The Role of Prostaglandin E2 in Innate Immune Dysfunction in Cirrhotic Liver Disease

Liver cirrhosis is one of the greatest causes of mortality in the world in the 21st century. The prevalence of liver disease is predicted to continue to rise precipitously and liver disease accounts for between 2% and 3% of annual worldwide deaths. Bacterial infection is the major cause of mortality in liver cirrhosis and these patients are highly prone to nosocomial infection. Innate immune dysfunction is strongly implicated in this process. O’Brien et al (Nature Med, 2014) showed prostaglandin E2 (PGE2) was markedly increased in these patients. However, traditional approaches to reducing PGE2 (such as NSAIDs) are contraindicated due to renal and gastrointestinal side effects. This study aimed to investigate PGE2 downstream signalling pathways to identify a more specific druggable target to reverse immune dysfunction in acute-on-chronic liver failure (ACLF) and cirrhotic patients in general. ACLF patients (mean modified End-Stage Liver Disease (MELD) score 19) were compared to outpatients with resistant ascites admitted for elective paracentesis and drainage, ‘ambulant’, cirrhotic patients and healthy volunteers (HV). PGE2 levels in plasma were significantly increased between HV (163.9pg/ml) and ACLF (563.8pg/ml). I demonstrated increased microsomal Prostaglandin-E-Synthase-1 expression in cirrhotic liver parenchyma and increased phospholipase A2 expression and cyclooxygenase (COX)-2:COX-1 expression ratio in monocytes. ACLF and ambulant patients had increased circulating cytokines, including IL-6, IL-8, and TNF-a, as well as demonstrating a monocyte phenotype of immune fatigue, with low HLA-DR. Ex vivo lipopolysaccharide (LPS)-whole blood stimulation demonstrated monocyte deactivation with significantly lower levels of TNF-a and IL-6 in ACLF vs HV (2.178ng/109monocytes vs 6.649ng/109monocytes and 4.492ng/109monocytes vs 12.256ng/109monocytes respectively). This was further reduced by addition of exogenous PGE2 at inflammatory site concentrations. PGE2 acts through four membrane-bound G protein-coupled receptors with different activities, EP1-4. Blockade of the EP4 receptor completely reversed reduction in both TNF-a and IL-6. Similar changes were seen locally using an in vivo model of inflammation, including increased PGE2 concentrations at a local inflammatory site. In summary, ACLF patients have PGE2-mediated monocyte deactivation via the EP4 receptor. Blockade of this receptor restored innate immune function. EP4 blockade has been shown to have a safe renal profile and I suggest this is a valid target for future immune-restorative therapy in ACLF

A rare case of hepatic vein puncture during attempted pericardiocentesis mimicking right atrium perforation

Emergency pericardiocentesis done for hemodynamically significant cardiac tamponad is associated with rare but life-threatening complications including cardiac chamber perforation. Echocardiography is the usual tool to diagnose procedural complications of pericardiocentesis. We are reporting a case of attempted pericardiocentesis where apparent cardiac chamber perforation by saline contrast echo turned out to be an inconsequential hepatic vein puncture

Optimizing a diagnostic tool: coronary computed tomography angiography-guided percutaneous coronary intervention of anomalous coronary artery presenting as an acute coronary syndrome

Anomalous coronary artery presenting with acute coronary syndrome is relatively rare. Achilles heel of percutaneous coronary intervention in a such patient is difficult cannulation of the culprit artery. Coronary CT angiography provides detailed information about the origin and course of the anomalous coronary artery. A few additional information like exit angle and orifice configuration provided exclusively by CT helps in appropriate hardware selection for angiographic success

Implementation of enterprise applications based on service oriented architecture

In current scenario, It has become important to integrate business and its Information system to achieve their competitiveness. Today a large number of projects fail in achieving business to IT integration. Distributed systems which are large in nature are difficult to develop due to their complexity. The Service Oriented Architecture (SOA) has been identified as the most suitable solution which facilitates to development of distributed systems. SOA helps in developing such distributed system as it supports modular design, inter-interoperability, application integration and software reuse. Enterprises systems which are large in nature need to focus on characteristics i.e. scalability and availability that enhance interoperability and integration of elements. An enterprise is an organization of resources i.e. people, computers, and machines, which performs a process. Enterprise Architecture (EA) is the discipline control resources of the enterprise. EA tasked to ensure Business-IT alignment. Enterprise SOA can be defined as a set of business-aligned IT-services that collectively address an organization's business processes (work-flow) and goals. Services can be orchestrated in many ways to support enterprise business process. Services and Processes are guided by the business architecture and it can be traced back to the business outcomes. Service Oriented Architecture (SOA) help in bridging the gap between business and IT by well defined, business-oriented services developed by using design principles, frameworks, pattern and methods. The objectives of EA and SOA are quite similar