Hirschprung's disease and imperforate anus in Pallister-Hall syndrome: a new association

Hirschprung’s disease and imperforate anus are described concurrently in a newborn with Pallister-Hall syndrome as well as the difficulties in making this diagnosis. Awareness of this new association should prompt the exclusion of Hirschprung’s disease before repair of imperforate anus in infants with Pallister-Hall syndrome. The known genetic parallels between these conditions is discussed briefly in terms of etiology.     

Smo蛋白在人结肠癌中的表达及其与新生血管的关系

目的 研究豪猪蛋白(Hedgehog)信号途径中Smo蛋白在人结肠癌组织中的表达,初步探讨Smo与结肠癌血管生成的关系.方法 用免疫组化方法研究人结肠癌组织中Smo蛋白的表达;同时用CD34单克隆抗体标记结肠癌组织切片中新生血管,计算微血管密度(micro-vascular density,MVD),并统计Smo蛋白的表达与MVD的关系.结果 在总共39例结肠癌标本中,Smo阳性24例,阴性15例,阳性率61.54%;MVD平均值68.70±11.65,Smo的阳性组MVD均值71.25±12.56,Smo阴性组MVD均值64.05±8.88,两组统计分析差别有统计学意义(t检验,P＜0.05).结论 Smo蛋白在人结肠癌中活化,并参与了结肠癌的发生发展.促进新生血管的生成是其可能的机制之一.     

Sonic hedgehog and Glis famliy expression in the human neonatal of congenital esophageal atresia and tracheoesophageal fistula

目的 研究Sonic hedgehog基因及Gli家族在人类先天性食管闭锁并气管食管瘘(esophageal atresia and tracheoesophageal fistula,EA-TEF)的表达特点,探讨EA-TEF病因及发病机制的可能影响因素.方法 食管吻合术中留取22例EA-TEF患儿近端食管盲端及远端气管食管瘘管组织,7例行HE染色,10例行real-time RT-PCR处理,5例行免疫荧光染色处理.观察食管盲端及气管食管瘘管形态上的变化及各指标的差异.结果 ①形态学:瘘管组织内皮下可见粘液腺体,肌层稀疏且肌肉组织结构紊乱；②Shh表达:食管盲端组织中可见表达,瘘管组织中未有表达；③Glis表达:Gli-1、Gli-3mRNA表达无差异,Gli-2mRNA表达差异有统计学意义(P＜0.05),瘘管中表达低于食管盲袋.结论 气管食管瘘组织具有气管源性特征.EA-TEF的发生可能与Shh信号通路表达下调有关.Gli-2的功能缺失在EA-TEF的发生中可能发挥重要作用.     

Toward an understanding of the role of notochordal cells in the adult intervertebral disc: From discord to accord

The goal of this mini‐review is to address the long standing argument that the pathogenesis of disc disease is due to the loss and/or the replacement of the notochordal cells by other cell types. We contend that, although cells of different size and morphology exist, there is no strong evidence to support the view that the nucleus pulposus contains cells of distinct lineages. Based on lineage mapping studies and studies of other notochordal markers, we hypothesize that in all animals, including human, nucleus pulposus retains notochordal cells throughout life. Moreover, all cells including chondrocyte‐like cells are derived from notochordal precursors, and variations in morphology and size are representative of different stages of maturation, and or, function. Thus, the most critical choice for a suitable animal model should relate more to the anatomical and mechanical characteristics of the motion segment than concerns of cell loss and replacement by non‐notochordal cells. Developmental Dynamics 239:2141–2148, 2010. © 2010 Wiley‐Liss, Inc.     

Sonic hedgehog signaling during nervous system development*☆

The Hedgehog signaling pathway plays a key role in embryonic development and organ formation. Sonic hedgehog signaling participates in nervous system development, regulates proliferation and differentiation of neural stem cells, controls growth and targeting of axons, and contributes to specialization of oligodendrocytes. For further studies of the Sonic hedgehog signaling pathway and for the development of new drugs in the treatment of nervous system diseases, it is beneficial to understand these mechanisms.     

Indian hedgehog supports definitive erythropoiesis

Indian hedgehog (Ihh) has been reported to stimulate haematopoiesis ex vivo. In this study we studied the consequences of loss of function of Ihh for murine haematopoietic development. Ihh has no essential role in primitive erythropoiesis, but it is required in a non cell autonomous fashion for definitive erythropoieisis. Many components of the hedgehog signaling pathway are present in the fetal liver, with Ihh and Gli1 being most highly expressed in the stroma and Ptc1 being most highly expressed in haematopoietic stem and progenitor cells. Ihh knockout HSC and progenitor cell populations are produced in normal numbers in vivo and respond normally to haematopoietic cytokines in vitro, but terminal erythroid differentiation is defective leading to fatal anemia in mid gestation in many Ihh knockout embryos. These loss-of-function studies are consistent with previous gain-of-function studies which show Ihh can induce blood from ectoderm or expand HSCs in stroma-dependent culture.     

Tumor Resistance Explained by Hormesis

Enhanced drug (GDC 0449) resistance in a mouse model for human medulloblastoma is shown in the present paper to act via an hormetic response. This has significant implications, imposing constraints on the quantitative features of the dose response of the chemotherapeutic agent, affecting optimal study design, mechanism assessment strategy, potential for tumor rebound, patient relapse and disease outcome.     

Modeling the complex etiology of holoprosencephaly in mice

Holoprosencephaly (HPE) is a common developmental defect caused by failure to define the midline of the forebrain and/or midface. HPE is associated with heterozygous mutations in Nodal and Sonic hedgehog (SHH) pathway components, but clinical presentation is highly variable, and many mutation carriers are unaffected. It is therefore thought that such mutations interact with more common modifiers, genetic and/or environmental, to produce severe patterning defects. Modifiers are difficult to identify, as their effects are context-dependent and occur within the complex genetic and environmental landscapes that characterize human populations. This has made a full understanding of HPE etiology challenging. We discuss here the use of mice, a genetically tractable model sensitive to teratogens, as a system to address this challenge. Mice carrying mutations in human HPE genes often display wide variations in phenotypic penetrance and expressivity when placed on different genetic backgrounds, demonstrating the existence of silent HPE modifier genes. Studies with mouse lines carrying SHH pathway mutations on appropriate genetic backgrounds have led to identification of both genetic and environmental modifiers that synergize with the mutations to produce a spectrum of HPE phenotypes. These models favor a scenario in which multiple modifying influences—both genetic and environmental, sensitizing and protective—interact with bona fide HPE mutations to grade phenotypic outcomes. Despite the complex interplay of HPE risk factors, mouse models have helped establish some clear concepts in HPE etiology. A combination of mouse and human cohort studies should improve our understanding of this fascinating and medically important issue.