Axial tissue diffusion can account for the disparity between current models of hepatic elimination for lipophilic drugs

An assumption of previous models of hepatic elimination is that there is negligible axial diffusion in the liver. We show, by construction of a stochastic model and analysis of published data, that compounds which are readily diffusible and partitioned into hepatocytes may undergo axial tissue diffusion. The compounds most likely to be affected by axial tissue diffusion are the lipophilic drugs for which the cell membranes provide little resistance and which are highly extracted, thereby creating steep concentration gradients along the sinusoid at steady state. This phenomenon greatly modifies the availability of the compound under conditions of altered hepatic blood flow and protein binding. For moderately diffusible compounds, these relationships are similar to those predicted by the simplistic venous-equilibrium model. Hence, the paradoxical ability of the venous-equilibrium model to describe the steady-state kinetics of lipophilic drugs such as lidocaine, meperidine, and propranolol may be finally resolved. The effects of axial tissue diffusion and vascular dispersion on hepatic availability of drugs are compared. Vascular dispersion is of major importance to the availability of poorly diffusible compounds, whereas axial tissue diffusion becomes increasingly dominant for highly diffusive and partitioned substances.This study was supported by the National Health and Medical Research Council of Australia.     

Dorsal root ganglia cocultured with macrophages: an in vitro model to study experimental demyelination

The present investigation introduces an in vitro model to study macrophage properties during demyelination. Rat dorsal root ganglia (DRG) were cultured for obtaining myelinated peripheral nerve fibers. These cultures were exposed to non-resident macrophages. In untreated control cultures, there was no indication of myelin removal by the added macrophages. DRG were exposed to enzymatically generated oxygen radicals using the xanthin/xanthin oxidase or the glucose/glucose oxidase system. Assessment of Schwann cell viability and ultrastructural morphology revealed different patterns of cell cytotoxicity and morphological changes in different experiments. High concentrations caused complete tissue necrosis of the DRG, while low concentrations did not affect either cell viability or ultrastructural morphology. Under intermediate experimental conditions, oxygen radicals caused non-lethal Schwann cell damage leading to Schwann cell retraction and myelin sheath rejection. Myelin lamellae were disrupted and decompacted. These changes were followed by a selective macrophage attack on myelin sheats, resulting in demyelination. Axons, Schwann cells and sensory ganglion cells survived this attack. The specificity of the oxygen radical effects was tested in experiments using the oxygen radical scavengers catalase and superoxide dismutase. Catalase prevented the described effects on cell morphology and subsequently blocked demyelination by non-resident macrophages.Supported by a grant from the Deutsche Forschungsgemeinschaft (DFG) (Br 1274/1-1)     

Diabetes prevalence in England, 2001--estimates from an epidemiological model.

AIMS: To estimate the total prevalence of diabetes mellitus (diagnosed and undiagnosed) at national, regional and local level in England to support health-care planning and delivery. METHODS: An epidemiological model was constructed by applying age-sex-ethnic-specific reference prevalence rates from epidemiological studies to resident populations (2001 census) of England at national, regional, and local authority/Primary Care Trust levels. RESULTS: Estimated prevalence of total diabetes for all persons in England was 4.41% in 2001, equating to 2 168 000 persons. Type 2 diabetes was estimated to affect 2 002 000 persons (92.3%) and Type 1 diabetes 166 000 persons (7.7%). Diabetes prevalence was estimated to be higher in women (5.17%) than men (3.61%). People from ethnic minority groups had higher crude prevalence than White Europeans (4.29, 5.69, 6.63 and 2.13% among White Europeans, Black African/Caribbeans, South Asians and 'other' groups, respectively). Prevalence increased sharply with age (0.33, 3.37 and 13.92%, respectively, in those aged 0-29, 30-59 and 60+ years). The model allows use of user-defined population denominator estimates to derive numbers and prevalence of people with diabetes for a given local population group, such as at ward or general practice level. CONCLUSIONS: Self-reported diabetes prevalence estimates from community surveys underestimate the true burden of diabetes. The model can be used to derive the expected total prevalence of diabetes in health areas that lack reliable data to facilitate the implementation of the National Service Framework for diabetes. It will also allow estimates of future diabetes prevalence to be derived, and can potentially be used for prevalence estimates in all of the UK.     

Therapeutic Effect of Berberine on 60 Patients with Non－Insulin Dependent Diabetes Mellitus and Experimental Research

ＴｈｅｒａｐｅｕｔｉｃＥｆｆｅｃｔｏｆＢｅｒｂｅｒｉｎｅｏｎ６０ＰａｔｉｅｎｔｓｗｉｔｈＮｏｎ－ＩｎｓｕｌｉｎＤｅｐｅｎｄｅｎｔＤｉａｂｅｔｅｓＭｅｌｌｉｔｕｓａｎｄＥｘｐｅｒｉｍｅｎｔａｌＲｅｓｅａｒｃｈＮｉＹａｎ－ｘｉａ（倪艳霞）；ＬｉｕＡｎ－ｑ...     

Detection of linkage under heterogeneity: comparison of the two-locus vs. admixture models.

Linkage analysis under the two-locus model and the admixture model was compared on pedigree data for a common disease stimulated under a model of genetic heterogeneity. The ascertainment of families was designed so that the samples had a large proportion of families segregating for both disease loci. The two-locus linkage analysis model did not demonstrate increased power of detecting linkage or more accurate estimates of the recombination fraction, theta than did the admixture model linkage analysis. When a sample was purposely chosen so that all of the families were segregating for both loci, then the two-locus lod score analysis was better. However, the increased power depended on assuming the correct gene frequency for the linked locus. It can be concluded that under the conditions of genetic heterogeneity examined here, testing for linkage under the admixture model is the preferred method of analysis. However, this is not a general conclusion that can apply to all two-locus disease models.     

医院治理结构改革与医院管理职业化

通过对当前两种医院治理结构的六个要素比较，认为这两种改革模式的主要问题在于不能很好地解决委托人(或董事会)人员来源和委托人的所有权约束和激励以及代理人的约束和激励等两个问题。并据此提出政策建议，认为解决委托人与经营者的约束和激励问题是医院治理中非常关键的一环，国资委应在医院经营中培育一个专业化、职业化的委托人和代理人阶层。     

Role of intercellular adhesion molecule-1 in a murine model of toluene diisocyanate-induced asthma

BACKGROUND: Adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1) are thought to contribute to the airway inflammation and airway hyper-responsiveness (AHR) of allergic asthma. Some differences from allergic asthma have been noted, including airway neutrophilia, and the involvement of ICAM-1 in toluene diisocyanate (TDI) asthma is currently unclear. OBJECTIVE: We utilized mice lacking ICAM-1 expression (ICAM-1(-/-)) to investigate the role of ICAM-1 in airway inflammation and AHR in TDI-induced asthma. METHODS: Male C57BL/6J mice (ICAM-1(+/+)) and ICAM-1(-/-) mice were intranasally sensitized to TDI solution or solvent alone. Airway inflammation, AHR and cytokine secretion were assessed 24 h after challenge by TDI or solvent. The production of antigen-specific IgG and IgE by TDI sensitized and non-sensitized mice was determined. RESULTS: TDI challenge to ICAM-1(+/+) mice induced an increase in airway inflammatory cell numbers, AHR and cytokine secretion of TNF-alpha, macrophage inflammatory protein-2 (MIP-2), IL-4, IL-5 and IFN-gamma into the bronchoalveolar lavage fluid. All these pathophysiological changes were reduced in ICAM-1(-/-) mice. Serum levels of TDI-specific IgG and IgE of ICAM-1(-/-) and ICAM-1(+/+) mice were comparable. CONCLUSION: These results suggest that ICAM-1 plays an essential role in airway inflammation and AHR in TDI-induced asthma.     

运用Cox模型和Sokal,Hasford积分系统对慢性髓细胞白血病患者的预后分析

本研究分析影响慢性髓细胞白血病（CML）患者预后的危险因素。采用回顾性研究分析204例CML患者的临床及实验室检查资料，用Kaplan—Meier法绘制生存曲线，用Logrank检验比较生存率，运用Cox回归模型进行单因素及多因素分析，并分别计算Sokal，Hasford积分。结果表明：204例患者中位生存时间为50（32—65）月，5年生存率32．3％（95％CI，23．7％-42．6％）。干扰素组与羟基脲组的中位生存时间分别为56（41—67）月和41（19—56）月，5年生存率分别为45．4％（95％CI，37．5％-54．2％）和26．8％（95％CI，21．6％-33．3％）（P〈0．001）。经Cox回归分析，Ph染色体阴性、乳酸脱氢酶含量增高、外周血嗜碱性粒细胞≥10％、出现有核红细胞、骨髓原粒细胞≥4％、骨髓原始＋早幼粒细胞≥10％和红细胞压积降低是CML预后不良的危险因素，而治疗方法也是影响CML预后的重要因素。羟基脲组经Sokal积分检验，高危组占72．9％，中危组占21．5％，而低危组占5．6％，中位生存时间分别为34（23—49）月、43（32—58）月、50（38—62）月；干扰素组经Hasford积分检验，高危组占17．6％，中危组占25．1％，低危组占57．3％，中位生存时间分别为44（33—57）月、56（45—70）月和66（52—76）月。结论：Ph染色体、乳酸脱氢酶含量、红细胞压积、外周血嗜碱性粒细胞、出现有核红细胞、骨髓原始和早幼粒细胞以及治疗方法是影响CML预后的重要因素。以Sokal积分系统评价羟基脲组患者不能很好区分危险组，而Hasford积分系统评价干扰素组患者，能够区分危险组。     

根管细菌渗漏体外模型的建立

目的：建立检测微细菌培养模型，以用于评价根管充填封闭情况。方法：牙根的冠根两端各连接一细菌培养储室，冠方储室置1mL无菌培养基并接种0．1mL菌液，根方储室起始为无菌培养基。每隔3d将冠方储室中菌液吸出1mL，并注入1mL新鲜BHI培养基，共90d。当根尖储室中培养基发生浑浊即为细菌渗漏发生，记录细菌渗漏发生时的天数。选择18个直根管前牙，其中牙胶充填组6个，用冷牙胶侧方加压充填技术充填；空管组6个，根管只预备不充填；根管密封组6个，根管充填并严密封闭根管口和根尖孔。用设计的模型检测密封状况。结果：全部空管组6个样本在1d内根方储室中出现浑浊；根管密封组6个样本的根方储室在90d内均未发生浑浊。牙胶充填组有2个样本分别在44d和46d发生浑浊。结论：此模型方法简单易行且实用有效，具有一定的临床相关性和可行性。     

Evaluation of allergenicity of genetically modified soybean protein extract in a murine model of oral allergen-specific sensitization

Background With the development of genetically modified crop plants there has been a growing interest in the approaches available to assess the potential allergenicity of novel gene products. For additional assessment of the potential allergenicity of expressed proteins, informative data can be generated using animal models. Soybean is one of the major source of protein in human and animal nutrition, and has also been well characterized as a major allergenic source. Advances in biotechnology have resulted in an increasing number of genetically engineered foods, and among these soybean is one of the most widespread. Objective To develop and characterize a murine model of IgE‐mediated soybean sensitization induced by intragastric immunization, in the presence of Cholera Toxin, with wild‐type soybean extract (wt‐SE) or with genetically modified soybean extract (gm‐SE). Methods Balb/c mice born in our animal facilities, from females fed on soy‐free food, were fed with the same soy‐free food and used in all the experiments. Mice were sensitized by gavages with soybean extracts, and allergen‐specific IgE and IgG responses were studied by direct ELISA and ELISA inhibition. Antigen‐specific cell proliferation and cytokine production were evaluated in spleen cell cultures. Results Sensitization with both soybean extracts induced high levels of antigen‐specific IgE and IgG1 and low levels of specific IgG2a. Both wt‐SE and gm‐SE were able to inhibit the binding of specific IgE from mice immunized with gm‐SE to the same antigen used for the ELISA coating. A comparable proliferative response was obtained with the homologous as well as with the heterologous extracts. Conclusion In sensitized mice, we observed a predominantly T‐helper type 2 (Th2)‐type immune response, with increased soybean‐specific IgE and IgG1 antibodies and a concomitant increase of IL‐4 and IL‐5 production. Results obtained by specific IgE ELISA inhibition and by antigen‐specific T cell proliferation demonstrated that wt‐SE and gm‐SE shared B and T epitopes. The present murine model of soybean sensitization established by the oral route should provide valuable information about risk assessment for food allergy from new proteins of genetically modified foods.