Resolving the composite trait of hypertension into its pharmacogenetic determinants by acute pharmacological modulation of blood pressure regulatory systems

Acute pharmacogenetic analysis was carried out in an intercross F2 population derived from Prague hypertensive-hypertriglyceridemic and Lewis rats. Quantitative trait loci (QTL) mapping was performed for baseline blood pressure (BP) and for BP after blockade of the renin-angiotensin system by losartan, of the sympathetic nervous system (SNS) by pentolinium, and of the nitric oxide system by N(G)-nitro- L-arginine methyl ester. Two significant loci for baseline BP were found on chromosome (Chr) 3 (logarithm of likelihood, LOD, 3.8) and Chr 5 (LOD 3.6), and one suggestive locus on Chr 1 (LOD 2.7). The QTL on Chr 3 persisted after treatment with the three agents while the QTL on Chr 5 and Chr 1 disappeared after pentolinium administration. This suggests independence of the locus on Chr 3 from each acute BP regulatory system examined, whereas the loci on Chr 5 and Chr 1 appeared to be controlled mainly by the SNS. Although not apparent at baseline, a significant locus appeared on Chr 8 (LOD 7.0) after blockade of the SNS, and NO system blockade led to the appearance of a new QTL on Chr 1 (LOD 3.6), indicating the contribution of the inhibited systems to these loci. Pharmacogenetic dissection of the BP trait is a powerful tool to unravel the underlying physiological mechanisms of QTL affecting baseline BP and to identify specific QTL for the response to drugs. This pharmocogenetic approach enabled us to determine the main causative acute BP regulatory systems and should lead to better selection of suitable antihypertensive drugs for individual patients.     

动物实验模型中多极导管心室除颤系统电除颤对心脏功能的影响

评价新型的双极和三极导管自动心室除颤系统电除颤对左心室收缩和舒张功能的影响。动物麻醉后,在X光机指导下,分别在10只犬心脏内装置双极导管自动除颤系统（组Ⅰ）;在10只猪心脏内装置三极导管自动除颤系统（组Ⅱ）;并行电除颤试验。使用食管超声心动图在电除颤前后记录二维、M型和多谱勒超声图像。组I动物接受4次电除颤,电量为64J;组Ⅱ接受平均8次电除颤,电量为210J。结果显示：左室收缩面积分数、左室等容舒张时间和二尖瓣血流E波与A波速度比值以及时间-流速积分比值等反映左室舒缩功能的指标在两组动物除颤后均无显著改变。研究表明：两种经静脉导管自动心室除颤系统中反复低能量心内膜电除颤对左室舒缩功能无明显损伤作用;研究结果为经静脉多极导管自动心室除颤系统在临床的应用和电生理研究提供了可靠的实验数据。     

构建7q32区域鼻咽癌和正常鼻咽上皮细胞部分基因的表达图谱

目的构建７ｑ３２区域鼻咽癌细胞和组织及原代培养人正常鼻咽上皮细胞的部分基因表达图谱。方法通过差异ＲＴ－ＰＣＲ和Ｎｏｒｔｈｅｒｎ杂交的方法检测定位于７ｑ３２区域的２０个ＥＳＴ在鼻咽癌细胞和鼻咽癌组织及原代培养人正常鼻咽上皮细胞ｍＲＮＡ的表达水平。结果８个ＥＳＴ在鼻咽癌细胞ＨＮＥ１和原代培养人正常鼻咽上皮细胞中表达量较一致，７个ＥＳＴ在两种细胞中均无表达，３个ＥＳＴ（Ｗ７２６８８、Ｈ１９８３０、ＡＡ１３０６３０）在鼻咽癌细胞株中表达上调，而２个ＥＳＴ（ＡＡ０７０４３７、Ｈ９０８８２）在原代培养人鼻咽上皮细胞中表达上调。在１３例鼻咽癌活检组织中３０．７％（４／１３）的ＡＡ０７０４３７表达下调，７７％（１０／１３）的Ｗ７２６８８和７７％（１０／１３）的Ｈ１９８３０表达上升。结论构建了７ｑ３２区域鼻咽癌细胞和组织及原代培养人正常鼻咽上皮细胞部分基因表达图谱，并初步认为Ａ０７０４３７的表达下调和Ｗ７２６８８、Ｈ１９８３０的过表达与鼻咽癌的发生有关。     

Age-dependent DNA methylation changes in the ITGAL (CD11a) promoter

DNA methylation patterns change with age in a complex fashion, typically with an overall decrease in genomic deoxymethylcytosine (d(m)C) content, but with local increases in some promoters that contain GC-rich sequences known as CpG islands. While the consequences of age-dependent CpG island methylation have recently been studied in organs such as the colon, less is known about the functional significance of the progressive hypomethylation of promoters lacking CpG islands, and the significance of age-dependent changes in T cell DNA methylation is completely unexplored. We asked if age-dependent DNA hypomethylation might contribute to overexpression of the T cell ITGAL gene, which encodes CD11a, a subunit of LFA-1. CD11a mRNA increased with age as well as with experimentally induced DNA hypomethylation. This increase correlated with hypomethylation of sequences flanking the ITGAL promoter in vitro and in aging. 'Patch' methylation of the region suppressed promoter function. DNA methyltransferases 1 and 3a also decreased with aging. These results indicate that hypomethylation of regions flanking the ITGAL promoter may increase CD11a expression, and suggest that age-dependent hypomethylation of promoters lacking CpG islands, perhaps due to decreased DNA methyltransferase expression, may be one mechanism contributing to increased T cell gene expression with aging.     

琥珀酸美托洛尔HPMC骨架片释放影响因素研究

以羟丙基甲基纤维素（HPMC）为骨架材料，乙基纤维素（EC）为阻滞剂，采用湿颗粒压片法制备琥珀酸美托洛尔亲水凝胶骨架片，考察HPMC用量、HPMC黏度、EC用量、制备方法、压片压力、释放介质及转速对琥珀酸美托洛尔（MS）骨架片体外释药的影响。结果表明，MS骨架片体外释药符合Higuchi方程，药物释放机制是骨架溶蚀和药物扩散的综合效应；HPMC用量与黏度、阻滞剂用量、制备方法、压片压力对释放速率均有显著性影响；释放介质的pH值及转速对释放速率无显著性影响。     

Characterization of damage modes in dental ceramic bilayer structures

Results of contact tests using spherical indenters on flat ceramic coating layers bonded to compliant substrates are reported for selected dental ceramics. Critical loads to produce various damage modes, cone cracking, and quasiplasticity at the top surfaces and radial cracking at the lower (inner) surfaces are measured as a function of ceramic-layer thickness. It is proposed that these damage modes, especially radial cracking, are directly relevant to the failure of all-ceramic dental crowns. The critical load data are analyzed with the use of explicit fracture-mechanics relations, expressible in terms of routinely measurable material parameters (elastic modulus, strength, toughness, hardness) and essential geometrical variables (layer thickness, contact radius). The utility of such analyses in the design of ceramic/substrate bilayer systems for optimal resistance to lifetime-threatening damage is discussed.     

下颌第一前磨牙根管系统和根尖孔解剖及临床意义

采用牙髓透明法对 347颗下颌第一前磨牙根管系统的数目和形态进行观察。下颌第一前磨牙根管可分为Ⅰ、Ⅱ、Ⅲ、Ⅳ型。其中Ⅰ型 (单根单管型 )占 83 86 % ,Ⅱ型 (单根双管型 )占 4 6 1% ,Ⅲ型 (单双管混合型 )占 11 2 4 % ,Ⅳ型 (双根双管型 )占 0 2 9%。应用XTT— 3A连续变倍体视显微镜对 347颗下颌第一前磨牙的根管系统形态进行观察 ,根尖分歧出现率 15 6 3% ,根尖分叉出现率 2 4 3% ,根管侧支出现率 1 0 8%。并对 347颗下颌第一前磨牙的根尖孔与根尖顶的位置关系进行观察 ,根尖孔位于根尖顶者占 88 14 % ,位于旁侧者占 11 86 %。并就上述内容的临床意义进行了讨论。     

广西三江县侗族青少年头发中9种元素的含量

目的　确定广西三江县侗族青少年头发中 9种人体必需元素含量的正常值。方法　用偏振塞曼原子吸收仪 ,检测了来自三江县的 993名 7～ 16岁中小学生头发中镍、硒、钴、铬、铁、锌、钙、铜和镁 9种人体必需元素的含量 ,并用SPSS统计软件进行统计分析。结果　广西三江县侗族中小学生头发中 ,镍、硒、钴、铬、铁、锌、钙、铜和镁 9种人体必需元素的含量没有性别差异 ;硒、铬、铁、锌、钙和铜与年龄呈负相关 ;制订了镍、硒、钴、铬、铁、锌、钙、铜、镁 9种元素的头发含量的正常值范围。结论　广西三江县中学生头发中硒、铬、铁、锌、钙和铜含量有明显年龄差异 ,而镍、钴和镁却没有年龄差异。     

2,8-Dihydroxyadenine urolithiasis in a patient with considerable residual adenine phosphoribosyltransferase activity in cell extracts but with mutations in both copies of APRT

We have examined the mutational basis of adenine phosphoribosyltransferase (APRT, EC 2.4.2.7) deficiency (MIM 102600) in a patient of Polish origin who has been passing 2,8-dihydroxyadenine (DHA) stones since birth, but has considerable residual enzyme activity in lymphocyte extracts. The five exons and flanking regions of APRT were amplified by PCR and then sequenced. A single T insertion was identified at the intron 4 splice donor site (TGgtaa to TGgttaa:IVS4+2insT) in one allele from the proband, his mother, and brother. A G-to-T transversion in exon 5 (GTC-to-TTC:c.448G>T, V150F) was identified in the other allele, and this mutation was also present in one allele from the father and the paternal grandmother. Tru91 and AvaII digestions of PCR products spanning exons 4 and 5, respectively, confirmed the mutations. The mother was heterozygous for an intragenic TaqI site, but all other family members were homozygous for the presence of this site. IVS4+2insT, located on the allele containing the TaqI site, has been identified previously in several families from Europe, suggesting a founder effect, but the substitution in exon 5 is a novel mutation. IVS4+2insT is known to result in complete loss of enzyme activity, and our results suggest that V150F produces an enzyme that is nonfunctional in vivo but has considerable residual activity in vitro.