Treadmill exercise exerts a synergistic effect with bone marrow mesenchymal stem cell-derived exosomes on neuronal apoptosis and synaptic-axonal remodeling

Treadmill exercise and mesenchymal stem cell transplantation are both practical and effective methods for the treatment of cerebral ischemia.However,whether there is a synergistic effect between the two remains unclear.In this study,we established rat models of ischemia/reperfusion injury by occlusion of the middle cerebral artery for 2 hours and reperfusion for 24 hours.Rat models were perfused with bone marrow mesenchymal stem cell-derived exosomes(MSC-exos)via the tail vein and underwent 14 successive days of treadmill exercise.Neurological assessment,histopathology,and immunohistochemistry results revealed decreased neuronal apoptosis and cerebral infarct volume,evident synaptic formation and axonal regeneration,and remarkably recovered neurological function in rats subjected to treadmill exercise and MSC-exos treatment.These effects were superior to those in rats subjected to treadmill exercise or MSC-exos treatment alone.Mechanistically,further investigation revealed that the activation of JNK1/c-Jun signaling pathways regulated neuronal apoptosis and synaptic-axonal remodeling.These findings suggest that treadmill exercise may exhibit a synergistic effect with MSC-exos treatment,which may be related to activation of the JNK1/c-Jun signaling pathway.This study provides novel theoretical evidence for the clinical application of treadmill exercise combined with MSC-exos treatment for ischemic cerebrovascular disease.

The effect of fasting plasma glucose on in-hospital mortality after acute myocardial infarction in patients with and without diabetes:findings from a prospective,nationwide,and multicenter registry

OBJECTIVES To evaluate the predictive value of fasting plasma glucose(FPG)for in-hospital mortality in patients with acute myocardial infarction(AMI)with different glucose metabolism status.METHODS We selected 5,308 participants with AMI from the prospective,nationwide,multicenter CAMI registry,of which 2,081 were diabetic and 3,227 were nondiabetic.Patients were divided into high FPG and low FPG groups according to the optim-al cutoff values of FPG to predict in-hospital mortality for diabetic and nondiabetic cohorts,respectively.The primary endpoint was in-hospital mortality.RESULTS Overall,94 diabetic patients(4.5%)and 131 nondiabetic patients(4.1%)died during hospitalization,and the optimal FPG thresholds for predicting in-hospital death of the two cohorts were 13.2 mmol/L and 6.4 mmol/L,respectively.Compared with individuals who had low FPG,those with high FPG were significantly associated with higher in-hospital mortality in diabet-ic cohort(10.1%vs.2.8%;odds ratio[OR]=3.862,95%confidence interval[CI]:2.542-5.869)and nondiabetic cohort(7.4%vs.1.7%;HR=4.542,95%CI:3.041-6.782).After adjusting the potential confounders,this significant association was not changed.Further-more,FPG as a continuous variable was positively associated with in-hospital mortality in single-variable and multivariable models regardless of diabetic status.Adding FPG to the original model showed a significant improvement in C-statistic and net reclassification in diabetic and nondiabetic cohorts.CONCLUSIONS This large-scale registry indicated that there is a strong positive association between FPG and in-hospital mor-tality in AMI patients with and without diabetes.FPG might be useful to stratify patients with AMI.

Resolution of siderotic glaucoma correlated with decreased pigmentation in the anterior chamber angle after removal of a retained ferrous foreign body

Dear Sir,I am Dr.Zhe Xu,from the Eye Center,Second Affiliated Hospital,School of Medicine,Zhejiang University,Hangzhou,China.We write to present a case of resolution of siderotic glaucoma after removal of a retained ferrous foreign body.This study has been performed in accordance with the Declaration of Helsinki and was approved by the Ethics Committee of the Second Affiliated Hospital.

Chinese Medicine for Idiopathic Parkinson's Disease:A Meta Analysis of Randomized Controlled Trials

Objective：To evaluate the efficacy of Chinese medicine（CM）adjunct to conventional medications for idiopathic Parkinson’s disease（PD）.Methods：Electronic English and Chinese databases including Pub Med,Cochrane Library,Web of Science,Chinese Medical Current Contents,China National Knowledge Infrastructure,China Science and Technology Journal Database,Wanfang Med Database,and Traditional Chinese Medical Database System were used for key words searching in a highly sensitive search strategy.The extracted data was analyzed by the Review Manager 5.0.Results：Twelve trials involving 869 participants were included in the meta-analysis.Unified PD Rating Scale（UPDRS）Ⅰ,Ⅱ,Ⅲ,Ⅳscores and UPDRSⅠ–Ⅳtotal scores were used to be the primary outcomes,Parkinson Disease Question-39（PDQ-39）and Scores of Chinese Medical Symptoms were the secondary outcomes.CM adjunct therapy had greater improvement in UPDRSⅠ[2 trials;standardized mean difference（SMD）–0.40,95%confidence interval（CI）–0.71 to–0.09;Z=2.49（P=0.01）],Ⅱ[5 trials;SMD–0.47,95%CI–0.69 to–0.25;Z=4.20（P〈0.01）],Ⅲ[5 trials;SMD-0.35,95%CI–0.57 to–0.13;Z=3.16（P=0.002）],Ⅳscores[3 trials;SMD-0.32,95%CI–0.60 to–0.03;Z=2.17（P=0.03）],UPDRSⅠ–Ⅳtotal scores[7 trials;SMD-0.36,95%CI–0.53 to–0.20;Z=4.24（P〈0.05）].PDQ-39 and Chinese medical symptoms compared to the conventional medication only.Conclusion：CM adjunct therapy has potential therapeutic benefits by decreasing UPDRS scores and reducing adverse effect.

Sleep fragmentation as an important clinical characteristic of sleep disorders in Parkinson's disease: a preliminary study

Background:Sleep disorders are one of the earliest non-motor symptoms of Parkinson's disease (PD).Sleep disorders could,therefore,have value for recognition and diagnosis in PD.However,no unified classification and diagnostic criteria exist to evaluate sleep disorders by polysomnography (PSG).Utilizing PSG to monitor sleep processes of patients with PD and analyze sleep disorder characteristics and their relationship with demographic parameters could aid in bridging this gap.This preliminary study aimed to evaluate the clinical characteristic of sleep disorders in PD using PSG.Methods:PSG was used to evaluate sleep disorders in 27 patients with PD and 20 healthy volunteers between August 2015 and July 2018 in Fujian Medical University Union Hospital.Total sleep time (TST),sleep efficiency (SE),total wake time,and other parameters were compared between the two groups.Finally,the correlation between sleep disorders and age,disease duration,Unified Parkinson's Disease Rating Scale-Ⅲ scores,Hoehn-Yahr stage,and levodopa dose were analyzed.The main statistical methods included Chi-square test,two independent samples t test,Fisher exact test,and Pearson correlation.Results:Sleep fragmentation in the PD group was significantly increased (74.1%) while difficulty falling asleep and early awakening were not,as compared to healthy controls.No significant differences were found in time in bed,sleep latency (SL),non-rapid eye movement (NREM) stage 1 (N1),N1%,N2,N2%,N3%,and NREM% between PD and control groups;but TST (327.96± 105.26 min vs.414.67 ± 78.31 min,P =0.003),SE (63.26%± 14.83% vs.76.8%± 11.57%,P =0.001),R N3 (20.00 [39.00] min vs.61.50 [48.87] min,P=0.001),NREM (262.59 ± 91.20 min vs.337.17± 63.47 min,P=0.003),rapid-eyemovement (REM)(32.50 [33.00] min vs.85.25 [32.12] min,P < 0.001),REM%(9.56 ± 6.01 vs.15.50 ± 4.81,P =0.001),REM sleep latency (157.89 ± 99.04 min vs.103.47 ± 71.70 min,P =0.034) were significantly reduced in PD group.Conclusion:This preliminary study supported that sleep fragmentation was an important clinical characteristic of sleep disorders in PD.Whether sleep fragmentation is a potential quantifiable marker in PD needs to be further investigated in the future study.

Treatment of 30 Patients with Diarrhea of Spleen-yang Deficiency Type by Indirect Moxibustion with Salt on Point Shenque(CV 8)

To treat 30 cases of diarrhea of insufficiency of the spleen-yang type by moxibustion with salt at Shenque (CV 8 ). The total effective rate was 93.3%.

Melatonin ameliorates tau-related pathology via the miR-504-3p and CDK5 axis in Alzheimer’s disease

Background:Intracellular accumulation of the microtubule-associated protein tau and its hyperphosphorylated forms is a key neuropathological feature of Alzheimer’s disease(AD).Melatonin has been shown to prevent tau hyperphosphorylation in cellular and animal models.However,the molecular mechanisms by which melatonin attenuates tau hyperphosphorylation and tau-related pathologies are not fully understood.Methods:Immunofluorescence,immunoblotting analysis and thioflavin-S staining were employed to examine the effects of early and late treatment of melatonin on tau-related pathology in hTau mice,in which nonmutated human tau is overexpressed on a mouse tau knockout background.High-throughput microRNA(miRNA)sequencing,quantitative RT-PCR,luciferase reporter assay and immunoblotting analysis were performed to determine the molecular mechanism.Results:We found that both early and late treatment of melatonin efficiently decreased the phosphorylation of soluble and insoluble tau at sites related to AD.Moreover,melatonin significantly reduced the number of neurofibrillary tangles(NFTs)and attenuated neuronal loss in the cortex and hippocampus.Furthermore,using miRNA microarray analysis,we found that miR-504-3p expression was upregulated by melatonin in the hTau mice.The administration of miR-504-3p mimics dramatically decreased tau phosphorylation by targeting p39,an activator of the well-known tau kinase cyclin-dependent kinase 5(CDK5).Compared with miR-504-3p mimics alone,co-treatment with miR-504-3p mimics and p39 failed to reduce tau hyperphosphorylation.Conclusions:Our results suggest for the first time that melatonin alleviates tau-related pathologies through upregulation of miR-504-3p expression by targeting the p39/CDK5 axis and provide novel insights into AD treatment strategies.

Clinical features and genetic spectrum in Chinese patients with recessive hereditary spastic paraplegia

Background:Although many causative genes of hereditary spastic paraplegia(HSP)have been uncovered in recent years,there are still approximately 50% of HSP patients without genetically diagnosis,especially in autosomal recessive(AR)HSP patients.Rare studies have been performed to determine the genetic spectrum and clinical profiles of recessive HSP patients in the Chinese population.Methods:In this study,we investigated 24 Chinese index AR/sporadic patients by targeted next-generation sequencing(NGS),Sanger sequencing and multiplex ligation-dependent probe amplification(MLPA).Further functional studies were performed to identify pathogenicity of those uncertain significance variants.Results:We identified 11 mutations in HSP related genes including 7 novel mutations,including two(p.V1979_L1980delinsX,p.F2343 fs)in SPG11,two(p.T55 M,p.S308 T)in AP5Z1,one(p.S242N)in ALDH18A1,one(p.D597fs)in GBA2,and one(p.Q486X)in ATP13A2 in 8 index patients and their family members.Mutations in ALDH18A1,AP5Z1,CAPN1 and ATP13A2 genes were firstly reported in the Chinese population.Furthermore,the clinical phenotypes of the patients carrying mutations were described in detail.The mutation(p.S242 N)in ALDH18A1 decreased enzyme activity of P5CS and mutations(p.T55 M,p.S308 T)in AP5Z1 induced lysosomal dysfunction.Conclusion:Our results expanded the genetic spectrum and clinical profiles of AR-HSP patients and further demonstrated the efficiency and reliability of targeted NGS diagnosing suspected HSP patients.

Construction of Risk Prediction Model of Cardiac Arrest in Patients with Chronic Obstructive Pulmonary Disease Complicated with Respiratory Failure

Objective:To construct a risk prediction model for in-hospital cardiac arrest(IHCA)in patients with chronic obstructive pulmonary disease(COPD)complicated with respiratory failure.Methods:The clinical data of 550 patients with COPD complicated with respiratory failure in our hospital from January 2016 to June 2022 were retrospectively analyzed.According to the occurrence of IHCA,they were divided into the IHCA group and non-IHCA group.The general data and clinical indicators of the two groups were compared,and logistic regression analysis was performed,R software was used to establish the risk prediction model(nomogram model)for predicting the occurrence of IHCA in patients with COPD complicated with respiratory failure.The risk prediction model(line graph model)for patients with IHCA was validated by the Bootstrap method,and the predictive value was analyzed by applying the receiver operating characteristic(ROC)curve.Results:Among 550 COPD patients complicated with respiratory failure,95 cases(17.27%)had IHCA.There were significant differences in age,old myocardial infarction,heart failure,moderate and severe chronic kidney disease,assisted breathing mode,state of consciousness,body temperature,heart rate,respiratory rate,systolic blood pressure,lactic acid,Sa O,Pa CO,serum creatinine,albumin,and prealbumin between the non-IHCA group and IHCA group(P<0.05).Logistic regression analysis showed that age,heart failure,heart rate,respiratory rate,systolic blood pressure,unclear state of consciousness,serum creatinine and prealbumin were independent influencing factors of IHCA in COPD patients complicated with respiratory failure(P<0.05).According to the results of binary logistic regression analysis,a nomogram model for predicting the incidence of IHCA in COPD patients complicated with respiratory failure was constructed.The fitting degree of the model was determined by the H-L test.The calibration curve showed that the incidence of IHCA in COPD patients complicated with respiratory failure predicted by nomogram was in good agreement with the actual incidence of IHCA in patients with COPD complicated with respiratory failure(χ~2=2.017,P=0.334).The ROC curve showed an AUC of 0.627(95%CI:0.593-0.689,P<0.005),and the optimal cut point value for diagnosis was 0.69,at which the sensitivity and specificity were 42.57%and 96.03%,respectively.Conclusion:According to the independent influencing factors of IHCA in COPD patients complicated with respiratory failure,the establishment of a risk prediction nomogram model has high predictive value,which is worthy of clinical promotion.

Relationship between composite hydration volume (Intravenous plus oral) and contrast-induced nephropathy after emergent percutaneous coronary intervention

Background Few studies have investigated the safe limits of total intravenous plus oral hydration to prevent contrast-induced nephropathy （CIN）. The present study was conducted to evaluate the effects of different composite hydration rate （intravenous plus oral） on CIN prevention in patients undergoing emergent percutaneous coronary intervention （PCI）. Methods This was a retrospective observational study that included 307 eligible patients, who were stratified into quartiles of rate of the composite hydration volumn to body weight and time （HV/ W/T）. CIN was defined as an absolute≥0.5 mg/dL or a relative ≥25% increase in the serum creatinine level within 72 hours after the procedure. Results In terms of risks of CIN, there were no statistical differences among individuals in four groups with different composite HV/W/T （27.6%, 19.0%, 23.0%, and 26.9% respectively in quartiles Q1, Q2, Q3, and Q4, P=0.565）. Additionally, higher composite hydration ratio seemed not to decrease the risk of in-hospital death, worsening heart failure and stroke （all P〉0.05）. After adjusting for other risk factors, multivariate analysis showed no statistical difference between Q2, Q3 or Q4, compared with Q1 （Q2 vs. QI： adjusted odds ratio [OR], 0.67, P=0.383; Q3 vs QI： adjusted OR, 0.77, P=0.550; Q4 vs. QI： adjusted OR, 0.75, P= 0.489）. Conclusion Excessive composite hydration may not provide supplemental benefit of CIN prevention and in-hospital outcomes in patients following emergent PCI, and moderate and prophylactic hydration is warranted.