In Vitro-In Vivo Extrapolation and Hepatic Clearance-Dependent Underprediction

Accurately predicting the hepatic clearance of compounds using in vitro to in vivo extrapolation (IVIVE) is crucial within the pharmaceutical industry. However, several groups have recently highlighted the serious error in the process. Although empirical or regression-based scaling factors may be used to mitigate the common underprediction, they provide unsatisfying solutions because the reasoning behind the underlying error has yet to be determined. One previously noted trend was intrinsic clearance-dependent underprediction, highlighting the limitations of current in vitro systems. When applying these generated in vitro intrinsic clearance values during drug development and making first-in-human dose predictions for new chemical entities though, hepatic clearance is the parameter that must be estimated using a model of hepatic disposition, such as the well-stirred model. Here, we examine error across hepatic clearance ranges and find a similar hepatic clearance-dependent trend, with high clearance compounds not predicted to be so, demonstrating another gap in the field.     

肝癌间质及癌旁病变的病理分析

目的　研究肝癌间质及癌旁病变的临床病理意义。方法　在 2 0例肝癌组织标本中取 45个癌结节 ,分别在癌结节中间、癌旁肝组织等部位取组织 4块 ,连续切片 ,显微镜下观察。结果　 19个结节有完整窦内皮细胞围绕癌巢 ,其中癌结节肉眼小于3cm者 13个 ,大于 3cm者 6个。 2 6个癌结节无完整窦内皮细胞围绕癌巢 ,其中癌结节直径大于 3cm者 2 4个 ,小于 3cm者 2个。2 0例中有 13例合并肝硬化 ,17例有乙型肝炎病毒感染和HBsAg阳性。 结论　病理连续切片 ,显微镜下观察肝癌间质及癌旁病变是预测肝癌患者预后的重要病理学指标     

Development of a new sensor based on micro-electro-mechanical systems for objective in vivo measurement of the cutaneous temperature: application to foundations

BACKGROUND/AIMS: The purpose of this work was to develop a new sensor for objective in vivo measurement of the cutaneous temperature based on micro-electro-mechanical systems (MEMS), and to compare these performances with those of a classical thermocouple. Research on this new sensor was carried out to allow the quantification of the thermal properties of the made-up skin. METHODS: Sixteen female subjects divided into two different age groups (18-35 and >50 years old) were recruited for this study. Several zones of the face and forearms were made up at random with foundations containing or not a thermoregulator raw material. The quantity of foundation applied on the skin was standardized and measurements were carried out first before make-up, and then 10 s and 5 min after make-up. The new sensor and the thermocouple were used successively on each zone. The cutaneous temperature was expressed in degrees celsius. RESULTS/CONCLUSION: The two systems are similar in terms of repeatability and reproducibility, with some differences in sensibility. The data measured by the MEMS sensor appear lower than those measured by the thermocouple. After make-up, the MEMS sensor detects a progressive increase of the temperature in time whereas the thermocouple detects a decrease. We found the same evolution on the face but in a more attenuated way. These results tend to show that the devices do not measure the same phenomenon. The thermocouple appears more sensitive to the thermal response of the made-up surface whereas the MEMS sensor appears more sensitive to the heat transfers in the interface between the skin and make-up.     

妊娠期糖尿病62例临床分析

目的 探讨妊娠期糖尿病的合理处理及预后.方法 选择62例妊娠期糖尿病患者进行回顾性分析.结果 妊娠期糖尿病62例,其中单纯饮食控制17例,饮食控制 胰岛素治疗43例,2例未治疗.剖宫产42例,阴道产20例.合并妊高症3例,羊水过多2例,羊水过少4例,羊水栓塞1例,早产5例,高胆红素血症3例,真性红细胞增多症2例,死胎2例,新生儿窒息4例,新生儿畸形1例.结论 对妊娠合并糖尿病的孕妇进行早期的诊断及治疗,选择合适的时间及方式终止妊娠可以减少母儿并发症的发生率.     

孕妇血清与初乳中分泌型IgA含量的关系

目的探讨孕妇营养与初乳中分泌型免疫球蛋白Ａ（ＳＩｇＡ）含量的关系。方法对１０１例孕妇作了膳食营养评价，并对其血液营养学指标与产后第３ｄ初乳ＳＩｇＡ含量进行相关分析。结果孕妇血清ＩｇＡ与初乳ＳＩｇＡ呈明显的正相关（ｒ＝０．４９８Ｐ＜０．０１）；血清甘油三酯与初乳ＳＩｇＡ呈明显的负相关（ｒ＝－０．３３８Ｐ＜０．００５）；血清叶酸与初乳ＳＩｇＡ呈明显正相关（孕中期ｒ＝０．７３７Ｐ＜０．００１，孕晚期ｒ＝０．３６２Ｐ＜０．０１）相关呈高度显著性。结论初乳ＳＩｇＡ与孕妇个体免疫状态以及孕期代谢状态有关。     

Changes in glial fibrillary acidic protein mRNA expression after corticospinal axotomy in the adult hamster

We examined changes in the expression of glial fibrillary acidic protein (GFAP) mRNA during Wallerian degeneration in the corticospinal system of the adult Golden hamster following axotomy. GFAP is the product of a type III intermediate filament (IF) gene that is expressed specifically in mature astrocytes. A well-studied component of a complex response termed reactive astrogliosis that occurs after various types of CNS injury is the increased production of astrocytic processes filled with GFAP-containing IFs. While increased expression of GFAP during reactive astrogliosis has been well established at the protein level, little is known about whether or not changes in GFAP mRNA levels occur after CNS injury. In the present study we used in situ hybridization methods to examine this issue. A 35S-labeled mouse GFAP cDNA probe was used for in situ hybridizations of sections of the brain stem obtained 2, 7, and 14 days after unilateral transections of the corticospinal tract in the caudal medulla. Film as well as emulsion autoradiography showed a dramatic increase in GFAP mRNA labeling associated with the degenerating corticospinal tract. GFAP mRNA levels were already dramatically increased in the injured corticospinal tract by 2 days post axotomy and remained elevated at 14 days. Interestingly, in addition to the robust increase in GFAP mRNA levels specifically associated with the degenerating tract, a diffuse increase in GFAP mRNA labeling was observed throughout the grey matter of the brain stem at 2 days post-axotomy, but not after this time. Immunoblotting and immunocytochemical experiments verified that the increased GFAP mRNA levels in the degenerating corticospinal system were accompanied by an increased expression of the protein. These results demonstrate that an increase in GFAP mRNA levels occurs during Wallerian degeneration in the CNS and suggest that increased expression of the GFAP gene is a major contributor to CNS scarring that results after direct traumatic injury.     

Effects of galanin on insulin and glucagon secretion in the rat

Galanin-like immunoreactivity has been visualized in nerve fibers in the islets of Langerhans, suggesting an involvement of galanin in the neural regulation of islet function. In this study, we investigated the effects of galanin on basal and stimulated insulin and glucagon secretion by infusing the peptide at three different dose rates in rats. We also studied the direct effect of galanin on insulin secretion from freshly isolated rat islets. At 320 pmol/kg/min, but not at 20 or 80 pmol/kg/min, galanin lowered basal plasma insulin levels. In contrast, basal plasma glucagon levels were lowered by galanin already at 20 and 80 pmol/kg/min. Furthermore, galanin inhibited both glucose- and arginine-induced insulin release at all three dose levels, whereas arginine-induced glucagon release was not affected by galanin. Glucose-stimulated insulin secretion from isolated rat islets was dose-dependently suppressed by galanin (10^-6-10^-8M). Therefore, it is concluded that galanin in rats inhibits insulin secretion, both in vivo and in vitro, and that at lower dose levels, the peptide also inhibits basal glucagon release.