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OBJECTIVE@#To explore the correlation of mitochondrial DNA (mtDNA) variants and coronary heart disease (CHD) in a Chinese pedigree and the possible molecular mechanisms.@*METHODS@#A Chinese pedigree featuring matrilineal inheritance of CHD who visited Hangzhou First People's Hospital in May 2022 was selected as the study subject. Clinical data of the proband and her affected relatives was collected. By sequencing the mtDNA of the proband and her pedigree members, candidate variants were identified through comparison with wild type mitochondrial genes. Conservative analysis among various species was conducted, and bioinformatics software was used to predict the impact of variants on the secondary structure of tRNA. Real-time PCR was carried out to determine the copy number of mtDNA, and a transmitochondrial cell line was established for analyzing the mitochondrial functions, including membrane potential and ATP level.@*RESULTS@#This pedigree had contained thirty-two members from four generations. Among ten maternal members, four had CHD, which yielded a penetrance rate of 40%. Sequence analysis of proband and her matrilineal relatives revealed the presence of a novel m.4420A>T variant and a m.10463T>C variant, both of which were highly conserved among various species. Structurally, the m.4420A>T variant had occurred at position 22 in the D-arm of tRNAMet, which disrupted the 13T-22A base-pairing, while the m.10463T>C variant was located at position 67 in the acceptor arm of tRNAArg, a position critical for steady-state level of the tRNA. Functional analysis revealed that patients with the m.4420A>T and m.10463T>C variants exhibited much fewer copy number of mtDNA and lower mitochondrial membrane potential (MMP) and ATP contents (P < 0.05), which were decreased by approximately 50.47%, 39.6% and 47.4%, respectively.@*CONCLUSION@#Mitochondrial tRNAMet 4420A>T and tRNAArg 10463T>C variants may underlay the maternally transmitted CHD in this pedigree, which had shown variation in mtDNA homogeneity, age of onset, clinical phenotype and other differences, suggesting that nuclear genes, environmental factors and mitochondrial genetic background have certain influence on the pathogenesis of CHD.
Subject(s)
Humans , Female , Mutation , Pedigree , RNA, Transfer, Met , East Asian People , RNA, Transfer, Arg , DNA, Mitochondrial/genetics , Coronary Disease/genetics , Adenosine TriphosphateABSTRACT
Objective:To analyze clinical characteristics of 17α-hydroxylase deficiency, and to facilitate the understanding and management of the disease.Methods:A retrospective analysis of the clinical characteristics and biochemical results of 5 cases with 17α-hydroxylase deficiency diagnosed and treated from 2018 to 2020.Results:All 5 patients were female as social gender, and reached adulthood upon first clinic visit to our department and got diagnosed. All 5 cases had hypertension, hypokalemia, bilateral adrenal hyperplasia or adenoma, osteoporosis, and typical hormone changes related to steroid synthesis.Conclusion:Steroid hormone tests with liquid chromatography tandem mass spectrometry(LC-MS/MS) enable early diagnosis of 17α-hydroxylase deficiency, assessment of the type and degree of enzyme deficiency, and choice of treatment. For such patients, it is necessary to give appropriate anti-osteoporosis therapy.
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Severe aplastic anemia II (SAA-II) progresses from non-severe aplastic anemia (NSAA). The unavailability of efficacious treatment has prompted the need for haploidentical bone marrow transplantation (haplo-BMT) in patients lacking a human leukocyte antigen (HLA)-matched donor. This study aimed to investigate the efficacy of haplo-BMT for patients with SAA-II. Twenty-two patients were included and followed up, and FLU/BU/CY/ATG was used as conditioning regimen. Among these patients, 21 were successfully engrafted, 19 of whom survived after haplo-BMT. Four patients experienced grade II-IV aGvHD, including two with grade III-IV aGvHD. Six patients experienced chronic GvHD, among whom four were mild and two were moderate. Twelve patients experienced infections during BMT. One was diagnosed with post-transplant lymphoproliferative disorder and one with probable EBV disease, and both recovered after rituximab infusion. Haplo-BMT achieved 3-year overall survival and disease-free survival rate of 86.4% ± 0.73% after a median follow-up of 42 months, indicating its effectiveness as a salvage therapy. These promising outcomes may support haplo-BMT as an alternative treatment strategy for patients with SAA-II lacking HLA-matched donors.
Subject(s)
Humans , Anemia, Aplastic/therapy , Bone Marrow Transplantation , Graft vs Host Disease , HLA Antigens , Hematopoietic Stem Cell Transplantation , Transplantation ConditioningABSTRACT
Objective@#To investigate the influencing factors of smoking tendency of adolescents and to analyze the influence of e-cigarette on smoking tendency of teenagers and the possible interaction, to provide evidence for tobacco control measures.@*Methods@#Stratified multistage cluster probability sampling method was used to select 6 178 students from junior middle school, high school and vocational high school students in Shanghai for questionnaire survey from September to October 2019. Students with smoking tendency were taken as case group, adolescents with same sex and similar age(within 1 year) were mathed in 1∶3 ratio. A total of 631 adolescents with smoking tendency and 1 870 non-smoking tendency were included in the study. Conditional Logistic regression was used to analyze the influencing factors and possible interactions.@*Results@#After adjusting gender, age and other covariates, conditional Logistic analysis results showed that the smoking tendency of middle school students was associated with factors such as their friends smoking, trying cigarettes and trying e-cigarettes. The OR value and 95%CI were 3.26(2.47-4.29), 5.90(3.76-9.24), and 3.28(2.11-5.10), respectively. The interaction analysis results showed that the OR value and 95%CI of the multiplying interaction between friends smoking and trying e-cigarettes, trying smoking and trying e-cigarettes were 8.62(4.90-15.17) and 12.01(6.02-23.95), respectively. There was no additive interaction.@*Conclusion@#Tobacco control interventions, such as e-cigarette harm publicity and peer education, can help to change teenagers smoking tendency and further reduce their tobacco use rate.
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Chronic obstructive pulmonary disease (COPD) is well known as a chronic lung disease. In recent years, with the deepening of its understanding, various complications of COPD, especially pulmonary hypertension(PH) have received more and more attention. COPD patients with PH have an increased fatality rate and a poor prognosis, which seriously affects the quality of life of the patients, and the treatment of the disease lacks effective drugs. In order to fully understand the current status of the treatment of the disease, the research progress of the drug treatment of COPD combined with PH was reviewed. The results show that for patients with COPD and PH, the best treatment should be given to their underlying diseases. The use of statins and fasudil may be beneficial, but the effect of targeted drugs is still controversial. In the future, more large randomized controlled trials need to be carried out to further clarify the efficacy of various drugs on COPD.
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OBJECTIVE： To study the relationship of CYP3A4， CYP2C8 and CYP3A5 gene polymorphism with ADR/blood concentration of hydroxychloroquine in patients with autoimmune disease （AID）， and to provide reference for individual medication of hydroxychloroquine. METHODS： Totally 77 AID patients，who were treated with hydroxychloroquine （daily dose of 200 mg to 400 mg） for a long-term （＞6 months）， were selected from the department of rheumatology and immunology， the First Affiliated Hospital of Anhui Medical University during Jul. 2017 to Aug. 2018. The information， blood sample and ADR of them were collected. Those patients were divided into normal liver function group， abnormal liver function group， normal renal function group， abnormal renal function group， normal eye group and abnormal eye group according to the site of ADR. The concentration of hydroxychloroquine was determined by HPLC. Genotype of CYP3A4， CYP2C8 and CYP3A5 were detected by MassARRAY microarray system. The differences of hydroxychloroquine-induced ADR in different genotypes were analyzed by χ2 test. The blood concentration difference of hydroxychloroquine in different genotypes were analyzed by independent sample t-test and one-way ANOVA. RESULTS： There was statistical significance in the distribution of CYP3A5 rs4646453 locus between normal renal function group and abnormal renal function group（P＜0.05）. The incidence of CC genotype was higher than that of AA+AC genotype in abnormal renal function group. There was statistical significance in the distribution of CYP2C8 rs10882526 locus between normal liver function group and abnormal liver function group（P＜0.05）. The incidence of allele G was higher than that of allele A in abnormal liver function group， and the incidence of AG genotype was higher than that of AA genotype. There was no significant correlation of the gene polymorphisms of CYP3A4， CYP2C8 and CYP3A5 with blood concentration among 77 AID patients. In subgroup analysis， blood concentration of GT， GG and TT genotypes of CYP2C8 rs10882521 in 58 patients with systemic lupus erythematosus （SLE） were 514.1，735.3 and 785.9 ng/mL， respectively； GG and TT genotypes were significantly higher than GT genotype （P＜0.05）. CONCLUSIONS： AID patients with CYP3A5 rs4646453 CC genotype have a higher incidence of renal dysfunction due to taking hydroxychloroquine； patients with CYP2C8 rs10882526 locus allele G and AG have a relatively high incidence of renal dysfunction due to taking hydroxychloroquine. When SLE patients taking the same dose of hydroxychloroquine， the blood concentration of hydroxychloroquine in patients carrying CYP2C8 rs10882521 GT genotype is lower than other genotypes.
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The effect of cholesterol ester transfer protein(CETP) on SR-B1 mRNA expression in mouse liver was investigated.The results demonstrated that CETP transgenic mice showed lower serum total cholesterol and high density lipoprotein-cholesterol levels but higher total cholesterol and cholesterol ester content in liver when compared with wild type mice(P＜0.05).The expression of SR-B1 mRNA in liver of CETP transgenic mice was significantly lower as compared with the control group(P＜0.05).