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.

Detection of an equilibrium intermediate in the folding of a monomeric insulin analog.

To determine the conformational properties of the C-terminal region of the insulin B-chain relative to the helical core of the molecule, we have investigated the fluorescence properties of an insulin analog in which amino acids B28 and B29 have been substituted with a tryptophan and proline residue respectively, ([WB28,PB29]insulin). The biological properties and far-UV circular dichroism (CD) spectrum of the molecule indicate that the conformation is similar to that of native human insulin. Guanidine hydrochloride (GdnHCl)-induced equilibrium denaturation of the analog as monitored by CD intensity at 224 nm indicates a single cooperative transition with a midpoint of 4.9 M GdnHCl. In contrast, when the equilibrium denaturation is observed by steady-state fluorescence emission intensity at 350 nm, two distinct transitions are observed. The first transition accounts for 60% of the observed signal and has a midpoint of 1.5 M GdnHCl. The second transition roughly parallels that observed by CD measurements with an approximate midpoint of 4.5 M GdnHCl. The near-UV CD spectrum, size-exclusion, and ultracentrifugation properties of [WB28,PB29]insulin indicate that this analog does not self-associate in a concentration-dependent manner as does human insulin. Thus, the observed fluorescence changes must be due to specific conformational transitions which occur upon unfolding of the insulin monomer with the product of the first transition representing a stable folding intermediate of this molecule.

Correlation of electrophoretic mobilities from capillary electrophoresis with physicochemical properties of proteins and peptides.

Excellent correlation was observed for the electrophoretic mobilities measured by capillary zone electrophoresis versus q/MW2/3, where q is the calculated charge and MW is the molecular weight. Mobilities of a set of 33 diverse peptides from enzymatic digests and 10 intact proteins were measured for separations at pH 2.35, 8.0, and 8.15 with constant ionic strength, temperature, and viscosity. The correlation suggests that the frictional drag is proportional to the surface area of a sphere that has a volume proportional to the MW. The correlation of electrophoretic mobility with physicochemical properties will facilitate the elucidation of optimum separation strategies for protein and peptide mixtures.