Cost-effective Hybrid Airway Model to Improve Airway Cricothyroidotomy Outcomes.

To the editor: Cricothyrotomy has been the technique used when ventilation/intubation has failed, and emergent oxygenation must be delivered.

Apneic Oxygenation: A Method to Prolong the Period of Safe Apnea.

A difficult intubation poses one of the most challenging tasks for anesthesia professionals, representing 27% of all adverse respiratory events, 93% of which are unanticipated. Unanticipated difficult mask ventilation and intubation may result in serious complications. Safe airway management requires a proper and thorough preoperative airway evaluation and a plan to secure the airway, with alternate plans available when the initial plan fails. Pediatric, obese, and obstetric patients undergoing general anesthesia with endotracheal intubation are considered to be at risk of rapid desaturation. As an adjunct to conventional preoxygenation techniques, continuous oxygen administration during the apneic period, termed apneic oxygenation, assists in the maintenance of oxygenation when tracheal intubation is attempted. Nine articles were selected for appraisal in this literature review: 6 randomized control trials, 2 prospective studies, and 1 retrospective study. Multiple apneic oxygenation techniques, including nasopharyngeal catheter, nasal prongs, endotracheal tube, intratracheal catheter, and high-flow transnasal humidified oxygen, demonstrated effectiveness at delaying the onset of hypoxemia during the apnea period. Prolonging the apneic window changes the nature of airway management in patients at high risk of desaturation and when an unanticipated difficult airway arises.

Inhibition of the tumor necrosis factor-alpha-converting enzyme by its pro domain.

Tumor necrosis factor-alpha-converting enzyme (TACE) is a disintegrin metalloproteinase that processes tumor necrosis factor and a host of other ectodomains. TACE is biosynthesized as a zymogen, and activation requires the removal of an inhibitory pro domain. Little is known about how the pro domain exerts inhibition for this class of enzymes. To study the inhibitory properties of the pro domain of TACE, we have expressed it in isolation from the rest of the protease. Here we show that the TACE pro domain (TACE Pro) is a stably folded protein that is able to inhibit this enzyme. TACE Pro inhibited the catalytic domain of TACE with an IC(50) of 70 nm. In contrast, this inhibitory potency decreased over 30-fold against a TACE form containing the catalytic plus disintegrin/cysteine-rich domains (IC(50) greater that 2 microm). The disintegrin/cysteine-rich region in isolation also decreases the interaction of TACE Pro with the catalytic domain. Surprisingly, we found that the cysteine switch motif located in TACE Pro was not essential for inhibition of the enzymatic activity of TACE; the pro domain variant C184A showed the same inhibitory potency against both TACE forms as wild type TACE Pro. X-ray absorption spectroscopy experiments indicate that binding of TACE Pro to the catalytic domain does include ligation of the catalytic zinc ion via the sulfur atom of its conserved Cys(184) residue. Moreover, the binding of TACE Pro to the catalytic zinc ion partially oxidizes the catalytic zinc ion of the enzyme. Despite this, the nature of the interaction between the pro and catalytic domains of TACE is not consistent with a simple competitive model of inhibition based on cysteine switch ligation of the zinc ion within the active site of TACE.

X-ray crystal structure of the liver X receptor beta ligand binding domain: regulation by a histidine-tryptophan switch.

The x-ray crystal structures of the human liver X receptor beta ligand binding domain complexed to sterol and nonsterol agonists revealed a perpendicular histidinetryptophan switch that holds the receptor in its active conformation. Hydrogen bonding interactions with the ligand act to position the His-435 imidazole ring against the Trp-457 indole ring, allowing an electrostatic interaction that holds the AF2 helix in the active position. The neutral oxysterol 24(S),25-epoxycholesterol accepts a hydrogen bond from His-435 that positions the imidazole ring of the histidine above the pyrrole ring of the tryptophan. In contrast, the acidic T0901317 hydroxyl group makes a shorter hydrogen bond with His-435 that pulls the imidazole over the electron-rich benzene ring of the tryptophan, possibly strengthening the electrostatic interaction. Point mutagenesis of Trp-457 supports the observation that the ligand-histidine-tryptophan coupling is different between the two ligands. The lipophilic liver X receptor ligand-binding pocket is larger than the corresponding steroid hormone receptors, which allows T0901317 to adopt two distinct conformations. These results provide a molecular basis for liver X receptor activation by a wide range of endogenous neutral and acidic ligands.

Hepatocyte nuclear factor 4 is a transcription factor that constitutively binds fatty acids.

The 2.7 A X-ray crystal structure of the HNF4gamma ligand binding domain (LBD) revealed the presence of a fatty acid within the pocket, with the AF2 helix in a conformation characteristic of a transcriptionally active nuclear receptor. GC/MS and NMR analysis of chloroform/methanol extracts from purified HNF4alpha and HNF4gamma LBDs identified mixtures of saturated and cis-monounsaturated C14-18 fatty acids. The purified HNF4 LBDs interacted with nuclear receptor coactivators, and both HNF4 subtypes show high constitutive activity in transient transfection assays, which was reduced by mutations designed to interfere with fatty acid binding. The endogenous fatty acids did not readily exchange with radiolabeled palmitic acid, and all attempts to displace them without denaturing the protein failed. Our results suggest that the HNF4s may be transcription factors that are constitutively bound to fatty acids.