The vertebrate inner ear develops from initially 'simple' ectodermal placode and vesicle stages into the complex three-dimensional structure which is necessary for the senses of hearing and equilibrium. Although the main morphological events in vertebrate inner ear development are known, the genetic mechanisms controlling them are scarcely understood. Previous studies have suggested that the otic placode is induced by signals from the chordamesoderm and the hindbrain, notably by fibroblast growth factors (Fgfs) and Wnt proteins. Here we study the role of Fgf8 as a bona-fide hindbrain-derived signal that acts in conjunction with Fgf3 during placode induction, maintenance and otic vesicle patterning. Acerebellar (ace) is a mutant in the fgf8 gene that results in a non-functional Fgf8 product. Homozygous mutants for acerebellar (ace) have smaller ears that typically have only one otolith, abnormal semi-circular canals, and behavioral defects. Using gene expression markers for the otic placode, we find that ace/fgf8 and Fgf-signaling are required for normal otic placode formation and maintenance. Conversely, misexpression of fgf8 or Fgf8-coated beads implanted into the vicinity of the otic placode can increase ear size and marker gene expression, although competence to respond to the induction appears restricted. Cell transplantation experiments and expression analysis suggest that Fgf8 is required in the hindbrain in the rhombomere 4-6 area to restore normal placode development in ace mutants, in close neighbourhood to the forming placode, but not in mesodermal tissues. Fgf3 and Fgf8 are expressed in hindbrain rhombomere 4 during the stages that are critical for placode induction. Joint inactivation of Fgf3 and Fgf8 by mutation or antisense-morpholino injection causes failure of placode formation and results in ear-less embryos, mimicking the phenotype we observe after pharmacological inhibition of Fgf-signaling. Fgf8 and Fgf3 together therefore act during induction and differentiation of the ear placode. In addition to the early requirement for Fgf signaling, the abnormal differentiation of inner ear structures and mechanosensory hair cells in ace mutants, pharmacological inhibition of Fgf signaling, and the expression of fgf8 and fgf3 in the otic vesicle demonstrate independent Fgf function(s) during later development of the otic vesicle and lateral line organ. We furthermore addressed a potential role of endomesomerm by studying mzoep mutant embryos that are depleted of head endomesodermal tissue, including chordamesoderm, due to a lack of Nodal-pathway signaling. In these embryos, early placode induction proceeds largely normally, but the ear placode extends abnormally to midline levels at later stages, suggesting a role for the midline in restricting placode development to dorsolateral levels. We suggest a model of zebrafish inner ear development with several discrete steps that utilize sequential Fgf signals during otic placode induction and vesicle patterning.

To identify the prognostic factors of overall survival in a series of patients with paraneoplastic pemphigus (PNP).

The microphthalmia-associated transcription factor (MITF) is a basic helix-loop-helix leucine zipper transcription factor, which regulates melanocyte development and the biosynthetic melanin pathway. A notable relationship has been described between non-truncating mutations of its basic domain and Tietz syndrome, which is characterized by albinoid-like hypopigmentation of the skin and hair, rather than the patchy depigmentation seen in Waardenburg syndrome, and severe hearing loss. Twelve patients with new or recurrent non-truncating mutations of the MITF basic domain from six families were enrolled in this study. We observed a wide range of phenotypes and some unexpected features. All the patients had blue irides and pigmentation abnormalities that ranged from diffuse hypopigmentation to Waardenburg-like patches. In addition, they showed congenital complete hearing loss, diffuse hypopigmentation of the skin, freckling and ocular abnormalities, more frequently than patients with MITF mutations outside the basic domain. In conclusion, the non-truncating mutations of the basic domain do not always lead to Tietz syndrome but rather to a large range of phenotypes. Sun-exposed freckles are interestingly observed more frequently in Asian populations. This variability argues for the possible interaction with modifier loci.

疥疮是一个重要的全球健康问题。在发展中国家可能受到感染,导致心脏和肾脏疾病。疥疮在发达国家的患病 率也正在增高,影响欧洲和美国 2-4% 人群。这部分是由于治疗不当。已经研究了住院或卧床患者(如养老院 中的痴呆患者,他们发生疥疮的风险高)治疗失败的原因。但是,尚未研究门诊患者(即可活动的患者,代表了大 多数患者)中的治疗失败。来自法国鲁昂大学皮肤病学系和生物统计学系的作者们试图确定到医院或私人皮 肤诊所就诊的疥疮临床诊断患者中治疗失败的预测因素。他们研究了 210 名患者,其中 98 名已成功治疗,112 名在治疗后 3 个月有疥疮持续存在的证据。他们发现,治疗失败的一个主要原因是仅使用苯甲酸苄酯局部外 用治疗(用于皮肤)或伊维菌素口服治疗(通过口服),而非联合这两者。另一个主要原因是使用单剂量伊维菌素, 而非连续两剂。治疗失败的其他原因包括随食物服用伊维菌素而非推荐的空腹服用、亲属和密切接触者治疗 不当、缺乏关于治疗的书面信息和可能的家具清洁不当(一个争议话题)。增加苯甲酸苄酯的使用频率似乎并 不影响结局,由于其刺激性,作者并未推荐这一做法。总而言之,作者们认为应在局部外用基础上连续口服两剂 伊维菌素(而非一剂)。这对全世界都有意义,因为单剂量伊维菌素在某些国家是推荐治疗。