Attributes and outcomes of end stage liver disease as compared with other noncancer patients admitted to a geriatric palliative care unit.

BACKGROUND: End stage liver disease (ESLD) is increasingly more prevalent as a noncancer disease to manage in palliative care. Because of the clear lack of a "terminal phase" in ESLD, palliative care is often initiated only when death is perceived as being imminent. Palliative care units (PCUs) serve as an option for continued care for patients living with ESLD and are a limited resource, often not able to accommodate longer patient admissions. Concerns have been raised that ESLD patients may be admitted late in their disease course, not allowing for equitable access to such a service because of a perceived longer length of stay (LOS). The aim of this study is to better characterize the illness experience of patients with ESLD on a geriatric PCU comparing ESLD patients and other noncancer patients in terms of admission PPS, estimated prognosis and LOS. METHODS: This was a single-center retrospective chart review of all noncancer patients admitted to Baycrest Health Sciences Palliative Care Unit (PCU) in Toronto, Canada over a four-year period. We measured the association between demographic data, estimated prognosis, Palliative Performance Score (PPS), and LOS between patients with ESLD and other noncancer diagnoses. RESULTS: There were 235 patients with noncancer diagnoses admitted to the PCU during the study period, of which 19% had ESLD. Patients with ESLD were both significantly younger (P<0.001) and were admitted with a significantly higher PPS (P<0.001) than patients with other noncancer diagnoses. Estimated prognoses for patients with ESLD compared to other noncancer patients were similar. There were no significant difference in LOS between patients with ESLD and other noncancer patients (P=0.18), although there was a non-significant trend towards a shorter LOS for patients with ESLD. There was no significance in disposition (P=0.30); the vast majority of patients with ESLD and other noncancer diagnoses died on the PCU. CONCLUSIONS: Patients with ESLD were younger and had a higher PPS score with no significant difference in estimated prognosis, LOS, or disposition when compared to other noncancer patients. Our findings suggest that patients with ESLD have a short LOS on the PCU with a unique illness experience compared to other noncancer patients.

Inhibition of mitogen-activated protein kinase signalling by Bacillus anthracis lethal toxin causes destabilization of interleukin-8 mRNA.

Bacillus anthracis must overcome host innate immune defences to establish a systemic anthrax infection. This is facilitated in part by lethal toxin (LT), a secreted virulence factor that consists of a cell-binding moiety, protective antigen (PA), and an enzymatic moiety, lethal factor (LF). PA binds cells through protein receptors and mediates the delivery of LF to the cytosol. LF is a protease that cleaves amino-terminal fragments from mitogen-activated protein kinase kinases (MAPKKs), preventing phosphorylation of their downstream targets. Here we report that LT reduces the amount of interleukin (IL)-8 produced and secreted by human endothelial cells. The reduction of IL-8 levels by LT was not attributable to reduced expression from the IL-8 promoter, but resulted from destabilization of IL-8 mRNA. Destabilization by LT was mediated through the 3' untranslated region of the IL-8 transcript and could be mimicked by pharmacological inhibitors of MAPK pathways. LT diminished the induction of IL-8 mRNA and protein by lipopolysaccharide, indicating that the toxin can impair the ability of these cells to initiate an immune response. Destabilization of a cytokine transcript represents a new interference strategy used by either a bacterial or viral pathogen to reduce cytokine expression and may help B. anthracis to evade host immune defences.

Differentiation of human monocytic cell lines confers susceptibility to Bacillus anthracis lethal toxin.

Anthrax lethal toxin (LT) is comprised of protective antigen and lethal factor. Lethal factor enters mammalian cells in a protective antigen-dependent process and cleaves mitogen-activated protein kinase kinases. Although LT has no observable effect on many cell types, it causes necrosis in macrophages derived from certain mouse strains and apoptosis in activated mouse macrophages. In this study, we observed that LT treatment of three different human monocytic cell lines U-937, HL-60 and THP-1 did not induce cell death. Cells did become susceptible to the toxin, however, after differentiation into a macrophage-like state. Treatment with LT resulted in decreased phosphorylation of p38, ERK1/2 and JNK in both undifferentiated and differentiated HL-60 cells, suggesting that the change in susceptibility does not result from differences in toxin delivery or substrate cleavage. Death of differentiated HL-60 cells was accompanied by chromosome condensation and DNA fragmentation, but was not inhibited by the pan-caspase inhibitor Z-VAD-FMK. In addition, we observed that the macrophage differentiation process could be inhibited by LT. Our results indicate that LT-mediated death of mouse and human macrophages may occur through distinct processes and that the differentiation state of human cells can determine susceptibility or resistance to LT.

Retinoid X receptor (RXR) agonist-induced antagonism of farnesoid X receptor (FXR) activity due to absence of coactivator recruitment and decreased DNA binding.

The bile salt export pump (BSEP) plays an integral role in lipid homeostasis by regulating the canalicular excretion of bile acids. Induction of BSEP gene expression is mediated by the farnesoid X receptor (FXR), which binds as a heterodimer with the retinoid X receptor (RXR) to the FXR response element (FXRE) located upstream of the BSEP gene. RXR ligands mimic several partner ligands and show additive effects upon coadministration. Using real-time quantitative PCR and cotransfection reporter assays, we demonstrate that the RXR agonist LG100268 antagonizes induction of BSEP expression mediated by endogenous and synthetic FXR ligands, CDCA and GW4064, respectively. Moreover, this antagonism is a general feature of RXR agonists and is attributed to a decrease in binding of FXR/RXR heterodimers to the BSEP-FXRE coupled with the inability of RXR agonists to recruit coactivators to FXR/RXR. Our data suggest that FXR/RXR is a conditionally permissive heterodimer and is the first example of RXR ligand-mediated antagonism of FXR activity. Because FXR agonists lower triglyceride levels, our results suggest a novel role for RXR-mediated antagonism of FXR activity in the development of hypertriglyceridemia observed with RXR agonists in rodents and humans.

Generation of multiple farnesoid-X-receptor isoforms through the use of alternative promoters.

Bile acid biosynthesis is regulated by both feed-forward and feedback mechanisms involving a cascade of nuclear hormone receptors. Feed-forward regulation of the rate limiting enzyme in bile acid biosynthesis is provided by oxysterols through liver-X-receptor alpha (NR1H3), while feedback regulation is provided by bile acids through farnesoid-X-receptor (FXR) (NR1H4). The Syrian golden hamster provides a useful model for studying lipid metabolism. The hamster metabolizes and transports dietary cholesterol in a similar manner to humans, with the resulting lipid profile being more similar to the human profile than that of other rodent models. Cloning of Fxr from Syrian golden hamster revealed four hamster Fxr splice variants that altered the N-terminal activation domain or the hinge region between the DNA and ligand binding domains. Human genomic sequence and data from hamster Fxr were used to identify and clone a novel human FXR isoform resulting from the use of an alternative promoter. RNA expression analysis indicates that the two human FXR isoforms are differentially expressed in developmental and tissue-specific patterns and are likely to provide a mechanism for cell-specific FXR-dependent transcriptional activity.