Apolipoprotein E polymorphisms contribute to statin response in Chinese ASCVD patients with dyslipidemia.

BACKGROUND: Apolipoprotein E (ApoE) plays an important role in lipid metabolism and clearance. Statins are the most common drugs used to modulate the lipid profile in the clinic therapy; the associations between ApoE polymorphisms and statin response to lipids were inconsistent in previous studies among different ethnicities. Our study aimed to demonstrate the relationships among the statins response and the ApoE gene common polymorphisms and lifestyle risk factors in Chinese arteriosclerotic cardiovascular disease (ASCVD) patients with dyslipidemia. METHODS: A total of 1002 dyslipidemia ASCVD patients were recruited in this study, including 311 patients with a history of type 2 diabetes mellitus (T2DM). These patients were all treated with drugs atorvastatin (10 mg/d) or rosuvastatin (5 mg/d) for at least 4 weeks and genotyped for ApoE e2/e3/e4 alleles, using Kompetitive Allele Specific PCR (KASP) and Sanger sequencing. The plasma lipids levels were determined before and after statins treatment. RESULTS: The results of ApoE genotyping with KASP method were consistent with the sequencing analysis. In the total 1002 patients, the E2 phenotypes (e2/e3, e2/e2) had significant lower low-density lipoprotein cholesterol (LDL-C) baseline levels than subjects with E3 (e3/e3, e2/e4) and E4 (e3/e4, e4/e4) phenotypes (P = 0.007, 0.005, respectively), and E2 phenotypes had the highest triglyceride (TG) baseline levels. To statins treatment, E2 phenotypes had a better response in TG, Total cholesterol (TC) and LDL-C reduction percentage compared with other phenotypes, and smoking/alcohol drinking status also had a significant influence on statins response of LDL-C lowering. No significant difference was found in the effects of lipids decreasing between atorvastatin and rosuvastatin drugs in all patients. CONCLUSIONS: We developed the KASP technique for the ApoE genotyping, and demonstrated ApoE polymorphisms interacted with smoking/drinking to influence the declining extent of TG, TC and LDL-C levels after statins therapy in Chinese dyslipidemia ASCVD patients. These discoveries developed our cognition with the genetic polymorphisms effects on statin response, which should be taken more seriously in smoking/drinking E4 amino acid isoform carriers.

Cost-effectiveness analysis of neonatal hearing screening program in China: should universal screening be prioritized?

BACKGROUND: Neonatal hearing screening (NHS) has been routinely offered as a vital component of early childhood care in developed countries, whereas such a screening program is still at the pilot or preliminary stage as regards its nationwide implementation in developing countries. To provide significant evidence for health policy making in China, this study aims to determine the cost-effectiveness of NHS program implementation in case of eight provinces of China. METHODS: A cost-effectiveness model was conducted and all neonates annually born from 2007 to 2009 in eight provinces of China were simulated in this model. The model parameters were estimated from the established databases in the general hospitals or maternal and child health hospitals of these eight provinces, supplemented from the published literature. The model estimated changes in program implementation costs, disability-adjusted life years (DALYs), average cost-effectiveness ratio (ACER), and incremental cost-effectiveness ratio (ICER) for universal screening compared to targeted screening in eight provinces. RESULTS AND DISCUSSION: A multivariate sensitivity analysis was performed to determine uncertainty in health effect estimates and cost-effectiveness ratios using a probabilistic modeling technique. Targeted strategy trended to be cost-effective in Guangxi, Jiangxi, Henan, Guangdong, Zhejiang, Hebei, Shandong, and Beijing from the level of 9%, 9%, 8%, 4%, 3%, 7%, 5%, and 2%, respectively; while universal strategy trended to be cost-effective in those provinces from the level of 70%, 70%, 48%, 10%, 8%, 28%, 15%, 4%, respectively. This study showed although there was a huge disparity in the implementation of the NHS program in the surveyed provinces, both universal strategy and targeted strategy showed cost-effectiveness in those relatively developed provinces, while neither of the screening strategy showed cost-effectiveness in those relatively developing provinces. This study also showed that both strategies especially universal strategy achieve a good economic effect in the long term costs. CONCLUSIONS: Universal screening might be considered as the prioritized implementation goal especially in those relatively developed provinces of China as it provides the best health and economic effects, while targeted screening might be temporarily more realistic than universal screening in those relatively developing provinces of China.

[The phenotypes of a hypercholesterolemia family with low density lipoprotein receptor exon 13 A606T mutation].

OBJECTIVE: To investigate the clinical phenotypes of familial hypercholesterolemia (FH) caused by exon 13 A606T mutation in low density lipoprotein receptor. METHODS: Clinical data of the suffered family were collected and analyzed, as well as measurement of perivascular intima-medial thickness and follow-mediated-dilation function by ultrasonography. RESULTS: There were totally 11 sufferers including 4 males and 9 females, aged 8-90 years, with 2 homozygotes and 9 heterozygotes. Among them, one homozygote showed angina pectoris and hematuria, both homozygotes had skin xanthomata. TC, TG, LDL-C and HDL-C were (7.39 ± 1.30) mmol/L, (0.93 ± 0.36) mmol/L, (11.76 ± 1.10) mmol/L and (1.22 ± 0.17) mmol/L, respectively. The left/right sided intima-medial thickness of the common, internal, external and bulb carotid artery were (1.15 ± 0.45) mm/(1.30 ± 0.60) mm, (0.82 ± 0.30) mm/(1.00 ± 0.66) mm, (0.77 ± 0.28) mm/(0.78 ± 0.30) mm and (1.40 ± 0.59) mm/(1.46 ± 0.71) mm respectively. The brachial artery flow mediated dilation rate was (4.85 ± 4.80)%. Echocardiography revealed 2 patients with cardiac valvular disease and 3 with atrium septum aneurysm. CONCLUSION: FH patients show a variety of phenotypes including extraordinary hypercholesterolemia, subcutaneous xanthomata and premature coronary heart disease.

Reduced numbers of T cells and B cells correlates with persistent SARS-CoV-2 presence in non-severe COVID-19 patients.

COVID-19 has been widely spreading. We aimed to examine adaptive immune cells in non-severe patients with persistent SARS-CoV-2 shedding. 37 non-severe patients with persistent SARS-CoV-2 presence that were transferred to Zhongnan hospital of Wuhan University were retrospectively recruited to the PP (persistently positive) group, which was further allocated to PPP group (n = 19) and PPN group (n = 18), according to their testing results after 7 days (N = negative). Epidemiological, demographic, clinical and laboratory data were collected and analyzed. Data from age- and sex-matched non-severe patients at disease onset (PA [positive on admission] patients, n = 37), and lymphocyte subpopulation measurements from matched 54 healthy subjects were extracted for comparison (HC). Compared with PA patients, PP patients had much improved laboratory findings. The absolute numbers of CD3+ T cells, CD4+ T cells, and NK cells were significantly higher in PP group than that in PA group, and were comparable to that in healthy controls. PPP subgroup had markedly reduced B cells and T cells compared to PPN group and healthy subjects. Finally, paired results of these lymphocyte subpopulations from 10 PPN patients demonstrated that the number of T cells and B cells significantly increased when the SARS-CoV-2 tests turned negative. Persistent SARS-CoV-2 presence in non-severe COVID-19 patients is associated with reduced numbers of adaptive immune cells. Monitoring lymphocyte subpopulations could be clinically meaningful in identifying fully recovered COVID-19 patients.

Molecular Characteristics, Antimicrobial Resistance and Virulence Gene Profiles of Staphylococcus aureus Isolates from Wuhan, Central China.

PURPOSE: This study aimed to investigate the molecular characteristics, antimicrobial resistance and virulence genes profiles of S. aureus isolates from Wuhan, central China. MATERIALS AND METHODS: A total of 302 non-duplicate S. aureus isolates were collected successively during January-December 2018 and subjected to multi-locus sequence typing (MLST), staphylococcal protein A (spa) typing and Panton-Valentine leucocidin (PVL) and staphylococcal enterotoxin A, B, C, D, E, G, H and I (sea, seb, sec, sed, see, seg, seh and sei) detection. All methicillin-resistant S. aureus (MRSA) isolates were additionally subjected to staphylococcal chromosomal cassette mec(SCCmec) typing. RESULTS: Of the 302 S. aureus isolates, 131 were categorised as MRSA, yielding a rate 1.4 times the average rate in China during 2018 (43.4% vs 30.9%). Thirty-one sequence types (STs) and 82 spa types were identified. The most prevalent clones were ST5-t2460 (10.9%), ST239-t030 (9.3%), ST188-t189 (7.9%) and ST59-t437 (6.3%). Notably, the continued prevalence of ST239-t030 in Wuhan differs from other areas in China. SCCmec types and subtypes I, II, III, IVa and V were present in 0.8%, 36.6%, 26.0%, 20.6% and 8.4% of MRSA isolates. A comprehensive analysis identified ST5-t2460-SCCmec II (25.2%,), ST239-t030-SCCmec III (19.8%) and ST59-t437-SCCmec IVa (7.6%) as the major clones among MRSA isolates. The genes pvl, sea, seb, sec, sed, see, seg, seh and sei were detected at respective frequencies of 11.9%, 42.1%, 49.7%, 45.0%, 20.9%, 33.8%, 60.5%, 25.8% and 66.9%. CONCLUSION: ST239-t030 remains one of the most prevalent clones in S. aureus isolates from Wuhan, leading us to conclude that S. aureus isolates from Wuhan possess unique molecular characteristics. The S. aureus isolates also exhibit unique antimicrobial resistance profiles and harbour relatively high numbers of enterotoxin virulence genes, compared with other reports from China.

Two mutations in LDLR gene were found in two Chinese families with familial hypercholesterolemia.

Familial hypercholesterolemia (FH) (OMIM 143890) is an autosomal dominantly inherited disease mainly caused by mutations of the gene encoding the low density lipoprotein receptor (LDLR) and Apolipoprotein (Apo) B. First the common mutation R3500Q in ApoB gene was determined using PCR/RFLP method. Then the LDLR gene was screened for mutations using Touch-down PCR, SSCP and sequencing techniques. Furthermore, the secondary structure of the LDLR protein was predicted with ANTHEPROT5.0. The R3500Q mutation was absent in these two families. A heterozygous p.W483X mutation of LDLR gene was identified in family A which caused a premature stop codon, while a homozygous mutation p.A627T was found in family B. The predicted secondary structures of the mutant LDLR were altered. We identified two known mutations (p.W483X, p.A627T) of the LDLR gene in two Chinese FH families respectively.

[Analysis on gene mutations in a Chinese pedigree with autosomal dominant inheritance cataract].

OBJECTIVE: The aim of this study was to reveal the genetic defect of the autosomal dominant inheritance cataract in a Chinese pedigree. METHODS: Case-control study. There were 26 individuals investigated with clinical examination in a Chinese four generations pedigree. The genome DNA of the individuals was extracted by the improved NaI method. The exons of six cataract candidate genes in 204 normal controls and 42 senile cataract patients were screened for the mutation by PCR restriction fragment length polymorphism (PCR-RFLP) methods. RESULTS: The phenotype of the cataract was pulverulent nuclear cataract. A novel C/T transition at nucleotide position 827 was identified in the GJA8 gene that led to a serine to phenylalanine change in codon 276. This mutation was not found in 42 senile cataract patients and in 204 controls. Four single nucleotide polymorphisms (SNPs) were also found in a cataract candidate gene in the family members. CONCLUSIONS: A novel GJA8 gene mutation was found in a Chinese autosomal dominant inheritance cataract pedigree. A substitution, C276T in GJA8 gene, was identified as the most likely causative mutation underlying the phenotype of pulverulent nuclear cataract in all affected family members.

Pandoraea sputorum Bacteremia In A Patient Who Had Undergone Allogeneic Liver Transplantation Plus Immunosuppressive Therapy: A Case Report.

Pandoraea sputorum (P. sputorum), an emerging pathogen, is able to trigger a pronounced pro-inflammatory response that results in lung dysfunction in cystic fibrosis (CF) patients. All previous P. sputorum isolates have been obtained from the respiratory samples of CF patients, with no reported cases of P. sputorum bacteremia. For the first time, we report P. sputorum isolates recovered twice from the blood cultures of a patient with liver cancer who had undergone allogeneic liver transplantation. These isolates were successfully identified by combining mass spectrometry and molecular techniques based on 16S rRNA sequencing methods. At the onset of the P. sputorum bacteremia, the patient's peripheral T, B and NK cell counts were 181.68/µL, 59.57/µL and 70.66/µL, respectively. The serum procalcitonin level, C-reactive protein level and peripheral neutrophil granulocyte percentage were 0.56 ng/mL, 61.00 mg/L and 96.8%, respectively. We found these isolates to be susceptible to ciprofloxacin and piperacillin/tazobactam and to be intermediate to amikacin. Previous studies have found P. sputorum isolates to be resistant. All of the data combined showed that compromised immune function from allogeneic liver transplantation plus immunosuppressive therapy contributes to the occurrence of P. sputorum bacteremia. Furthermore, the P. sputorum isolates demonstrated characteristic resistance profiles.

The Pharmacogenomics "Side-effect" of TP53/EGFR in Non-small Cell Lung Cancer Accompanied with Atorvastatin Therapy: A Functional Network Analysis.

BACKGROUND: Atorvastatin belongs to the group of statins and is the leading drug for hypercholesterolemia treatment. Although, its anticancer effects are highly appreciated, its properties are still unclear. The aim of this study was to explore the underlying anticancer mechanisms induced by atorvastatin and enlarge the potential target in non-small cell lung cancer. METHODS: Target genes of atorvastatin were collected by the DrugBank database. Prediction of interaction between primary targets and secondary targets was performed, and protein-protein interaction network was constructed though the STRING. Then, KEGG pathway enrichment analysis was performed with WebGestalt and ClueGO, including the pathways in non-small cell lung cancer. Furthermore, a genomic alteration analysis of the selected seed genes of atorvastatin benefit and non-small cell lung cancer pathway was conducted by cBioPortal. Finally, a survival analysis with the selected seed genes in lung cancer (lung adenocarcinoma, lung squamous cell carcinoma) was conducted using Kaplan-Meier (KM) plotter. RESULTS: To identify seed genes, 65 potential candidate genes were screened as targets for atorvastatin using STRING with DrugBank database, while the KEGG pathway was enriched to get the overlap match of pathways in non-small cell lung cancer. Then 4 seed genes, Epidermal Growth Factor Receptor (EGFR), erb-b2 receptor tyrosine kinase 2 (ERBB2), AKT serine/threonine kinase 1 (AKT1) and tumor protein p53 (TP53), were selected and their genomic alternation were evaluated by cBioPortal. Survival analysis found that TP53 and EGFR showed a significant correlation (log rank P = 3e-07 and 0.023) with lung adenocarcinoma and lung squamous cell carcinoma, according to the KM analysis. CONCLUSION: Gene-phenotype connectivity for atorvastatin in non-small cell lung cancer was identified using functional/activity network analysis method, and our findings demonstrated that TP53 and EGFR could be the potential targets in cancer patients with atorvastatin therapy.

[Mutation screening and functional analysis of low density lipoprotein receptor in a familial hypercholesterolemia family].

OBJECTIVE: To screen the mutations of the low density lipoprotein receptor (LDLR) gene in a familial hypercholesterolemia (FH) family, and analyze the LDL-uptaking function of LDLR on lymphocytes of patients. METHODS: Genomic DNA was extracted from four affected members in a Chinese FH family. The presence of apoB100 gene R3500Q mutation which results in familial defective apolipoprotein B100 (FDB) was excluded first. Fragments of the LDLR gene were amplified by touch-down polymerase chain reaction (Touch-down PCR) and analyzed by single-strand conformational polymorphism (SSCP). The suspect fragments of the LDLR gene were cloned and sequenced. Furthermore, the lymphocytes bounded with fluorescent-labeled LDL (DiI-LDL) were measured by fluorescence flow cytometry. RESULTS: A nonsense mutation was identified in exon 10 of LDLR gene. This mutation gave rise to a premature stop codon (W462X), resulting in the absence of most of the LDLR domains. It was detected in all the affected members of the FH family. The ratios of functional LDLR in lymphocytes from patients and normal controls were 63.7% and 77.3% respectively. As a result, the activity of the functional LDLR in patients was just 82.4% of that in the normal controls. CONCLUSION: It is possible that the W462X mutation of LDLR gene is the main cause for the disease in this family.

Novel compound heterozygous mutations in low density lipoprotein receptor gene causes a severe phenotype in a Chinese hypercholesterolemia family.

Mutations in the low density lipoprotein receptor (LDLR) gene serve a causative role in the pathophysiology of familial hypercholesterolemia (FH), a common autosomal inherited disorder characterized by abnormal lipid metabolism. The aim of the present study was to investigate genetic defects in a Chinese family with FH. Clinical features and family histories were collected, as were the results of various laboratory tests, including determinations of serum lipid concentrations, ultrasonography and angiography results. Potential mutations in LDLR were screened using direct polymerase chain reaction (PCR) sequencing. Multiple sequence alignments, structure and hydrophobicity predictions were performed in silico. Novel compound heterozygote mutations in LDLR of the proband were identified, with a Trp577Term-bearing maternal allele and a Pro685Leu-bearing paternal allele. The proband, a 27-year-old male, had severe and diffuse coronary stenosis and non-ST segment elevation myocardial infarction, as well as multiple skin xanthomas and high serum lipid levels. The allele-dosage-dependent clinical features, including hypercholesterolemia and peripheral arterial atherosclerosis, were observed in the proband and the other heterozygous patients. Therefore, the coexistence of Pro685Leu and Trp577Term mutations in LDLR is a novel compound heterozygosis in Chinese patients and may lead to a severe FH phenotype. The explanation for the existence of compound heterozygous mutations instead of homozygous mutations in this particular family requires further study.