Congestive Heart Failure Is Associated With Worse Outcomes in Patients With Ischemic Colitis: A Nationwide Study.

INTRODUCTION: Ischemic colitis (IC) results from compromised blood flow to the colon. Risk factors include atrial fibrillation (A.Fib), peripheral artery disease (PAD), coronary artery disease (CAD), and congestive heart failure (CHF). However, few studies compared the mortality rate and colectomy between patients with IC with CHF and IC alone. OBJECTIVE: We aim to investigate the possibility of worse outcomes in patients with IC and CHF compared to IC alone. METHODOLOGY: Using the National Inpatient Sample database from 2016 to 2019, we obtained baseline demographic data, total hospital charge, rate of colectomy, length of hospital stay (LOS), and in-hospital mortality. Data were compared using a t-test and chi-squared. Odds ratios for comorbidities including A.Fib, CAD, PAD, end-stage renal disease, chronic obstructive pulmonary disease, hyperlipidemia, hypertension, diabetes, and cirrhosis were calculated. RESULTS: 106,705 patients with IC were identified, among which 15,220 patients also had CHF. IC patients with CHF had a longer LOS (6.6 days vs 4.4 days; P<0.0001), higher total hospital charge ($71,359 vs $45,176; P<0.0001), higher mortality rate (8.5% vs 2.9%; P<0.0001), and higher colectomy rate (9.2% vs 5.9%; P<0.0001). CONCLUSION: CHF is associated with poor outcomes in patients with IC. Our study showed an increased risk of mortality and colectomy compared to patients with IC alone. The findings suggest it may be warranted to have a heightened clinical suspicion of IC in patients with CHF who present with bleeding per rectum.

Lack of UCP2 reduces Fas-mediated liver injury in ob/ob mice and reveals importance of cell-specific UCP2 expression.

Fatty liver is vulnerable to conditions that challenge hepatocellular energy homeostasis. Lipid-laden hepatocytes highly express uncoupling protein-2 (UCP2), a mitochondrial carrier that competes with adenosine triphosphate (ATP) synthesis by mediating proton leak. However, evidence for a link between UCP2 expression and susceptibility of liver to acute injury is lacking. We asked whether absence of UCP2 protects ob/ob mice from Fas-mediated acute liver damage. UCP2-deficient ob/ob mice (ob/ob:ucp2-/-) and UCP2-competent littermates (ob/ob:ucp2+/+) received a single dose of agonistic anti-Fas antibody (Jo2). Low-dose Jo2 (0.15 mg/kg intraperitoneally) caused less serum alanine aminotransferase (ALT) elevation and lower apoptosis rates in ob/ob:ucp2-/- mice. High-dose Jo2 (0.40 mg/kg intraperitoneally) proved uniformly fatal; however, ob/ob:ucp2-/- mice survived longer with less depletion of liver ATP stores, indicating that fatty hepatocytes may benefit from lack of UCP2 during Jo2 challenge. Although UCP2 reportedly controls mitochondrial oxidant production, its absence had no apparent effect on fatty liver tissue malondialdehyde levels augmented by Jo2. This finding prompted us to determine UCP2 expression in Kupffer cells, a major source of intrahepatic oxidative stress. UCP2 expression was found diminished in Kupffer cells of untreated ob/ob:ucp2+/+ mice, conceivably contributing to increased oxidative stress in fatty liver and limiting the impact of UCP2 ablation. In conclusion, whereas UCP2 abundance in fatty hepatocytes exacerbates Fas-mediated injury by compromising ATP stores, downregulation of UCP2 in Kupffer cells may account for persistent oxidative stress in fatty liver. Our data support a cell-specific approach when considering the therapeutic effects of mitochondrial uncoupling in fatty liver disease.

Enhanced colon tumor induction in uncoupling protein-2 deficient mice is associated with NF-kappaB activation and oxidative stress.

Oxidative stress has a complex effect on cancer development. To further study this process, we induced colon tumors with azoxymethane (AOM) in mice deficient for uncoupling protein-2 (UCP2). UCP2 has recently emerged as a negative regulator of mitochondrial oxidant production. When overexpressed, UCP2 protects cells from oxidative stress, while its absence may cause abundance of reactive oxygen species, release of pro-inflammatory cytokines and persistent activation of nuclear factor kappaB (NF-kappaB), a pleiotropic transcription factor with an increasingly recognized role in cancer. Here we show that Ucp2-/- mice develop more aberrant crypt foci and colon tumors than Ucp2+/+ littermates when examined 24 weeks after the completion of treatment with AOM (10 mg/kg i.p. weekly for a total of 6 weeks, n = 8-12). This effect is primarily seen in the proximal colon of Ucp2-/- mice (P < 0.05), in association with changes indicative of increased oxidative stress (increased staining for malondialdehyde and inducible nitric oxide synthase), enhanced NF-kappaB activation (increased levels of phosphorylated IkappaB and increased nuclear presence of p65) and a disrupted balance between intestinal epithelial cell proliferation (greater 5-bromo-2'-deoxy-uridine incorporation rates and increased phosphorylation of ERK1/2 and AKT) and apoptosis (decreased number of terminal deoxynucleotidyltransferase-mediated nick-end-labeling (TUNEL)-positive cells and increased expression of Bcl-2). In conclusion, our findings provide the first in vivo evidence for a link between UCP2 and tumorigenesis and indicate the need for additional studies to assess the role of mitochondrial uncoupling in cancer development.

The molecular pathogenesis of cholangiocarcinoma.

Cholangiocarcinoma is rising in clinical importance because of increasing incidence, poor prognosis, and suboptimal response to therapy. Recent investigations into the underlying molecular mechanisms involved in cholangiocarcinogenesis and tumor growth have contributed greatly to our understanding of this disease. To review this topic, we discuss the molecular mechanisms in sections reflecting the unique features that allow cancer cells to develop and maintain a growth advantage. Through a better understanding of these mechanisms, improved and more specific diagnostic, therapeutic, and preventative strategies may be developed and hopefully improve the outcome of this devastating disease.