Cadherins are calcium-dependent cell adhesion molecules which show developmental and tissue-specific expression. Here we report the cloning of a mouse cadherin which is predominantly expressed in tissues of mesodermal origin. In contrast to other cadherins, cadherin-11 expression is largely restricted to mesenchymal tissues surrounding various organs but is not found in epithelia. Sequence analysis suggests that this cadherin is the mouse homologue of the previously reported human cadherin-11 and is a member of a cadherin subfamily, which is evolutionarily distinct from other cadherin subfamilies identified so far.

During vertebrate embryogenesis retinoic acid (RA) synthesis must be spatiotemporally regulated in order to appropriately stimulate various retinoid signaling pathways. Various forms of mammalian aldehyde dehydrogenase (ALDH) have been shown to oxidize the vitamin A precursor retinal to RA in vitro. Here we show that injection of Xenopus embryos with mRNAs for either mouse Aldh1 or mouse Raldh2 stimulates RA synthesis at low and high levels, respectively, while injection of human ALDH3 mRNA is unable to stimulate any detectable level of RA synthesis. This provides evidence that some members of the ALDH gene family can indeed perform RA synthesis in vivo. Whole-mount immunohistochemical analyses of mouse embryos indicate that ALDH1 and RALDH2 proteins are localized in distinct tissues. RALDH2 is detected at E7.5-E10.5 primarily in trunk tissue (paraxial mesoderm, somites, pericardium, midgut, mesonephros) plus transiently from E8.5-E9.5 in the ventral optic vesicle and surrounding frontonasal region. ALDH1 is first detected at E9.0-E10. 5 primarily in cranial tissues (ventral mesencephalon, dorsal retina, thymic primordia, otic vesicles) and in the mesonephros. As previous findings indicate that embryonic RA is more abundant in trunk rather than cranial tissues, our findings suggest that Raldh2 and Aldh1 control distinct retinoid signaling pathways by stimulating high and low RA biosynthetic activities, respectively, in various trunk and cranial tissues.

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An 18-month-old cross-bred goat was presented with generalized erythema and thinning of the hair coat, as well as localized moderate scaling. Histopathological evaluation of skin biopsies showed hyperplasia and marked disruption of the infundibular epithelium owing to a predominant infiltrate of macrophages with multinucleated histiocytic giant cells and some lymphocytes, plasma cells, and eosinophils. Examination of peripheral blood and skin by polymerase chain reaction gave positive results for ovine herpesvirus type 2 consistent with a diagnosis of malignant catarrhal fever.

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Objective: To evaluate the safety and exploratory efficacy of intratympanic administration of OTO-313 in patients with tinnitus. Study Design: Single intratympanic injection of OTO-313 evaluated in a randomized, double-blind, placebo-controlled Phase 1/2 clinical study. Setting: Tertiary referral centers. Patients: Patients with unilateral tinnitus (moderate-severe) with tinnitus duration 1 to 6 months. Interventions: Intratympanic OTO-313. Main Outcome Measures: Safety and change from baseline in tinnitus functional index (TFI), daily ratings of tinnitus loudness and annoyance, and patient global impression of change (PGIC). Results: OTO-313 was well-tolerated with lower incidence of adverse events than placebo. Mean TFI reduction from baseline favored OTO-313 at Week 2, 4, and 8. A clinically meaningful, 13-point improvement on the TFI was observed in 43% (6/14) of OTO-313 patients at both Weeks 4 and 8 versus 13% (2/16) of placebo patients (ad hoc responder analysis, p-value < 0.05). Reductions in daily ratings of tinnitus loudness and annoyance favored OTO-313 compared with placebo. In OTO-313 responders, a strong correlation existed between change from baseline in TFI score and changes in tinnitus loudness, tinnitus annoyance, and PGIC. Conclusions: OTO-313 was well-tolerated and demonstrated a higher proportion of responders than placebo across consecutive visits (Weeks 4 and 8) supporting further clinical development of OTO-313 for the treatment of tinnitus.

Mammalian class I aldehyde dehydrogenase (ALDH1) has been implicated as a retinal dehydrogenase in the biosynthesis of retinoic acid, a modulator of gene expression and cell differentiation. As the first step towards studying the regulation of ALDH1 and its physiological role in the biosynthesis of retinoic acid, mouse ALDH1 cDNA and genomic clones have been characterized. During the cloning process, an additional closely related gene was also isolated and named Aldh-pb, owing to its high amino acid sequence identity (92%) with the rat phenobarbitol-inducible ALDH protein (ALDH-PB). Aldh1 spans about 45 kb in length, whereas Aldh-pb spans about 35 kb. Both genes are composed of 13 exons, and the positions of all the exon/intron boundaries are conserved with those of human ALDH1. The promoter regions of Aldh1 and Aldh-pb demonstrate high sequence similarity with those of human ALDH1 and rat ALDH-PB. Expression of Aldh1 and Aldh-pb is tissue-specific, with mRNAs for both genes being found in the liver, lung and testis, but not in the heart, spleen or muscle. Expression of Aldh-pb, but not Aldh1, was also detected at high levels in the kidney. Aldh1 and Aldh-pb encode proteins of 501 amino acids with 90% positional identity. To examine the relative roles of these two enzymes in retinoic acid synthesis in vivo, Xenopus embryos were injected with mRNAs encoding these enzymes to assay the effect on conversion of endogenous retinal into retinoic acid. Injection of ALDH1, but not ALDH-PB, mRNA stimulated retinoic acid synthesis in Xenopus embryos at the blastula stage. Thus our results indicate that Aldh1 can function in retinoic acid synthesis under physiological conditions, but that the closely related Aldh-pb does not share this property.