Characterization of the prostaglandin E2 pathway in a rat model of esophageal adenocarcinoma.

UNLABELLED: Accumulating evidence indicates that the cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2) pathway plays a key role in esophageal carcinogenesis. A better understanding of the pathway downstream of COX-2 may reveal novel targets for the prevention of esophageal adenocarcinoma (EAC). The objective of this study was to characterize the profile of genes involved in PGE2 metabolism and signaling in an experimental model of EAC. Esophagojejunostomy with gastric preservation was performed in wistar rats to induce gastroduodenal reflux. Rats were sacrificed 2 or 4 months after surgery. Nine non-operated rats were used to obtain normal (control) esophageal tissues. RESULTS: All rats that underwent esophagojejunostomy developed inflammation. In addition, 90% of the animals showed intestinal metaplasia; of those, 40% progressed to AC. This process was accompanied by a significant increase in esophageal PGE2 levels and the induction of both mRNA and protein levels of COX-2, COX-1, prostaglandin E synthase, 15-hydroxyprostaglandin dehydrogenase, and PGE2 receptors EP3, EP4 and especially EP2, which rose to particularly high levels in experimental rats. In addition, exposure to a selective COX-2 inhibitor (SC58125) or an EP1/EP2 antagonist (AH6809), but not an EP4 antagonist (AH23848B), significantly reduced cell proliferation of esophageal explants in 24 hour-organ culture experiments. Our data suggest that, in addition to COX-2, other components of the PGE2 pathway, including COX-1, may play important roles in the development of EAC induced by gastroduodenal reflux in the rat. Although it must be confirmed in vivo, the EP2 receptor may represent a promising selective target in the prevention of Barrett's associated AC.

Cystatin C level as a predictor of death and cardiovascular events after liver transplantation.

BACKGROUND: The diagnosis of renal failure is important in cirrhosis. Cystatin C (Cys) has been suggested not only to be a sensitive marker of renal function, but also a stronger predictor of the risk of death and cardiovascular events in heart failure. Our aims were to investigate plasma Cys concentrations for the detection of moderately impaired renal function and its association with mortality and cardiovascular events among cirrhotic patients after liver transplantation (OLT). METHODS: Clinical and biochemical data, including Cys levels, were analyzed in 99 cirrhotic candidates for OLT. We recorded cardiovascular events. RESULTS: Receiver-operator characteristics curves showed a similar efficiency to detect a creatinine clearance <60 mL/min per 1.73m(2) (Cys = 0.753; creatinine [Cr] = 0.799; glomerular filtration rate [GFR, Cockcroft-Gault formula] = 0.842; urea = 0.823; P = .001). However, at cutoff concentrations of 1.3 mg/dL, Cr showed great specificity (96%) but poor sensitivity (13%), while the sensitivity of Cys was superior (83%) with moderate specificity (55%) at a cutoff of 1400 ng/mL. Over a median follow-up of 2.7 years, 14 patients developed a cardiovascular event, including, 11 who displayed Cys levels >1400 ng/mL before OLT, showing a significant difference (P < .05) compared to patients who showed no cardiovascular event. Kaplan-Meier analysis Cys discriminated significantly better than the Model for End-Stage Liver Disease score between survivors and nonsurvivors (P < .05). CONCLUSION: Cys determinations could be a valuable tool for early diagnosis of renal dysfunction among cirrhotic patients. Furthermore, it may predict the risk of death and cardiovascular events after OLT.

Cardiac hemodynamic profiles and pro-B-type natriuretic Peptide in cirrhotic patients undergoing liver transplantation.

BACKGROUND: The aim of our study was to determine concentrations of amino-terminal pro-B-type natriuretic peptide (NT-proBNP) in patients with cirrhosis, thereby describing the hemodynamic and cardiac profiles to verify the existence of cirrhotic cardiomyopathy. METHODS: Clinical data, NT-proBNP levels, echocardiography, and right heart hemodynamic measurements were performed on all patients undergoing liver transplantation for cirrhosis. RESULTS: Our patients showed a hyperdynamic circulation with elevated left-sided pressures despite high cardiac outputs. This observation suggested abnormalities in left ventricular diastolic compliance. We verified these results, because our cohort showed a significant left ventricular mass index and, consequently, diastolic dysfunction. Mean NT-proBNP levels were high. The great expansion of central volume may explain these results and the later development of left ventricular hypertrophy. CONCLUSION: We concluded that elevated concentrations of NT-proBNP indicated the presence of hyperdynamic syndrome and cardiac dysfunction.

N-terminal brain natriuretic peptide as a diagnostic test in cirrhotic patients with pulmonary arterial hypertension.

BACKGROUND: The aim of this study was to assessed the correlation of N-terminal natriuretic peptide type B (NT-proBNP) with echocardiographic and hemodynamic indexes of right ventricular (RV) function and to evaluate the sensitivity and specificity of Doppler echocardiography in the diagnosis of portopulmonary hypertension. METHODS: All patients underwent liver transplantation for cirrhosis. We obtained clinical data, NT-proBNP levels, echocardiography, and right heart hemodynamic measurements before transplantation. RESULTS: Patients with pulmonary hypertension displayed significantly higher levels of NT-proBNP. They also showed higher model for End-stage Liver Disease scores and higher indices of RV overload on cardiac hemodynamics. The negative predictive value of echocardiography to identify pulmonary hypertension was 83%. A correlation was not observed between systolic pulmonary artery pressures measured by the two methods; however, NTproBNP showed a trend toward a significant correlation with mean pulmonary pressure as determined by hemodynamics (r = .3; P < .01). CONCLUSION: We concluded that NT-proBNP values showed significant correlations with pulmonary hypertension that could assist in a noninvasive diagnoseis for this group of patients.