Objective:To explore the robust relationship between insomnia and type 2 diabetes mellitus by two-sample Mendelian randomization analysis to overcome confounding factors and reverse causality in observational studies.Methods:We identified strong,independent single nucleotide polymorphisms(SNPs)of insomnia from the most up to date genome wide association studies(GWAS)within European ancestors and applied them as instrumental variable to GWAS of type 2 diabetes mellitus.After excluding SNPs that were significantly associated with smoking,physical activity,alcohol consumption,educational attainment,obesity,or type 2 diabetes mellitus,we assessed the impact of insomnia on type 2 diabetes mellitus using inverse variance weighting(IVW)method.Weighted median and MR-Egger regression analysis were also conducted to test the robustness of the association.We calculated the F statistic of the selected SNPs to test the applicability of instrumental variable and F statistic over than ten indicated that there was little possibility of bias of weak instrumental variables.We further examined the existence of pleiotropy by testing whether the intercept term in MR-Egger regression was significantly different from ze-ro.In addition,the leave-one-out method was used for sensitivity analysis to verify the stability and relia-bility of the results.Results:We selected 248 SNPs independently associated with insomnia at the genome-wide level(P＜5 ×10-8)as a preliminary candidate set of instrumental variables.After clum-ping based on the reference panel from 1000 Genome Project and removing the potential pleiotropic SNPs,a total of 167 SNPs associated with insomnia were included as final instrumental variables.The F statistic of this study was 39.74,which was in line with the relevance assumption of Mendelian randomi-zation.IVW method showed insomnia was associated with higher risk of type 2 diabetes mellitus that po-pulation with insomnia were 1.14 times more likely to develop type 2 diabetes mellitus than those without insomnia(95％CI:1.09-1.21,P＜0.001).The weighted median estimator(WME)method and MR-Egger regression showed similar causal effect of insomnia on type 2 diabetes mellitus.And MR-Egger re-gression also showed that the effect was less likely to be triggered by pleiotropy.Sensitivity analyses pro-duced directionally similar estimates.Conclusion:Insomnia is a risk factor of type 2 diabetes mellitus,which has positively effects on type 2 diabetes mellitus.Our study provides further rationale for indivi-duals at risk for diabetes to keep healthy lifestyle.

Objective·To explore the role of advanced platelet-rich fibrin(A-PRF)in osteochondral regeneration.Methods·Bone-marrow mesenchymal stem cells(BMSCs)and knee joint chondrocytes were obtained from New Zealand rabbits.A-PRF was obtained by low-speed centrifugation of the heart blood of rabbits.The histological structure of A-PRF was observed by an optical microscope.The release of growth factors in A-PRF was detected by ELISA,including platelet-derived growth factor,transforming growth factor-β,insulin-like growth factor,vascular endothelial growth factor,epidermal growth factor and fibroblast growth factor.A-PRF's cytotoxicity and capability for promoting the proliferation of rabbit BMSCs were detected by live/dead double staining and MTT methods.The effect of A-PRF on the gene expression of type Ⅱ collagen,aggrecan,alkaline phosphatase(ALP)and osteocalcin(OCN)in rabbit BMSCs was detected by real-time fluorescence quantitative polymerase chain reaction(qRT-PCR).Transwell chambers were used to determine the effect of A-PRF on the migration ability of rabbit BMSCs and the chondrocytes.Rabbit knee osteochondral defect models were established,and 18 rabbits were randomly divided into 3 groups.The A-PRF group(n=6)was implanted with A-PRF in the defect,the A-PRF+BMSCs group(n=6)was implanted with rabbit BMSCs on A-PRF,and the control group(n=6)did not undergo implantation.The rabbits were sacrificed 12 weeks after surgery and the knee joint specimens were stained with hematoxylin-eosin(H-E),toluidine blue and safranin O/fast green.Based on the surface morphology and histology of the knee joints,the International Cartilage Repair Society(ICRS)scoring system was used for macroscopic and histological scoring.Results·A-PRF had a loose network structure and can slowly release growth factors.No cytotoxicity to rabbit BMSCs was observed after adding A-PRF,and the the capability for promoting the proliferation of rabbit BMSCs was significantly increased at 24,48 and 72 h after adding A-PRF(all P<0.05).Chondrogenesis-related gene Ⅱ collagen and aggrecan,as well as osteogenesis-related genes ALP and OCN were significantly up-regulated(all P<0.05).After adding A-PRF,the migration abilities of rabbit BMSCs and chondrocytes were significantly enhanced(both P<0.05),and the migration ability of rabbit BMSCs was significantly higher than that of chondrocytes(P=0.025).The joint surface morphology in the rabbit knee joint defect models was observed.It can be seen that the defects in the A-PRF group and the A-PRF+BMSCs group were basically restored,while the the defects in the control group were only covered by soft tissue.In the ICRS macroscopic score,there was no statistical difference between the A-PRF group and the A-PRF+BMSCs group,but the scores of the two groups were all significantly higher than those of the control group(all P<0.05).According to the histological results,both the A-PRF group and the A-PRF+BMSCs group formed osteochondral repair,but the cartilage in the A-PRF group was more mature,while the control group formed fibrous repair.In the ICRS histological score,there was no statistical difference between the A-PRF group and the A-PRF+BMSCs group,but the scores of both the groups were significantly higher than those of the control group(both P<0.05).Conclusion·Autologous A-PRF has good biocompatibility and the capability for promoting the proliferation of BMSCs.It can promote the repair of cartilage and subchondral bone both in vitro and in vivo.

BACKGROUND:Acupotomy is effective in the treatment of knee osteoarthritis,but its mechanism is not very clear. OBJECTIVE:To observe the effect of acupotomy on the apoptosis of knee chondrocytes in knee osteoarthritis rats based on osteoclast associated receptor(OSCAR)-tumor necrosis factor-associated apoptosis-inducing ligand(TRAIL)-osteoprotetin(OPG)pathway. METHODS:Twenty-seven Sprague-Dawley rats were randomly divided into normal group(n=9),model group(n=9)and acupotomy group(n=9).Rats in the normal group were routinely housed without any treatment.Animal models of knee osteoarthritis were established by knee injection of papain.Acupotomy intervention was performed 1 week after modeling,once a week for a total of three times.Relevant tests were performed at the end of the intervention. RESULTS AND CONCLUSION:The Lequesne MG behavioral scores of rats in the model group were elevated compared with the normal group(P<0.01),while the Lequesne MG behavioral scores of rats in the acupotomy group were decreased comparedwith the model group(P<0.01).Hematoxylin-eosin staining results showed that compared with the normal group,the cartilage surface of the rat's knee joints in the model group was worn and uneven and the chondrocytes were swollen,ruptured,reduced in number,and arranged disorderly;while the cartilage surface of the rat's knee joints in the acupotomy group was relatively smooth,and the chondrocytes were high in number and arranged in an orderly manner,with the structure basically clear.Immunohistochemical staining results showed that compared with the normal group,the positive expressions of OSCAR and TRAIL were increased in the model group(P<0.01),while the positive expression of OPG was decreased(P<0.01).Compared with the model group,the positive expressions of OSCAR and TRAIL in the acupotomy group were decreased(P<0.01),while the positive expression of OPG was increased(P<0.01).TUNEL staining results showed that compared with the normal group,the number of apoptotic cells in the model group were increased(P<0.01);compared with the model group,the number of apoptotic cells in the acupotomy group decreased(P<0.01).RT-qRCR and western blot results showed that compared with the normal group,the protein expressions of OSCAR,TRAIL and Bax in the model group were increased(P<0.01),and the protein expressions of OPG and Bcl-2 were decreased(P<0.01);compared with the model group,the protein expressions of OSCAR,TRAIL,and Bax in the acupotomy group were decreased(P<0.01),and the protein expressions of OPG and Bcl-2 were increased(P<0.01).To conclude,acupotomy can reduce cartilage injury of the knee joint in rats with knee osteoarthritis,which may be related to the blockage of mitochondrial pathway apoptotic signaling release by the OSCAR-TRAIL-OPG pathway.

BACKGROUND:This meta-analysis aimed to assess the efficacy of high-dose glucose-insulin-potassium(GIK)therapy on clinical outcomes in acute coronary syndrome(ACS)patients receiving reperfusion therapy. METHODS:We searched the PubMed,Web of Science,MEDLINE,Embase,and Cochrane Library databases from inception to April 26,2022,for randomized controlled trials(RCTs)that compared high-dose GIK and placebos in ACS patients receiving reperfusion therapy.The primary endpoint was major adverse cardiovascular events(MACEs). RESULTS:Eleven RCTs with 884 patients were ultimately included.Compared with placebos,high-dose GIK markedly reduced MACEs(risk ratio[RR]0.57,95％confidence interval[95％CI]:0.35 to 0.94,P=0.03)and the risk of heart failure(RR 0.48,95％CI:0.25 to 0.95,P=0.04)and improved the left ventricular ejection fraction(LVEF)(mean difference[MD]2.12,95％CI:0.40 to 3.92,P=0.02)at 6 months.However,no difference was observed in all-cause mortality at 30 d or 1 year.Additionally,high-dose GIK was significantly associated with increased incidences of phlebitis(RR 4.78,95％CI:1.36 to 16.76,P=0.01),hyperglycemia(RR 9.06,95％CI:1.74 to 47.29,P=0.009)and hypoglycemia(RR 6.50,95％CI:1.28 to 33.01,P=0.02)but not reinfarction,hyperkalemia or secondary reperfusion.In terms of oxidative stress-lowering function,high-dose GIK markedly reduced superoxide dismutase(SOD)activity but not glutathione peroxidase(GSH-Px)or catalase(CAT)activity. CONCLUSION:Patients with ACS receiving reperfusion therapy exhibited a reduction in MACEs and good oxidative stress-lowering efficacy in response to high-dose GIK.Moreover,with a higher incidence of complications such as phlebitis,hyperglycemia,and hypoglycemia.Furthermore,there were no observed survival benefits associated with high-dose GIK.More trials with long-term follow-up are still needed.

Objective To explore the mechanism underlying the protective effect of α2-macroglobulin (A2M) against glucocorticoid-induced femoral head necrosis. Methods In a human umbilical vein endothelial cell (HUVEC) model with injuries induced by gradient concentrations of dexamethasone (DEX;10-8-10-5 mol/L), the protective effects of A2M at 0.05 and 0.1 mg/mL were assessed by examining the changes in cell viability, migration, and capacity of angiogenesis using CCK-8 assay, Transwell and scratch healing assays and angiogenesis assay. The expressions of CD31 and VEGF-A proteins in the treated cells were detected using Western blotting. In BALB/c mouse models of avascular necrosis of the femoral head induced by intramuscular injections of methylprednisolone, the effects of intervention with A2M on femoral trabecular structure, histopathological characteristics, and CD31 expression were examined with Micro-CT, HE staining and immunohistochemical staining. Results In cultured HUVECs, DEX treatment significantly reduced cell viability, migration and angiogenic ability in a concentration- and time-dependent manner (P<0.05), and these changes were obviously reversed by treatment with A2M in positive correlation with A2M concentration (P<0.05). DEX significantly reduced the expression of CD31 and VEGF-A proteins in HUVECs, while treatment with A2M restored CD31 and VEGF-A expressions in the cells (P<0.05). The mouse models of femoral head necrosis showed obvious trabecular damages in the femoral head, where a large number of empty lacunae and hypertrophic fat cells could be seen and CD31 expression was significantly decreased (P<0.05). A2M treatment of the mouse models significantly improved trabecular damages, maintained normal bone tissue structures, and increased CD31 expression in the femoral head (P<0.05). Conclusion A2M promotes proliferation, migration, and angiogenesis of DEX-treated HUVECs and alleviates methylprednisolone-induced femoral head necrosis by improving microcirculation damages and maintaining microcirculation stability in the femoral head.

Objective To evaluate the clinical efficacy and safety of intensive insulin therapy in the pa-tients with acute myocardial infarction and provide guidance for improving the prognosis.Methods The articles involving the randomized controlled trials(RCT)focusing on the effects of intensive versus conventional insulin therapy on the clinical outcomes of the patients with acute myocardial infarction were retrieved from Cochrane,Embase,PubMed,CNKI,Wanfang Data,VIP,and CBM with the time interval from inception to October 2022.The data of each RCT were extracted and used for meta-analysis in RevMan5.4.Results A total of 8 arti-cles were included in this study,involving 726 patients(372 in the intensive insulin group and 354 in the nor-mal insulin group).The meta-analysis results showed that the intensive insulin group had lower incidence of major cardiovascular adverse events(RR =0.53,95%CI =0.44-0.64,P<0.001),lower all-cause mortality(RR = 0.51,95%CI =0.33-0.78,P =0.002),lower high-sensitivity C-reactive protein level on day 7(WMD =-2.00,95%CI =-2.17--1.83,P<0.001),higher left ventricular ejection fraction on day 30(WMD = 3.94,95%CI =2.45-5.43,P<0.001),and higher incidence of hypoglycemia events(RR =2.96,95%CI =1.12-7.83,P =0.030)than the normal insulin group.There was no significant difference between the two groups in terms of no-reflow event after percutaneous coronary intervention(RR =0.39,95%CI =0.14-1.13,P =0.080).Conclusion Intensive insulin therapy might be associated with more clinical benefits in the patients with acute myocardial infarction,while the conclusion remains to be confirmed by more studies.

BACKGROUND:This meta-analysis aimed to assess the efficacy of high-dose glucose-insulin-potassium(GIK)therapy on clinical outcomes in acute coronary syndrome(ACS)patients receiving reperfusion therapy. METHODS:We searched the PubMed,Web of Science,MEDLINE,Embase,and Cochrane Library databases from inception to April 26,2022,for randomized controlled trials(RCTs)that compared high-dose GIK and placebos in ACS patients receiving reperfusion therapy.The primary endpoint was major adverse cardiovascular events(MACEs). RESULTS:Eleven RCTs with 884 patients were ultimately included.Compared with placebos,high-dose GIK markedly reduced MACEs(risk ratio[RR]0.57,95％confidence interval[95％CI]:0.35 to 0.94,P=0.03)and the risk of heart failure(RR 0.48,95％CI:0.25 to 0.95,P=0.04)and improved the left ventricular ejection fraction(LVEF)(mean difference[MD]2.12,95％CI:0.40 to 3.92,P=0.02)at 6 months.However,no difference was observed in all-cause mortality at 30 d or 1 year.Additionally,high-dose GIK was significantly associated with increased incidences of phlebitis(RR 4.78,95％CI:1.36 to 16.76,P=0.01),hyperglycemia(RR 9.06,95％CI:1.74 to 47.29,P=0.009)and hypoglycemia(RR 6.50,95％CI:1.28 to 33.01,P=0.02)but not reinfarction,hyperkalemia or secondary reperfusion.In terms of oxidative stress-lowering function,high-dose GIK markedly reduced superoxide dismutase(SOD)activity but not glutathione peroxidase(GSH-Px)or catalase(CAT)activity. CONCLUSION:Patients with ACS receiving reperfusion therapy exhibited a reduction in MACEs and good oxidative stress-lowering efficacy in response to high-dose GIK.Moreover,with a higher incidence of complications such as phlebitis,hyperglycemia,and hypoglycemia.Furthermore,there were no observed survival benefits associated with high-dose GIK.More trials with long-term follow-up are still needed.

BACKGROUND:This meta-analysis aimed to assess the efficacy of high-dose glucose-insulin-potassium(GIK)therapy on clinical outcomes in acute coronary syndrome(ACS)patients receiving reperfusion therapy. METHODS:We searched the PubMed,Web of Science,MEDLINE,Embase,and Cochrane Library databases from inception to April 26,2022,for randomized controlled trials(RCTs)that compared high-dose GIK and placebos in ACS patients receiving reperfusion therapy.The primary endpoint was major adverse cardiovascular events(MACEs). RESULTS:Eleven RCTs with 884 patients were ultimately included.Compared with placebos,high-dose GIK markedly reduced MACEs(risk ratio[RR]0.57,95％confidence interval[95％CI]:0.35 to 0.94,P=0.03)and the risk of heart failure(RR 0.48,95％CI:0.25 to 0.95,P=0.04)and improved the left ventricular ejection fraction(LVEF)(mean difference[MD]2.12,95％CI:0.40 to 3.92,P=0.02)at 6 months.However,no difference was observed in all-cause mortality at 30 d or 1 year.Additionally,high-dose GIK was significantly associated with increased incidences of phlebitis(RR 4.78,95％CI:1.36 to 16.76,P=0.01),hyperglycemia(RR 9.06,95％CI:1.74 to 47.29,P=0.009)and hypoglycemia(RR 6.50,95％CI:1.28 to 33.01,P=0.02)but not reinfarction,hyperkalemia or secondary reperfusion.In terms of oxidative stress-lowering function,high-dose GIK markedly reduced superoxide dismutase(SOD)activity but not glutathione peroxidase(GSH-Px)or catalase(CAT)activity. CONCLUSION:Patients with ACS receiving reperfusion therapy exhibited a reduction in MACEs and good oxidative stress-lowering efficacy in response to high-dose GIK.Moreover,with a higher incidence of complications such as phlebitis,hyperglycemia,and hypoglycemia.Furthermore,there were no observed survival benefits associated with high-dose GIK.More trials with long-term follow-up are still needed.

BACKGROUND:This meta-analysis aimed to assess the efficacy of high-dose glucose-insulin-potassium(GIK)therapy on clinical outcomes in acute coronary syndrome(ACS)patients receiving reperfusion therapy. METHODS:We searched the PubMed,Web of Science,MEDLINE,Embase,and Cochrane Library databases from inception to April 26,2022,for randomized controlled trials(RCTs)that compared high-dose GIK and placebos in ACS patients receiving reperfusion therapy.The primary endpoint was major adverse cardiovascular events(MACEs). RESULTS:Eleven RCTs with 884 patients were ultimately included.Compared with placebos,high-dose GIK markedly reduced MACEs(risk ratio[RR]0.57,95％confidence interval[95％CI]:0.35 to 0.94,P=0.03)and the risk of heart failure(RR 0.48,95％CI:0.25 to 0.95,P=0.04)and improved the left ventricular ejection fraction(LVEF)(mean difference[MD]2.12,95％CI:0.40 to 3.92,P=0.02)at 6 months.However,no difference was observed in all-cause mortality at 30 d or 1 year.Additionally,high-dose GIK was significantly associated with increased incidences of phlebitis(RR 4.78,95％CI:1.36 to 16.76,P=0.01),hyperglycemia(RR 9.06,95％CI:1.74 to 47.29,P=0.009)and hypoglycemia(RR 6.50,95％CI:1.28 to 33.01,P=0.02)but not reinfarction,hyperkalemia or secondary reperfusion.In terms of oxidative stress-lowering function,high-dose GIK markedly reduced superoxide dismutase(SOD)activity but not glutathione peroxidase(GSH-Px)or catalase(CAT)activity. CONCLUSION:Patients with ACS receiving reperfusion therapy exhibited a reduction in MACEs and good oxidative stress-lowering efficacy in response to high-dose GIK.Moreover,with a higher incidence of complications such as phlebitis,hyperglycemia,and hypoglycemia.Furthermore,there were no observed survival benefits associated with high-dose GIK.More trials with long-term follow-up are still needed.

BACKGROUND:This meta-analysis aimed to assess the efficacy of high-dose glucose-insulin-potassium(GIK)therapy on clinical outcomes in acute coronary syndrome(ACS)patients receiving reperfusion therapy. METHODS:We searched the PubMed,Web of Science,MEDLINE,Embase,and Cochrane Library databases from inception to April 26,2022,for randomized controlled trials(RCTs)that compared high-dose GIK and placebos in ACS patients receiving reperfusion therapy.The primary endpoint was major adverse cardiovascular events(MACEs). RESULTS:Eleven RCTs with 884 patients were ultimately included.Compared with placebos,high-dose GIK markedly reduced MACEs(risk ratio[RR]0.57,95％confidence interval[95％CI]:0.35 to 0.94,P=0.03)and the risk of heart failure(RR 0.48,95％CI:0.25 to 0.95,P=0.04)and improved the left ventricular ejection fraction(LVEF)(mean difference[MD]2.12,95％CI:0.40 to 3.92,P=0.02)at 6 months.However,no difference was observed in all-cause mortality at 30 d or 1 year.Additionally,high-dose GIK was significantly associated with increased incidences of phlebitis(RR 4.78,95％CI:1.36 to 16.76,P=0.01),hyperglycemia(RR 9.06,95％CI:1.74 to 47.29,P=0.009)and hypoglycemia(RR 6.50,95％CI:1.28 to 33.01,P=0.02)but not reinfarction,hyperkalemia or secondary reperfusion.In terms of oxidative stress-lowering function,high-dose GIK markedly reduced superoxide dismutase(SOD)activity but not glutathione peroxidase(GSH-Px)or catalase(CAT)activity. CONCLUSION:Patients with ACS receiving reperfusion therapy exhibited a reduction in MACEs and good oxidative stress-lowering efficacy in response to high-dose GIK.Moreover,with a higher incidence of complications such as phlebitis,hyperglycemia,and hypoglycemia.Furthermore,there were no observed survival benefits associated with high-dose GIK.More trials with long-term follow-up are still needed.