University of Wisconsin

In 2014 the faculty of the Department of Anesthesiology have received approximately $1.7 million external funding, mostly from the NIH, and have published 26 original investigations in peer-reviewed publications excluding reviews, editorials, case reports, or book chapters. We have selected the following 5 publications as representative of the most significant research advances from our department in 2014. The publication citation and a brief paragraph describing the work and its significance follows.

1.

Wynn MM, Acher CW. A modern theory of spinal cord ischemia/injury in thoracoabdominal aortic surgery and its implications for prevention of paralysis. J Cardiothorac Vasc Anesth. 2014;28(4):1100-1111. PMID: 25107722 PMCID Policy Exempt - Not the result of NIH funding
Paralysis is a significant risk of thoracoabdominal aortic (TAA) surgery. Over the last 15 years paralysis after TAA surgery has been reduced from 30% to 5% in the most extensive aneurysms. This improvement is in large part the result of applying experimentally validated interventions to clinical treatment and evaluating their effects. Reperfusion after ischemia results in the formation of free radicals, the release of proinflammatory cytokines, hyperemia, and edema that potentiate ischemic injury. In the course of 25 years the paradigm explaining spinal cord injury has moved from a focus on anatomic solutions to the interruption of spinal cord blood supply to physiologic interventions that improve spinal cord perfusion and oxygen supply/demand balance and reduce ischemia-reperfusion injury. Although the cause of paralysis in repair of TAA is primarily anatomic, prevention of paralysis is largely physiologic.This paradigm shift came - not from asking, “Why are more than 25% of patients paralyzed after repair of the most extensive thoracoabdominal aortic aneurysms? - but from asking instead, “Why are 75% of patients NOT paralyzed?

2.

Skarpedinsdottir SJ, Sigurdsson MI, Coursin DB, Head DE, Springman SR, Wang S, Chen G, Li Q, Krueger DC, Binkley N, Sigurdsson GH, Hogan KJ. Vitamin D deficiency in anesthesia department caregivers at the end of winter. Acta Anaesthesiol Scand. 2014;58(7):802-806. PMID: 25040952 PMCID Policy Exempt - Not the result of NIH funding
Vitamin D plays a major role in over 300 metabolic pathways in human cells and tissues. It is increasingly recognized as an important contributor to extra-skeletal health and well-being. Because the major source of vitamin D is photosynthesis in skin we proposed that anesthesia department caregivers working at high northern latitudes may have deficient 25(OH)D concentrations at the end of winter. A total of 230 healthy adult anesthesia caregivers from Madison, WI (124) and Reykjavik, Iceland (106) were enrolled at the end of winter. One in 20 participants were profoundly deficient (<10 ng/ml), a level consistent with that observed in rickets, and over half, including many of child-bearing age, were well below concentrations (30 ng/ml)] advised by the Endocrine Society. On the strength of these data, we urge that anesthesia caregivers learn their seasonal vitamin D status and use safe, effective and low cost supplementation to target a 25(OH)D level compatible with optimal health.

3.

Raz A, Grady SM, Krause BM, Uhlrich DJ, Manning KA, Banks MI. Preferential effect of isoflurane on top-down vs. bottom-up pathways in sensory cortex. Front Syst Neurosci. 2014;8:191. PMCID: PMC4188029.
In order to improve our understanding of the mechanisms underlying anesthetic action, we measured the effects of isoflurane in-vivo and in brain slices, at concentrations relevant to loss of consciousness. We found that in both models ‘top-down’, feedback, cortico-cortical pathways were suppressed by the anesthetic at doses that produce loss of consciousness, whereas ‘bottom-up’, feed-forward thalamo-cortical pathways were minimally affected. This finding is inconsistent with a ‘thalamic-switch’ mechanism underlying hypnotic effects of anesthetics, rather providing experimental support for mechanisms based on suppression of cotico-cortical network activity.

4.

Duellman T, Warren C, Yang J. Single nucleotide polymorphism-specific regulation of matrix metalloproteinase-9 by multiple miRNAs targeting the coding exon. Nucleic Acids Res. 2014;42(9):5518-5531. PMCID: PMC4027190
Single nucleotide polymorphism (SNPs) constitute the largest number of genetic polymorphism that occur in nature. Traditional thinking dictates that if a nucleotide switch does not result in an amino acid change it is functionally silent and therefore not important. We discovered that SNPs can alter miRNA binding sites and therefore even a synonymous SNP that results in no amino acid change can have a profound effect on the expression of a gene. Such SNP-dependent miRNA binding site is predominantly located in the coding exon of a gene and wide-spread in the human genome. This discovery requires a re-examination of genetic association studies investigating SNPs contributory to a phenotype (disease) to include synonymous SNPs.

5.

Goldschen-Ohm MP, Haroldson A, Jones MV, Pearce RA. A nonequilibrium binary elements-based kinetic model for benzodiazepine regulation of GABAA receptors. J Gen Physiol. 2014;144(1):27-39. PMCID: PMC4076519

Kinetic models can serve as useful frameworks that aid in understanding the dynamic characteristics of ion channels and other functional proteins. Here we present a general approach to kinetic modeling that is based on the energetics of interactions between collections of “binary elements” that transition between two metastable configurations (e.g. a gate that is open or closed, or a binding site that is occupied or not). The approach incorporates principles of both allosteric theory of steady-state interactions and Eyring’s rate theory of kinetic transitions. We illustrate its use by modeling benzodiazepine modulation of GABAA receptors, and show that a model based on agonist interactions with an intermediate transduction element can resolve conflicting interpretations of prior experiments that pointed toward modulation of gating versus agonist binding.