OBJECTIVES: The gut microbiota plays a crucial role in the pathophysiology of various types of diabetes. However, the causal relationship between them has yet to be systematically elucidated. This study aims to explore the potential causal associations between gut microbiota and diabetes using a two-sample Mendelian randomization (MR) analysis, based on multiple taxonomic levels. METHODS: Eligible instrumental variables were extracted from the selected genome-wide association study (GWAS) data on gut microbiota. These were combined with GWAS datasets on type 1 diabetes (T1D), type 2 diabetes (T2D), and gestational diabetes mellitus (GDM) to conduct forward MR analysis, sensitivity analysis, reverse MR analysis, and validation of significant estimates. Microbial taxa with causal effects on T1D, T2D, and GDM were identified based on a comprehensive assessment of all analytical stages. RESULTS: A total of 2 179, 2 176, and 2 166 single nucleotide polymorphisms (SNP) were included in the MR analyses for gut microbiota with T1D, T2D, and GDM, respectively. MR results indicated causal associations between: Six microbial taxa (Eggerthella, Lachnospira, Bacillales, Desulfovibrionales, Parasutterella, and Turicibacter) and T1D; 9 microbial taxa (Verrucomicrobia, Deltaproteobacteria, Actinomycetales, Desulfovibrionale, Actinomycetaceae, Desulfovibrionaceae, Actinomyces, Alcaligenaceae, and Lachnospiraceae NC2004 group) and T2D; 10 microbial taxa (Betaproteobacteria, Coprobacter, Ruminococcus2, Tenericutes, Clostridia, Methanobacteria, Mollicutes, Methanobacteriales, Methanobacteriaceae, and Methanobrevibacter) and GDM. CONCLUSIONS This study identified specific gut microbial taxa that may significantly increase or decrease the risk of developing diabetes. Some findings were fully replicated in independent validation datasets. However, the underlying biological mechanisms of these causal relationships warrant further investigation through mechanistic studies and population-based research.
Gastrointestinal Microbiome/genetics* ; Humans ; Mendelian Randomization Analysis ; Genome-Wide Association Study ; Diabetes Mellitus, Type 2/genetics* ; Diabetes Mellitus, Type 1/genetics* ; Female ; Polymorphism, Single Nucleotide ; Diabetes, Gestational/genetics* ; Pregnancy

OBJECTIVE: To compare the effects of different chest compression rates (60-140 times/min) on hemodynamic parameters, return of spontaneous circulation (ROSC), resuscitation success, and survival in a porcine model of cardiac arrest (CA) followed by cardiopulmonary resuscitation (CPR). METHODS: Forty healthy male domestic pigs were randomly divided into five groups based on chest compression rate: 60, 80, 100, 120, and 140 times/min (n = 8). All animals underwent standard anesthesia and tracheal intubation. A catheter was inserted via the left femoral artery into the thoracic aorta to monitor aortic pressure (AOP), and another via the right external jugular vein into the right atrium to monitor right atrial pressure (RAP). In each group, animals were implanted with a stimulating electrode via the right external jugular vein to the endocardium, and ventricular fibrillation (VF) was induced by delivering alternating current stimulation, resulting in CA. After a 1-minute, manual chest compressions were performed at the assigned rate with a compression depth of 5 cm. The first defibrillation was delivered after 2 minutes of CPR. No epinephrine or other pharmacologic agents were administered during the entire resuscitation process. From 1 minute before VF induction to 10 minutes after ROSC, dynamic monitoring of AOP, coronary perfusion pressure (CPP), and partial pressure of end-tidal carbon dioxide (P_ETCO₂). Cortical ultrastructure was examined 24 hours post-ROSC using transmission electron microscopy. RESULTS: With increasing compression rates, both the total number of defibrillations and cumulative defibrillation energy significantly decreased, reaching their lowest levels in the 120 times/min group. The number of defibrillations decreased from (4.88±0.83) times in the 60 times/min group to (2.25±0.71) times in the 120 compressions/min group, and energy from (975.00±166.90)J to (450.00±141.42)J. However, both parameters increased again in the 140 times/min group [(4.75±1.04)times, (950.00±207.02)J], the differences among the groups were statistically significant (both P < 0.01). As compression frequency increased, P_ETCO₂, pre-defibrillation AOP and CPP significantly improved, peaking in the 120 times/min group [compared with the 60 times/min group, P_ETCO₂ (mmHg, 1 mmHg≈0.133 kPa): 18.69±1.98 vs. 8.67±1.30, AOP (mmHg): 95.13±7.06 vs. 71.00±6.41, CPP (mmHg): 14.88±6.92 vs. 8.57±3.42]. However, in the 140 times/min group, these values declined significantly again [P_ETCO₂, AOP, and CPP were (10.59±1.40), (72.38±11.49), and (10.36±4.57) mmHg, respectively], the differences among the groups were statistically significant (all P < 0.01). The number of animals achieving ROSC, successful resuscitation, and 24-hour survival increased with higher compression rates, reaching a peak in the 120 times/min group (compared with the 60 times/min group, ROSC: 7 vs. 2, successful resuscitation: 7 vs. 2, 24-hour survival: 7 vs.1), then decreased again in the 140 times/min group (the animals that ROSC, successfully recovered and survived for 24 hours were 3, 3, and 2, respectively). Transmission electron microscopy revealed that in the 60, 80, and 140 times/min groups, nuclear membranes in cerebral tissue were irregular and incomplete, nucleoli were indistinct, and mitochondria were swollen with reduced cristae and abnormal morphology. In contrast, the 100 times/min and 120 times/min groups exhibited significantly attenuated ultrastructural damage. CONCLUSIONS Among the tested chest compression rates of 60-140 times/min, a chest compressions frequency of 120 times/min is the most favorable hemodynamic profile and outcomes during CPR in a porcine CA model. However, due to the wide spacing between groups, further investigation is needed to determine the optimal compression rate range more precisely.
Animals ; Cardiopulmonary Resuscitation/methods* ; Swine ; Male ; Heart Arrest/therapy* ; Heart Massage/methods* ; Hemodynamics

Objective:To explore the association of human betaine-homocysteine methyltransferase ( BHMT) and BHMT2 gene polymorphisms with non-syndromic congenital heart disease (CHD). Methods:A hospital-based case-control study was conducted, in which children with CHD who attended Hunan Children′s Hospital from January 2018 to May 2019 were enrolled as the case group, and children without any congenital deformity who attended the hospital during the same period were enrolled as the control group on a 1∶1 basis. A self-administered questionnaire survey was performed to collect information about the study subjects and their mothers, and then venous blood samples were collected from the subjects to detect BHMT and BHMT2 gene polymorphisms. Logistic regression analyses were used to evaluate the association of BHMT and BHMT2 gene polymorphisms and their haplotypes with CHD. Crossover analyses and logistic regression were used to explore the gene-gene and gene-environment interactions. Results:The case and control group both enrolled 620 children. The multivariate logistic regression showed that BHMT gene polymorphisms at rs3733890 (AA vs. GG: OR=3.476, Q FDR<0.001; GA vs. GG: OR=1.525, Q FDR=0.036), at rs1915706 (CC vs. TT: OR=3.464, Q FDR<0.001) and at rs1316753 (GG vs. CC: OR=1.875, Q FDR=0.020) increased the risk of CHD. Children with haplotype of A-G-A had an increased risk of CHD ( OR=1.468, 95% CI: 1.222-1.762). Interaction analysis showed that a statistically significant positive interaction between rs3733890 and rs1915706 on both additive ( RERI=0.628, 95% CI: 0.298-0.958) and multiplicative ( OR=3.754, 95% CI: 1.875-7.519) scales. Gene-environment interactions were found between the BHMT gene with secondhand smoke exposure before pregnancy and in early pregnancy, tea consumption before pregnancy and in early pregnancy, alcohol consumption before pregnancy, and folic acid supplementation before or during pregnancy. Conclusion:BHMT gene rs3733890, rs1915706 and rs1316753 polymorphisms may be associated with the risk of CHD. In addition, there is an association of cooperative interaction between rs3733890 and rs1915706 on both additive and multiplicative scales with the risk of CHD, and the BHMT gene interacts with multiple environmental factors.

Objective:To explore the association of human betaine-homocysteine methyltransferase ( BHMT) and BHMT2 gene polymorphisms with non-syndromic congenital heart disease (CHD). Methods:A hospital-based case-control study was conducted, in which children with CHD who attended Hunan Children′s Hospital from January 2018 to May 2019 were enrolled as the case group, and children without any congenital deformity who attended the hospital during the same period were enrolled as the control group on a 1∶1 basis. A self-administered questionnaire survey was performed to collect information about the study subjects and their mothers, and then venous blood samples were collected from the subjects to detect BHMT and BHMT2 gene polymorphisms. Logistic regression analyses were used to evaluate the association of BHMT and BHMT2 gene polymorphisms and their haplotypes with CHD. Crossover analyses and logistic regression were used to explore the gene-gene and gene-environment interactions. Results:The case and control group both enrolled 620 children. The multivariate logistic regression showed that BHMT gene polymorphisms at rs3733890 (AA vs. GG: OR=3.476, Q FDR<0.001; GA vs. GG: OR=1.525, Q FDR=0.036), at rs1915706 (CC vs. TT: OR=3.464, Q FDR<0.001) and at rs1316753 (GG vs. CC: OR=1.875, Q FDR=0.020) increased the risk of CHD. Children with haplotype of A-G-A had an increased risk of CHD ( OR=1.468, 95% CI: 1.222-1.762). Interaction analysis showed that a statistically significant positive interaction between rs3733890 and rs1915706 on both additive ( RERI=0.628, 95% CI: 0.298-0.958) and multiplicative ( OR=3.754, 95% CI: 1.875-7.519) scales. Gene-environment interactions were found between the BHMT gene with secondhand smoke exposure before pregnancy and in early pregnancy, tea consumption before pregnancy and in early pregnancy, alcohol consumption before pregnancy, and folic acid supplementation before or during pregnancy. Conclusion:BHMT gene rs3733890, rs1915706 and rs1316753 polymorphisms may be associated with the risk of CHD. In addition, there is an association of cooperative interaction between rs3733890 and rs1915706 on both additive and multiplicative scales with the risk of CHD, and the BHMT gene interacts with multiple environmental factors.

OBJECTIVES: Maternal periconceptional folic acid supplement is by far the most effective primary prevention strategy to reduce the incidence of congenital heart disease (CHD) in offspring. It was revealed that the underlying mechanisms are complex, including a combination of genetic and environmental factors. The purpose of this study is to investigate the association between periconceptional folic acid supplement, the genetic polymorphisms of maternal folic acid receptor 1 gene (FOLR1) and folic acid receptor 2 gene (FOLR2) and the impact of their interaction on the risk of CHD in offspring, and to provide epidemiological evidence for individualized folic acid dosing in hygienic counseling. METHODS: A case-control study on 569 mothers of CHD infants and 652 mothers of health controls was performed. The interesting points were periconceptional folate supplements, single nucleotide polymorphisms (SNPs) of maternal FOLR1 gene and FOLR2 gene. RESULTS: Mothers who took folate in the periconceptional period were observed a decreased risk of CHD [adjusted odds ratio (aOR)=0.58, 95% CI 0.35 to 0.95]. Our study also found that polymorphisms of maternal FOLR1 gene at rs2071010 (G/A vs G/G: aOR=0.67, 95% CI 0.47 to 0.96) and FOLR2 gene at rs514933 (T/C vs T/T: aOR=0.60, 95% CI 0.43 to 0.84; C/C vs T/T: aOR=0.55, 95% CI 0.33 to 0.90; the dominant model: T/C+ C/C vs T/T: aOR=0.59, 95% CI 0.43 to 0.81; and the addictive model: C/C vs T/C vs T/T: aOR=0.70, 95% CI 0.56 to 0.88) were significantly associated with lower risk of CHD [all P<0.05, false discovery rate P value (FDR_P)<0.1]. Besides, significant interaction between periconceptional folate supplements and rs2071010 G→A (aOR=0.59, 95% CI 0.41-0.86) and rs514933 T→C (aOR=0.52, 95% CI 0.37 to 0.74) on CHD risk were observed (all P<0.05, FDR_P<0.1). CONCLUSIONS Periconceptional folate supplements, polymorphisms of FOLR1 gene and FOLR2 gene and their interactions are significantly associated with risk of CHD. However, more studies in different ethnic populations with a larger sample and prospective designs are required to confirm our findings.
Case-Control Studies ; Dietary Supplements ; Female ; Folate Receptor 1/genetics* ; Folate Receptor 2/genetics* ; Folic Acid/administration & dosage* ; Heart Defects, Congenital/genetics* ; Hospitals ; Humans ; Infant ; Polymorphism, Single Nucleotide ; Prospective Studies ; Risk Factors

To evaluate whether the in vitro fertilization-embryo transfer (IVF-ET) procedures could increases the risks of adverse pregnancy outcomes (APOs) in offspring.
 Methods: A hospital-based prospective cohort design was conducted, which contained a control group of singleton pregnancies with indicators of subfertility who were still conceived naturally after using simple medical treatment (e.g. minimal medical intervention or ovulation induction), and an exposure group consisted of singleton pregnancies who had a history of infertility and IVF-ET treatment. All factors different between two groups in the univariate analysis were included in the multivariable logistic regression to evaluate the independent effect of IVF-ET procedures themselves on APOs.
 Results: After controlling for confounding factors by using multivariate logistic regression analysis, our results showed that pregnancies after IVF-ET experienced a higher risk of preterm birth (OR=1.28, 95% CI 1.05 to 1.56), low birth weight (OR=1.69, 95% CI 1.27 to 2.31), perinatal mortality (OR=5.33, 95% CI 2.44 to 11.81), and congenital malformations (OR=1.83, 95% CI 1.12 to 2.94).
 Conclusion: The IVF-ET operational factors may increase the risk of APOs.
Cohort Studies ; Embryo Transfer ; statistics & numerical data ; Female ; Fertilization in Vitro ; statistics & numerical data ; Humans ; Infant, Newborn ; Logistic Models ; Pregnancy ; Pregnancy Outcome ; Prospective Studies

Objective:To investigate the effect of nimodipine liposomes for injection(NOLI)on focal cerebral ischemia/reperfusion(I/R)injury in rats.Methods:Seventy SD rats were divided into NDLI 1.00 mg/kg,NDLI 0.50 mg/kg,NDLI 0.25 mg/kg,nimodipine 1.00mg/kg,solvent 10 mL/kg,sham-operation and ischemic model groups.The model of middle cerelral artery occlusion in rat was replicated.The behavioral scores in rats were assessed in all groups.The infarct volume,brain water content,biochemical indices of brain homogenate and histology were detected.Results:1he NDLI 1.00mg/kg,0.50 mg/kg and 0.25 mg/kg groups could significantly improve the behavior scores in focal cerebral ischemic rats,reduce the volume of cerebral infarction,decrease the brain water content,improve the activities of Na+,K+-ATPase,Ca2+-ATPase,glutathione(GSH)and superoxide dismutazse(SOD)in brain tissues,reduce conteras of malondialdehyde(MDA),lactic acid(LA)and nitric oxide(NO),and improve histo logical injury.Conclusions:NDLI has the protective effect on focal cerebral ischemia/reperfusion injury in rats.

AIM: To study the protective effects of nimodipine liposomes for injection (NDLI) on injuries of total cerebral ischemia/reperfusion(I/R) in rats and anoxia in mice. METHODS: Acute anoxia in mice was produced by hypoxia under normal pressure and decapitation. In these two models the survival time and persistent time of gasping were observed. Ameliorated pulsinelli four-vessel occlusion method was used to make global brain ischemia model. The EEG, the time of righting reflex recovery and Evans blue content in the homogenate of the brain tissues were recorded. RESULTS: NDLI obviously prolonged the survival time and persistent time of gasping in mice subjected to acute anoxia, remarkably shortened the time of EEG recovery and righting reflex recovery, and reduced Evens blue content in the homogenate. CONCLUSION: NDLI has significantly protective effects on injuries of total cerebral I/R and anoxia.

Objective To investigate the significance of cyclin E and p27 in genital epidermal benign and malignant tumors. Methods HPV DNA was examined and typed by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) in 99 biopsy specimens taken from skin lesions of condyloma acuminatum, external genital carcinoma in situ and invasive squamous cell carcinoma. The expression of cyclin E and p27 in the lesions was examined by immunohistochemistry technique. Results (1) The cyclin E expression in epidermis was notably higher in the lesions than that in normal skin. In HPV-positive samples, the cyclin E expression was higher than that in HPV-negative ones. The cyclin E expression was strongest in invasive squamous cell carcinoma lesions and lowest in condyloma acuminatum lesions. (2) The p27 expression in condyloma acuminatum was slightly higher than that in normal epidermis. But it was notably lower in the lesions of carcinoma in situ and invasive squamous cell carcinoma than that in the normal skin. The expression was also lower in HPV-positive lesions than that in HPV-negative ones. Comparing the three kinds of HPV positive lesions, the intensity of expression was highest in condyloma acuminatum and lowest in invasive squamous cell carcinoma. (3) The study also showed that cyclin E expression was correlated with p27 expression in the lesions. Conclusions The expression of cyclin E and p27 is associated with HPV infection in the lesions. HPV infection might induce epidermal proliferation and malignant transformation by influencing the expression and interaction of cyclin E and p27.

Objective To observe the clinical efficacy and safety of topical interferon alfa-1b cream in the treatment of herpes zoster. Methods A randomized, double-blind, parallel placebo-controlled clinical study was conducted. The test drug was topically used in herpes zoster patients, three times a day for 2 weeks. Patients whose skin lesions cleared completely were followed for 29 days to observe postherpetic neuralgia. Results One hundred and twenty-eight patients with herpes zoster were enrolled into this trial. Sixty-five patients were randomly selected to receive interferon alfa-1b cream and sixty-three patients received vehicle cream. After following up for 11, 14, 22, 29 days the cure rates were 69.2%, 81.5%, 90.8%, 95.4% respectively in the study group and were 57.1%, 71.4%, 84.1% and 84.1% respectively in the control group(P