Innominate artery dissection due to selective cerebral antegrade perfusion.

We present the first case of successfully treated innominate artery dissection as a complication of selective cerebral antegrade perfusion during reoperative aortic valve and hemiarch replacements. Innominate artery dissection was suspected based on unilateral decreases in the right radial arterial pressure and right cerebral oximetry value. Intraoperative ultrasonography demonstrated minimal flow in the right internal carotid. A right aortoaxillary bypass graft was performed leading to immediate improvements in the right radial arterial pressure waveform and right cerebral oximetry. The patient was discharged neurologically intact on postoperative day six.

Anesthetic Considerations During Heart Transplantation Using Donation After Circulatory Death.

Worldwide, the majority of heart transplant organs are from donation after brain death. However, the shortage of suitable donors places severe limitations on this route. One option to increase the donor pool is to use organs from donation after circulatory death (DCD). Transplant centers for solid organs have been using DCD organs for years. At this time, 40% of solid organ transplantation in the United Kingdom uses organs from DCD. Use of DCD for solid organ transplants in Canada is also rising. Recently, there has been interest in using DCD organs for heart transplantation. The authors will discuss their experience of 4 heart transplants with organs from DCD donors after normothermic regional perfusion (NRP). The authors' first heart transplant using a DCD organ was in January 2020, and the fourth was in March 2020, just before the coronavirus disease 2019 (COVID-19) pandemic. The authors' protocol using NRP allows adequate evaluation of the donor heart to confidently determine organ acceptance. The co-location of the donor and the recipient in neighboring operating rooms limits ischemic times. Avoidance of an expensive ex vivo organ perfusion machine is an additional benefit for programs that may not have the resources required to purchase and maintain the machine. Some hospitals may not have the resources and space to be able to co-locate both the donor and recipient. Use of cold storage may be an option to transport the procured organ, similar to donation after brain death organs. The authors hope that this technique of NRP in DCD donors can help further increase the donor pool for heart transplantation in the United States.

Incoherent feed-forward regulatory logic underpinning glucocorticoid receptor action.

The complexity and specificity of metazoan transcription are determined by combinatorial control of the composition and activity of regulatory complexes. To investigate the basis of this specificity, we focused on the glucocorticoid receptor (GR), a single regulatory factor that integrates multiple signals to give rise to many distinct patterns of expression. We measured the expression of a set of genes, each directly GR-regulated, but by different mechanisms in two cell lines. We varied ligand (dose, chemistry, and duration of treatment), GR (expression level and functionality), and a non-GR regulatory factor that commonly interacts with GR. Our study revealed distinct expression patterns within this set of genes, but all could be modeled by an incoherent feed-forward regulatory logic. Cellular signals, operating on GR and other factors within regulatory complexes, may define and modulate the kinetics and strength of the activating or inhibitory paths of the regulatory logic. Thus, characterizing systems behavior by perturbing single or multiple signals can reveal general principles of regulation, providing an approach to the dissection and deconvolution of combinatorial control.

Expression profiling identifies Klf15 as a glucocorticoid target that regulates airway hyperresponsiveness.

Glucocorticoids (GCs), which activate GC receptor (GR) signaling and thus modulate gene expression, are widely used to treat asthma. GCs exert their therapeutic effects in part through modulating airway smooth muscle (ASM) structure and function. However, the effects of genes that are regulated by GCs on airway function are not fully understood. We therefore used transcription profiling to study the effects of a potent GC, dexamethasone, on human ASM (HASM) gene expression at 4 and 24 hours. After 24 hours of dexamethasone treatment, nearly 7,500 genes had statistically distinguishable changes in expression; quantitative PCR validation of a 40-gene subset of putative GR-regulated genes in 6 HASM cell lines suggested that the early transcriptional targets of GR signaling are similar in independent HASM lines. Gene ontology analysis implicated GR targets in controlling multiple aspects of ASM function. One GR-regulated gene, the transcription factor, Kruppel-like factor 15 (Klf15), was already known to modulate vascular smooth and cardiac muscle function, but had no known role in the lung. We therefore analyzed the pulmonary phenotype of Klf15(-/-) mice after ovalbumin sensitization and challenge. We found diminished airway responses to acetylcholine in ovalbumin-challenged Klf15(-/-) mice without a significant change in the induction of asthmatic inflammation. In cultured cells, overexpression of Klf15 reduced proliferation of HASM cells, whereas apoptosis in Klf15(-/-) murine ASM cells was increased. Together, these results further characterize the GR-regulated gene network in ASM and establish a novel role for the GR target, Klf15, in modulating airway function.

Discovery of selective glucocorticoid receptor modulators by multiplexed reporter screening.

Glucocorticoids are widely used to suppress inflammation and treat various immune-mediated diseases. Some glucocorticoid receptor (GR)-regulated genes mediate the therapeutic response, whereas others cause debilitating side effects. To discover selective modulators of the GR response, we developed a high-throughput, multiplexed system to monitor regulation of 4 promoters simultaneously. An initial screen of 1,040 natural products and Food and Drug Administration-approved drugs identified modulators that caused GR to regulate only a subset of its target promoters. Some compounds selectively inhibited GR-mediated gene activation without altering the repression of cytokine expression by GR. This approach will facilitate identification of genes and small molecules that augment beneficial effects of GR and diminish deleterious ones. Our results have important implications for the development of GR modulators and the identification of cross-talk pathways that control selective GR gene regulation.