Pseudo-immortalization of postnatal cochlear progenitor cells yields a scalable cell line capable of transcriptionally regulating mature hair cell genes.

The mammalian cochlea is a highly specialized organ within the inner ear. Sensory hair cells (HC) in the cochlea detect and transduce sound waves into electrical impulses that are sent to the brain. Studies of the molecular pathways regulating HC formation are hindered by the very sparse nature of HCs, where only ~3300 are found within an entire mouse cochlea.

Histone deacetylase inhibition protects hearing against acute ototoxicity by activating the Nf-B pathway.

Auditory hair cells have repeatedly been shown to be susceptible to ototoxicity from a multitude of drugs including aminoglycoside antibiotics. Here, we found that systemic HDAC inhibition using suberoylanilide hydroxamic acid (SAHA) on adult mice offers almost complete protection against hair cell loss and hearing threshold shifts from acute ototoxic insult from kanamycin potentiated with furosemide. We also found that the apparent lack of hair cell loss was completely independent of spontaneous or facilitated (ectopic induction) hair cell regeneration.

In Vivo Cochlear Hair Cell Generation and Survival by Coactivation of β-Catenin and Atoh1.

Unlabelled: The mammalian cochlea exhibit minimal spontaneous regeneration, and loss of sensory hair cells (HCs) results in permanent hearing loss. In nonmammalian vertebrates, spontaneous HC regeneration occurs through both proliferation and differentiation of surrounding supporting cells (SCs). HC regeneration in postnatal mammalian cochleae in vivo remains limited by the small HC number and subsequent death of regenerated HCs.

Epigenetic regulation in the inner ear and its potential roles in development, protection, and regeneration.

The burgeoning field of epigenetics is beginning to make a significant impact on our understanding of tissue development, maintenance, and function. Epigenetic mechanisms regulate the structure and activity of the genome in response to intracellular and environmental cues that direct cell-type specific gene networks. The inner ear is comprised of highly specialized cell types with identical genomes that originate from a single totipotent zygote.

CHD7 and retinoic acid signaling cooperate to regulate neural stem cell and inner ear development in mouse models of CHARGE syndrome.

CHARGE syndrome is a multiple congenital anomaly disorder that leads to life-threatening birth defects, such as choanal atresia and cardiac malformations as well as multiple sensory impairments, that affect hearing, vision, olfaction and balance. CHARGE is caused by heterozygous mutations in CHD7, which encodes an ATP-dependent chromatin remodeling enzyme. Identification of the mechanisms underlying neurological and sensory defects in CHARGE is a first step toward developing treatments for CHARGE individuals.

Epigenetic alterations by NuRD and PRC2 in the neonatal mouse cochlea.

Mammalian cochlear supporting cells remain quiescent at postnatal ages and age-dependent changes in supporting cell proliferative capacity are evident. Ectopic Atoh1 expression in neonatal supporting cells converts only a small percentage of these cells into hair cell-like cells. Despite tremendous potential for therapeutics, cellular reprogramming in the mammalian inner ear remains a slow inefficient process that requires weeks, with most cells failing to reprogram.

Mature middle and inner ears express Chd7 and exhibit distinctive pathologies in a mouse model of CHARGE syndrome.

Heterozygous mutations in the gene encoding chromodomain-DNA-binding-protein 7 (CHD7) cause CHARGE syndrome, a multiple anomaly condition which includes vestibular dysfunction and hearing loss. Mice with heterozygous Chd7 mutations exhibit semicircular canal dysgenesis and abnormal inner ear neurogenesis, and are an excellent model of CHARGE syndrome. Here we characterized Chd7 expression in mature middle and inner ears, analyzed morphological features of mutant ears and tested whether Chd7 mutant mice have altered responses to noise exposure and correlated those responses to inner and middle ear structure.

Reproductive dysfunction and decreased GnRH neurogenesis in a mouse model of CHARGE syndrome.

CHARGE is a multiple congenital anomaly disorder and a common cause of pubertal defects, olfactory dysfunction, growth delays, deaf-blindness, balance disorders and congenital heart malformations. Mutations in CHD7, the gene encoding chromodomain helicase DNA binding protein 7, are present in 60-80% of individuals with the CHARGE syndrome. Mutations in CHD7 have also been reported in the Kallmann syndrome (olfactory dysfunction, delayed puberty and hypogonadotropic hypogonadism).

Chromodomain proteins in development: lessons from CHARGE syndrome.

In humans, heterozygous mutations in the adenosine triphosphate-dependent chromatin remodeling gene CHD7 cause CHARGE syndrome, a common cause of deaf-blindness, balance disorders, congenital heart malformations, and olfactory dysfunction with an estimated incidence of approximately 1 in 10,000 newborns. The clinical features of CHARGE in humans and mice are highly variable and incompletely penetrant, and most mutations appear to result in haploinsufficiency of functional CHD7 protein. Mice with heterozygous loss of function mutations in Chd7 are a good model for CHARGE syndrome, and analyses of mouse mutant phenotypes have begun to clarify a role for CHD7 during development and into adulthood.

Molecular and phenotypic aspects of CHD7 mutation in CHARGE syndrome.

CHARGE syndrome [coloboma of the eye, heart defects, atresia of the choanae, retardation of growth and/or development, genital and/or urinary abnormalities, and ear abnormalities (including deafness)] is a genetic disorder characterized by a specific and a recognizable pattern of anomalies. De novo mutations in the gene encoding chromodomain helicase DNA binding protein 7 (CHD7) are the major cause of CHARGE syndrome. Here, we review the clinical features of 379 CHARGE patients who tested positive or negative for mutations in CHD7.

Defects in neural stem cell proliferation and olfaction in Chd7 deficient mice indicate a mechanism for hyposmia in human CHARGE syndrome.

Mutations in CHD7, a chromodomain gene, are present in a majority of individuals with CHARGE syndrome, a multiple anomaly disorder characterized by ocular Coloboma, Heart defects, Atresia of the choanae, Retarded growth and development, Genital hypoplasia and Ear anomalies. The clinical features of CHARGE syndrome are highly variable and incompletely penetrant. Olfactory dysfunction is a common feature in CHARGE syndrome and has been potentially linked to primary olfactory bulb defects, but no data confirming this mechanistic link have been reported.

Synthesis of 2H-1,2-benzothiazine 1,1-dioxides via heteroannulation reactions of 2-iodobenzenesulfonamide with ketone enolates under S(RN)1 conditions.

[Reaction: see text]. 2-iodobenzenesulfonamide (1a) underwent photostimulated S(RN)1 reactions in liquid NH3 with the potassium enolates derived from acetone, pinacolone, butanone, and 3-methyl-2-butanone to give fair to good yields of 2H-1,2-benzothiazine 1,1-dioxides 2. Reductive dehalogenation of 1a was found to predominate in photoinduced reactions of 1a with 3-pentanone, 2-methyl-3-pentanone, and 2,4-dimethyl-3-pentanone, the extent of reduction being proportional to the number of beta-hydrogen atoms present in the ketone enolate.

Allaying loneliness in freshman medical students: an outcome of an elective course.

An empirical study of the effects of a psychiatry elective on first-year medical students' reported satisfaction with school and their reported level of loneliness is described in this article. Surveys before and after the class provided evidence that satisfaction with school decreased significantly among freshmen not taking the course. In contrast, male course participants' levels of satisfaction with school and with faculty-student relationships did not drop significantly, nor did female participants' levels of satisfaction with faculty-student relationships.

Anabolic steroids and acute schizophrenic episode.

The use of anabolic steroids by athletes to increase physical performance has vastly increased over the last 10 years. A case is described which temporally relates the use of these organic compounds with the development of an acute schizophreniform illness. The dearth of literature on this particular "side-effect" is noted, as are the diagnostic implications vis-a-vis anabolic steroids and the anamnestic interview in an athlete who presents with an acute schizophrenic mental status examination.

The effects of long-term psychotherapy on patients' self-perception.

A review of the literature regarding the effects of long-term psychotherapy indicates that it has rarely been examined purely from the standpoint of the patient. This study attempts to determine how the patients perceive attitudinal change in themselves and their therapists during the treatment process. Twenty patients who received dynamically oriented psychotherapy in excess of one year in a typical outpatient clinic participated.