纤维连接蛋白基因型多态性与草酸钙肾结石相关性研究

目的:探讨纤维连接蛋白基因(FN)型多态性与草酸钙肾结石的关系。方法:用聚合酶链式反应-限制性片段长度多态性(PCR-RFLP)方法,检测所有研究对象的FN第2内含子rs10202709位点及第26内含子rs35343644位点的基因型,探讨其基因型与草酸钙肾结石的关系。结果:FNAA基因型与草酸钙肾结石的发病率相关(P<0.05),未发现其他基因型与草酸钙肾结石有相关性。结论:FN基因型多态性与草酸钙肾结石有相关性,FN的AA基因型可作为肾结石患者草酸钙结石危险因素的标志。     

耳穴贴压联合涌泉穴按摩对老年原发性高血压患者血压变异性的影响

目的:探讨耳穴贴压联合涌泉穴按摩治疗老年原发性高血压的效果及对患者血压变异性(BPV)的影响。方法:将94例老年原发性高血压患者随机分为对照组(n=47)和观察组(n=47)。常规西医治疗基础上,观察组给予王不留行籽耳穴贴压联合涌泉穴按摩治疗。比较两组治疗前后收缩压(SBP)、舒张压(DBP)水平、SBP/DBP下降幅度并评估降压疗效,BPV根据24 h动态血压监测结果评估,计算两组治疗前后24h SBP标准差(24h SBP)、24h DBP标准差(24h DBP)、白天SBP标准差(dSSD)、白天DBP标准差(dDSD)、夜间SBP标准差(nSSD)和夜间DBP标准差(nDSD),记录两组治疗期间不良反应情况。结果:观察组治疗后SBP、DBP水平和下降幅度均优于对照组(P<0.05); 观察组降压总有效率97.87%明显高于对照组82.98%,差异有统计学意义(P<0.05); 对照组治疗后24h SBP、24h DSD、dSSD、dDSD较治疗前有明显下降(P<0.05),观察组治疗后24h SBP、24h DSD、dSSD、dDSD、nSSD显著低于治疗前(P<0.05),观察组治疗后24h SBP、24h DSD、dSSD均显著低于对照组,差异有统计学意义(P<0.05); 两组不良反应以头晕、头痛、恶心和眩晕为主,症状程度均较轻,患者耐受性好,组间不良反应率比较差异均无统计学意义(P<0.05)。结论:常规西医治疗基础上给予中医耳穴贴压联合涌泉穴按摩,不仅能有效降低老年原发性高血压患者血压水平和增益降压疗效,而且能显著降低BPV。     

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??OBJECTIVE To investigate the association between methylene tetrahydrofolate reductase (MTHFR)C677T polymorphism and the efficacy of the adjuvant chemotherapy with XELOX regimen for patients who had underwent radical resection of colorectal cancer. METHODS Sixty-two patients who had received chemotherapy with XELOX regimen following radical resection of colorectal cancer were tested for MTHFR C677T polymorphism using Kompetitive Allele-Specific PCR to analyze the association of MTHFR C677T polymorphism with the prognosis and adverse reactions to chemotherapy. RESULTS Among the 62 patients with colorectal cancer, there were 3 allelotypes (C/C, C/T and T/T)at the MTHFR C677T locus, and their frequencies were 46.8%,40.3%,and 12.9%, respectively. The recurrence free survival time was prolonged in C/T and T/T group than C/C group(Log-rank=4.778, P<0.05). Specifically, the relapse rate was 58.6% in patients with C/C allelotype, which was significantly higher than 33.3% in patients with T/T and C/T allelotype(Log-rank=3.985,P??0.05). TNM stage(HR=5.326, P<0.05) and MTHFR C677T polymorphism(HR=0.284,P<0.05) were shown to be the prognostic factors for postoperative adjuvant chemotherapy. The toxicities of chemotherapy were primarily gastrointestinal reactions and bone marrow suppression, without statistically significant differences across different allelotypes (P>0.05). CONCLUSION MTHFR C677T polymorphism is associated with the prognosis with adjuvant chemotherapy with XELOX regimen, and is not associated with the toxicities of chemotherapy. TNM stage IV is predicative of worse prognosis with postoperative adjuvant chemotherapy.     

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??OBJECTIVE To investigate the pharmacokinetic characteristics of enteric-coated sodium mycophenolate(EC-MPS) or mycophenolate mofetil (MMF) dispersible tablets after multiple oral doses in early renal transplant patients, providing references for the rational use of the study drugs in clinical practice. METHODS Thirty-eight first-time renal transplant patients were selected and randomly divided into EC-MPS group (n=18) or MMF dispersible tablets group (n=19). The patients received EC-MPS (540 mg, q12h) or MMF dispersible tablets (750 mg, q12h), combined with tacrolimus and methylprednisolone to prevent acute rejection, respectively. Blood samples were collected at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 h after oral administration on the postoperative day 5. Enzyme multiplied immunoassay technique (EMIT) was employed to determine the plasma concentration of MPA. The main pharmacokinetic parameters of the two durgs were assessed. RESULTS Pharmacokinetic parameters on the postoperative day 5 of EC-MPS and MMF dispersible tablet were as follows: AUC_{0-12 h} were(43.62??16.20) and(42.02??14.40)mg??h??L^-1(P>0.05);??_max were (17.85??11.32) and (13.96??5.11) mg??L^-1(P>0.05);t_max were (2.72??1.74) and(1.32??0.42)h(P<0.05); ??₀ were (1.63??1.18) and (1.66??0.93) mg??L^-1(P>0.05); ??₁₂ were(1.84??2.09) and (1.81??1.76) mg??L^-1(P>0.05); CL were (14.12??5.30) and (19.66??5.99) L??h^-1(P<0.05). Most of the patients revealed a second small peak in the 4-12 h after taking MPA in the two study groups. CONCLUSION There are large individual differences of pharmacokinetic between EC-MPS and MMF dispersible tablets in early renal transplant patients. It is necessary to carry out therapeutic drug monitoring of MPA to guide the adjustment of drug dosage.     

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??OBJECTIVE To evaluate the anti-hepatitis B virus (HBV) activity of herpetrione nanosuspension (PEDX-NS) both in vitro and in vivo. METHODS HepG2 2.2.15 cells and duck hepatitis B virus (DHBV) infected ducks as in vitro and in vivo models were used to compare the anti-HBV activity of PEDX-NS and PEDX coarse suspension (PEDX-CS). RESULTS In the HepG2 2.2.15 cell, PEDX-NS effectively suppressed the secretion of the HBV antigens (HBsAg and HBeAg) in a dose-dependent manner with significant difference from PEDX-CS (P<0.05 or P<0.01). In the in vivo evaluation, PEDX-NS with high dose (100 mg??kg^-1) and middle dose (60 mg??kg^-1) significantly reduced the serum HBV DNA level (P<0.05 or P<0.01) and the effect was better than that of PEDX-CS (P<0.05 or P<0.01). CONCLUSION The result revealed that PEDX-NS exhibits anti-HBV activity both in vitro and in vivo and its effect was superior to that of PEDX-CS. The mechanism is probably that the small particle size of PEDX-NS provides a large specific surface area that resulted in better absorption in vivo, thus enhancing its anti-HBV activity.
     

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??OBJECTIVE To determine the effects of saxagliptin and exenatide on humerus cancellous bone of diabetes-induced osteopenia rats by histomorphometry. METHODS Thirty-five Cases of female SD rats were randomly divided into normal group (N group, n=7), control group (C group, n=7), and the remaining rats were used to establish the type 2 diabetic model by combination of high-fat&sugar-diet feeding for 4 weeks and then low-dose streptozotocin injection(STZ, 30 mg??kg^-1) . After 10 d, the oral glucose tolerance test and the fasting blood glucose were measured, rats with high OGTT(2 h) above 11.1 mmol??L^-1 and high FBG above 16.7 mmol??L^-1 were divided into model group (M group, n=5), saxagliptin group (G group, n=5) and exenatide group (D group, n=6), and continuously treated for 30 d. The left humerus (proximal humeru metaphometry, PHM) were fixed with 4% paraformaldehyde for 48 h, uncalcified embedded in methyl methacrylate after dehydrated and cleared, and sections were taken for bone histomorphometry after Masson-Goldner Trichrome stained. RESULTS In PHM, there was no statistical significance between N and C group, the trabecular bone area ratio( BV/TV) and trabecular quantity were significantly decreased (P??0.01) in M group, while the trabecular separation degree was increased, comparing with those in C group (P??0.01), and the trabecular bone area ratio( BV/TV) and trabecular quantity in G and D group were higher (P??0.01) than those of model rats, while the trabecular separation degree was decreased, comparing with those in M group (P??0.01). Cell parameters showed no statistical significance between N and C group, the osteocllast number and percentage of osteocllast surface perimeter were significantly reduced(P??0.05, P??0.01) in M group, while the osteoclast number and percent osteocllast surface perimeter were significantly increased (P??0.01) as compared with those in C group, saxagliptin and exenatide were found to significantly induce osteocllast number (P??0.01) and percentage of osteoblast surface perimeter (G group P??0.05, D group P??0.01), while reduce osteoclast number (P??0.01) and percent osteoblast surface perimeter (P??0.05) compared with M group. In growth-plate, there was no statistical significance between N and C group, the thickness of growth-plate and the diameter of the mast cells were reduced in M groups (P??0.01), while the thickness of growth-plate (P??0.01) and the diameter of the mast cells (P??0.05) were increased in G and D group,compared with M group. CONCLUSION Therapeutic effects of saxagliptin and exenatide on diabetes -induced osteopenia rats was showed, and the mechanism may be related to the improved growth rate of growth-plate and the changed bone turnover status.     

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??OBJECTIVE To investigate the interindividual variabilities of plasma concentration and lipid-regulating efficacy of atorvastatin in patients with hyperlipidemia through the genotyping of CYP3A4*18A, *18B and MDR1 C3435T genes.METHODS One hundred and fifteen Chinese Han population with hyperlipidemia were genotyped by the PCR-RFLP (restriction fragment length polymorphism).The steady-state plasma trough concentrations of atorvastatin were measured by high performance liquid chromatography (HPLC)-UV.The levels of serum total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) were monitored by the homogeneous enzyme method before treatment and 1 month after medication.RESULTS The mutation frequencies of CYP3A4*18A,*18B and MDR1 C3435T were 3.48%,23.48% and 31.74% respectively.It shows no statistically significant difference for the SNPs frequencies between the normal population reported and patients selected.Patients with CYP3A4*18B homozygous mutant (AA) showed a significantly higher plasma concentration of ATV compared with the G/A heterozygous mutat patients or the G/G wild-type homozygous (P=0.016).However,no significant difference could be shown in the patients with CYP3A4*18A and MDR1 C3435T genotypes(P??0.05).Neither CYP3A4*18A nor MDR1 C3435T could be shown a significant difference in the lipid lowering efficiency(P>0.05).Patients carrying the homozygous mutant (AA) of the CYP3A4*18B gene showed a significantly higher TC lipid-regulating effect compared with patients with the GA or GG genetic variant (P=0.02). The LDL-C change rates among the three genotype groups were significantly different, with AA group >GA group >GG group (P=0.01) and the regulation of TG and HDL-C for AA,GA or GG was compared without finding any significant difference (P>0.05).The TC changerates and plasma concentration were significantly correlated (P=0.031) before and after treatment,while there was no statistical significance in the correlation of the other three lipid change rates with plasma concentration (P??0.05).CONCLUSION The SNPs MDR1 C3435T and CYP3A4*18A do not affect the plasma concentration and efficacy of ATV. In ATV therapy, patients with the CYP3A4*18B gene exhibit higher plasma concentrations than the non-carriers, and the lipid-lowering efficacy was more pronounced.     

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??OBJECTIVE To investigate the protective effect and possible mechanism of Rhizoma Coptis(RC) on lipopolysaccharide(LPS)-induced inflammatory injury in rat hepatocytes(BRL). METHODS LPS-induced BRL cells injury model was established in vitro, then the damaged cells were given different interventions and treatment with 0.175, 0.1 mg?? mL^-1 RC aqueous extract as the test drug, and dexamethasone(Dex) as positive control drug. The optimal test doses of LPS and RC aqueous extract were selected and determined by cell counting kit-8(CCK-8), the cellular apoptosis rate was determined by flow cytometry, TLR4/NF-??B and TLR4/IRF3 signaling pathways and the mRNA level of related inflammatory mediators(TNF-??, IL-1??, IL-6) were detected by RT-PCR, the NF-??B p65 protein expression was analysed by Western blot and immunofluorescence techniques. RESULTS ??Compared with normal control group, 0.1 mg??mL^-1 LPS affected on BRL cells for 24 h, the cell survival rate was decreased significantly(P<0.01), the apoptotic rate increased significantly(P<0.01), the mRNA level of TLR4, NF-??B, IRF3, TNF-??, IL-1??, IL-6 were significantly increased(P<0.01), and the NF-??B p65 protein expression was increased. ??Compared with the model group, 0.1 and 0.175 mg??mL^-1 RC affected on LPS-induced BRL cells for 24 h, the survival rate of BRL cells was increased significantly(P<0.05), the apoptotic rate decreased significantly(P<0.01), the mRNA level of TLR4, NF-??B, IRF3, TNF-??, IL-1??, IL-6 and the NF-??B p65 protein expression were decreased significantly(P<0.01). CONCLUSION Rhizoma Coptis has obviously protective effect on LPS-induced inflammatory injury in rat hepatocytes(BRL), the mechanism of which may be related with inhibiting apoptosis, reducing the release of inflammatory factors such as TNF-????IL-1?? and IL-6, blocking NF-??B p65 protein nuclear translocation, interfering the R4/NF-??B and TLR4/IRF3 signaling pathway.     

环氧化物水解酶1基因多态性对华法林剂量影响的研究

 目的 探讨苏南地区心脏机械瓣膜置换术后汉族人群环氧化物水解酶1(EPHX1)基因rs4653436和rs2292566多态性对华法林剂量的影响,为以后利用基因多态性指导临床合理用药提供理论依据。方法 采用碱基淬灭探针技术,检测197名心脏机械瓣膜置换术后患者的EPHX1 rs4653436和EPHX1 rs2292566的基因型,分析对华法林剂量的影响。结果 EPHX1基因 rs4653436多态性检测有127例纯合子GG型,62例患者为AG型杂合子,8例突变纯合子AA型; GG型患者华法林的平均稳定剂量为（2.64±0.93） mg·d^-1, AG型为（2.52±0.68） mg·d^-1,AA型为（3.25±1.63） mg·d^-1,采用方差分析方法得到各组间华法林剂量差异P值大于0.05,无显著性差异;而EPHX1基因 rs2292566多态性检测有107例纯合子GG型,70例AG型杂合子,20例突变纯合子AA型; GG型患者华法林的平均稳定剂量为（2.47±0.85） mg·d^-1,AG型为（2.49±0.77）mg·d^-1,AA型为（2.81±0.96）mg·d^-1,方差分析方法得到各组间华法林剂量差异P值小于0.05,有显著性差异。结论 在苏南地区心脏机械瓣膜置换术后汉族人群中,EPHX1基因 rs4653436多态性与华法林剂量相关性无显著性差异,对华法林剂量影响较小;而rs2292566多态性与华法林剂量相关性有显著性差异,对华法林剂量有影响。     

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??OBJECTIVE To investigate associations between CYP3A4/5 and POR single nucleotide polymorphisms(SNPs)and tacrolimus dose-corrected concentrations(??₀/D) in Chinese adult heart transplant recipients, providing individualized dose-adjustment for this population. METHODS A total of 90 Chinese adult heart transplant recipients in the early stage were enrolled. CYP3A4*1G G??A(rs2242480) genotype was assessed by pyrophosphate sequencing. CYP3A5*3 A>G(rs776746) and POR*28 C>T(rs1057868) genotype were determined by Sanger sequencing. Tacrolimus trough concentration(??₀) was evaluated by enzyme multiplied immunoassay technique(EMIT). Associations between genotypes and ??₀/D as well as time and dose to get the target range were completely analyzed. RESULTS Allele frequencies of all the evaluated SNPs were consistent with Hardy-Weinberg equilibrium (P>0.05). The ??₀/D in CYP3A5*3/*3 carriers was considerably higher than that in *1/*1and *1/*3 carriers. Moreover, time to get the target range was significantly shortened and required dosage was also significantly reduced in CYP3A5*3/*3 carriers. The ??₀/D in CYP3A4*1/*1G carriers was remarkably decreased in comparison with the wild type. After stratification by CYP3A5*3 genotypes, no associations were observed between CYP3A4*1G and POR*28 genotypes and tacrolimus ??₀/D. POR*28 was not related to ??₀/D, but significantly prolonged time to target range. CONCLUSION This study demonstrats that CYP3A4*1G and CYP3A5*3 polymorphisms are associated with tacrolimus concentrations, the test of these genotypes before transplantation may be useful for individualized medicine of tacrolimus.