The molecular basis for autosomal dominant progressive nonsyndromic hearing loss in an Israeli Jewish family, Family H, has been determined. Linkage analysis placed this deafness locus, DFNA15, on chromosome 5q31. The human homolog of mouse Pou4f3, a member of the POU-domain family of transcription factors whose targeted inactivation causes profound deafness in mice, was physically mapped to the 25-centimorgan DFNA15-linked region. An 8-base pair deletion in the POU homeodomain of human POU4F3 was identified in Family H. A truncated protein presumably impairs high-affinity binding of this transcription factor in a dominant negative fashion, leading to progressive hearing loss.

CXCL12 is expressed by normal IECs and upregulated and differentially distributed in IBD IECs. CXCR4 is expressed by IECs and LPTs, and CXCR4+ cells are significantly increased in IBD LP. CXCL12 is chemotactic for both PBTs and LPTs. Thus, CXCL12 and CXCR4 have a constitutive and inflammatory role in the intestinal mucosa and their selective therapeutic manipulation may be considered in IBD management.

Curcumin inhibited the development of TAA-induced liver cirrhosis mainly due to its anti-inflammatory activities and not by a direct anti-fibrotic effect. As curcumin ingestion is safe in humans, it may be reasonable to assess in clinical studies the beneficial effect of curcumin in slowing the development of liver cirrhosis.

A mutation in the POU4F3 gene (BRN-3.1, BRN3C) is responsible for DFNA15 (MIM 602459), autosomaldominant nonsyndromic hearing loss. POU4F3 is a member of the POU family of transcription factors and is essential for inner-ear hair cell maintenance. To test the potential effects of the human POU4F3 mutation, we performed a series of experiments in cell culture to mimic the human mutation. Mutant POU4F3 loses most of its transcriptional activity and most of its ability to bind to DNA and does not function in a dominantnegative manner. Moreover, whereas wild-type POU4F3 is found exclusively in the nucleus, our studies demonstrate that the mutant protein is localized both to the nucleus and the cytoplasm. Two nuclear localization signals were identified; both are essential for proper nuclear entry of POU4F3 protein. We found that the mutant protein half-life is longer than that of the wild type. We propose that the combination of defects caused by the mutation on the function of the POU4F3 transcription factor eventually leads to hair cell morbidity in affected family H members.The POU domain transcription factors play an important role in tissue-specific gene regulation. They were originally defined by sequence homology between four transcription factors: mammalian Pit-1, Oct-1, and Oct-2 and nematode Caenorhabditis elegans 7,15,16). The region of homology, referred to as the POU domain, is a bipartite DNAbinding domain that contains a POU-specific (POU S ) domain and the POU-homeodomain (POU HD ) joined by a variable linker. High-affinity DNA binding of POU transcription factors requires both domains (1, 32). Based on sequence homology in the POU domain, the POU transcription factors were divided into six subclasses from I to VI (37). The class IV POU subfamily includes POU4F1 (Brn3a/Brn-3.0), POU4F2 (Brn3b/ Brn-3.2), and POU4F3 (Brn3c/Brn-3.1) in mammals (11,14,21,25,35,44), C. elegans Unc-86, and Drosophila factors I-POU and tI-POU (37).The three mammalian members of the POU IV subfamily are expressed in distinct but overlapping populations of neuronal cells during development and in the adult organism (11,25,35). Gene-targeted mutagenesis in the mouse of each of these class IV transcription factors demonstrates that the cell type in which it is first expressed is the system that is most affected (6,10,23,39,40). In the inner ear, Pou4f3 is uniquely and strongly expressed in cochlear and vestibular hair cells. Targeted deletion of Pou4f3 results in profound deafness and impaired balance due to complete loss of auditory and vestibular hair cells. This is followed by a partial secondary loss of spiral and vestibular ganglion neurons (6,39,42). Pou4f3 is required for the final differentiation and survival of hair cells (41).A mutation in the POU4F3 gene is associated with hearing loss in a large Israeli Jewish family, family H (36). Affected members of family H suffer from progressive autosomal-dominant sensorineural hearing loss (9). In hearing impaired members of family H, an 8-bp deletion was identified in exon 2...

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Thirty patients with seasonal allergic rhinitis entered a double blind study comparing budesonide (nasal spray, 400 micrograms/d) and i.m. injection of 80 mg methylprednisolone acetate. Symptoms were assessed over a "run in" period of 3-7 days followed by a treatment period of 3 weeks. Pollen counts were evaluated daily. Both the systemic and topical corticosteroid treatment resulted in a significant improvement of nasal and ocular symptoms and were accompanied by reduced antihistamine intake. A comparison of the two treatments in relation to the pollen count yielded statistically significantly fewer nasal symptoms, such as itching, secretion, and sneezing in the budesonide-treated group. Nasal blockage and ocular symptoms remained unchanged, but the use of eyedrops was significantly reduced in the methylprednisolone-treated group. Side effects of both treatments were mild and the incidence negligible. Methylprednisolone-treated patients had a significantly lower cortisol value after 7 days but still had a normal response to ACTH-stimulation. We conclude that the acute symptoms of allergic rhinitis are at least as well ameliorated by regular topical application of budesonide as by a single injection of methylprednisolone acetate. The accompanying allergic conjunctivitis may require additional treatment.

Clinically significant hearing loss affects 1 in 1000 infants and it is estimated that at least 50% of these cases are due to a genetic cause. Some forms of inherited deafness are syndromic and affected individuals have a specific pattern of additional features while in other families the deafness is non-syndromic and there is no other recognizable phenotype. Analysis of several large families with syndromic and non-syndromic forms of deafness have been used in genetic linkage analysis to identify genes or gene locations that cause deafness. Here, we describe a large Middle-Eastern Druze family with recessive non-syndromic deafness and demonstrate linkage between deafness in this family and human chromosome 7q31 with a lod score exceeding 5.5. This is the first evidence for a gene at this location that causes deafness. In addition, we found that deafness in three other Druze pedigrees, one related to the linked family, is not linked to this chromosomal location. This suggests that there are multiple nonallelic mutations for deafness in this genetic isolate.

Our results indicate that POU4F3 mutation-associated deafness cannot be identified through clinical evaluation, but only through molecular analysis. Intrafamilial variability suggests that other genetic or environmental factors may modify the age at onset and rate of progression.