New live mycobacterial vaccines: the Geneva consensus on essential steps towards clinical development

As the disease caused by Mycobacterium tuberculosis continues to be a burden, which the world continues to suffer, there is a concerted effort to find new vaccines to combat this problem. Of the various vaccines strategies, one viable option is the development of live mycobacterial vaccines. A meeting with researchers, regulatory bodies, vaccines developers and manufactures was held to consider the challenges and progress, which has been achieved with live mycobacterial vaccines (either modified BCG or attenuated M. tuberculosis). Discussion led to the production of a consensus document of the proposed entry criteria for Phase I clinical trials of candidate live mycobacterial vaccines. The vaccine must be characterised thoroughly to prove identity and consistency, as clinical trial lots are prepared. In pre-clinical studies, greater protective efficacy as well as improved safety potential relative to BCG should be considered when assessing potential vaccine candidates. A standard way to measure the protective efficacy to facilitate comparison between vaccine candidates was suggested. Additional safety criteria and verification of attenuation must be considered for attenuated M. tuberculosis. Two non-reverting independent mutations are recommended for such vaccines. When entering Phase I trials, enrollment should be based upon an acceptable characterisation of the study population regarding mycobacterium status and exclude HIV(+) individuals. BCG could be used as a comparator for blinding during the trials and to properly assess vaccine-specific adverse reactions, while assays are being developed to assess immunogenicity of vaccines. The proposed criteria suggested in this consensus document may facilitate the movement of the most promising vaccine candidates to the clinic and towards control of tuberculosis.     

Positional cloning of a gene involved in hereditary multiple exostoses

Hereditary multiple exostosis (EXT) is an autosomal dominant condition mainly characterized by the presence of multiple exostoses on the long bones. These exostoses are benign cartilaginous tumors (enchondromata). Three different EXT loci on chromosomes 8q (EXT1), 11p (EXT2) and 19p (EXT3) have been reported, and recently the EXT1 gene was identified by positional cloning. To isolate the EXT2 gene, we constructed a contig of yeast artificial chromosomes (YAC) and P1 clones covering the complete EXT2 candidate region on chromosome 11p11-p12. One of the transcribed sequences isolated from this region corresponds to a novel gene with homology to the EXT1 gene, and harbours inactivating mutations in different patients with hereditary multiple exostoses. This indicates that this gene is the EXT2 gene. EXT2 has an open reading frame encoding 718 amino acids with an overall homology of 30.9% with EXT1, suggesting that a family of related genes might be responsible for the development of EXT.      

结核病控制策略对患者涂阳率的影响

目的：探讨不同结核病控制策略与复治涂阳患形成的关系。方法：对宁夏实施世界银行贷款结构病控制项目前后两个不同时期结核病统计报表进行统计学X^2检验及直线相关分析。结果：宁夏实施项目以前的结核病控制策略导致新发涂阳肺结核患治愈率仅为34．33％，同期复治涂阳结核患比例高达68．79％，实施直接面视下短程化学疗法策略，使新发涂阳患治愈率提高到95％以上，同期复治涂阳肺结核患比例最低下降到18．27％，经相关处理，新发涂阳肺结核患的治愈率与复治涂阳患的比例之间呈明显的负相关。结论：现代结核商控制的直接面视下短程化学疗法策略能大幅度地养活复治涂阳患和耐多药结核患的产生。     

归口管理对缩短新发涂阳肺结核诊断延迟的影响

目的　了解实施肺结核病人归口管理对涂阳肺结核病人诊断延迟的影响。方法 调查1993和 2001年肺结核病人归口管理检查和病人的卡片、病志等有关资料，分析归口管理前后诊断延迟情况。结果 归口转诊率由 48.5%，提高到 89.0%，归口到位率由 29.0%提高到 72.4%，确诊延迟率由 29.4%降到 10.6%，平均延迟天数由 22.2d降到 7.7d，就诊延迟率分别为 63.4%、68.8%和平均延迟天数分别为 48.9d、50.3d，延迟病人时间分布中 20周有一个高峰。结论 归口管理对缩短确诊延迟有明显影响，对就诊延迟无影响，加大结防宣传力度，提高群体对结防意识是缩短就诊延迟的关键。     

The anticoagulant mechanism of action of heparin in contact-activated plasma: inhibition of factor X activation

The effects of heparin on the activation of blood coagulation factors IX and X in contact-activated plasma were determined in the present study. In the presence and absence of 0.5 U/mL heparin, the amounts of factor IX that were cleaved 30 minutes after the addition of calcium and phospholipid to plasma exposed to glass (ie, contact activated) were essentially identical. In the absence of heparin, however, the plasma clotting time was between three and four minutes, while in the presence of heparin, the clotting time was approximately 40 minutes. More factor IXa was inhibited by antithrombin III in the presence of heparin than in its absence, but factor IXa levels sufficient for factor X activation appeared to be present in the heparinized plasma. Neither an increase in factor Xa nor a decrease in factor X was detected, however, in heparinized plasma. We conclude that the step in the intrinsic pathway of coagulation that is inhibited in the presence of heparin is at the level of factor X activation.     

人工髋关节材料改进及固定技术探索

目的:回顾人工髋关节从设计应用、改进历史,展望未来发展趋势,从材料学及临床应用方面阐述提高人工髋关节性能的重要性,为提高人工髋关节置换质量提供依据。方法:应用计算机检索Medline 1994-01/2006-12关于人工髋关节的文章。检索词“Artificial HipJoint”并限定文章的语言种类为English。同时利用计算机检索中国期刊全文数据库1994-01/2006-12的相关文章,限定文章语言种类为中文,检索词“人工髋关节”。结果:人工髋关节从设计应用、改进、再应用已经经历了100余年历史,目前已成为一种效果非常肯定的治疗手段。虽然假体材料及临床技术渐趋成熟,但对材料改进及技术探索从未停止,近年,国外生物陶瓷材料被广泛研制、已应用于临床,硬质耐磨的钴铬钼合金关节假体在临床试用。人们仍在寻找更加理想的人工关节材料。结论:低磨损型人工髋关节是提高治疗质量的重要因素,临床技术的改进依赖于材料改进,需要多方向不断探索。     

The antimicrobial resistance patterns and associated determinants in Streptococcus suis isolated from humans in southern Vietnam, 1997-2008

Background

Our objective was to determine the frequency and determinants of presentation to care with advanced HIV disease in patients who discover their HIV diagnosis at this stage as well as those with delayed presentation to care after HIV diagnosis in earlier stages.

Methods

We collected data on 1,819 HIV-infected patients in Brussels (Belgium) and Northern France from January 1997 to December 2007. "Advanced HIV disease" was defined as CD4 count <200/mm³ or clinically-defined AIDS at study inclusion and was stratified into two groups: (a) late testing, defined as presentation to care with advanced HIV disease and HIV diagnosis ≤6 months before initiation of HIV care; and (b) delayed presentation to care, defined as presentation to care with advanced HIV disease and HIV diagnosis >6 months before initiation of HIV care. We used multinomial logistic regression to determine the factors associated with delayed presentation to care and late testing.

Results

Of the 570 patients initiating care with advanced HIV disease, 475 (83.3%) were tested late and 95 (16.7%) had delayed presentation to care. Risk factors for delayed presentation to care were: age 30-50 years, injection drug use, and follow-up in Brussels. Risk factors for late testing were: sub-Saharan African origin, male gender, and older age. HIV transmission through heterosexual contact was associated with an increased risk of both delayed presentation to care and late testing. Patients who initiated HIV care in 2003-2007 were less likely to have been tested late or to have a delayed presentation to care than patients who initiated care before 2003.

Conclusion

A considerable proportion of HIV-infected patients present to care with advanced HIV disease. Late testing, rather than a delay in initiating care after earlier HIV testing, is the main determinant of presentation to care with advanced HIV disease. The factors associated with delay presentation to care differ from those associated with late testing. Different strategies should be developed to optimize early access to care in these two groups.     

Pharmacologic properties of AG-012986, a pan-cyclin-dependent kinase inhibitor with antitumor efficacy

AG-012986 is a multitargeted cyclin-dependent kinase (CDK) inhibitor active against CDK1, CDK2, CDK4/6, CDK5, and CDK9, with selectivity over a diverse panel of non-CDK kinases. Here, we report the potent antitumor efficacies of AG-012986 against multiple tumor lines in vitro and in vivo. AG-012986 showed antiproliferative activities in vitro with IC(50)s of <100 nmol/L in 14 of 18 tumor cell lines. In vivo, significant antitumor efficacy induced by AG-012986 was seen (tumor growth inhibition, >83.1%) in 10 of 11 human xenograft tumor models when administered at or near the maximum tolerated dose for 8 or 12 days. AG-012986 caused dose-dependent hypophosphorylation at Ser(795) of the retinoblastoma protein, cell cycle arrest, and apoptosis in vitro. Colony-forming assays indicated that the potency of AG-012986 substantially decreased with treatment time of <24 h. In vivo, AG-012986 also showed dose-dependent retinoblastoma Ser(795) hypophosphorylation, cell cycle arrest, decreased Ki-67 tumor staining, and apoptosis in conjunction with antitumor activity. Studies comparing i.p. bolus with s.c. implanted minipump dosing regimens revealed that in vivo efficacy correlated with the duration of minimally effective plasma levels rather than maximal drug plasma levels. Dosing optimization of AG-012986 provided guidance for selecting a treatment schedule to achieve the best antitumor efficacy while minimizing the risk of adverse side effects.