BACKGROUND:Rheumatoid arthritis is widely prevalent worldwide,with its high incidence and universality that considerably affects patients' quality of life.Previous studies have focused on a few immune cells or cytokines,whereas this study comprehensively provides a more complete view of the immune mechanisms in rheumatoid arthritis.OBJECTIVE:To explore the causal relationship between 731 immune cell phenotypes and rheumatoid arthritis using the Mendelian randomization method,thereby providing evidence of causality.METHODS:The 731 immune cell phenotypes used in this study were sourced from the GWAScatalog database,jointly developed by the National Human Genome Research Institute(NHGRI)and the European Bioinformatics Institute(EBI).The rheumatoid arthritis data were from the Finngen database,developed by the Finnish Institute for Molecular Medicine(FIMM).The inverse variance weighting method was employed as the primary analytical approach.Additionally,multiple analytical methods,including MR-Egger,weighted mode,simple mode,and weighted median,were concurrently utilized to complement the final results.Sensitivity analyses(Cochran's Q test,MR-Egger regression,and MR-presso analysis)were also conducted to verify the stability and feasibility of the data.RESULTS AND CONCLUSION:(1)After excluding results through heterogeneity testing,the inverse variance weighting analysis indicated that 10 absolute cell counts,15 median fluorescence intensities of surface antigen levels,1 morphological characteristic,and 9 relative cell counts had a causal relationship with the occurrence of rheumatoid arthritis.(2)According to cell classification,this study found that seven types of B cells,seven types of classical dendritic cells,six types of mature T cells,four types of monocytes,three types of myeloid cells,three types of TBNK cells(lymphocyte subset T cells,B cells and natural killer cells),and five types of Tregs had a causal association with the occurrence of rheumatoid arthritis.(3)Through comprehensive bidirectional two-sample MR analysis,we demonstrated the complex causal relationships between multiple immune phenotypes and rheumatoid arthritis,highlighting the intricate interaction patterns between the immune system and rheumatoid arthritis.These results provide new biomarkers for the early screening and diagnosis of rheumatoid arthritis in China,and help to improve the diagnostic accuracy and sensitivity.

BACKGROUND:Rheumatoid arthritis is widely prevalent worldwide,with its high incidence and universality that considerably affects patients' quality of life.Previous studies have focused on a few immune cells or cytokines,whereas this study comprehensively provides a more complete view of the immune mechanisms in rheumatoid arthritis.OBJECTIVE:To explore the causal relationship between 731 immune cell phenotypes and rheumatoid arthritis using the Mendelian randomization method,thereby providing evidence of causality.METHODS:The 731 immune cell phenotypes used in this study were sourced from the GWAScatalog database,jointly developed by the National Human Genome Research Institute(NHGRI)and the European Bioinformatics Institute(EBI).The rheumatoid arthritis data were from the Finngen database,developed by the Finnish Institute for Molecular Medicine(FIMM).The inverse variance weighting method was employed as the primary analytical approach.Additionally,multiple analytical methods,including MR-Egger,weighted mode,simple mode,and weighted median,were concurrently utilized to complement the final results.Sensitivity analyses(Cochran's Q test,MR-Egger regression,and MR-presso analysis)were also conducted to verify the stability and feasibility of the data.RESULTS AND CONCLUSION:(1)After excluding results through heterogeneity testing,the inverse variance weighting analysis indicated that 10 absolute cell counts,15 median fluorescence intensities of surface antigen levels,1 morphological characteristic,and 9 relative cell counts had a causal relationship with the occurrence of rheumatoid arthritis.(2)According to cell classification,this study found that seven types of B cells,seven types of classical dendritic cells,six types of mature T cells,four types of monocytes,three types of myeloid cells,three types of TBNK cells(lymphocyte subset T cells,B cells and natural killer cells),and five types of Tregs had a causal association with the occurrence of rheumatoid arthritis.(3)Through comprehensive bidirectional two-sample MR analysis,we demonstrated the complex causal relationships between multiple immune phenotypes and rheumatoid arthritis,highlighting the intricate interaction patterns between the immune system and rheumatoid arthritis.These results provide new biomarkers for the early screening and diagnosis of rheumatoid arthritis in China,and help to improve the diagnostic accuracy and sensitivity.

ObjectiveTo explore the improvement effect of Flos Puerariae， Hoveniae Semen， and their compatibility on acute alcoholic gastric mucosal injury， and lay a foundation for further development of Flos Puerariae， Hoveniae Semen， and their compatibility in the prevention and treatment of alcohol-induced multiple organ injury. MethodThe acute alcohol-induced gastric mucosal injury model of mice was established by multiple intragastric administration of 56% Hongxing Erguotou liquor （15 mL·kg^-1）. A total of 120 male ICR mice were randomly divided into 8 groups， namely， the blank group， model group， omeprazole group （0.026 g·kg^-1）， Flos Puerariae-Hoveniae Semen （compatibility） high， medium， and low-dose groups （29.2，14.6， 7.3 g·kg^-1）， Flos Puerariae group （19.5 g·kg^-1）， and Hoveniae Semen group （19.5 g·kg^-1）， with 15 mice in each group. After one week of adaptive feeding， the animals were pre-administrated with the corresponding drug at the rate of 10 mL·kg^-1 for 3 d. From the 4^th day， after 1 h of administration， Erguotou liquid was administrated at the rate of 15 mL·kg^-1 and the blank group was administrated with the same volume of deionized water to record the drunkenness and sober up time. The administration was lasted for 3 d. One hour after the last administration， the eyeballs were removed and the mice were sacrificed. The concentration of ethanol in serum was determined by gas chromatograph， and the activity of ethanol dehydrogenase （ADH） in gastric mucosa was determined by ultraviolet-vis spectrophotometer. Hematoxylin-eosin （HE） staining was used to observe the pathological changes in gastric mucosa. Serum inflammatory factors were determined by enzyme-linked immunosorbent assay （ELISA）. The mRNA expression of nuclear transcription factor-κB （NF-κB） p65 and NF-κB inhibitory protein α （IκBα） were detected by real-time polymerase chain reaction （Real-time PCR）. ResultAs compared with the normal group， the content of interleukin-6 （IL-6）， interleukin-1β （IL-1β）， and tumor necrosis factor-α （TNF-α） in serum of mice in the model group was increased （P<0.05）， the mRNA expression of NF-κB p65 in gastric mucosa tissues was increased （P<0.01）， and the mRNA expression of IκBα was decreased （P<0.01）. As compared with the model group， the drunkenness time of the omeprazole group， high and medium-dose compatibility groups， and Flos Puerariae group was prolonged （P<0.05）， the sober up time of the high and medium-dose compatibility groups was shortened （P<0.05）， the ethanol concentration in the serum of the high-dose compatibility group was decreased （P<0.05）， the ADH activity in the gastric mucosa of the omeprazole group and high and medium-dose compatibility groups was increased （P<0.05）， the macroscopic injury score of the high， medium， and low-dose compatibility groups and Flos Puerariae group was decreased （P<0.05）， the score of pathological injury in the omeprazole group， high， medium， and low-dose compatibility groups， and Flos Puerariae group was decreased （P<0.01）， the expression of IL-6 in serum of all drug groups was decreased （P<0.05）， the expression of IL-1β in serum of the omeprazole group， high， medium， and low-dose Flos Puerariae groups， and Hoveniae Semen group was decreased （P<0.05）， the expression of TNF-α in serum of high and medium-dose groups was decreased （P<0.05）， the mRNA expression of NF-κB p65 in gastric mucosa tissues of all drug groups was decreased （P<0.05）， and the mRNA expression of IκBα in gastric mucosa tissues of the omeprazole group and high， medium， and low-dose compatibility groups was increased （P<0.05）. As compared with the high-dose compatibility group， the drunkenness time in the low-dose compatibility group and Hoveniae Semen group was shortened （P<0.01）， the sober up time in the Flos Puerariae and Hoveniae Semen groups was prolonged （P<0.01）， the concentration of ethanol in the serum of the medium and low-dose compatibility groups， Flos Puerariae group， and Hoveniae Semen group increased （P<0.05）， the macroscopic injury score of the medium and low-dose compatibility groups and Hoveniae Semen group was increased （P<0.05）， the pathological injury score of the medium and low-dose compatibility groups， Flos Puerariae group， and Hoveniae Semen group was increased （P<0.01）， the content of IL-1β in serum of low-dose compatibility group， Flos Puerariae group， and Hoveniae Semen group was increased （P<0.01）， and the mRNA expression of IκBα in gastric mucosa of the Flos Puerariae group and Hoveniae Semen group was decreased （P<0.05）. As compared with the medium-dose compatibility group， the drunkenness time in the Hoveniae Semen group was shortened （P<0.05）， the sober up time in the Flos Puerariae group was prolonged （P<0.05）， the pathological injury score in the Flos Puerariae group and Hoveniae Semen group was increased （P<0.01）， and the content of IL-1β in serum of the low-dose compatibility group， the Flos Puerariae group， and Hoveniae Semen group was increased （P<0.05）. As compared with the low-dose compatibility group， the pathological injury score of the Hoveniae Semen group was increased （P<0.05）. ConclusionFlos Puerariae， Hoveniae Semen， and their compatibility play a role in preventing and treating acute alcoholic gastric mucosal injury in mice， which may be related to the inhibition of the expression of NF-κB signal pathway in gastric mucosa， and the high-dose compatibility group has the optimal effect.

Previously, most fractures have been treated through bone reduction and immobilization. With an increase in the patients’ need for an early return to their normal function, development in surgical techniques and materials have accelerated. However, delayed union or non-union of the fracture site sometimes inhibits immediate return to normal life. To enhance fracture healing, diverse materials and methods have been developed. This is a review on the current modalities of fracture healing enhancement, which aims to provide a comprehensive knowledge regarding fracture healing for researchers and health practitioners.

Objective:To explore the relationship between cardiac discomfort symptoms, fear of disease progress and post-traumatic stress disorder (PTSD) in patients with acute myocardial infarction(AMI) after discharge, and to clarify main intervention direction of PTSD in patients with AMI.Methods:Patients with AMI who were discharged from Tangshan Gongren Hospital between 1 month and 1 year were selected from November 2019 to November 2020.The cardiac discomfort symptoms scale, fear of progress questionnaire(FoP-Q-SF) and post-traumatic stress disorder self-rating scale(PTSD-SS) were used to investigate cardiac discomfort symptoms, fear of disease progress level and post-traumatic stress disorder status.Spearman rank correlation analysis was used to analyze the relationship between cardiac discomfort symptoms, fear of disease progress and post-traumatic stress disorder by SPSS 24.0 software. The mediating effect of fear of disease progress was analyzed by AMOS 24.0 software.Results:The PTSD score was (32.78±12.38) of patients with AMI discharged from hospital for 1 month to 1 year and the incidence of PTSD was 12.3%.Spearman correlation test showed cardiac discomfort symptoms and fear of disease progress were positively correlated with PTSD( r=0.530, 0.723, both P<0.01) and cardiac discomfort symptoms was positively correlated with fear of disease progress( r=0.518, P<0.01). Mediating effect test showed that fear of disease progress was a complete mediator between cardiac discomfort symptoms and PTSD. Conclusion:Cardiac discomfort symptoms can affect PTSD through a complete mediator of fear of disease progress.

BACKGROUND AND PURPOSE: Cheyne-Stokes respiration (CSR) is frequently observed in patients with acute stroke. There have been conflicting opinions about the associations of CSR with the location and size of the lesion. We aimed to better define the clinical relevance and pathogenesis of CSR in acute stroke. METHODS: We investigated patients who had been admitted with acute ischemic stroke and received an overnight sleep apnea test. We collected data on demographics, risk factors, etiologic subtypes, initial vital signs, clinical course of the stroke, and parameters associated with respiratory events during the sleep apnea test. We performed a multivariate logistic regression analysis to determine the factors associated with CSR. RESULTS: Among 182 patients, 35 patients showed CSR in sleep apnea testing. Large-artery atherosclerosis or cardioembolism, bilateral hemispheric involvement, atrial fibrillation, low left-ventricle ejection fraction (LVEF), and left atrium (LA) enlargement were all associated with the presence of CSR. Multivariate analysis revealed that the previous modified Rankin Scale (mRS) score, bilateral hemispheric involvement, low LVEF, and LA enlargement were significantly associated with CSR. Subgroup analysis with large-artery atherosclerosis without cardiac disease revealed that the previous mRS score is the only independent factor associated with CSR. CONCLUSIONS: CSR frequently occurs in strokes involving large arteries or due to cardioembolism, regardless of the location and severity of the stroke. Predisposing conditions such as preexisting neurologic disability, low LVEF, and LA enlargement are associated with CSR in acute stroke.
Arteries ; Atherosclerosis ; Atrial Fibrillation ; Cheyne-Stokes Respiration* ; Demography ; Heart Atria ; Heart Diseases ; Humans ; Logistic Models ; Multivariate Analysis ; Risk Factors ; Sleep Apnea Syndromes ; Stroke* ; Vital Signs

Dehydration is one of the key steps in the biosynthesis of mycolic acids and is vital to the growth of Mycobacterium tuberculosis (Mtb). Consequently, stalling dehydration cures tuberculosis (TB). Clinically used anti-TB drugs like thiacetazone (TAC) and isoxyl (ISO) as well as flavonoids inhibit the enzyme activity of the β-hydroxyacyl-ACP dehydratase HadAB complex. How this inhibition is exerted, has remained an enigma for years. Here, we describe the first crystal structures of the MtbHadAB complex bound with flavonoid inhibitor butein, 2',4,4'-trihydroxychalcone or fisetin. Despite sharing no sequence identity from Blast, HadA and HadB adopt a very similar hotdog fold. HadA forms a tight dimer with HadB in which the proteins are sitting side-by-side, but are oriented anti-parallel. While HadB contributes the catalytically critical His-Asp dyad, HadA binds the fatty acid substrate in a long channel. The atypical double hotdog fold with a single active site formed by MtbHadAB gives rise to a long, narrow cavity that vertically traverses the fatty acid binding channel. At the base of this cavity lies Cys61, which upon mutation to Ser confers drug-resistance in TB patients. We show that inhibitors bind in this cavity and protrude into the substrate binding channel. Thus, inhibitors of MtbHadAB exert their effect by occluding substrate from the active site. The unveiling of this mechanism of inhibition paves the way for accelerating development of next generation of anti-TB drugs.
Amino Acid Sequence ; Bacterial Proteins ; chemistry ; metabolism ; Catalytic Domain ; Enzyme Inhibitors ; chemistry ; pharmacology ; Flavonoids ; chemistry ; pharmacology ; Hydro-Lyases ; antagonists & inhibitors ; chemistry ; Molecular Sequence Data ; Mycobacterium tuberculosis ; drug effects ; enzymology ; Protein Binding ; drug effects ; Protein Multimerization ; drug effects ; Protein Structure, Secondary ; Sequence Alignment

BACKGROUND/AIMS: Epstein-Barr virus (EBV) is involved in the pathogenesis of angioimmunoblastic T-cell lymphoma (AILT), but its precise role and prognostic impact are not clear. This study aimed to evaluate the incidence of EBV-postitivity in the tumor and bone marrow (BM) samples from AILT patients, and their correlations with the clinical variables and patient survival. METHODS: Seventy AILT cases were identified over a period of 8 years. Twenty seven cases were investigated for their EBV tumor status, and 10 BM samples of these patients were investigated for their EBV status with using in situ hybridization (ISH). EBV PCR was performed for the BM mononuclear cells in 8 cases. RESULTS: Among the 27 tumor specimens, ten (37%) were EBV-positive. Only CD20-negativity in tumor correlated with the EBV-positivity (p=0.035). In 13 (48%) patients, gross tumor involvement was recognized by hematoxylin-eosin staining at the time of diagnosis. Among the 10 patients who had additional BM slides available, there were 3 with BM involvement, and none showed EBV positive results on ISH. EBV PCR of the BM mononuclear cells revealed one-positive case among 8 patients. This patient was negative for both BM involvement and EBV ISH. The median overall survival of the 25 treated patients was 48.9 months (95% CI: 18.6~79.2 months). Neither overall survival nor progression-free survival was related with EBV-positivity of the tumor. CONCLUSIONS: EBV-positivity of tumor had no impact on the prognosis of AILT patients.
Adolescent ; Adult ; Aged ; Bone Marrow/virology ; DNA, Viral/isolation & purification ; Female ; Herpesvirus 4, Human/*isolation & purification ; Humans ; Immunoblastic Lymphadenopathy/mortality/*virology ; In Situ Hybridization ; Lymphoma, T-Cell/mortality/*virology ; Male ; Middle Aged ; Polymerase Chain Reaction ; Prognosis ; Survival Analysis

Rituximab, a chimeric monoclonal antibody directed against CD20, has become a part of the standard therapy for patients with non-Hodgkin's lymphoma either in combination with other drugs or as a single agent. The CD20 antigen is expressed on 95% of B-cell lymphoma cells and normal B-cells but, is not found on precursor B-cells or stem cells. Rituximab is now approved for patients with diffuse large B-cell lymphoma when combined with standard CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine and prednisone) or patients with follicular lymphoma who have failed first line chemotherapy. The monoclonal antibody is generally well tolerated. Most of the adverse events are infusion-associated, mild to moderate non-hematological toxicities. Severe respiratory adverse events have been infrequent. Here, we report two patients with non-Hodgkin's lymphoma in whom interstitial pneumonitis developed with rituximab therapy.
Prednisolone/therapeutic use ; Methylprednisolone/therapeutic use ; Male ; Lung Diseases, Interstitial/*chemically induced/diagnosis/drug therapy ; Humans ; Antineoplastic Agents/*adverse effects ; Antibodies, Monoclonal/*adverse effects ; Aged

BACKGROUND: Small cell lung cancer (SCLC) is very sensitive to both chemotherapy and radiation therapy. In limited disease of SCLC, the addition of radiation therapy to chemotherapy improves survival and decrease local relapse over chemotherapy alone. This study evaluated the response rate, duration of response, overall survival and toxicity for the combination of etoposide, ifosfamide, carboplatin given concurrently with thoracic irradiation in limited SCLC. METHODS: Twenty eight patients with histologically proven SCLC who have a measurable disease and previously untreated, were enrolled in this study. Each cycle consisted of VP-16 100 mg/m2 IV days 1~3, ifosfamide 1,200 mg/m2 IV days 1~3 with mesna, carboplatin AUC 6 IV day 1. Cycles were repeated every 21days. Patients received a total of median 6,000 cGy thoracic radiation therapy (180~200 cGy/day) starting on the first day of chemotherapy. Prophylactic cranial irradiation was given to complete remission after chemoradiotherapy. RESULTS: The overall response rate in 27 evaluable patients was 93% (41% of complete response, 52% of partial response). The median time to progression was 10.3 months. The median disease free survival was 18.4 months in patients with complete response. The median overall survival was 16.7 months in all evaluable patients. Hematologic toxicities (> or = Grade3) of 129 cycles of chemotherapy were leukopenia in 38% and fever with infection in 26%. Nonhematologic toxicities (> or = Grade2) of evaluable 27 patients included alopecia in 11%, post-irradiation esophagitis in 44% and pneumonitis in 11%. CONCLUSIONS: VIC combination chemotherapy with concurrent thoracic irradiation is effective in limited SCLC. It's maior toxicity is myelosuppression.
Alopecia ; Area Under Curve ; Carboplatin* ; Chemoradiotherapy ; Cranial Irradiation ; Disease-Free Survival ; Drug Therapy ; Drug Therapy, Combination* ; Esophagitis ; Etoposide* ; Fever ; Humans ; Ifosfamide* ; Leukopenia ; Mesna ; Pneumonia ; Recurrence ; Small Cell Lung Carcinoma*