Rab GTPases as regulators of endocytosis,targets of disease and therapeutic opportunities

Agola JO, Jim PA, Ward HH, BasuRay S, Wandinger‐Ness A. Rab GTPases as regulators of endocytosis, targets of disease and therapeutic opportunities. Rab GTPases are well‐recognized targets in human disease, although are underexplored therapeutically. Elucidation of how mutant or dysregulated Rab GTPases and accessory proteins contribute to organ specific and systemic disease remains an area of intensive study and an essential foundation for effective drug targeting. Mutation of Rab GTPases or associated regulatory proteins causes numerous human genetic diseases. Cancer, neurodegeneration and diabetes represent examples of acquired human diseases resulting from the up‐ or downregulation or aberrant function of Rab GTPases. The broad range of physiologic processes and organ systems affected by altered Rab GTPase activity is based on pivotal roles in responding to cell signaling and metabolic demand through the coordinated regulation of membrane trafficking. The Rab‐regulated processes of cargo sorting, cytoskeletal translocation of vesicles and appropriate fusion with the target membranes control cell metabolism, viability, growth and differentiation. In this review, we focus on Rab GTPase roles in endocytosis to illustrate normal function and the consequences of dysregulation resulting in human disease. Selected examples are designed to illustrate how defects in Rab GTPase cascades alter endocytic trafficking that underlie neurologic, lipid storage, and metabolic bone disorders as well as cancer. Perspectives on potential therapeutic modulation of GTPase activity through small molecule interventions are provided.     

Opposing trends in the prevalence of health professional-diagnosed asthma by sex: A Canadian National Population Health Survey study

BACKGROUND:

The prevalence of asthma is on the rise worldwide, with large variations in prevalence existing between and within countries. Little is known regarding the variation in asthma prevalence in adults living in rural and urban settings.

OBJECTIVES:

Using questionnaire data from the Canadian National Population Health Survey, the prevalence of asthma at four time periods (1994/1995 [cycle 1], 1996/1997 [cycle 2], 1998/1999 [cycle 3] and 2000/2001 [cycle 4]) was compared between rural and urban populations stratified by sex, smoking status and age group. Asthma was defined as a positive response to the question: “Do you have asthma diagnosed by a health professional?”

METHODS:

To account for the complexity of the survey design, the bootstrap method was used to calculate prevalences and 95% CIs.

RESULTS:

Overall, the prevalence of asthma increased from 7.3% (cycle 1) to 7.5% (cycle 4). After stratifying by sex, the asthma prevalence decreased among men, but in women, there was a steady increase. Asthma prevalence increased for both the rural population and the urban population. After stratifying each cycle by sex and location (rural or urban), both rural and urban men showed a decrease in asthma prevalence. On dividing according to age groups (0 to 14 years, 15 to 34 years, 35 to 64 years, and 65 years and older), the prevalence of asthma was greatest in the 15- to 34-year age group of urban and rural women.

CONCLUSIONS:

Asthma prevalence increased among rural and urban women. The prevalence of asthma was highest among female smokers and male nonsmokers when stratified by smoking status. Based on these findings, the rate of increase in asthma prevalence is different for men and women.     

Subgroup effects despite homogeneous heterogeneity test results

Background  

Statistical tests of heterogeneity are very popular in meta-analyses, as heterogeneity might indicate subgroup effects. Lack of demonstrable statistical heterogeneity, however, might obscure clinical heterogeneity, meaning clinically relevant subgroup effects.     

关节软骨脱细胞支架材料的制备

目的:探讨脱细胞关节软骨支架材料的制备方法,制备软骨理想的组织工程支架材料。方法:实验于2005-12/2006-08在兰州大学第二医院骨科研究所实验室完成。实验方法:利用冷冻干燥、化学去污剂等方法制备脱细胞的兔关节软骨。在无菌状态下取青紫蓝兔的新鲜兔关节软骨,剪成3.5mm×3.5mm,厚度0.2～2.0mm,在冷冻干燥器中冻干12h。在10g/L Triton X-100、Tris-HCl液内加入蛋白酶抑制剂-苯甲基黄酰氟,持续振荡48h后标本以双蒸馏水连续冲洗后置于DNase I酶和RNase A酶混合液中消化。置于10g/L Triton X-100、Tris-HCl液中洗脱。实验评估:①大体观察:肉眼观察脱细胞后关节软骨的外观形态。②组织学观察:将制备的脱细胞关节软骨行石蜡包埋切片,行苏木精-伊红染色、Massion三色染色并在光镜下观察。③扫描电镜观察:将制备的脱细胞关节软骨以戊二醛-锇酸双固定后,行扫描电镜观察。结果:①脱细胞后关节软骨外观形态:肉眼下可见正常关节软骨呈白色或淡黄色,脱细胞后关节软骨色呈灰白,半透明状,无光泽,外形与软骨相似并且仍维持了关节软骨的结构。②脱细胞后关节软骨的组织学变化:苏木精-伊红染色显示,软骨细胞消失,软骨巢分辨不清,在巢内没有蓝染的核物质,核细胞碎屑,只有红染为残留的细胞外基质。Massion三色染色显示,脱细胞后关节软骨内主要含有胶原纤维。③脱细胞后关节软骨的超微结构:扫描电镜下显示,脱细胞后关节软骨陷窝呈蜂窝状,未见到残余的细胞核、细胞器,残余的空穴高低不平。结论:经冷冻干燥、化学去污剂等方法可完整去除软骨中的细胞成分,保留胶原纤维等细胞外基质。