Major liver resection, systemic fibrinolytic activity, and the impact of tranexamic acid

The final publication is available at Elsevier via http://dx.doi.org/10.1016/j.hpb.2016.09.005 © 2016. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/Background: Hyperfibrinolysis may occur due to systemic inflammation or hepatic injury that occurs during liver resection. Tranexamic acid (TXA) is an antifibrinolytic agent that decreases bleeding in various settings, but has not been well studied in patients undergoing liver resection. Methods: In this prospective, phase II trial, 18 patients undergoing major liver resection were sequentially assigned to one of three cohorts: (i) Control (no TXA); (ii) TXA Dose I - 1 g bolus followed by 1 g infusion over 8 h; (iii) TXA Dose II - 1 g bolus followed by 10 mg/kg/hr until the end of surgery. Serial blood samples were collected for thromboelastography (TEG), coagulation components and TXA concentration. Results: No abnormalities in hemostatic function were identified on TEG. PAP complex levels increased to peak at 1106 mu g/L (normal 0-512 mu g/L) following parenchymal transection, then decreased to baseline by the morning following surgery. TXA reached stable, therapeutic concentrations early in both dosing regimens. There were no differences between patients based on TXA. Conclusions: There is no thromboelastographic evidence of hyperfibrinolysis in patients undergoing major liver resection. TXA does not influence the change in systemic fibrinolysis; it may reduce bleeding through a different mechanism of action

The Na+/H+ Exchanger Controls Deoxycholic Acid-Induced Apoptosis by a H+-Activated, Na+-Dependent Ionic Shift in Esophageal Cells

Apoptosis resistance is a hallmark of cancer cells. Typically, bile acids induce apoptosis. However during gastrointestinal (GI) tumorigenesis the cancer cells develop resistance to bile acid-induced cell death. To understand how bile acids induce apoptosis resistance we first need to identify the molecular pathways that initiate apoptosis in response to bile acid exposure. In this study we examined the mechanism of deoxycholic acid (DCA)-induced apoptosis, specifically the role of Na+/H+ exchanger (NHE) and Na+ influx in esophageal cells. In vitro studies revealed that the exposure of esophageal cells (JH-EsoAd1, CP-A) to DCA (0.2 mM -0.5 mM) caused lysosomal membrane perturbation and transient cytoplasmic acidification. Fluorescence microscopy in conjunction with atomic absorption spectrophotometry demonstrated that this effect on lysosomes correlated with influx of Na+, subsequent loss of intracellular K+, an increase of Ca2+ and apoptosis. However, ethylisopropyl-amiloride (EIPA), a selective inhibitor of NHE, prevented Na+, K+ and Ca2+ changes and caspase 3/7 activation induced by DCA. Ouabain and amphotericin B, two drugs that increase intracellular Na+ levels, induced similar changes as DCA (ion imbalance, caspase3/7 activation). On the contrary, DCA-induced cell death was inhibited by medium with low a Na+ concentrations. In the same experiments, we exposed rat ileum ex-vivo to DCA with or without EIPA. Severe tissue damage and caspase-3 activation was observed after DCA treatment, but EIPA almost fully prevented this response. In summary, NHE-mediated Na+ influx is a critical step leading to DCA-induced apoptosis. Cells tolerate acidification but evade DCA-induced apoptosis if NHE is inhibited. Our data suggests that suppression of NHE by endogenous or exogenous inhibitors may lead to apoptosis resistance during GI tumorigenesis

The Genealogy of the Labor Hoarding Concept

The modern concept of labor hoarding emerged in early 1960s, and soon became a standard part of mainstream economists' explan ation of the working of labor markets. The concept represents the convergence of three importa nt elements: an empirical fi nding that labor productivity was procyclical; a framing of this fi nding as a "puzzle" or anomaly fo r the basic neoclassical theory of the firm, and a proposed resolu tion of the puzzle based on optimizing behavior of the firm in the presence of costs of hiring, firing, and training workers. Th is paper recounts the history of each of these elements, and how they were woven together into the labor hoarding concept. Each history involves people associated with various research traditions and motivated by an array of questions, many of which were unrelated to the qu estions that the modern labor hoarding concept was ultimately created to address