is widely expressed in T,B lymphocytes,NK cells and other immune cells.As a self-binding receptor for homotypic interactions,SLAMF6 is a type Ⅰ transmembrane protein belonging to the immunoglobulin superfamily,composed of the proximal IgC2 domain and distal IgV domain,the extracellular membrane,and three unique tyrosine cytoplasmic signaling motifs.This article summarizes the structure,expression,function and implication for au-toimmunity and tumor immunity of SLAMF6.

BACKGROUND:There are still great controversies in the etiology,clinical manifestations,diagnosis and treatment of pigmented villonodular synovitis.Bibliometric and visualization studies on pigmented villonodular synovitis can clarify the research development context and point out the direction for future research.OBJECTIVE:To analyze the global research status,hotspot,and trend of pigmented villonodular synovitis.METHODS:All publications related to pigmented villonodular synovitis from 1995 to 2023 were retrieved from Web of Science and CNKI.Citespace and bibliometrics were used to analyze the clustering,co-occurrence,and emergent words of all articles.The Web of Science database adopts subject headings plus free words for retrieval,while the CNKI database retrieves through subject headings.Finally,986 English articles and 599 Chinese articles were included.RESULTS AND CONCLUSION:(1)The United States has an absolute leading position in research in this field,ranking first in the number of published papers,H index,and cited times.China ranks the 4th in the total volume of published articles and 12th in the H index.The quality of published articles and international cooperation still need to be improved.(2)Cluster analysis of pigmented villonodular synovitis studies showed that the top five clusters were radiotherapy,soft tissue sarcoma,rheumatoid arthritis,magnetic resonance imaging,and diagnosis.(3)The key words that continued to emerge until 2023 were colony-stimulating factor 1,giant cell tumor of tendon sheath,case report,chromosome translocation,radiotherapy,expression,and kinase.(4)Based on keyword analysis and co-citation analysis,it is found that the research on the clinical characteristics of pigmented villonodular synovitis,the development of new colony-stimulating factor 1 inhibitors,and the application of colony-stimulating factor 1 inhibitors in the treatment process are current research hotspots.(5)Combining thematic evolution with the analysis of current research hotspots,based on clarifying the etiology,pathogenesis,and clinical characteristics of pigmented villonodular synovitis,improving the diagnostic accuracy of pigmented villonodular synovitis,enhancing the precision of treatment,and reducing the recurrence rate after treatment will be key issues that require focus in the future.

Objective To analyze the temporal trends of gout disezse burden in China from 1990 to 2021,and construct an age-period-cohort(APC)model to explore the independent effects of age,period,and birth cohort on epidemiological indicators,and predict the future burden of gout disease in China from 2022 to 2035.Methods Data on gout disease burden in China during 1990-2021 were extracted from the Global Burden of Disease(GBD)2021 database.Joinpoint regression analysis was used to assess temporal trends.The APC model was applied to evaluate the age,period and cohort effects on prevalence risk and disability-adjusted life years(DALYs).A Bayesian age-period-cohort(BAPC)model was employed to project the age-standardized prevalence rate(ASPR)and age-standardized DALY rate(ASDR)of gout in China from 2022 to 2035.Results From 1990 to 2021,the incidence,prevalence and DALYs of gout in China all increased substantially,with overall rising trends in the age-standardized incidence rate(ASIR),ASPR and ASDR.Compared with 1990,the incidence,prevalence and DALYs in 2021 increased by 160.45%,181.12%,and 175.93%,respectively,while their age-standardized rates increased by 23.74%,26.48%and 25.89%.Joinpoint regression analysis revealed that average annual percentage changes(AAPCs)of 0.73%for ASIR,0.82%for ASPR and 0.80%for ASDR during 1990-2021.In 2021,the number of cases and DALYs reached their peaks in males aged 55-59 years and females aged 65-69 years.Both prevalence and DALY rates increased steadily with age,with marked rises starting at age 30 in men and age 40 in women.Overall,males showed higher prevalence,DALYs and corresponding rates than those of females across all age groups.APC model results indicated that the age effect,period effect and cohort effects on prevalence and DALY rates presented an overall upward tread.Decomposition analysis showed that population aging contributed the most to the increase in incidence and DALYs from 1990 to 2021.BAPC projections suggested that by 2035,the ASPR and ASDR of gout in China reached 890.50 per 100,000 and 27.26 per 100,000,respectively.Conclusion The ASPR and ASDR of gout in China are projected to continue increasing from 2022 to 2035.Targeted public health strategies for high-risk populations are urgently needed to reduce the growing burden of gout.

The objective of this study was to examine the effects of tributyrin(TB)on energy me-tabolism,oxidative stress and immune function in dairy cows with negative energy balance(NEB).In this study,25 perinatal Holstein cows from a dairy farm in Heilongjiang Province were selected.Five healthy cows were designated as the control group,and 20 cows with NEB were randomly di-vided into NEB control group,Propylene glycol(PG)group(300 mL PG),TB group(37.5 g TB)and PG+TB group(300 mL PG+37.5 g TB)with 5 cows in each group,and were continuously fed for 14 days.Blood samples were collected at 0,7,14 and 21 days.The indexes of oxidative stress,energy metabolism and immune function in the serum of dairy cows were quantified using commercially available kits.The results showed that compared with the NEB group,the contents of T-AOC,GSH-Px,CAT and SOD in the TB group were significantly increased,whereas the content of MDA was significantly decreased.These results indicated that TB can effectively alleviate the oxidative stress of cows with NEB.The contents of BHB,NEFA and BUN in the TB group were significantly decreased,indicating that TB can regulate energy metabolism disorders in cows with NEB.The contents of IL1β,IL-2,IL-6,IL-21,MIP-1 and IP-10 in the TB group were significantly decreased,while the contents of IgA,IgM and IgG were significantly increased.These results sug-gest that TB has shown significant effects in inhibiting inflammatory response and improving im-mune function.Furthermore,compared with the PG group,the contents of T-AOC,GSH-Px,CAT,SOD,IgA,IgM and IgG in the TB group and the PG+TB group were significantly in-creased,whereas the contents of MDA,BHB,NEFA,BUN,IL-1β,IL-2,IL-6,IL-21,MIP-1 and IP-10 were significantly decreased.These results indicated that feeding TB alone was effective in alle-viating oxidative stress,improving energy metabolism and inhibiting inflammation in dairy cows compared to feeding the traditional drug PG,and the effect of feeding a mixture of PG and TB was particularly significant.This study provides a new theoretical basis for the prevention and treat-ment of oxidative stress and immune function decline caused by perinatal cows with NEB.

The aim of this study is to investigate whether β-hydroxybutyrate(BHB)impaired the mitochondrial function of dairy cow monocytes through the peroxisome proliferator-activated re-ceptor γ coactivator 1 alpha(PGC-1α)signaling pathway.According to the clinical symptoms and the concentration of BHB in whole blood,the tail vein blood of 12 healthy cows(BHB＜1.2 mmol/L)and 12 clinical ketotic cows(CK,BHB＞3.0 mmol/L)was collected.In vivo,after isolation and purification of CD14+monocytes,the intracellular mitochondrial membrane potential was detected by flow cytometry.The protein abundance of oxidative phosphorylation complex cytochrome c oxi-dase subunit Ⅰ(CO Ⅰ),CO Ⅱ,CO Ⅲ,COⅣ,CO Ⅴ,PGC-1 α,mitochondrial transcription factor A(TFAM)and nuclear respiratory factor 1(NFR1)were determined by Western blot.In vitro,CD14+monocytes were co-cultured with 3.0 mmol/L BHB for 0,6,12,24 h.Flow cytometry was applied for intracellular mitochondrial membrane potential detection,and determination the protein abundance of PGC-1α,TFAM and NFR1 by Western blot.The results showed that compared with control group,the mitochondrial membrane potential in CD14+monocytes of ketotic cows was sig-nificantly increased,and the protein abundance of CO Ⅰ,CO Ⅱ,CO Ⅲ,CO Ⅳ,CO Ⅴ PGC-1α,TFAM,and NRF1 in CD14+monocytes of ketotic cows were significantly decreased.Compared with 0 h,the mitochondrial membrane potential of CD14+monocytes was significantly increased after BHB treatment for 6,12,24 h,and the protein abundance of PGC-1α,TFAM and NRF1 were significantly decreased.The results indicated that BHB induced mitochondrial dysfunction in CD14+monocytes of ketotic cows by inhibiting PGC-1α signaling pathway.Therefore,the PGC-1αsignaling pathway may be a preventive and therapeutic target to the mitochondrial dysfunction of monocytes in ketotic cows caused by BHB.

The objective of this study was to examine the effects of tributyrin(TB)on energy me-tabolism,oxidative stress and immune function in dairy cows with negative energy balance(NEB).In this study,25 perinatal Holstein cows from a dairy farm in Heilongjiang Province were selected.Five healthy cows were designated as the control group,and 20 cows with NEB were randomly di-vided into NEB control group,Propylene glycol(PG)group(300 mL PG),TB group(37.5 g TB)and PG+TB group(300 mL PG+37.5 g TB)with 5 cows in each group,and were continuously fed for 14 days.Blood samples were collected at 0,7,14 and 21 days.The indexes of oxidative stress,energy metabolism and immune function in the serum of dairy cows were quantified using commercially available kits.The results showed that compared with the NEB group,the contents of T-AOC,GSH-Px,CAT and SOD in the TB group were significantly increased,whereas the content of MDA was significantly decreased.These results indicated that TB can effectively alleviate the oxidative stress of cows with NEB.The contents of BHB,NEFA and BUN in the TB group were significantly decreased,indicating that TB can regulate energy metabolism disorders in cows with NEB.The contents of IL1β,IL-2,IL-6,IL-21,MIP-1 and IP-10 in the TB group were significantly decreased,while the contents of IgA,IgM and IgG were significantly increased.These results sug-gest that TB has shown significant effects in inhibiting inflammatory response and improving im-mune function.Furthermore,compared with the PG group,the contents of T-AOC,GSH-Px,CAT,SOD,IgA,IgM and IgG in the TB group and the PG+TB group were significantly in-creased,whereas the contents of MDA,BHB,NEFA,BUN,IL-1β,IL-2,IL-6,IL-21,MIP-1 and IP-10 were significantly decreased.These results indicated that feeding TB alone was effective in alle-viating oxidative stress,improving energy metabolism and inhibiting inflammation in dairy cows compared to feeding the traditional drug PG,and the effect of feeding a mixture of PG and TB was particularly significant.This study provides a new theoretical basis for the prevention and treat-ment of oxidative stress and immune function decline caused by perinatal cows with NEB.

The aim of this study is to investigate whether β-hydroxybutyrate(BHB)impaired the mitochondrial function of dairy cow monocytes through the peroxisome proliferator-activated re-ceptor γ coactivator 1 alpha(PGC-1α)signaling pathway.According to the clinical symptoms and the concentration of BHB in whole blood,the tail vein blood of 12 healthy cows(BHB＜1.2 mmol/L)and 12 clinical ketotic cows(CK,BHB＞3.0 mmol/L)was collected.In vivo,after isolation and purification of CD14+monocytes,the intracellular mitochondrial membrane potential was detected by flow cytometry.The protein abundance of oxidative phosphorylation complex cytochrome c oxi-dase subunit Ⅰ(CO Ⅰ),CO Ⅱ,CO Ⅲ,COⅣ,CO Ⅴ,PGC-1 α,mitochondrial transcription factor A(TFAM)and nuclear respiratory factor 1(NFR1)were determined by Western blot.In vitro,CD14+monocytes were co-cultured with 3.0 mmol/L BHB for 0,6,12,24 h.Flow cytometry was applied for intracellular mitochondrial membrane potential detection,and determination the protein abundance of PGC-1α,TFAM and NFR1 by Western blot.The results showed that compared with control group,the mitochondrial membrane potential in CD14+monocytes of ketotic cows was sig-nificantly increased,and the protein abundance of CO Ⅰ,CO Ⅱ,CO Ⅲ,CO Ⅳ,CO Ⅴ PGC-1α,TFAM,and NRF1 in CD14+monocytes of ketotic cows were significantly decreased.Compared with 0 h,the mitochondrial membrane potential of CD14+monocytes was significantly increased after BHB treatment for 6,12,24 h,and the protein abundance of PGC-1α,TFAM and NRF1 were significantly decreased.The results indicated that BHB induced mitochondrial dysfunction in CD14+monocytes of ketotic cows by inhibiting PGC-1α signaling pathway.Therefore,the PGC-1αsignaling pathway may be a preventive and therapeutic target to the mitochondrial dysfunction of monocytes in ketotic cows caused by BHB.

The aim of this study was to investigate whether β-hydroxybutyric acid(BHB)inhibits the phagocytic function of CD14+monocytes in dairy cows through the ROS(reactive oxygen spe-cies)-NLRP3(NOD-like receptor thermal protein domain associated protein 3)pathway.CD14+monocytes in the blood of postpartum healthy cows were extracted,and 3 mmol/L BHB was added after transfection of small interfering RNA targeting NLRP3(si-NLRP3).Monocytes were pre-treated with 10 nmol/L NLRP3 inhibitor MCC950(CP-456773)or 10 mmol/L ROS scavenger N-acetyl cysteine(NAC),and then was treated with 3 mmol/L BHB for 24 h.The protein abundance of NLRP3 was detected by Western blot and the phagocytosis of monocytes was determined by flow cytometry and immunofluorescence.The results showed that compared with the si-Control+BHB group,the phagocytic function of monocytes in the si-NLRP3+BHB treatment group was significantly increased,while the protein abundance of NLRP3 was significantly decreased.Com-pared with DMSO+BHB group,the phagocytic function of monocytes in MCC950+BHB group was significantly increased.In addition,compared with DMSO+BHB group,the protein abundance of NLRP3 in monocytes was significantly decreased in MCC950+BHB group.Compared with the PBS+BHB group,the phagocytosis of monocytes was significantly increased after the addition of ROS scavenger NAC,while the protein abundance of NLRP3 was significantly decreased.These results indicated that BHB inhibited the phagocytosis of CD14+monocytes in cows via the ROS-NLRP3 pathway.Therefore,regulating the activation of NLRP3 inflammasome may be an effective method to improve the decrease of monocyte phagocytosis in perinatal dairy cows.