基于贝叶斯的苯并(α)芘PBPK模型优化与健康风险评估应用

应用基于生理的药代动力学(PBPK)模型预测苯并(α)芘(BaP)暴露的人体内部剂量,基于贝叶斯的马尔科夫链蒙特卡洛模拟(MCMC)方法对模型参数进行校准和优化,最后运用已优化的模型对BaP内暴露基准值进行推导.研究发现,基于贝叶斯的MCMC方法对模型后验参数校准后,模型精度明显提高,两个数据集验证结果显示残差平方和分别降低了72%和94%.PBPK模型以BaP和子代谢物3-羟基苯并(α)芘(3-OHBaP)的体内动力学过程为结构基础,模拟BaP体内浓度分布大小为脂肪>肾脏>皮肤>缓慢灌注组织>快速灌注组织>静脉血>肝脏;3-OHBaP体内浓度分布大小为肾脏>快速灌注组织>脂肪>肺>静脉血>缓慢灌注组织>肝脏>皮肤.敏感性分析显示,快速灌注组织-血分配系数对模型输出影响最大,灵敏度系数超过了200%;排泄系数影响最小,只有肾小球过滤率K_BR的灵敏度系数超过了1%.以美国国家环境保护局推荐的参考浓度2.0×10^-6mg/m³为外暴露安全基准值,基于PBPK模型推导了职业暴露的BaP生物监测当量(BE),结果显示BE值为0.405pmol/mol肌酐(尿液3-OHBaP平均浓度),为基于人体内暴露剂量水平进行定量健康风险评估奠定了基础.     

Environmental resource footprinting of drug manufacturing: Effects of scale-up and tablet dosage

The formulation and scale-up of batch processes is one of the major challenges in the development of pharmaceutical dosage forms and at the same time a significant resource demanding process which is generally overlooked in environmental sustainability assessments. First, this paper proposes general trends in the experience curve of cumulative resource consumption of pharmaceutical tablet manufacturing of PREZISTA^® 800 mg through wet granulation (WG) at four consecutive scales in both R&D and manufacturing environments (resp. WG1 = 1 kg/h, WG5 = 5 kg/h, WG30 = 30 kg/h and WG240 = 240 kg/h). Second, the authors aim at evaluating the environmental impact from a life cycle perspective of a daily consumption of PREZISTA^® 2× 400 mg tablets versus the bioequivalent PREZISTA^® 800 mg tablet which was launched to enhance patient compliance. Environmental sustainability assessment was conducted at three different system boundaries, which enables identification, localization and eventually reduction of burdens, in this case natural resource extraction. Exergy Analysis (EA) was used at process level (α) and plant level (β) while a cradle-to-gate Exergetic Life Cycle Assessment (ELCA) was conducted at the overall industrial level (γ) by means of the CEENE method (Cumulative Exergy Extraction from the Natural Environment). Life cycle stages taken into account are Active Pharmaceutical Ingredient (API) production, Drug Product (DP) production and Packaging. At process level (α), the total resource extraction for the manufacturing of one daily dose of PREZISTA^® (800 mg tablet) amounted up to 0.44 MJ_ex at the smallest scale (WG1) while this amount proved to be reduced by 58%, 79% and 83% at WG5, WG30 and WG240 respectively. Expanding the boundaries to the overall industrial level (γ) reveals that the main resource demand is at the production of the Active Pharmaceutical Ingredient (API), excipients, packaging materials and cleaning media used in DP production. At the largest scale (WG240) the use of cleaning media during DP production contributes considerably less to the total resource extraction. Overall, the effect of scale-up and learning on resource consumption during DP production showed to possess a power-law experience curve y = 2.40 * x^−0.57 when shifting from WG1 (smallest lab scale) to WG240 (industrial manufacturing). Tablet dosage (2× 400 mg versus 1× 800 mg) did not significantly affect the absolute environmental burden. However, the relative contribution of resource categories did change due to the different production technology. It could be concluded that in meeting social and economic demands by launching the PREZISTA^® 800 mg tablet, no trade-off in environmental burden occurred. On the long term, future research should strive to take into account R&D processes and all services related to pipeline activities taking place prior to market launch and eventually to allocate impacts to the final product.     

基于安全可靠度的云南松茸冷链物流库存策略优化

安全可靠度对冷链物流库存策略优化起着至关重要的作用.以云南松茸为研究对象,将安全可靠度纳入冷链物流库存操作流程中,建立基于安全可靠度的冷链物流库存理论模型,从安全可靠度管理产生的高额成本等方面分析存在的困难,据此提出应从实施联合库存管理、基于安全可靠度的冷库软硬件优化升级等方面对基于安全可靠度的云南松茸冷链物流库存策略进行优化.     

鄂西生态文化旅游产业集群发展研究

在分析鄂西生态文化旅游产业集群发展的效应和意义的基础上,提出了鄂西生态文化旅游产业集群发展所遵循的市场导向、规划指导、产业互动、择优扶强、注重创新和可持续发展的原则,重点发展以旅游中心城市为依托的旅游服务业集群、以核心吸引物为中心的综合旅游产业集群、以旅游景观廊道为依托的餐饮购物业集群、以特色村镇为依托的旅游文化产业集群、以生产基地为依托的旅游商品产业集群,需要在产业要素整合、龙头企业培育、公共服务提供、重点项目建设、产品结构优化、区域品牌建设等方面推进鄂西生态文化旅游产业集群发展.     

Domestic or imported? An assessment of carbon footprints and sustainability of seafood consumed in Australia

The distance between where food is produced and consumed is increasing, and is often taken as evidence of an unsustainable global food system. Seafood is a highly traded commodity yet seafood sustainability assessments do not typically consider the impacts of the movement of products beyond the fishery or farm. Here we use life cycle assessment to examine the carbon footprint of the production and distribution of select seafood products that are consumed in Australia and determine differences in the sustainability of imports and their domestically produced counterparts. We found that the distance food is transported is not the main determinant of food sustainability. Despite the increased distance between production and consumption, carbon footprints of meals from imported seafood are similar to meals consisting of domestically produced seafood, and sometimes lower, depending on the seafood consumed. In combining LCA with existing seafood sustainability criteria the trade-offs between sustainability targets become more apparent. Carbon ‘footprinting’ is one metric that can be incorporated in assessments of sustainability, thereby demonstrating a broader perspective of the environmental cost of food production and consumption.     

An approach to preimplantation diagnosis of β-thalassaemia

Using the polymerase chain reaction (PCR), it was possible to amplify a single copy fragment of the β-globin gene from 2–32 human embryonic cells obtained from arrested preimplantation embryos. For the detection of β-thalassaemia mutations, allele specific priming of the PCR using nested primers was employed using approximately 10 pg of DN A from individuals known to carry these mutations. This approach was successful in detecting the presence or absence of five Asian Indian β-thalassaemia mutations that were selected for this study. In spite of meticulous precautions against contamination, false-positive amplification was observed, a problem that will have to be overcome before this approach can be used in clinical practice.     

氯化石蜡产品中短链和中链同系物的指纹分布

使用气相色谱-电子捕获负化学电离质谱（GC-ECNI-MS）,对包含CP-42、CP-52和CP-70三种常见氯含量的22个CPs产品进行了测定,分析了不同氯含量的CPs产品中短链氯化石蜡（SCCPs）和中链氯化石蜡（MCCPs）同系物的分布模式.SCCPs同系物呈现5种分布特征,分别是CP-42型、三类CP-52型和CP-70型,MCCPs同系物呈现4种分布特征,分别是CP-42型和三类CP-52型,CP-70产品中MCCPs同系物未呈现出一致的分布规律.CPs生产原料石蜡中烷烃的成分组成和CPs生产工艺的不同,是造成产品同系物分布模式不一致的原因.通过统计学分析,得到CPs产品中SCCPs和MCCPs同系物的指纹分布,这是开展环境中CPs的源解析、迁移转化、归趋和毒性风险评价等研究的有利工具.     

Prenatal diagnosis of NADH:ubiquinone oxidoreductase deficiency

NADH:ubiquinone oxidoreductase (complex I of the mitochondrial respiratory chain) deficiency is a severe disorder with an often early fatal outcome. Prenatal diagnosis for complex I defects currently relies mainly on biochemical assays of complex I in fetal tissues such as chorionic villi (CV), and is only in a minority of cases possible by means of mutational analysis of nuclear-encoded genes of complex I. We report on our experience to date with prenatal diagnosis in pregnancies at risk for complex I deficiency. We measured complex I activity in native CV and/or cultured CV in 23 pregnancies in 15 families. In accordance with the results of the investigations in CV, 15 children were born clinically unaffected. Two prenatally diagnosed unaffected fetuses and two prenatally diagnosed affected fetuses were lost prematurely with spontaneous or provoked abortions, respectively. Two affected children were born (prenatally found to be affected). In two pregnancies a discrepancy between native and cultured cells was found. We conclude that prenatal diagnosis for complex I deficiency can be reliably performed. Pitfalls were encountered in using cultured CV as a result of maternal cell contamination (MCC). Future research on pathogenic nuclear mutations underlying complex I deficiency will extend the possibilities for prenatal diagnosis at the molecular level. Copyright © 2001 John Wiley & Sons, Ltd.     

江淮流域大洪水的因子分析及成因链初步构造

结合 1998年长江流域的特大洪水 ,提出了洪水成因链的概念 ,分析了各个物理因子对江淮洪水的影响。指出影响江淮洪水的物理因子都是层层相接、环环相扣的 ,它们组成了一个互相联系、互为因果的洪水成因链。成因链上物理因子之间的正反馈作用和消长作用 ,导致成因链上各个因子的致洪理论都不能完全地自圆其说 ,因而也无法完全确定地用于洪水预测。只有深入探讨洪水成因链上物理因子之间的正反馈作用和消长作用 ,对它们进行全面综合的诊断分析 ,才能提高江淮洪水预测的准确率。