To mine tacrolimus-related adverse event signals affecting the cardiovascular system based on an international authoritative database, aiming to provide a reference for clinical safe drug use.

Objective To investigate the clinical efficacy and safety of intravenous thrombolysis with tenecteplase in the treatment of CWS.Methods A prospective study was conducted on 136 CWS patients consecutively admitted in Department of Neurology of Zhengzhou People's Hospital from March 2019 to March 2024.They were randomly divided into a tenecteplase group(67 cases)and a control group(69 cases).NIHSS was used to evaluate the recovery of neurological function after treatment.mRS was employed to assess long-term prognosis.Results Significantly larger proportion of white matter lesions and higher baseline SBP level were observed in the tenecteplase group than the control group(P＜0.05).The tenecteplase group obtained obviously greater ratio of overall recovery than the control group,with notably lower NIHSS score,incidence of new CWS attacks and proportion of new acute cerebral infarction at 24 and 72 h and 7 d after treat-ment(P＜0.05,P＜0.01).Moreover,the proportion of mRS score of 0-2 was notably greater,while that of the score of 3-6 was lower in the tenecteplase group than the Control group(P＜0.05).Intravenous thrombolysis with tenecteplase was an influencing factors for 90-day mRS score of 0-2 and of 3-6 in the CWS patients(OR=0.264,95％CI:0.089-0.813;OR=4.144,95％CI:1.184-14.506,P＜0.05).Conclusion Intravenous thrombolysis with tenecteplase for CWS significantly improves the proportion of patients with good prognosis.

BACKGROUND:Skeletal muscle insulin resistance is the key pathological link of type 2 diabetes.The traditional Chinese medicine compound Roujishuncuiyin can effectively improve skeletal muscle insulin resistance,but its mechanism has not been clarified.OBJECTIVE:To explore the mechanism of Roujishuncuiyin on skeletal muscle insulin resistance in type 2 diabetes mice.METHODS:Forty db/db mice with type 2 diabetes mellitus were randomized into a model group,a low-dose Roujishuncuiyin group,a high-dose Roujishuncuiyin group,and a positive drug group,with 10 mice in each group.The latter three administration groups were given 157.5 mg/g and 630 mg/g Roujishuncuiyin and 200 mg/g metformin hydrochloride aqueous solution by gavage once a day,respectively.In addition,10 db/dm mice were selected as the blank control group.Mice in the model and blank control groups were given the same dose of 0.9％NaCl solution by gavage.After 12 weeks of intervention,fasting blood glucose was measured in each group of mice,and oral glucose tolerance test was performed to calculate the area under the blood glucose curve.ELISA was used to detect serum insulin level and calculate the resistance index.Mitochondrial structure of skeletal muscle tissue was observed under transmission electron microscopy.Western blot was used to detect the expression levels and phosphorylation levels of protein kinase B(AKT)and glycogen synthase kinase 3β(GSK-3β)proteins in skeletal muscle.RESULTS AND CONCLUSION:(1)Compared with the blank control group,fasting blood glucose,fasting insulin and insulin resistance index were significantly higher in the model group(P＜0.05),the area under the curve of the oral glucose tolerance test was significantly increased(P＜0.05),the expression of p-AKT and p-GSK3β proteins in tibialis anterior muscle was significantly decreased(P＜0.05),and there was a large amount of mitochondrial damage in tibialis anterior muscle and a large number of lipid droplets in the interstitium.(2)Compared with the model group,fasting blood glucose,fasting insulin,and insulin resistance index were significantly reduced in the low-and high-dose Roujishuncuiyin groups and the positive control group(P＜0.05),the area under the curve of the oral glucose tolerance test was reduced(P＜0.05),the expression of p-AKT and p-GSK3β proteins in the tibialis anterior muscle was significantly elevated(P＜0.05),and mitochondrial damage in the tibialis anterior muscle was significantly ameliorated,with decreased lipid droplets in the interstitium.(3)The above indexes were better in the high-dose Roujishuncuiyin group than the low-dose Roujishuncuiyin group(P＜0.05),while there was no significant difference between the high-dose Roujishuncuiyin group and positive control group(P＞0.05).To conclude,by upregulating the protein levels of p-AKT and p-GSK3β in skeletal muscle tissue,the traditional Chinese medicine compound Roujishuncuiyin can improve structural disorders and mitochondrial morphology in skeletal muscle tissue,reduce insulin resistance in the skeletal muscle and regulate glucose homeostasis in the body.

Objective To investigate the value of multiple quantitative parameters derived from Hawk spectral CT in predicting lymph node metastasis in papillary thyroid carcinoma(PTC).Methods Preoperative Hawk spectral CT images of 57 cancerous foci from 44 PTC patients confirmed by surgery and pathology were retrospectively collected.All patients underwent lymph node dissection.Based on pathological results,the patients were categorized into metastatic group(26 patients with 35 cancerous foci)and non-metastatic group(18 patients with 22 cancerous foci).The CT morphological features of the primary PTC lesions included location,diameter,bite-cookie sign,and calcification,respectively.Quantitative parameters of Hawk spectral CT plain scan,arterial phase(AP)and venous phase(VP),including conventional CT values,virtual monoenergetic imaging(MonoE)CT values(40 keV,100 keV),effective atomic number(Zeff)and electron density(Rho),respectively.The rank sum test or chi-square test was used to compare the differences in CT morphological features and Hawk spectral CT quantitative parameters between the two groups.For parameters with significant differences,logistic regression was used to construct a combined model.Area under the curve(AUC),accuracy,sensitivity,and specificity were used to evaluate the effectiveness of the combined model.Results There was statistically significant difference in the diameter of the primary lesion between the metastatic group and the non-metastatic group(P＜0.05),and the diameter of the primary lesion in the metastatic group was larger than that in the non-metastatic group.The conventional CT value,MonoE CT values(40 keV,100 keV),Rho and Zeff in plain scan,AP-Rho,and VP-MonoE CT value(100 keV)of the primary lesion in the metastatic group were all significantly lower than those in the non-metastatic group(P＜0.05).The AUC,accuracy,sensitivity and specificity of the Hawk spectral CT plain scan parameter combination model were 0.765,0.754,0.800,and 0.682,respectively.The AUC,accuracy,sensitivity,and specificity of the Hawk spectral CT enhancement parameter combination model were 0.726,0.667,0.600,and 0.786,respectively.Conclusion Through the analysis of multiple quantitative parameters from Hawk spectral CT of PTC primary lesion,the primary lesion in the metastatic group exhibited significant differences from those in the non-metastatic group in multiple quantitative parameters,which can further improve the predictive efficacy for lymph node metastasis.

OBJECTIVE To investigate the effect of Curcumol on lipid metabolism in non-small cell lung cancer(NSCLC)and its related molecular mechanism.METHODS A nude mouse xenograft tumor model was established,and Curcumol was administered for 14 d.The volume and weight of subcutaneous tumors were recorded.Hematoxylin-eosin(HE)and immunohistochemical staining were used to observe the pathological morphology of tumor tissues and organs,as well as the expression levels of Ki67 protein.Bio-chemical kits were used to detect the levels of lipids in tumor tissues.Western blot was used to detect the expression levels of SREBP-1,FASN,and EGFR proteins in tumor tissues.The qPCR and immunofluorescence were used to detect the expression of SREBP-1 in tumor tissues.Curcumol was used to treat human NSCLC cell line A549 and A549 cells overexpressing SREBP-1.The EdU assay was used to detect the proliferation ability of lung cancer cells;the MTT colorimetric method was used to detect cell viability;the Transwell assay was used to detect tumor cell migration and invasion;flow cytometry was used to detect cell apoptosis;biochemical kits were used to detect lipid levels in cells;and Western blot was used to detect the expression levels of SREBP-1,FASN,and EGFR proteins.RE-SULTS In the in vivo experiment,compared with the control group,Curcumol significantly inhibited the growth of subcutaneous xen-ografts,inhibited tumor cell proliferation(P<0.05,P<0.01),reduced the levels of triglycerides(TG),total cholesterol(T-CHO),and free fatty acids(FFA)in tumor tissues(P<0.05,P<0.01),downregulated the expression of SREBP-1,FASN,and p-EGFR pro-teins(P<0.01),and inhibited the expression of SREBP-1 mRNA in tumor tissues(P<0.05,P<0.01).In the in vitro experiment,compared with the control group,Curcumol significantly inhibited the proliferation,migration,and invasion of A549 cells,reduced cell viability(P<0.05,P<0.01),promoted tumor cell apoptosis(P<0.01),downregulated the levels of FFA,T-CHO,and TG in A549 cells(P<0.05,P<0.01),and inhibited the expression of SREBP-1,FASN,and p-EGFR proteins(P<0.05,P<0.01).Additionally,overexpression of SREBP-1 antagonized the inhibitory effects of Curcumol on lipid synthesis and EGFR activation,and weakened the inhibitory effects of Curcumolc on tumor cells.CONCLUSION Curcumol inhibits the expression levels of SREBP-1 and FASN,re-duces lipid synthesis,blocks EGFR signal transduction,and slows down the occurrence and development of NSCLC.

In order to explore the relationship between ubiquitin proteasome system(UPS)and au-tophagy after macrophage was infected with Brucella.On the one hand,the levels of LC3 Ⅱ、P62 and 20S proteasomes in cell supernatant and peritoneal fluid were determined respectively after RAW264.7 cells were infected and BALB/c mice were intraperitoneal inoculated with Brucella suis(B.suis).The results displayed that UPS was activated firstly,followed by autophagy after B.suis infection.On the other hand,we prepared the UPS-inhibited-cells and ALP-inhibited-cells by lacta-cystin and 3-methy ladenine(3-MA),and then the cells were infected by B.suis and the levels of LC3 Ⅱ、P62 与 20S proteasomes in cell supernatant were determined.The results showed that the ALP function was significantly improved when the effect of M

Objective·To investigate the genetic etiology of a rare and complex case clinically suspected to be methylmalonic acidemia(MMA),but with negative whole exome sequencing(WES)results,using a multi-omics sequencing approach.Methods·DNA and RNA samples were extracted from the peripheral blood of the proband and both parents.Targeted MMA-related gene Panel sequencing and WES were first performed.Subsequently,RNA sequencing(RNA-seq)and whole genome sequencing(WGS)were conducted to comprehensively analyze the child's genetic variants,their origins and potential inheritance patterns.Results·No pathogenic variants associated with the patient's phenotype were identified through the MMA Panel or standard WES analysis.Extended analysis of WES suggested the possibility of uniparental disomy(UPD)of chromosome 4.WGS revealed a homozygous splice-site variant(c.-66+2T>C)in the non-coding region of the metabolism of cobalamin associated A(MMAA)gene.The variant was located in the 5'untranslated region(5'UTR),specifically at the second base downstream of the splice donor site of exon 1(reference sequence:NM_172250).In genomic coordinates(hg19),the variant was located at base 146540561 on chromosome 4(chr4:146540561).Sanger sequencing confirmed that the mother was heterozygous for this variant,while the father did not carry it.RNA-seq showed no detectable expression of the MMAA gene on chromosome 4 in the patient.This was further confirmed by reverse transcription real time quantitative PCR,indicating nearly absent mRNA expression,suggesting that the non-coding splice-site variant affected transcriptional expression.Conclusion·A homozygous splice-site variant(c.-66+2T>C)in the non-coding region of the MMAA gene—outside the coverage of WES—is likely the pathogenic cause in this case,presumably resulting from maternal UPD of chromosome 4.

Objective To explore the effects of exosomes of mesenchymal stem cells(MSC-Exos)on the proliferation,apoptosis,migration and invasion of esophageal cancer ECA109 cells.Methods Human umbilical cord mesenchymal stem cells were cultured,exosomes were extracted and isolated,and identified by transmission electron microscopy.The nanoparticle size determination and protein characterization(TSG101,CD63)were measured by transmission electron microscope.There were the MSC-Exo group(MSC-Exos co-cultured with esophageal cancer ECA109 cells)and the blank control group(only esophageal cancer ECA109 cells),and cells were cultured for 0,24 and 48 h,respectively.CCK-8 proliferation test and scratch test were used to detect the proliferation and migration ability of esophageal cancer EAC109 cells in each group,respectively.After 48 h of culture,cell apoptosis and cell cycle changes were detected by flow cytometry.The protein expression levels of phosphoinositol 3-kinase phosphorylation(p-PI3K),rabbit phosphorylated protein kinase B phosphorylation(p-Akt)and β-catenin were detected by Western blot assay.Results After identification,the obtained MSC-Exos meeted the required standard.Transmission electron microscopy,particle size measurement and marker protein results confirmed that the extracted exosomes of mesenchymal stem cells meeted the identification criteria.At 0 h of cell culture,there were no significant differences in cell proliferation and migration healing rate between the two groups(P＞0.05).After 24 h culture,the cell proliferation ability was lower in the MSC-Exo group than that of the blank control group(P＜0.05).After 48 h culture,the cell proliferation and migration healing rate were lower in the MSC-Exo group than those of the blank control group(P＜0.05).The apoptosis rate of the MSC-Exo group was higher than that of the blank control group,and the proportion of G2+S phase cells was lower than that of blank control group(P＜0.05).The expression levels of p-PI3K,p-Akt and β-catenin protein were significantly lower in the MSC-Exo group than those in the blank control group(P＜0.05).Conclusion MSC-Exos can inhibit the proliferation and migration of esophageal cancer cells and promote cell apoptosis.The inhibitory effect of MSC-Exos on esophageal cancer cells may be related to inhibiting the activation of PI3K and Akt protein and the down-regulating expression of β-catenin protein.

Anti-leucine-rich glioma-inactivated 1 protein (LGI1) antibody-associated encephalitis is an autoimmune encephalitis mediated by LGI1 antibodies, which can occur in both adults and children. Its common clinical manifestations include epileptic seizures, cognitive and psychiatric disorders; rare symptoms include sleep disorders and autonomic disorders; and its characteristic manifestations are faciobrachial dystonic seizures and refractory hyponatremia. Since anti-LGI1 antibody-associated encephalitis is relatively rare in clinical practice, this article reviews the disease in terms of etiology and pathogenesis, clinical manifestations, auxiliary examinations, diagnosis and differential diagnosis, treatment, recurrence and prognosis. It aims to improve clinicians′ understanding of this disease, provide references for its early diagnosis and treatment, and thereby improve patients′ prognosis.

Objective:To investigate the efficacy of two types of micro-focused ultrasound devices combined with botulinum toxin type A (BoNT-A) injection for facial rejuvenation.Methods:A retrospective study was conducted, including 60 female patients aged 28-70 (41.3±7.9) years, who received facial rejuvenation treatment at the Department of Plastic and Reconstructive Surgery, Zhongnan Hospital of Wuhan University, from April 2023 to April 2024. Patients were divided into two groups based on the treatment method: the control group (received only micro-focused ultrasound treatment, n=30) and the combined group (received both micro-focused ultrasound and BoNT-A injection, n=30). Additionally, patients were further categorized into four subgroups based on the type of micro-focused ultrasound device used: Peninsula Microultra? (PM) device group ( n=15), Intelligent Ultrasound? (IU) device group ( n=15), PM device + BoNT-A injection group ( n=15), and IU device + BoNT-A injection group ( n=15). The severity of facial wrinkles was assessed using the wrinkle severity rating scale (WSRS), the Merz aesthetic scale (MAS), and the global aesthetic improvement scale (GAIS) at baseline and 6 months post-treatment. Adverse event rates were also recorded. Results:At 6 months post-treatment, the combined group showed significantly lower WSRS and MAS scores than the control group (both P<0.001). No significant differences were found between the PM and IU device groups, or between the PM + BoNT-A and IU + BoNT-A groups regarding WSRS and MAS scores (all P>0.05). Self-reported GAIS improvement was 56.7% (17/30) for the control group and 80.0% (24/30) for the combined group, with the combined group showing superior results ( P=0.015). The physician-assessed GAIS improvement was 70.0% (21/30) for the control group and 96.7% (29/30) for the combined group, again with the combined group showing superior results ( P=0.007). No significant differences were found in self-reported or physician-assessed GAIS improvement between the PM and IU device groups, or between the PM + BoNT-A and IU + BoNT-A groups (all P>0.05). No severe adverse reactions, such as blisters, scabbing, purpura, bruising, scarring, peripheral facial paralysis, allergies, muscle weakness, dysphagia, or dysphonia, were observed in any patient. Conclusion:The combination of micro-focused ultrasound and BoNT-A injection for facial rejuvenation is more effective than micro-focused ultrasound alone, while there are no significant differences in efficacy between the two micro-focused ultrasound devices.