广东河源地区脑梗死患者氯吡格雷CYP2C19相关基因多态性分析

目的分析广东河源地区脑梗死患者CYP2C19基因多态性特点,以利于指导用药和疾病防治。方法对316例脑梗死患者进行检测,并比较与梅州地区和汕头地区差异。结果在316份检测标本中,快代谢型(CYP2C19*1/*1)占40.82%,中代谢型(CYP2C19*1/*2、CYP2C19*1/*3)占43.04%,慢代谢型(CYP2C19*2/*2、CYP2C19*2/*3、CYP2C19*3/*3)占16.14%。与同为客家族群的广东梅州地区差异无统计学意义(P>0.05),与广东汕头地区差异有统计学意义(P<0.05)。结论河源地区脑梗死患者CYP2C19基因主要为中代谢型及快代谢型。     

The metabolism of CYP2C9 and CYP2C19 for gliclazide by homology modeling and docking study

With homology modeling techniques, a 3D structure model of CYP2C19 was built and refined with molecular mechanics and molecular dynamics simulations. The refined model was assessed to be reasonable by Profile-3D and PROCHECK programs. With the aid of the automatic molecular docking, one substrate and two inhibitors were docked to CYP2C19 by InsightII/Affinity program. The docking results, which are in well agreement with the reported results, demonstrate that the refined model of CYP2C19 is reliable. Then, with the refined model of CYP2C19 and the crystal structure of CYP2C9, the metabolisms of them for gliclazide in two different metabolic pathways were studied and the results show that both enzymes have more favorable interaction energies and stronger affinity with gliclazide in methylhydroxylation pathway than in 6beta-hydroxylation pathway. It is exciting that substrate inhibition phenomenon can be found in metabolisms of CYP2C9 and CYP2C19 for gliclazide in two metabolic pathways. Gliclazide can change the conformation of the active sites and decrease obviously the affinities between gliclazide in the active site and enzymes when it is docked in the second active sites in CYP2C9 and CYP2C19. These results are in well agreement with the kinetic experimental results.     

氯吡格雷与阿司匹林联合治疗急性脑梗死患者的临床研究

目的观察氯吡格雷与阿司匹林联用对急性脑梗死患者的血小板聚集和血液流变学的影响,探讨联合用药的安全性。方法选择62例急性脑梗死患者,分为联合用药组(氯吡格雷+阿司匹林)和阿司匹林组,予氯吡格雷50mg/d,阿司匹林100mg/d,疗程2周,对两组患者检测治疗前后血小板聚集率及血液流变学检查,观察用药安全性。结果联合用药组治疗后GMP140、全血粘度和血小板聚集率降低,明显优于阿司匹林组(P<0.05)。两组副作用发生率无统计学意义。结论氯吡格雷与阿司匹林联合治疗急性脑梗死,具有明显抑制血小板聚集和改善血液流变学的作用,副作用无增加。     

Routine screening for syphilis in neurology is not useful]

In a retrospective study the results of the screening for syphilis in one of the neurological wards of the Academic Medical Centre in Amsterdam were analysed. The Venereal Disease Research Laboratory test (VDRL) and the Treponema Pallidum Haemagglutination Assay (TPHA) in serum were used for screening. The data for analysis were obtained via the hospital computer data base and via the medical files of the department of neurology. During the 5-year study period (1986-1990) 2378 adult patients were admitted and 1247 (52.4%) of them were screened. In seven (0.56%) patients both tests were positive. Three of them had been treated for syphilis in the past and showed no symptoms of active syphilis. Four (0.32%) patients suffered from active neurosyphilis. In three of these four patients syphilis was suspected on admission and confirmed by the tests. In one patient the diagnosis of syphilis was not considered. The positive test results became available shortly before she died of pneumonia and were without consequences. None of the 32 (2.6%) patients with a positive TPHA and a negative VDRL was diagnosed as having (neuro-)syphilis. Two (0.16%) patients had a false-positive VDRL. We conclude that routine serological examination for syphilis of every patient admitted to a neurological ward is not useful. We advise a limited screening of patients who belong to a group with high risk for syphilis and patients with symptoms and signs that can be caused by syphilis, such as dementia or ischaemic strokes at a relatively young age.     

Strongyloides Hyperinfection Syndrome among COVID-19 Patients Treated with Corticosteroids

Widespread use of corticosteroids for COVID-19 treatment has led to Strongyloides reactivation and severe disease in patients from endemic areas. We describe a US patient with COVID-19 and Strongyloides hyperinfection syndrome and review other reported cases. Our findings highlight the need for Strongyloides screening and treatment in high-risk populations.     

CYP2D6 C188T单核苷酸多态与肺癌易感性

[目的]分析CYP2D6(cytochromes P450 2D6)基因C188T单核苷酸多态与肺癌风险的关系,探讨肺癌的敏感基因型.[方法]以病例-对照研究方法,采用聚合酶链反应-限制性片段长度多态性方法(PCR-RFLP),检测118例肺癌患者和按性别、年龄频数匹配的118例正常对照者的CYP2D6基因C188T多态,分析各基因型与肺癌易感性的关系.[结果]肺癌组和对照组人群188T等位基因频率分别为53.39%和61.86%,T188/T基因型频率分别为29.66%和42.38%,差异均无统计学意义(P＞0.05).经年龄、性别、吸烟情况调整后非突变基因型T188/T(即野生基因型C188/C和杂合基因型C188/T合并)与肺癌有中等强度的关联OR=1.70(95%CI:1.01～2.92),尤其在鳞癌中关联更明显,OR=2.49(95%CI:1.07～5.79);对吸烟程度所作分层分析结果表明,在不吸烟者及轻度吸烟者中非T188/T基因型的个体患肺癌的风险显著增高,其调整OR值分别为2.28(95%CI:1.08～4.81)和3.64(95%CI:1.13～11.79);CYP2D6非T188/T基因型与吸烟在肺癌的发生过程中不存在交互作用(x2=1.46,P=0.227).[结论]T188/T基因型在不吸烟者、轻度吸烟者中及肺鳞癌中可能作为保护因素而降低肺癌的易感性.     

CYP2C19基因芯片检测的临床应用

目的:应用CYP2C19基因芯片对单独口服氟西汀患者进行细胞色素酶P4502C19基因检测,指导临床用药并评价基因芯片技术应用在CYP2C19基因快速检测的实用性和可靠性。方法:研究对象为52例单独口服氟西汀患者,取外周血2 ml,分离提取全血基因组DNA,用CYP2C19基因芯片检测中国人中最常见的2个热点突变——CYP2C19*2和CYP2C19*3。结果:在52例样本中,纯合快代谢型CYP2C19*1/*1(636GG,681 GG)23例;杂合快代谢型CYP2C19*1/*2(636 GG,681 GA)11例;杂合快代谢型CYP2C19*1/*3(636 GA,681 GG)5例;慢代谢型CYP2C19*2/*2(636 GG,681 AA)8例;慢代谢型CYP2C19*3/*3(636AA,681 GG)1例;慢代谢型CYP2C19*2/*3(636 GA,681 GA)4例。结论:CYP2C19基因芯片对中国人常见细胞色素酶P4502C19基因突变位点检出率高,可满足临床CYP2C19基因检测要求,具有广阔的临床应用前景。     

Association of Genetic Variants of CYP2C19 and CYP2D6 with Esophageal Squamous Cell Carcinoma Risk in Northern India,Kashmir

Genetic polymorphism in xenobiotic metabolizing enzymes (XMEs) is associated with various malignancies. However, the association of esophageal cancer with XMEs is mixed. The current study was aimed to explore the association of genetic polymorphisms of cytochrome (CYP) 2C19 and CYP2D6 genotypes with esophageal squamous cell carcinoma (ESCC) risk in Kashmir, India. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and sequencing methods were used for genotyping of 492 ESCC cases and equal number of individually matched controls. Conditional logistic regression models were used to assess odds ratios (ORs) and 95% confidence intervals. Increased ESCC risk was observed in subjects with variant genotypes of CYP2C19 (OR = 3.3) or CYP2D6 (OR = 2.1) and risk was higher (OR = 4.6) in subjects who harbored both the genotypes. Almost same but higher risk turned when subjects were smokers and carried a variant genotype of CYP2C19 (OR = 4.4) or CYP2D6 (OR = 4.7). Risk was appreciably increased in subjects who had family history of any cancer and also harbored a variant genotype of either CYP2C19 (OR = 15.5) or CYP2D6 (OR = 9.7). Subjects harboring a variant genotype of CYP2D6 showed an added risk when they used biomass as fuel (OR = 4.6). In conclusion, variant genotypes of CYP2C19 and CYP2D6 are associated with an increased risk of ESCC.     

Variability of CYP2C8 Polymorphisms in Three Jordanian Populations: Circassians,Chechens and Jordanian-Arabs

CYP2C8 is a member of Cytochrome P450 enzymes system. It plays an important role in metabolizing a wide range of exogenous and endogenous compounds. CYP2C8 is involved in the metabolism of more than 100 drugs, typical substrates include: anticancer agents, antidiabetic agents, antimalarial agents, lipid lowering drugs and many others that constitute 20% of clinically prescribed drugs. Genetic variations of CYP2C8 have been reported with different frequencies in different populations. These genetic polymorphisms can lead to differences in the efficacy and safety of different types of medications metabolized by CYP2C8. The aim of this study was to investigate the allele frequencies of CYP2C8*3 (rs10509681 and rs11572080) and CYP2C8*4 (rs1058930) polymorphisms in three populations living in Jordan; Circassians and Chechens and Jordanian-Arabs and compare those frequencies with other populations. A total of 200 healthy Jordanians, 93 Circassians and 88 Chechens were included in this study. Genotyping of CYP2C8*3 and CYP2C8*4 polymorphisms was done by using polymerase chain reaction (PCR) followed by Restriction Fragment Length Polymorphism (RFLP). Using the Chi-square test, we found that the prevalence of CYP2C8*3 and *4 among the three populations were significantly different. Moreover, the mutant allele CYP2C8*3 (416A) was only detected in the Jordanian-Arab population with an allele frequency of 0.082, while the mutant allele CYP2C8*4 (792G) was detected with frequencies of 0.065, 0.122, 0.017 in Jordanian-Arabs, Circassians and Chechens, respectively. As our results show, CYP2C8*3 was undetectable in our Circassians and Chechens samples, on the other hand, Circassians had the highest allele frequency of CYP2C8*4 compared to Chechens and Jordanian-Arabs. These genetic variations of the gene encoding the CYP2C8 drug metabolizing enzymes can lead to clinical differences in drug metabolism and ultimately variations in drug effectiveness and toxicities. This study provides evidence for the importance of personalized medicine in these populations and can be the foundation for future clinical studies.

     

CYP2C19基因多态性对侵袭性真菌感染患者药物治疗的指导效果

目的探索CYP2C19基因多态性对侵袭性真菌感染患者药物治疗的指导效果。方法选取2017年1月-2018年6月于医院接受治疗的103例侵袭性真菌感染患者为研究对象,按照患者DNA基因结果将患者分为高代谢型(EM)、中等代谢型(IM)、低代谢型(PM)3组。收集3组患者临床资料并进行对比,统计患者CYP2C19基因型频率,按照代谢类型将患者进行分组后对治疗参数进行分析。结果 3组患者BMI、糖尿病、长期吸烟史、NEU、TBil数据对比不具有统计学意义。EM组25例681GG-636GG基因型,IM组共47例双位基因,分别为30例681GA-636GG基因型和17例681GG-636GA基因型,PM组共31例双位基因,分别为18例681AA-636GG基因型和13例681GA-636GA基因型。IM组ICU停留时间(45.76±5.49)d、抗菌治疗花费(5867.90±342.16)元明显高于EM组和PM组(P<0.05),PM组并发症发生率(16.13%)显著高于EM组、IM组(P<0.05)。结论侵袭性真菌感染患者以双位基因型为主,结合CYP2C19基因多态性指导药物治疗,患者ICU停留时间和抗菌治疗花费及并发症发生率具有差异。     

贵州省苗族及布依族人群CYP1A1＊2C基因多态性研究

[目的]检测贵州省苗族及布依族正常人群细胞色素氧化酶1A1＊2C（CYP1A1＊2C）基因多态性。[方法]采用Taqman-MGB探针,通过实时定量PCR（real-time PCR）对贵州省三都县125名苗族及122名布依族人群的血液样本进行CYP1A1＊2C基因多态性分析,并采用χ2检验比较两民族该基因分布的差异。[结果]CYP1A1＊2C野生纯合子（基因型AA）、突变杂合子（基因型AG）、突变纯合子（基因型GG）在苗族及布依族中基因型频率分别为65.6%、28.0%、6.4%及68.9%、25.4%、5.7%;A和G在苗族及布依族中基因频率分别为79.6%、20.4%及81.6%、18.4%,两民族人群的基因多态性分布差异无统计学意义。[结论]中国贵州省苗族及布依族人群中CYP1A1＊2C基因型频率分布没有明显不同。     

Influence of smoking and CYP2C19 genotypes on H. pylori eradication success

CYP2C19 polymorphisms and smoking influence the efficacy of H. pylori eradication therapy, but interaction between the two have hitherto not been examined. A total of 142 H. pylori-positive patients who received triple drug therapy with lansoprazole, amoxicillin and clarithromycin were categorized into three groups with regard to diplotypes of CYP2C19: homozygous extensive metabolizer (homEM), heterozygous EM (hetEM), and poor metabolizer (PM). The overall success rate was 61.3%. Smoking was an independent risk factor of eradication failure (OR 2.81, 95% CI 1.14-6.91), whereas CYP2C19 polymorphisms were less influential. Among non-smokers, the homEM and hetEM groups showed worse eradication rates (58.5 and 67.3%) relative to PM (76.2%) as expected; however, an opposite trend was observed among smokers (homEM 50.0%, hetEM 46.7%, PM 20.0%), indicating possible interactions with CYP2C19 polymorphisms. Smoking has a greater influence on H. pylori eradication than the CYP2C19 genotype. Interaction between smoking and CYP2C19 should be examined in the future.     

CYP2C19基因多态性与幽门螺杆菌感染后胃癌易感性研究

目的探讨CYP2C19基因多态性与幽门螺杆菌(Helicobacter pylori,Hp)感染后胃癌易感性。方法选择2015年4月-2018年4月北京市和平里医院收治的原发性胃癌患者119例作为胃癌组,同期收治的慢性胃炎患者100例作为对照组,检测两组患者幽门螺杆菌感染情况,并分析胃癌组与对照组患者CYP2C19基因多态性,以及Hp阳性胃癌组与Hp阳性对照组CYP2C19基因多态性。结果胃癌组患者Hp感染率为73.11%(87/119),对照组患者Hp感染率为63.00%(63/100),两组Hp感染率比较无显著差异。胃癌组患者中纯合子快代谢型33例(27.73%)、杂合子快代谢型47例(39.50%)、慢代谢型39例(32.77%),对照组患者中纯合子快代谢型31例(31.00%)、杂合子快代谢型42例(42.00%)、慢代谢型27例(27.00%),两组患者CYP2C19基因型分布比较差异无统计学意义。Hp阳性胃癌患者中纯合子快代谢型20例(22.99%)、杂合子快代谢型37例(42.53%)、慢代谢型35例(40.23%),Hp阳性对照组患者中纯合子快代谢型19例(30.16%)、杂合子快代谢型29例(46.03%)、慢代谢型15例(23.81%),两组Hp阳性患者CYP2C19基因型分布比较差异有统计学意义(P<0.05),其中Hp阳性胃癌患者慢代谢型患者构成比高于Hp阳性对照组。结论 CYP2C19慢代谢型可增加Hp阳性患者胃癌发生风险,需引起临床工作者的重视。     

Prevalence of Five Pharmacologically Most Important CYP2C9 and CYP2C19 Allelic Variants in the Population from the Republic of Srpska in Bosnia and Herzegovina

The enzymes of the cytochrome P450 superfamily play a critical role in phase I drug metabolism. Among them, CYP2C9 and CYP2C19 are clinically important, as they can mediate severe toxicity, therapy failure, and increased susceptibility to cancer and other diseases caused by chemicals. The aim of this study was to determine the prevalence of pharmacologically most important allelic variants of the CYP2C9 and CYP2C19 genes in the general population of the Republic of Srpska (Bosnia and Herzegovina) and to compare them with other populations. For this purpose we determined the genotype profile and allele frequency of 216 randomly selected healthy volunteers using real-time polymerase chain reaction (RT-PCR). The prevalence of the CYP2C9 *2 and *3 alleles was 13.6 and 7.4 %, respectively. Based on these frequencies, of the 216 participants four (1.86 %) were predicted to be poor metabolisers, 78 (36.11 %) intermediate, and the remaining 134 (62.03 %) normal metabolisers. Based on the prevalence of CYP2C19 *2 and *17 variants – 16.2 and 20.4 %, respectively – nine (4.17 %) were predicted to be poor, 57 (26.39 %) rapid, and nine (4.17 %) ultra-rapid metabolisers. We found no significant differences in allele frequencies in our population and populations from other European countries. These findings suggest that genetically determined phenotypes of CYP2C9 and CYP2C19 should be taken into consideration to minimise individual risk and improve benefits of drug therapy in the Republic of Srpska.Key words: cytochrome P450 enzymes, pharmacogenetics, polymorphic allele     

农村性病患者首诊机构是否正规的影响因素研究

目的：探讨影响农村性病患者首诊是否去正规机构的因素。方法：在山东省7所性病医疗机构对前来就诊的232名农村性病患者进行结构问卷访谈。结果：患者的年龄、职业、收入、是否第一次得性病、第一次得性病时居住地、患者感受疾病的严重程度、首诊带钱数量、从家里拿钱是否方便、首诊机构离住所距离，以及职业和收入的交互作用，对患者首诊去正规机构有一定影响。     

泸州地区冠心病PCI治疗患者CYP2C19基因多态性分布的研究

目的探讨泸州地区冠心病PCI治疗患者CYP2C19基因多态性分布情况。方法选取泸州地区冠心病PCI治疗患者120例作为试验组,选取本地区健康汉族人群108例作为对照组,抽取2组对象的外周血5 mL,提取基因组DNA,并采用实时荧光定量PCR方法检测CYP2C19的基因型,分析2组对象的CYP2C19基因多态性分布。结果试验组患者检测出CYP2C19的6种基因型,~*1/~*1型(CC,CC),~*1/~*2型(CC,TC),~*1/~*3型(TC,CC),~*2/~*2型(CC,TT),~*3/~*3型(TT,CC),~*2/~*3型(TC,TC)明显高于对照组(P<0.05);检测出CYP2C19的3种代谢型,快代谢型,中间代谢型,慢代谢型明显高于对照组(P<0.05)。结论对泸州地区冠心病PCI治疗患者CYP2C19基因多态性分布情况进行检测可以分析冠心病的发病情况,并为补充本地区冠心病PCI治疗患者CYP2C19基因多态性分布提供一定参考。     

Altered kidney CYP2C and cyclooxygenase-2 levels are associated with obesity-related albuminuria

OBJECTIVE: To determine cytochrome P450 (CYP450) and cyclooxygenase (COX) expression and metabolite regulation and renal damage in the early stages of obesity-related hypertension and diabetes. RESEARCH METHODS AND PROCEDURES: Obese and lean Zucker rats at 10 to 12 weeks of age were studied. Blood pressure was measured in the conscious state using radiotelemetry. Blood glucose levels and body weight were measured periodically. Protein expression of CYP450 and COX enzymes in the kidney cortex, renal microvessels, and glomeruli was studied. The levels of CYP450 and COX metabolites in urine were measured, and urinary albumin excretion, an indicator of kidney damage, was measured. RESULTS: Body weight and blood glucose averaged 432 +/- 20 grams and 105 +/- 5 mg/dl, respectively, in obese Zucker rats as compared with 320 +/- 8 grams and 91 +/- 5 mg/dl, respectively, in age-matched 10- to 12-week-old lean Zucker rats. Renal microvascular CYP4A and COX-2 protein levels were increased 2.3- and 17.0-fold, respectively, in obese Zucker rats. The protein expression of CYP2C11 and CYP2C23 was decreased 2.0-fold in renal microvessels isolated from obese Zucker rats when compared with lean Zucker rats. The urinary excretion rate of thromboxane B(2) was increased significantly in obese Zucker as compared with lean Zucker rats (22.0 +/- 1.8 vs. 13.4 +/- 1.0 ng/d). Urinary albumin excretion, an index of kidney damage, was increased in the obese Zucker rat at this early age. DISCUSSION: These results suggest that increased CYP4A and COX-2 protein levels and decreased CYP2C11 and CYP2C23 protein levels occur in association with microalbuminuria during the onset of obesity-related hypertension and type 2 diabetes.     

瑞易宁与格华止联合治疗2型糖尿病及其对自身胰岛β细胞功能及胰岛素抵抗的影响

目的 探讨瑞易宁与格华止联合治疗2型糖尿病，比较单用瑞易宁或格华止与联合使用2种药物对改善患者自身胰岛β细胞功能、降低胰岛素抵抗的效果。方法用Homa模型的胰岛素敏感指数（IAI）、胰岛素抵抗指数（IR）、胰岛素分泌指数（IS）及β细胞功能指数（HBCI）及标准馒头餐后患者的胰岛素和C-肽的分泌情况评估小剂量瑞易宁与格华止联合及单用治疗2型糖尿病患者18周前后胰岛素抵抗和胰岛素分泌的变化。结果2型糖尿病患者治疗前，以Homa模型的IAI、IR、IS、HBCl分析显示，均存在胰岛素抵抗和胰岛素分泌缺陷，经瑞易宁和格华止联用18周治疗后，IAI、IR、IS、及HBCI均有统计学意义（P〈0．05），服标准馒头餐后患者的胰岛素和C-肽的水平有一定程度的增高，与单用瑞易宁比较，其对IS和HBCI及标准馒头餐后胰岛素和C肽的改善更好，与单用格华止比较，其对IAI和IS的降低更为明显。结论瑞易宁与格华止联用不仅能显著降低空腹和餐后血糖，而儿能更有效地降低胰岛素抵抗，改善和保护患者自身β细胞功能。