ROR1 is essential for proper innervation of auditory hair cells and hearing in humans and mice

Hair cells of the inner ear, the mechanosensory receptors, convert sound waves into neural signals that are passed to the brain via the auditory nerve. Little is known about the molecular mechanisms that govern the development of hair cell–neuronal connections. We ascertained a family with autosomal recessive deafness associated with a common cavity inner ear malformation and auditory neuropathy. Via whole-exome sequencing, we identified a variant (c.2207G>C, p.R736T) in ROR1 (receptor tyrosine kinase-like orphan receptor 1), cosegregating with deafness in the family and absent in ethnicity-matched controls. ROR1 is a tyrosine kinase-like receptor localized at the plasma membrane. At the cellular level, the mutation prevents the protein from reaching the cellular membrane. In the presence of WNT5A, a known ROR1 ligand, the mutated ROR1 fails to activate NF-κB. Ror1 is expressed in the inner ear during development at embryonic and postnatal stages. We demonstrate that Ror1 mutant mice are severely deaf, with preserved otoacoustic emissions. Anatomically, mutant mice display malformed cochleae. Axons of spiral ganglion neurons show fasciculation defects. Type I neurons show impaired synapses with inner hair cells, and type II neurons display aberrant projections through the cochlear sensory epithelium. We conclude that Ror1 is crucial for spiral ganglion neurons to innervate auditory hair cells. Impairment of ROR1 function largely affects development of the inner ear and hearing in humans and mice.Sensorineural hearing loss (SNHL) is diagnosed in approximately 1 per 500 newborns (1). A genetic etiology is present in more than half of the cases. Inner ear anomalies (IEAs), demonstrated with computerized tomography or magnetic resonance imaging, are associated with SNHL in about one-third of individuals (2). Although IEAs can be diagnosed in patients with other clinical manifestations, such as those seen in Waardenburg [Mendelian Inheritance in Man (MIM) 193500], Pendred (MIM 274600), or BOR (MIM 113650) syndromes, the majority of cases fall into the category of nonsyndromic deafness. Despite recent progress in identifying genes that determine many forms of hearing loss (hereditaryhearingloss.org/), the genetic basis of IEAs in humans remains largely unknown.The inner ear is a complex organ that is built from a simple structure, referred to as the otocyst, through a series of morphogenetic events. Roughly, it consists of a dorsal vestibular and a ventral auditory component (3). Studies in model organisms have identified a number of genes that play roles in proper development of the inner ear. Mouse models have been particularly relevant because the anatomy and physiology of the murine auditory system are similar to those of humans. Mutations in human orthologs of many of these genes have been reported to cause deafness in humans as well (4).Next-generation sequencing technologies have allowed rapid identification of novel human deafness genes. Approximately 85% of disease-causing mutations in Mendelian disorders have been found in the protein-coding regions, despite the fact that this portion accounts for less than 2% of the entire human genome (5). Accordingly, whole exome sequencing (WES) has been frequently used because it allows for a targeted enrichment and resequencing of nearly all exons of protein-coding genes.In this study, via WES, we detected a mutation in ROR1 (receptor tyrosine kinase-like orphan receptor 1; MIM 602336), encoding receptor tyrosine kinase-like orphan receptor 1, that associates with an IEA and nonsyndromic deafness in a family. Further characterization of Ror1 mutant mice revealed that Ror1 deficiency results in defective hair cell innervation and abnormal cochlear development.     

论仲景保胃气思想及其在《金匮要略》妇人三篇中的运用

[目的]探讨仲景保胃气思想及其在《金匮要略》妇人三篇中的运用。[方法]通过综合分析的文献研究方法,研究总结仲景保胃气思想,及其在《金匮要略》妇人病治疗大法中的运用。[结果]仲景在治法用药、治疗禁忌、煎药服药、转归预后等疾病治疗的每一个环节都注意顾护胃气。在《金匮要略》妇人三篇中,虚则补之、实则泻之、虚实夹杂则补泻兼施治疗大法方面,仲景补则以养胃气,泻时不忘固护胃气,补泻兼施以和胃气,均体现保胃气思想的运用。[结论]仲景非常重视保护胃气,将《内经》确立的脾胃理论应用于临床实践,衍生出保胃气思想,对于后世医家进行疾病的诊疗施治有非常重要的指导意义。     

Unilateral renal agenesis and urethral atresia associated with ergotamine intake during pregnancy

Ergotamine, an ergot alkaloid, used for the treatment and prevention of migraine attacks, is considered as a teratogenic drug and, therefore, should be avoided in pregnancy. Here, we report a newborn infant with unilateral renal agenesis, urethral atresia, and pulmonary hypoplasia associated with the use of ergotamine for the treatment of migraine attacks at early pregnancy. Genitourinary anomalies in association with ergotamine usage were rarely reported and this was the third case of renal agenesia in association with ergotamine usage in literature. We suggest that ergotamine teratogenicity may be dose dependent and should be avoided in pregnancy for the possibility of genitourinary anomalies.     

Optimization of fermentation technology for composite fruit and vegetable wine by response surface methodology and analysis of its aroma components

Fruit wine has certain health care functions, but fruit wine made from a single fruit or vegetable does not have a good enough color, flavor or nutrient composition. Therefore, this study used fresh carrot (Daucus carota subsp. sativus) and pomegranate (Punica granatum) as raw materials to explore the brewing process of carrot and pomegranate compound wine. The fermentation technology of the composite carrot and pomegranate wine was optimized by a single-factor experiment and Box–Behnken design (BBD), which provided a theoretical foundation for the fermentation of this wine. As per the results, the alcohol content of this composite carrot and pomegranate wine was 12.35% vol. under the optimum fermentation conditions of 28 °C initial temperature, 24% initial sugar content, and with the addition of 64 mg L⁻¹ sulfur dioxide (SO₂). In the fermented fruit and vegetable wine, a total of 30 aroma components were detected; 21 composites (such as bornyl acetate, caryophyllene and 3-(2-nitrophenylmethyl)-2-thiazolidinone) were newly generated. The relative content of alcohol flavor composites (such as propionic acid 2-methyl-3-hydroxy-2,2,4-trimethylpentan-1-ol, 2-methyl-2-ethyl-3-hydroxycyclohexyl propanoate and terpinene-4-ol) showed an upward trend, and the relative content of alkene components increased significantly after fermentation. The findings of this study provide an experimental foundation for optimizing fermentation technology and for improving the product quality of composite carrot and pomegranate wine.

Fruit wine has certain health care functions, but fruit wine made from a single fruit or vegetable does not have a good enough color, flavor or nutrient composition.     

Evaluation of endometrial thickness with transvaginal ultrasonography and histopathology in premenopausal women with abnormal vaginal bleeding

Objective  

This study was undertaken to investigate cut-off value of the endometrial thickness by transvaginal ultrasonography (TvUSG), and to detect the accuracy of preoperative Pipelle biopsy in premenopausal women with abnormal vaginal bleeding.     

Changes in regional cerebral blood flow demonstrated by 99mTc-HMPAO SPECT in euthymic bipolar patients

Single photon emission computed tomography (SPECT) with ^99mTc-HMPAO was used to compare regional cerebral blood flow (rCBF) in patients with bipolar disorder and in healthy controls. The sample of this study consisted of 16 euthymic bipolar patients who met the DSM-IV criteria and 10 healthy control subjects. The mean regional cerebral blood flow values of the bipolar euthymic patients were significantly lower than those of the controls in the bilateral medial-basal temporal, occipital; medial frontal; parietal regions and in the cingulate gyrus; the hypoperfusion in the cingulate had the highest significant P value (.001, Bonferroni correction). No significant differences in rCBF emerged between right and left-brain regions. The most important findings of the current study are the presence of regional cerebral perfusion alterations, particularly in the cingulate gyrus in the euthymic bipolar patients. Our results imply that underlying brain dysfunction may be independent from manic or depressive episodes in bipolar disorder. Because of the small number of subjects, however, this finding should be viewed as preliminary. This study was presented as an oral presentation in the 7th International Congress of Nuclear Oncology and 18th National Congress of The Turkish Society of Nuclear Medicine 13–17 May 2006, Antalya, Turkey and in the International Conference on Mood Disorders 30 March–1 April 2006 Istanbul, Turkey.     

Tularemia, a reemerging disease in northwest Turkey: epidemiological investigation and evaluation of treatment responses

An outbreak of tularemia occurred in three provinces in Turkey in February 2004 and reemerged in the same provinces in February 2005. A total of 61 cases, 54 of which were confirmed with the micro-agglutination test, were diagnosed with oropharyngeal tularemia. No culture for Francisella tularensis was attempted, but PCR for F. tularensis was positive in aspiration material of suppurated lymphadenitis of 7 patients. F. tularensis detection with PCR was negative in water samples, but epidemiologic and environmental findings suggested that contaminated water or food was the cause of the outbreaks. Late initiation antibiotic therapy could not prevent suppuration and draining of the involved lymph nodes.