Inner ear sensory hair cell death is observed in the majority of hearing and balance disorders, affecting the health of more than 600 million people worldwide. While normal aging is the single greatest contributor, exposure to environmental toxins and therapeutic drugs such as aminoglycoside antibiotics and antineoplastic agents are significant contributors. Genetic variation contributes markedly to differences in normal disease progression during aging and in susceptibility to ototoxic agents. Using the lateral line system of larval zebrafish, we developed an in vivo drug toxicity interaction screen to uncover genetic modulators of antibiotic-induced hair cell death and to identify compounds that confer protection. We have identified 5 mutations that modulate aminoglycoside susceptibility. Further characterization and identification of one protective mutant, sentinel (snl), revealed a novel conserved vertebrate gene. A similar screen identified a new class of drug-like small molecules, benzothiophene carboxamides, that prevent aminoglycoside-induced hair cell death in zebrafish and in mammals. Testing for interaction with the sentinel mutation suggests that the gene and compounds may operate in different pathways. The combination of chemical screening with traditional genetic approaches is a new strategy for identifying drugs and drug targets to attenuate hearing and balance disorders.

Successful treatment of sinonasal disease may require postoperative delivery of topical therapies. Draf III frontal sinusotomy achieves superior topical access, and access to the frontal sinus with Draf IIa appears limited, despite large volumes and positioning.

The advantages of this approach are it provides unobstructed view and identifies anatomic limits early, bone removal is fast and efficient; it is safe, and it is a robust technique based upon fixed anatomic landmarks.

The medial flap inferior turbinoplasty provides consistent, robust results. Long-term relief of obstructive symptoms without additional risk of complication is expected with this procedure.

IMPORTANCE External nasal valve dysfunction (EVD) is a common cause of nasal obstruction.OBJECTIVE To evaluate costal cartilage lateral crural strut grafts vs cephalic crural turn-in to support the weak lateral crus in patients with EVD. DESIGN, SETTING, AND PARTICIPANTSIn this prospective cohort study, patients with clinically diagnosed EVD were assessed at the Tertiary Rhinologic Center and underwent a costal cartilage underlay graft to the lateral crus or a cephalic turn-in cruralplasty. MAIN OUTCOMES AND MEASURES Assessment of patient benefit was based on 22-Item Sinonasal Outcome Test (SNOT-22) and Nasal Obstruction Symptom Evaluation Scale (NOSE) scores. A Likert scale was also used to assess overall function and cosmesis. Objective assessment included postdecongestion nasal peak inspiratory flow, nasal airway resistance, and minimum cross-sectional area. RESULTS Forty-one patients (mean [SD] 35.38 [12.73] years of age; 25 [61%] female) were assessed. Cephalic turn-in maneuver was used for 25 (61%) patients; costal cartilage lateral crural strut grafts, 16 (39%) patients. Costal cartilage grafts were used in patients undergoing revision but other baseline data were similar. Follow-up was mean 10.58 (7.52) months. All patients had significantly improved visual analog scale, SNOT-22, NOSE, patient-reported function, and cosmesis scores. The only objective test that improved was nasal peak inspiratory flow (114.76 [60.48] L/min vs 126.46 [61.17] L/min; P = .02). CONCLUSIONS AND RELEVANCE Both techniques were effective in improving patient-reported outcomes and nasal peak inspiratory flow. Both are functionally and cosmetically viable options for correction of EVD. LEVEL OF EVIDENCE 2.

Endoscopic DCR with powered instrumentation is comparable to external DCR and also allows simultaneous adjunctive procedures while avoiding external scar. The powered endoscopic approach to DCR and methods to optimize success are described.

The medial flap turbinoplasty provided consistent, robust results. Long-term relief of obstructive symptoms without additional risk of complication was observed in the turbinoplasty group.

Abnormal hypothalamic-pituitary-adrenocortical (HPA) activity may provide clues to the neurochemistry of depression. Psychotic depression has one of the highest rates of elevated HPA activity and is most often responsive to the tricyclic class of antidepressants. Because successful treatment resolves HPA as well as psychiatric symptoms, we hypothesized, in light of evidence that tricyclic antidepressants can affect glucocorticoid receptor function, that these drugs would mimic glucocorticoid feedback inhibition of HPA activity. To test this hypothesis, we measured circadian nadir (morning) and peak (evening) as well as restraint stress-induced levels of plasma ACTH and corticosterone in adrenalectomized (ADX) and sham-ADX (Sham) male C57BL/6 mice after 8 wk of imipramine (20 mg/kg/d, ip) or saline treatment. Antidepressant efficacy was confirmed by decreased immobility in forced-swim testing. When glucocorticoids were low or absent, imipramine mimicked glucocorticoid action in inhibiting evening ACTH in ADX mice and tending to inhibit morning corticosterone in Shams. However, when glucocorticoid levels were high, imipramine appeared to interfere with feedback inhibition by increasing post-stress ACTH and tending to increase evening corticosterone in Sham mice. Imipramine also decreased thymus weight in ADX and increased thymus weight in Sham mice. Imipramine stimulated morning ACTH in ADX mice, possibly by mimicking facilitative effects of high glucocorticoids. Short-term imipramine treatment was capable of inducing nuclear translocation of hippocampal glucocorticoid receptors in ADX mice. We conclude that imipramine effects on glucocorticoid-sensitive endpoints in vivo resemble those of a glucocorticoid partial agonist.