小藤铃儿草的生物碱成分

自小藤铃儿草Dactylicapnos torulosa(Hook.f ct Thomas.)Hutchins中分得六个单体,通过UV,IR,MS,~1HNMR和~(13)CNMR解析,鉴定了四个,其中一个为新化合物,命名为紫金龙碱(zijinlongine,Ⅰ),其他三个为已知化合物:氯化1-甲氧基小檗碱(1-methoxylberberium chloride,Ⅱ),氯化三乙基苯胺(triethylphcnylamium chloride,Ⅲ)和异紫堇定(isocorydine,Ⅳ)。Ⅱ和Ⅲ系首次从植物中得到。     

Altered metabolism of familial Alzheimer's disease-linked amyloid precursor protein variants in yeast artificial chromosome transgenic mice

Missense mutations in the beta-amyloid precursor protein gene (APP) co- segregate with a small subset of autosomal dominant familial Alzheimer's disease (FAD) cases wherein deposition of the 39-43 amino acid beta-amyloid (A beta) peptide and neurodegeneration are principal neuropathological hallmarks. To accurately examine the effect of missense mutations on APP metabolism and A beta production in vivo, we have introduced yeast artificial chromosomes (YACs) containing the entire approximately 400 kbp human APP gene encoding APP harboring either the asparagine for lysine and leucine for methionine FAD substitution at codons 670 and 671 (APP(K670N/M671L)), the isoleucine for valine FAD substitution at codon 717 (APP(V7171)) or a combination of both substitutions into transgenic mice. We demonstrate that, relative to YAC transgenic mice expressing wild-type APP, high levels of A beta peptides are detected in the brains of YAC transgenic mice expressing human APP(K670N/M671L) that is associated with a concomitant diminution in the levels of apha-secretase-generated soluble APP derivatives. Moreover, the levels of longer A beta peptides (species terminating at amino acids 42/43) are elevated in YAC transgenic mice expressing human APP(V7171). These mice should prove valuable for detailed analysis of the in vivo effects of the APP FAD mutations in a variety of tissues and throughout aging and for testing therapeutic agents that specifically alter APP metabolism and A beta production.      

Genome-wide linkage analysis for celiac disease in North American families

Celiac disease (CD) is an autoimmune disease caused by sensitivity to the dietary protein gluten. It has a prevalence of 1 in 250 in the United States. Multiple-case families are common with a risk to siblings from 10-12%. Previous linkage studies have found no significant evidence for linkage other than to HLA. In this study, we performed a genome-wide search on 62 families with at least two cases of CD to identify non-HLA loci for CD. Two-point and multipoint parametric and nonparametric analyses were performed on the entire set of families and on sets stratified by the HLA genotype. Accounting for multiple testing, we found genome-wide intermediate linkage evidence at 18q (heterogeneity LOD (HLOD) = 3.6) and at 3p (HLOD = 3.2) and suggestive evidence at 5p (HLOD = 2.7). Good consensus between two-point and multipoint evidence was not found, and after genotyping with new markers in these regions, our results were inconclusive. The 18q region had intermediate two-point evidence, but weak multipoint evidence. At 3p and 5p, the addition of follow-up markers added flanking support, yet multipoint evidence was still lacking. Our results indicate that multipoint analyses may be hindered by the complexity of CD. Multipoint analyses are not robust to model misspecification, and further development of models is needed. Additional study of these and other families is necessary to validate or rule out the regions implicated in this study.     

HLA DQA1-DQB1 genotypes in Bedouin families with celiac disease

Celiac disease (CD) has a strong genetic association with human leukocyte antigens (HLA). The primary susceptibility for CD is HLA-DQA1*05 DQB1*02 (also known as DQ2), with the remainder of cases primarily HLA-DQA1*03 DQB1*03 (also known as DQ8). In a set of nine Bedouin multiplex celiac disease families and one simplex, we genotyped DNA samples at HLA DQA1 and DQB1. Nineteen celiac disease patients had at least one DQA1*05 DQB1*02 genotype (= DQ2), 4 affecteds had the second most common genotype of DQA1*03 DQB1*0302 (= DQ8), 9 were DQ2 and DQ8, and 4 had at least one copy of DQB1*02 without the DQA1*05 genotype. Using transmission disequilibrium testing, we observed a significant over-representation in affecteds of the DQA1*05 DQB1*02 genotype (p = 0.0089), as well as over-representation of the DQA1*03 DQB1*0302 genotype (p = 0.078). The HLA DQA1 DQB1 high-risk genotypes associated with celiac disease are similar in these Bedouin families with CD to what is observed in Northern and Southern Europeans.     

Risk factors and course of illness among children with invasive penicillin-resistant Streptococcus pneumoniae. The Streptococcus pneumoniae Working Group

OBJECTIVES: To assess differences in risk factors, clinical presentation, and course of illness between children infected with penicillin-sensitive and drug-resistant Streptococcus pneumoniae (DRSP). DESIGN: A retrospective cohort study conducted in Uruguay and Argentina using information from a hospital-based surveillance system. Hospitalized children 5 years of age and younger who had S pneumoniae isolated from a normally sterile site between June 1993 and October 1996 were eligible. Hospital records were linked with surveillance data. Both stratified univariate analysis and logistic regression was completed. RESULTS: Of the 380 children eligible for the study, 274 records (72%) were available for review. Ninety-nine children (36%) had DRSP; 46 showed intermediate susceptibility (minimum inhibitory concentration, 0.12-1.0 microg/mL) and 53 showed high-level resistance (minimum inhibitory concentration >/=2.0 microg/mL). Children with meningitis were less likely to have DRSP than those with other forms of invasive disease (relative risk = 0. 5; 95% confidence interval [CI], 0.2-0.9). Risk factors associated with DRSP were use of penicillin or ampicillin in the 3 months before illness (odds ratio = 2.9; 95% CI, 1.5-5.7) and possession of private medical coverage (odds ratio = 2.4; 95% CI, 1.2-5.0). Response to therapy, including response to penicillin or ampicillin among children with nonmeningeal invasive disease, course of illness, and clinical outcome did not differ significantly between children infected with penicillin-susceptible or penicillin-resistant isolates. CONCLUSION: In this study, previous use of penicillin or ampicillin and private medical coverage were associated with having DRSP. Children with nonmeningeal invasive disease responded equally well to penicillin regardless of the penicillin susceptibility of their pneumococcal isolate.     

胆道口括约肌功能失调及其肉毒毒素治疗

胰胆管末端、共同通道及十二指肠乳头均有不同厚度的平滑肌环绕,即胆道口括约肌(sphincter of Oddi,SO),此段长4mm～6mm.如SO不能正常地舒张,胆汁或(和)胰液引流不畅,导致胆汁瘀积或(和)胰腺炎,表现为反复发作的上腹痛、黄疸、淀粉酶升高等,谓之SO功能失调(SOD).一般将SOD分为狭窄性和功能性,前者包括纤维化、肥大、慢性乳头炎或腺肌炎;后者包括SO运动过速、收缩期基础压升高、逆向收缩过多、SO对CCK的反常反应.临床上SOD可分为3型:SOD-Ⅰ型:多为器质性狭窄,表现为典型的胆源性绞痛、肝酶(ALP,γ-GT)升高1.5～2倍、ERCP有梗阻表现、胆总管≥12mm,排泄延迟＞45min,胆道测压显示基础压升高.SOD-Ⅱ型(中间型):常有胆性疼痛,上述检查指标仅有1项异常.SOD-Ⅲ型(功能型):仅有胆性疼痛而无其他异常[1].     

土贝母水提物对体外培养人肝癌细胞增殖及代谢的影响

目的研究中药土贝母(BPF)水提物对体外培养的人肝癌细胞的抑癌活性.方法 BPF经粉碎、浸提、超速离心、减压浓缩、冷冻干燥得BPF水提物.人肝癌SMMC-7721细胞经BPF提取物处理不同时间后以MTT法测其对人肝癌细胞线粒体代谢活性的影响,以细胞记数法观察了其对细胞增殖的影响.结果①经200 mg/L BPF提取物处理48 h,人肝癌SMMC-7721细胞线粒体活性为对照组的31.3%,处理72 h为21.4%;②以100mg/L BPF提取物处理7d中,人肝癌细胞数分别为0.57,0.316,0.29,0.285,0.57,1.287,1.2,对照FCS组分别为1.82,3.67,6.2,9.4,10.1,11,9,NON组分别为1.7,3.35,5.6,8.4,8.9,9.3,7.6,实验组人肝癌细胞数不仅低于对照组,而且低于处理前细胞数(P＜0.01);③经BPF提取物处理24 h后,即使更换为正常培养基,人肝癌细胞数在96 h的恢复培养中基本无增加.结论中药BPF提取物能显著抑制体外培养的肝癌细胞增殖和降低线粒体代谢活性.     

肉毒毒素治疗贲门失弛缓症

贲门失弛缓症(achalasia,AC)的病因和发病机制尚未完全阐明,有学者认为下食管括约肌(LES)不能松弛的机制是肠肌丛内抑制性神经元的选择性丧失,导致乙酰胆碱引起肌缩神经的无对抗性兴奋[1].LES持续性收缩,引起咽下困难、食物反流和胸骨后疼痛等症状.曾有人[2]将本病分为典型(classic)型和高动力(vigorous)型,前者食管明显扩张且缺乏蠕动,后者食管扩张较轻,有高振幅的同步收缩,胸痛症状较突出.但后来Goldenbarg et al[3]证实两者并无明显差别,认为以食管的收缩振幅作为AC分类的标准是不可靠的.我院曾收治1例17岁的男性患者,病程12+mo,1 a前因急性上呼吸道感染,在输液抗炎治疗的过程中出现咽下困难等AC的症状,推测本病的发生是否与病毒感染或某些药物有关,尚待进一步探讨.     

抗肿瘤药物研究Ⅰ:去甲斑蝥素氨基酸衍生物的合成与抗癌活性

In order to search for new compounds with higher anti-cancer activities and lower toxicities, 19 amino acid derivatives of norcantharidin, of which 16 are unknown compounds, were designed and synthesized. Preliminary screening results revealed that 2-(syn-exo-7-oxabicyclo [2. 2. 1] heptane-2, 3-dicarboxylic imido)-N-phenyl glutaramic acid exhibited a fairly apparent inhibitory activity against human-hepatoma cells in vitro (inhibitory rate 39.4% at 0.025 μtmol/ml).