Partnership with Interventional Pulmonologist: An Anesthesiologist's Perspective.

Via the emergence of new bronchoscopic technologies and techniques, there is enormous growth in the number of procedures being performed in nonoperating room settings. This, coupled with a greater focus from the Centers for Medicare and Medicaid Services for mandated anesthesiology oversight of procedural sedation for bronchoscopy by the pulmonologists has led to a more frequent working partnership between interventional pulmonologists and anesthesiologists. This article offers the interventional pulmonologist insight into how the anesthesiologist thinks and approaches anesthetic care delivery.

Memory and hippocampal architecture following short-term midazolam in western diet-treated rats.

The impact of short-term benzodiazepine exposure on cognition in middle-aged or older patients is a highly debated topic among anesthesiologists, critical care physicians and public media. "Western diet" (WD) consumption is linked to impaired cognition as well. The combination of benzodiazepines with substantial exposure to WD might set the stage for increased hippocampal vulnerability for benzodiazepines leading to exaggerated cognitive impairment in the postoperative period. In this study, Fischer 344 rats were fed either WD or standard rodent diet from 5 to 10.5 months of age. Rats were exposed to midazolam or placebo two days prior to an MRI scan using Diffusional Kurtosis Imaging (DKI) to assess brain microstructural integrity, followed by behavioral testing using a water radial arm maze. Hippocampal tissue was collected to assess alterations in protein biochemistry in brain regions associated with learning and memory. Our results showed that rats exposed to the combination of midazolam and WD had significantly delayed time of learning and exhibited spatial memory impairment. Further, we observed an overall increase of kurtosis metrics in the hippocampus and increased expression of the mitochondrial protein VDAC2 in midazolam-treated rats. Our data suggest that both the short-acting benzodiazepine midazolam and WD contribute to negatively affect the brain in middle-aged rats. This study is the first application of DKI on the effects of midazolam and WD exposure, and the findings demonstrate that diffusion metrics are sensitive indicators of changes in the complexity of neurite architecture.

Functional influence of N-glycosylation in OCT2-mediated tetraethylammonium transport.

OCT2, an organic cation transporter critical for removal of many drugs and toxins from the body, contains consensus sites for N-glycosylation at amino acid position 71, 96, and 112. However, the extent to which these sites are glycosylated by the cell, and the influence glycosylation has on OCT2 function, remains unknown. To address these issues, the acquisition of N-glycosylation was disrupted by mutating the amino acid asparagine (N) to glutamine (Q) at these sites in the rabbit ortholog of OCT2, which was expressed in Chinese hamster ovary cells. Disruption of N-glycosylation followed by Western blotting indicated that each site is indeed glycosylated and that OCT2 contains no other sites of N-glycosylation. Plasma membrane expression (determined by surface biotinylation) of the N112Q mutant, but not N71Q or N96Q mutants, was fourfold lower than that of wild-type OCT2, and unglycosylated OCT2 (N71Q/N96Q/N112Q) was sequestered in an unidentified intracellular compartment. The N71Q, N96Q, and N112Q mutants had a higher affinity ( approximately 2-fold) for tetraethylammonium (TEA). Maximum transport rate was reduced in the N96Q (3-fold) and N112Q (5-fold) mutants, but not the N71Q mutant, and unglycosylated OCT2 failed to transport TEA (associated with its absence in the plasma membrane). Whereas the reduction in maximum transport rate of the N112Q mutant is consistent with its reduced plasma membrane expression, the lower rate of the N96Q mutant, which appeared to traffic properly, suggests that glycosylation at N96 increases the transporter turnover number.

Molecular determinants of substrate/inhibitor binding to the human and rabbit renal organic cation transporters hOCT2 and rbOCT2.

Organic cation transporters are important for the elimination of many drugs and toxins from the body. In the present study, substrate-transporter interactions were investigated in Chinese hamster ovary cells stably transfected with either the human or rabbit orthologs of the principal organic cation transporter in the kidney, OCT2. IC(50) values, ranging from 0.04 muM to >3 mM, for inhibition of [(14)C]tetraethylammonium transport were determined for more than 30 structurally diverse compounds. Although the two OCT orthologs displayed similar IC(50) values for some of these compounds, the majority varied by as much as 20-fold. Marked differences in substrate affinity were also noted when comparing hOCT2 to the closely related homolog hOCT1. These data suggest the molecular determinants of substrate binding differ markedly among both homologous and orthologous OCT transporters. The software package Cerius(2) (Accelrys, San Diego, CA) was used to generate a descriptor-based, two-dimensional, quantitative structure-activity relationship (QSAR) to produce a model relating the affinity of hOCT2 to particular physicochemical features of substrate/inhibitor molecules (r(2) = 0.81). Comparative molecular field analysis (Tripos, St. Louis, MO) was used to generate three-dimensional QSARs describing the structural basis of substrate binding to hOCT2 and rbOCT2 (q(2) = 0.60 and 0.53, respectively, and each with r(2) = 0.97). The quality of the models was assessed by their ability to successfully predict the inhibition of a set of test compounds. The current models enabled prediction of OCT2 affinity and may prove useful in the prediction of unwanted drug interactions at the level of the renal secretory process.