Origins of and implementation concepts for upper airway stimulation therapy for obstructive sleep apnea.

Upper airway stimulation, specifically hypoglossal (CN XII) nerve stimulation, is a new, alternative therapy for patients with obstructive sleep apnea hypopnea syndrome who cannot tolerate positive airway pressure, the first-line therapy for symptomatic patients. Stimulation therapy addresses the cause of inadequate upper airway muscle activation for nasopharyngeal and oropharyngeal airway collapse during sleep. The purpose of this report is to outline the development of this first-in-class therapy and its clinical implementation. Another practical theme is assessment of the features for considering a surgically implanted device and the insight as to how both clinical and endoscopic criteria increase the likelihood of safe and durable outcomes for an implant and how to more generally plan for management of CPAP-intolerant patients. A third theme is the team building required among sleep medicine and surgical specialties in the provision of individualized neurostimulation therapy.

Small molecule antagonists of the bradykinin B1 receptor.

Screening Pharmacopeia's encoded combinatorial libraries has led to the identification of potent, selective, competitive antagonists at the bradykinin B1 receptor. Libraries were screened using a displacement assay of [3H]-des-Arglo-kallidin ([3H]-dAK) at IMR-90 cells expressing an endogenous human B1 receptor (Bmax = 20,000 receptors/cell, K(D) = 0.5+/-0.1 nM) or against membranes from 293E cells expressing a recombinant human B1 receptor (Bmax = 8,000 receptors/cell, K(D) = 0.5 +/- 0.3 nM). Compound PS020990, an optimized, representative member from the class of compounds, inhibits specific binding of 3H-dAK at IMR-90 cells with a KI of 6 +/- 1 nM. The compound inhibits dAK-induced phosphatidyl inositol turnover (K(Bapp) = 0.4 +/- 0.2 nM) and calcium mobilization (K(Bapp) = 17 +/- 2 nM) in IMR-90 cells. Compounds from the lead series are inactive at the B2 receptor and are > 1000-fold specific for B1 vs. a variety of other receptors, ion channels and enzymes. PS020990 and other related chemotypes therefore offer an excellent opportunity to explore further the role of B1 receptors in disease models and represent a potential therapeutic avenue.

Characterization of determinants for envelope binding and infection in tva, the subgroup A avian sarcoma and leukosis virus receptor.

Tva is the cellular receptor for subgroup A avian leukosis and sarcoma virus (ALSV-A). The viral interaction domain of Tva is determined by a 40-residue, cysteine-rich module closely related to the ligand binding domain of the human low-density lipoprotein receptor (LDLR). In this report, we examined the role of the LDLR-like module of Tva in envelope binding and viral infection by mutational analysis. We found that the entire LDLR module in Tva is essential for efficient binding to the viral envelope protein. However, the 17 N-terminal residues of this module can be deleted without affecting receptor function, suggesting that the major determinants for viral entry are located at the C terminus of the module. The effect on viral infection of many amino acid substitutions and deletions in the LDLR module is context dependent, suggesting that the residues important for viral entry are dispersed throughout the LDLR module. In addition, we found that all 27 mutations at residues D46, E47, and W48 greatly reduced envelope binding. These results are discussed in relation to a recently elucidated structure for an LDLR module.