Complications after Liver Transplant Related to Preexisting Conditions: Diagnosis, Treatment, and Prevention.

Diagnostic imaging after orthotopic liver transplant focuses primarily on depicting complications related to surgical hepatic vascular and biliary anastomoses. Less common preexisting vascular conditions include congenital anatomic variants, atherosclerosis, chronic portal venous thrombosis, splenic artery and variceal steal phenomena, and transarterial embolization (TAE) for hepatocellular carcinoma (HCC). If unappreciated or left untreated preoperatively, these conditions negatively impact the transplant by impairing hepatic arterial or portal vascular inflow. Many of the complications related to preexisting vascular conditions can be prevented or mitigated by proper performance and careful evaluation of preoperative imaging studies. The authors describe the diagnosis and treatment of complications arising from narrowing of the celiac axis by atherosclerosis and the median arcuate ligament, variant anatomy of the hepatic artery, insufficiency of the portal vein requiring surgical conduits, and large varices or an enlarged splenic artery and spleen that may steal blood and compromise hepatic arterial or venous inflow. While preoperative evaluation primarily involves CT and MRI, postoperative diagnosis involves screening with sonography and confirmation with other modalities. We propose the use of a preoperative checklist of vascular status and measurements in patients undergoing liver transplant. Reports of imaging studies in recipients after transplant should include details of surgical vascular anastomoses and conduits, any history of HCC and preoperative TAE, details of the preoperative α-fetoprotein levels, and any unusual procedures or pathologic findings in the explanted liver that may affect postoperative surveillance. The authors review the pretransplant imaging evaluation of vascular and HCC issues that may affect surgical outcomes and methods to help recognize complications after transplant that can arise from these conditions.©RSNA, 2020.

Structure and function of multiple Ca2+-binding sites in a K+ channel regulator of K+ conductance (RCK) domain.

Regulator of K(+) conductance (RCK) domains control the activity of a variety of K(+) transporters and channels, including the human large conductance Ca(2+)-activated K(+) channel that is important for blood pressure regulation and control of neuronal firing, and MthK, a prokaryotic Ca(2+)-gated K(+) channel that has yielded structural insight toward mechanisms of RCK domain-controlled channel gating. In MthK, a gating ring of eight RCK domains regulates channel activation by Ca(2+). Here, using electrophysiology and X-ray crystallography, we show that each RCK domain contributes to three different regulatory Ca(2+)-binding sites, two of which are located at the interfaces between adjacent RCK domains. The additional Ca(2+)-binding sites, resulting in a stoichiometry of 24 Ca(2+) ions per channel, is consistent with the steep relation between [Ca(2+)] and MthK channel activity. Comparison of Ca(2+)-bound and unliganded RCK domains suggests a physical mechanism for Ca(2+)-dependent conformational changes that underlie gating in this class of channels.

A different mechanism for the inhibition of the carboxyltransferase domain of acetyl-coenzyme A carboxylase by tepraloxydim.

Acetyl-CoA carboxylases (ACCs) are crucial metabolic enzymes and are attractive targets for drug discovery. Haloxyfop and tepraloxydim belong to two distinct classes of commercial herbicides and kill sensitive plants by inhibiting the carboxyltransferase (CT) activity of ACC. Our earlier structural studies showed that haloxyfop is bound near the active site of the CT domain, at the interface of its dimer, and a large conformational change in the dimer interface is required for haloxyfop binding. We report here the crystal structure at 2.3 A resolution of the CT domain of yeast ACC in complex with tepraloxydim. The compound has a different mechanism of inhibiting the CT activity compared to haloxyfop, as well as the mammalian ACC inhibitor CP-640186. Tepraloxydim probes a different region of the dimer interface and requires only small but important conformational changes in the enzyme, in contrast to haloxyfop. The binding mode of tepraloxydim explains the structure-activity relationship of these inhibitors, and provides a molecular basis for their distinct sensitivity to some of the resistance mutations, as compared to haloxyfop. Despite the chemical diversity between haloxyfop and tepraloxydim, the compounds do share two binding interactions to the enzyme, which may be important anchoring points for the development of ACC inhibitors.