Osteoarthritis (OA), the most prevalent joint disease of late life, is closely linked to cellular senescence. Previously, we found that the senescence of fibroblast-like synoviocytes (FLS) played an essential role in the degradation of cartilage. In this work, single-cell sequencing data further demonstrated that cartilage acidic protein 1 (CRTAC1) is a critical secreted factor of senescent FLS, which suppresses mitophagy and induces mitochondrial dysfunction by regulating SIRT3 expression. In vivo, deletion of SIRT3 in chondrocytes accelerated cartilage degradation and aggravated the progression of OA. Oppositely, intra-articular injection of adeno-associated virus expressing SIRT3 effectively alleviated OA progression in mice. Mechanistically, we demonstrated that elevated CRTAC1 could bind with NRF2 in chondrocytes, which subsequently suppresses the transcription of SIRT3 in vitro. In addition, SIRT3 reduction could promote the acetylation of FOXO3a and result in mitochondrial dysfunction, which finally contributes to the degradation of chondrocytes. To conclude, this work revealed the critical role and underlying mechanism of senescent FLSs-derived CRTAC1 in OA progression, which provided a potential strategy for the OA therapy.

"Tendon Constraining Bone"is an essential theory in osteology and traumatology of traditional Chinese medicine,originating from the statement in Suwen(Plain Questions)that"convergent tendon controlling bones and joints".Since the Yuan and Ming dynasties,the theory of"Tendon Constraining Bone"was formed based on the understanding of anatomical relationships and the need for pathogenesis interpretation,developed by medical practitioners such as ZHU Danxi and ZHANG Jie.The"Tendon Constraining Bone"theory summarizes the physiological connections between tendons and bones and between tendons and zang-fu organs and meridians.Tendons and bones are structurally connected and functionally related,reflected in sturdy bones and tough tendons,upright bones and soft tendons with smoothly-flowing qi and blood,all tendons being related to joints,and thews being related to bones.Tendons and bones are related by meridians and zang-fu organs,specifically reflected in the Yangming channel governing the nourishment of tendons,liver governing tendons,kidneys governing bones,Taiyang channel governing tendons,and Shaoyang channel governing bones.The abnormality of"Tendon Constraining Bone"is the general pathogenesis of various tendon and bone diseases,and it can be caused by changes in the tendon and bone structure,nourishment deficiency,or the pathogenic qi retention.The pathological manifestations of abnormal"Tendon Constraining Bone"are manifested in form and state.Abnormalities in form can manifest as tendon rupture,bone fractures,tendon dislocation,and bone dislocation,whereas abnormalities in state can manifest as tendon urgency,bone pain,tendon laxity,and bone softness.The"Tendon Constraining Bone"theory has influenced the development of treatment principles such as combining motion and quiescence,paying equal attention to bone and flesh,and combining internal and external treatment.This theory has guided the application of basic treatment method such as connecting and rectifying tendons and bones,smoothing tendons and relieving bones,and nourishing tendons and strengthening bones.Therefore,the"Tendon Constraining Bone"theory can significantly guide tendon and bone disease diagnosis and treatment.

Patients with severe tumors do not refer to the patients with end-stage tumors,but rather to the patients with a performance status(PS)score between 2 and 4 in certain stages due to various reasons,such as acute or chronic comorbidities,tumor itself,or treatment-related adverse events.To these patients,there is a high probability of achieving survival benefit and/or improvement in PS scores after synergistic management of available life-support technologies and anti-tumor therapies based on dynamic and precise testing.Elderly patients with tumors frequently present with one or more chronic illnesses and have poor toler-ance and compliance to treatment.Moreover,their treatment regimens often lack high-quality clinical evidence,making them more susceptible to developing severe tumors.The management of severe tumors in the elderly is based on three basic diagnosis and treatment technologies:dynamic and precise detection,powerful life support technologies,and skillful application of current anti-tumor treatments.In specific clinical practice,the following 7 flexible and individualized treatment strategies should be adopted for different tumor types:1.concurrent management of cancer and comorbidities,2.upgrading and downgrading of anti-tumor drugs based on PS score,3.dynamic accurate detection,4.skillful combinations for increasing efficacy and reducing toxicity,5.complete overview,paying equal attention to systemic therapy and local therapy,6.safety first in medication for the elderly,7.multi-discipli-nary participation,individualized and comprehensive treatment.This article introduced the concept of severe tumors in the elderly and the associated management strategies,to increase awareness and provide feasible guidance for clinical practice.

Objective To investigate the differences in blood pressure phenotypes,renal pathological changes,and related pathogenic pathways in genetically diverse hypertensive mice obtained from 13 strains.Methods The genotypes of Cckbr+/+,Cckbr+/-and Cckbr-/-were obtained by hybridization of 13 strains of genetically diverse mice with Cckbr-/-mice.Blood pressure was measured with a noninvasive blood pressure analysis system(BP-2000).The expression of CCKBR protein in mouse kidney tissue was detected by Western Blot,and the pathological changes in mouse kidney tissue were detected by hematoxylin-eosin(HE)staining and immunohistochemistry(IHC).The pathogenic pathways related to essential hypertension were screened by RNA sequencing.Results In three specific mouse strains(A/J,LOT,and FIM),the systolic blood pressure(SBP)was significantly different between the Cckbr-/-and Cckbr+/+groups.HE staining and IHC showed that hypertension caused a certain degree of renal injury in the mice.Gene Ontology(GO)and pathway enrichment analysis showed that differentially expressed genes were enriched in metabolic processes and circadian rhythm regulation.Conclusions Genetically diverse mice can effectively simulate the genetic background of the population and provide a new resource for studying the pathogenic genes related to essential hypertension.

Objective To observe the effect of microRNA-155 (miR-155) on the inflammatory response of rat alveolar macrophages induced by lipopolysaccharide (LPS). Methods The alveolar macrophages NR8383 of rat were cultured in vitro, the macrophages in logarithmic growth phase were harvested to conduct experiment. ① The 1 mg/L LPS was used to stimulate the rat alveolar macrophages for 3, 6, 12, and 24 hours, a phosphate buffer solution (PBS) control group was also set up. Enzyme linked immunosorbent assay (ELISA) was used to detect the dynamic changes of interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) in the supernatant, and real-time quantitative reverse transcription-polymerase chain reaction (RT-qPCR) was used to detect the dynamics expression of miR-155 in the cells, which confirmed the optimal time for LPS stimulation was 12 hours. ② Carboxyfluorescein (FAM) labeled mimic (FAM mimic) and inhibitor (FAM inhibitor) were used to transfect the alveolar macrophage, and the transfection effect was observed under inverted fluorescence microscope 6 hours later to confirm the optimal transfection concentration of mimic was 20 nmol/L, and the optimal transfection concentration of inhibitor was 100 nmol/L. miR-155 mimic and miR-155 inhibitor were transfected to alveolar macrophages respectively at the optimal transfection concentration for 24 hours, and 1 mg/L LPS was used to stimulate the cells for 12 hours. A mimic negative control + LPS group and an inhibitor negative control + LPS group were set up. The expressions of IL-1β and TNF-α in the supernatant were determined by ELISA to observe the regulation of miR-155 on inflammatory response of alveolar macrophages. Results ① After stimulation of 1 mg/L LPS on alveolar macrophages, the contents of IL-1β and TNF-α in the supernatant and the expression of miR-155 in the cells were increased gradually with time prolongation, IL-1β and TNF-α contents peaked at 12 hours, and the expression of miR-155 peaked at 24 hours [as compared with PBS control group, IL-1β (ng/L): 910.43±36.09 vs. 22.66±7.84, TNF-α (ng/L): 3 138.39±394.10 vs. 233.92±8.84, miR-155 (2-ΔΔCt): 7.82±0.30 vs. 1, all P < 0.05]. ② Under inverted fluorescence microscope, after 20 nmol/L FAM mimic or 100 nmol/L FAM inhibitor transfected alveolar macrophages for 6 hours, a large number of cells showed green fluorescence, indicating that the transfection was successful. The expression of miR-155 in the cells transfected with 20 nmol/L miR-155 mimic was up-regulated by (236.73±46.49) times as much as that in the negative control group (P < 0.05), and the levels of IL-1β and TNF-α in the supernatant of the cells stimulated by 1 mg/L LPS for 12 hours were significantly lower than those in the negative control group [IL-1β (ng/L): 324.37±36.59 vs. 799.31±39.44, TNF-α (ng/L): 1 554.01±342.48 vs. 3 020.49±418.30, both P < 0.05]. The miR-155 activity was significantly inhibited in the cells transfected with 100 nmol/L miR-155 inhibitor, and the expression of miR-155 was decreased by (4.00±3.26)% as compared with the negative control group, but the difference was not statistically significant (P > 0.05), and the levels of IL-1β and TNF-α in the supernatant of the cells stimulated by 1 mg/L LPS for 12 hours were significantly higher than those in the negative control group [IL-1β (ng/L): 1 358.98±212.04 vs. 878.68±53.42, TNF-α (ng/L): 4 225.57±281.11 vs. 2 881.32±286.08, both P < 0.05]. Conclusion In LPS induced inflammatory response of alveolar macrophages, miR-155 plays an obvious inhibitory role.

Most of the current experiments are obsolete and verified,the students are not interested in and the experiments are out of touch with the actual work.These are the common problems in the experiment teaching of occupational health and occupational medicine.By taking the students who majored in preventive medicine as the subjects,this study aimed to explore the effects of independent designed experiment teaching mode,which was based on dividing the groups before class,choosing the projects by students themselves,deciding the design of the program via the discussion of teacher and students and doing the experimental reports and sharing the experience.The results showed that,in the premise of the preliminary master of the theory and basic skills of occupational health and occupational medicine,carrying out independent designed experiments in the last three weeks of semester,to a certain extent,could arouse students' interest in learning,cultivate their abilities of independent thinking,practice,problem analysis and solution,and team cooperation.However,restricted by lack of teachers,inadequate equipment and high cost and other factors,this teaching mode is only suitable for small class.

Objective: To analyze the treatment of advanced non-small cell lung cancer (NSCLC) with performance status (PS) scores between 2 and 4, in order to improve the diagnosis and treatment of these patients. Methods: A total of 36 patients with advanced NSCLC with hypoxemia were reviewed. The clinical data of disease characteristics, etiology, complications, manifestation, therapy, progression, and secondary biopsy were collected. The clinical efficacy was graded according to the Response Evaluation Criteria In Solid Tumors (RECIST): complete response (CR), partial response (PR), stable disease (SD) and disease progression (PD). Results: All patients had hypoxemia, of whom 86.1% (31 patients) had complications and 55.6% (20 patients) had noninvasive ventilator for respiratory support. 77.8% (28 cases) received broad-spectrum antibiotic treatment, and 78.6% of them got lung osmotic relief after the anti-infection treatment. 15 cases received bedside fiberoptic bronchoscopy suction, of whom two cases were treated with airway stent deposition due to airway obstruction, four cases with thoracic drainage, four cases with anticoagulation, and one with thrombolytic therapy. After these supportive treatment, the PS score of these patients decreased from 3.4±0.5 to 2.5±0.7, while SPO₂ improved from (89.0±5.2)% to (95.0±3.5)%. As first-ling anti-cancer treatment, nine patients were administrated with targeted medicine orally, 13 patients with a combined chemotherapy of pemetrexed plus bevacizumab or carboplatin, eight patients with paclitaxel plus carboplatin, four patients with gemcitabine plus carboplatin, and two patients with docetaxel plus gemcitabine. In the first response evaluation, there were one case of CR, 23 cases of PR, four cases of SD, and eight cases of PD, with a clinical benefit rate of 66.7% and a disease control rate of 77.8%. A total of 22 patients experienced disease progression, of whom eight cases had a secondary biopsy and six cases had gene sequencing. Of these 36 patients, 10 (27.8%) patients survived at the last follow-up, with a progression-free survival of (10.0±6.5) months. Conclusion Besides prompt anti-cancer treatment and best supportive treatment should be incorporated to improve PS and improve outcome.

OBJECTIVETo analyze the clinical efficacy and toxicity of vitamin support in lung adenocarcinoma patients treated with pemetrexed second-line chemotherapy.

METHODSTwo hundred and eighty-three patients with stage 3/4 lung adenocarcinoma treated at our hospital from August 2010 to August 2013 were included in this study. The lung adenocarcinomas in all the 283 patients were confirmed by pathology or cytology, all were EGFR-negative, and all patients received pemetrexed second line chemotherapy. The 283 patients were randomly divided into two groups: the improved treatment group (142 cases) and the conventional treatment group (141 cases). The patients of conventional treatment group received 400 µg folic acid per os daily for 7 days before the first dose of pemetrexed, and continued until 21 days after the last dose of pemetrexed. Besides, they received 1000 µg vitamin B12 injection at 7 days before the first dose of pemetrexed, and once per cycle of pemetrexed for 3 cycles after the last dose of pemetrexed. The patients of the improved treatment group took 400 µg folic acid daily per os from the day before the first dose to 21 days after the last dose of pemetrexed. They also received 500 µg vitamin B12 by injection one day before the first dose, and one day before each therapy cycle of pemetrexed therapy.

RESULTSThe mean number of cycles of pemetrexed chemotherapy was 4 in both groups. In the 142 patients of improved treatment group, complete response (CR) was observed in two cases, partial remission (PR) in 28, stable disease (SD) in 21, and progressive disease (PD) in 91 cases, with a total effective rate of 21.1%. While in the conventional treatment group, CR was observed in one case, PR in 27 cases, SD in 23 cases, and PD in 90 cases, with a total effective rate of 19.9%. The median progression-free survival (PFS) was 3.8 months in the improved treatment group and 4.2 months in the conventional treatment group (P=0.143). The toxicity of chemotherapy was mild in both groups, with no significant difference between the two groups (P>0.05). The most common side effects of hematological system were leukopenia and neutropenia, and the most common side effects of non-blood system were nausea and vomiting. The most common grade 3-4 toxic reaction in both groups was leukopenia and neutropenia, with no significant difference between the two groups (P>0.05). Multivariate analysis showed that the age of patients was an independent factor of grade 3-4 chemotherapy toxic reaction (P<0.05), while gender, the baseline level of PS score or blood system had no significant effect on the grade 3-4 chemotherapy toxic reaction (P>0.05).

CONCLUSIONSCompared with the conventional treatment scheme, the improved treatment scheme has similar therapeutic effects and could be used more conveniently, while the toxic effects of chemotherapy are not increased at the same time. Our results indicate that pemetrexed-based chemotherapy does not need to delay the chemotherapy because of vitamin support treatment.

Adenocarcinoma ; drug therapy ; Antineoplastic Agents ; therapeutic use ; Disease-Free Survival ; Folic Acid ; therapeutic use ; Humans ; Lung Neoplasms ; drug therapy ; Pemetrexed ; therapeutic use ; Treatment Outcome ; Vitamin B 12 ; therapeutic use ; Vitamin B Complex ; therapeutic use

Objective To explore the CT appearance of thoracic lymphonodus in AIDS patients with immune reconstitution in-flammatory syndrome(IRIS)after highly active antiretroviral therapy (HAART).Methods The data of thoracic CT in 24 AIDS pa-tients after HAART with enlarged thoracic lymphonodus in IRIS were collected,and the chest CT appearance was analyzed.Results Of the 24 cases of AIDS patients with IRIS after HAART,1 9 cases were complicated with pulmonary tuberculosis,which includ-ed 5 cases with cervical tuberculous lymphadenitis,3 cases were co-infected with bacterium and fungi,1 case was infected by penicil-lium marneffei,1 case by pneumocystis carinii.The enlarged thoracic lymphonodus were primarily located in 4R region(20/24), secondly in 2R region(1 1/24)and 4L region(1 1/24),in which the density was uniform or non-uniform,edge clear or unclear,some parts of lymphonodus were fused together but not calcified.The minor axis of enlarged lymphonodus was 1 1.0-25.0 mm except X region,enhanced uniformly in 2 cases.Obstructive pneumonia and pulmonary consolidation were found in 2 cases with enlarged lym-phonodus,which were located in 10R region.Pleural effusion was found in 13 cases with greatest depth of about 22 mm,pericardial effusion was found in 5 cases with greatest depth of about 24 mm.Conclusion The enlarged thoracic lymphonodus in AIDS patients with IRIS affer HAART are mainly involved in the region of 4R,2R and 4L,with or without pleural effusion and pericardial effusion.

Objective To study the risk factors of severe hand-foot-mouth disease (HFMD) among children.Methods The clinical data of 1 570 children with HFMD at Linyi People's Hospital in Shandong Province in 2011 were collected,retrospectively.The data were analyzed using univariate and multivariate Logistic regression.Results The mean age of severe HFMD (including severe and critical HFMD) was (25.0± 14.0) months old,predominantely aged between 1 and 5 years old,while mild HFMD was (27.1±15.8) months (t'=-2.717,P=0.007).There were 61.0％ and 65.9％ boys in two groups,respectively (x2 =3.894,P=0.048).Fever,convulsion,tremor,nausea and vomiting were more frequently seen in severe HFMD.The neutrophil count and the level of creatine kinase in severe HFMD were both significantly higher than that in mild HFMD.Univariate analysis revealed that age (odds ratio [OR]=1.799,95％CI:0.984-1.997),girl sex (OR=1.234,95％CI:1.001-1.522),high fever (OR=2.110,95％CI:1.816-2.452),convulsion (OR=1.878,95％CI:1.578-2.236),nausea and vomiting (OR=1.760,95％CI:1.456-2.128),neutrophil count (OR=1.031,95％CI:1.025-1.037) and creatine kinase (OR=1.002,95％CI:1.001-1.003) were risk factors for severe HFMD.Multivariate Logistic regression showed that high fever (OR =1.751,95％ CI:1.487-2.062),convulsion (OR=1.451,95％CI:1.204-1.749),nausea and vomiting (OR=1.269,95％CI:1.027-1.568),neutrophil count (OR=1.028,95％CI:1.021-1.035) were independent risk factors.Conclusions Body temperature,neurological manifestations and trend of neutrophil counts should be carefully monitored in children with HFMD.Prevention of the development of severe HFMD mainly relies on the identification of risk factors and adoption of precautions in time.