Vijay p Singh

Larsen and Toubro | L&T · technologies services

Background The role of fatty acid ethyl esters (FAEEs) during human alcoholic pancreatitis is unknown. We compared FAEE levels to their non-esterified fatty acids (NEFA) precursors during alcohol intoxication and clinical alcoholic pancreatitis. The pathophysiology underlying FAEE increase and their role as diagnostic biomarkers for alcoholic pancr...

Percutaneous transendocardial injections of therapeutic agents into the myocardium may not always be effective. We used an animal model for assessing the efficacy of the injections using linoleic acid as a testing agent. Efficacious delivery into the myocardium of a beating heart was indicated by rapidly developed local myocardial necrosis and wall...

Obesity sometimes seems protective in disease. This obesity paradox is predominantly described in reports from the Western Hemisphere during acute illnesses. Since adipose triglyceride composition corresponds to long-term dietary patterns, we performed a meta-analysis modeling the effect of obesity on severity of acute pancreatitis, in the context...

Bile acids (BA), with their large hydrophobic steroid nucleus and polar groups are amphipathic molecules. In bile, these exist as micelles above their critical micellar concentration (CMC). In blood at low concentrations, these exist as monomers, initiating cellular signals. This micellar to monomer transition may involve complex thermodynamic inte...

Objective: Ringer's lactate may improve early systemic inflammation during critical illnesses like severe acute pancreatitis, which are associated with hypocalcemia. Ringer's lactate is buffered and contains lactate and calcium. We, thus analyzed extracellular calcium or lactate's effects on the mechanisms, intermediary markers, and organ failure...

Visceral adipose tissue plays a critical role in numerous diseases. While imaging studies often show adipose involvement in abdominal diseases, their outcomes may vary from being a mild self limited illness to one with systemic inflammation and organ failure. We therefore compared the pattern of visceral adipose injury during acute pancreatitis and...

Objectives: Small intestinal bacterial overgrowth (SIBO) can complicate chronic pancreatitis (CP) and interfere with management. Its predisposing factors in CP and treatment response are unknown. In this review, we evaluated factors affecting disease burden. Methods: A computerized search of PubMed and EMBASE databases from inception through May...

Acute lipolysis of visceral fat or circulating triglycerides may worsen acute pancreatitis (AP)–associated local and systemic injury. The pancreas expresses pancreatic triacylglycerol lipase (PNLIP), pancreatic lipase-related protein 2 (PNLIPRP2), and carboxyl ester lipase (CEL), which may leak into the visceral fat or systemic circulation during p...

Background & aims: Acute pancreatitis (AP) of different etiologies is associated with the activation of different signaling pathways in pancreatic cells, posing challenges to the development of targeted therapies. We investigated whether local pancreatic hypothermia, without systemic hypothermia, could lessen the severity of AP induced by differen...

The exocrine pancreatic acinar cell is unique for its rapid protein synthesis and packaging in zymogen granules (ZGs). However, while crucial to the pathogenesis of pancreatitis, the signaling involved in the transit of proteins via the Golgi is poorly understood in these cells. Noting the evidence of c-Src in regulating transit of cargo via the Go...

Purpose of review: The obesity pandemic poses a unique set of problems for acute pancreatitis - both by increasing acute pancreatitis incidence, and worsening acute pancreatitis severity. This review explores these associations, underlying mechanisms, and potential therapies. Recent findings: We review how the obesity associated increase in gall...

Background: Recent studies suggest that lactated Ringer’s (LR) use is associated with a milder acute pancreatitis (AP) course than with normal saline. The mechanisms underlying this benefit are unclear. Hypocalcemia is a part of the Ranson’s and Glasgow criteria for severe AP (SAP) and LR contains 3 mEq Ca2+. Here, we tested the effects of increasi...

Background: We have previously shown that Src family of protein tyrosine kinases is involved in trypsinogen activation. However, the role of specific members is poorly understood. In this study we aimed at identifying the role of c-Src in zymogen synthesis and trafficking using a physiologic glucocorticoid stimulus of zymogen granule production, an...

Background: Multiple deleterious signaling cascades are simultaneously activated in AP, which may limit the success of targeted pharmacologic approaches. Hypothermia slows biologic processes, decreasing oxygen requirements and metabolic demand, but generalized hypothermia can compromise vital functions. Here we tested the efficacy of a novel transg...

Background: Being amphiphilic, BAs may regulate biliary AP severity by stabilizing hydrophobic FAs released from fat necrosis in our aqueous in vivo environment. We tested this hypothesis by studying interactions between BAs and FAs in the progression of peripancreatic fat necrosis (PPFN), which in isolation is known to be milder in humans than whe...

Objectives: To assess the relationship between alcoholic etiology, tobacco use, and severe acute pancreatitis (AP). Methods: Smoking and alcohol exposure were recorded upon admission in a cohort of patients with AP within the United States. Patients with first, "sentinel" attack of AP were identified for analysis.Associations between alcohol, sm...

Background: Studying the uptake of 2-deoxy glucose (2-DG) analogs such as 2-Deoxy-2-[18F] fluoroglucose (FDG) is a common approach to identify and monitor malignancies and more recently chronic inflammation. While pancreatitis is a common cause for false positive results in human studies on pancreatic cancer using FDG, the relevance of these findi...

Although ethanol causes acute pancreatitis (AP) and lipolytic fatty acid (FA) generation worsens AP, the contribution of ethanol metabolites of FAs, that is, FA ethyl esters (FAEEs), to AP outcomes is unclear. Previously, pancreata of dying alcoholics and pancreatic necrosis in severe AP, respectively, showed high FAEEs and FAs, with oleic acid (OA...

Objectives: Hypertriglyceridemia (HTG) represents a major health problem with prevalence exceeding 30% in the U.S. The present study aims to assess the effect of elevated serum triglyceride (TG) levels on the severity of acute pancreatitis (AP). Methods: Prospectively enrolled AP patients were categorized into normal, mild, moderate, and severe/...

Pancreatitis-Panniculitis-Polyarthritis (PPP) syndrome is rare and its physiopathology unclear. A 6-year old boy suffered traumatic pancreatitis complicated by PPP syndrome. Extensive investigations demonstrated high levels of pancreatic lipase and fatty acids in the affected peripheral tissues. These findings support the sequence of peripheral lip...

Visceral fat necrosis has been associated with severe acute pancreatitis (SAP) for over 100 years; however, its pathogenesis and role in SAP outcomes are poorly understood. Based on recent work suggesting that pancreatic fat lipolysis plays an important role in SAP, we evaluated the role of pancreatic lipases in SAP-associated visceral fat necrosis...

Peripancreatic fat necrosis occurs frequently in necrotising pancreatitis. Distinguishing markers from mediators of severe acute pancreatitis (SAP) is important since targeting mediators may improve outcomes. We evaluated potential agents in human pancreatic necrotic collections (NCs), pseudocysts (PCs) and pancreatic cystic neoplasms and used panc...

β-catenin regulates the establishment of hepatic metabolic zonation. To elucidate the functional significance of liver metabolic zonation in the chronically overfed state in vivo, we fed a high-fat diet (HFD) to hepatocyte-specific β-catenin transgenic (TG) and knockout (KO) mice. Chow-fed TG and KO mice had normal liver histologic findings and bod...

The role of obesity in relation to various disease processes is being increasingly studied, with reports over the last several years increasingly mentioning its association with worse outcomes in acute disease. Obesity has also gained recognition as a risk factor for severe acute pancreatitis (SAP).The mortality in SAP may be as high as 30% and is...

Background and objectives Multiple deleterious signaling cascades are simultaneously activated in acute pancreatitis (AP), which may limit the success of pharmacologic approaches targeting a single step. We explored whether cooling acinar cells slows distinct steps initiated from a stimulus causing pancreatitis simultaneously, and the temperature r...

Obese patients have worse outcomes during acute pancreatitis (AP). Previous animal models of AP have found worse outcomes in obese rodents who may have a baseline proinflammatory state. Our aim was to study the role of acute lipolytic generation of fatty acids on local severity and systemic complications of AP. Human postpancreatitis necrotic colle...

Parenteral nutrition (PN) has been associated with a higher rate of adverse outcomes compared with enteral feeding in patients with acute pancreatitis (AP). However, PN may be necessary when feeding via the enteral route is poorly tolerated or impossible, and PN is recommended as a second-line nutrition therapy in AP. Intravenous (IV) lipids are co...

Hepatic steatosis or fatty liver disease occurs when lipids accumulate within the liver and can lead to steatohepatitis, cirrhosis, liver cancer and eventual liver failure requiring liver transplant. Conventional brightness mode (B-mode) ultrasound (US) is the most common noninvasive diagnostic imaging modality used to diagnose hepatic steatosis in...

Hypertriglyceridemia (HTG) is a well-established but underestimated cause of acute pancreatitis and recurrent acute pancreatitis. The clinical presentation of HTG-induced pancreatitis (HTG pancreatitis) is similar to other causes. Pancreatitis secondary to HTG is typically seen in the presence of one or more secondary factors (uncontrolled diabetes...

Several deleterious intra-acinar phenomena are simultaneously triggered on initiating acute pancreatitis. These culminate in acinar injury or inflammatory mediator generation in vitro and parenchymal damage in vivo. Supraphysiologic caerulein is one such initiator which simultaneously activates numerous signaling pathways including non-receptor tyr...

Background & aims: Acute pancreatitis (AP) and chronic pancreatitis (CP) share etiologies, but AP can be more severe and is associated with a higher rate of mortality. We investigated features of CP that protect against severe disease. The amount of intrapancreatic fat (IPF) is increased in obese patients and fibrosis is increased in patients with...

Acute pancreatitis is a painful, life-threatening disorder of the pancreas whose etiology is often multi-factorial. It is of great importance to understand the interplay between factors that predispose patients to develop the disease. One such factor is an excessive elevation in pancreatic acinar cell Ca(2+). These aberrant Ca(2+) elevations are tr...

Biliary pancreatitis is the leading cause of acute pancreatitis in both children and adults. A proposed mechanism is the reflux of bile into the pancreatic duct. Bile acid exposure causes pancreatic acinar cell injury through a sustained rise in cytosolic Ca2+. Thus it would be clinically relevant to know the targets of this aberrant Ca2+ signal. W...

Pancreatitis is a complex, progressively destructive inflammatory disorder. Alcohol was long thought to be the primary causative agent, but genetic contributions have been of interest since the discovery that rare PRSS1, CFTR and SPINK1 variants were associated with pancreatitis risk. We now report two associations at genome-wide significance ident...

Several studies have suggested that autophagy might play a deleterious role in acute pancreatitis via intra-acinar activation of digestive enzymes. The prototype for this phenomenon is cathepsin B-mediated trypsin generation. To determine the organellar basis of this process, we investigated the subcellular distribution of the cathepsin B precursor...

Biliary pancreatitis is the most common etiology for acute pancreatitis, yet its pathophysiological mechanism remains unclear. Ca(2+) signals generated within the pancreatic acinar cell initiate the early phase of pancreatitis, and bile acids can elicit anomalous acinar cell intracellular Ca(2+) release. We previously demonstrated that Ca(2+) relea...

Unlabelled: The liver plays a central role in ethanol metabolism, and oxidative stress is implicated in alcohol-mediated liver injury. β-Catenin regulates hepatic metabolic zonation and adaptive response to oxidative stress. We hypothesized that β-catenin regulates the hepatic response to ethanol ingestion. Female liver-specific β-catenin knockout...

Obesity increases the risk of adverse outcomes during acute critical illnesses such as burns, severe trauma, and acute pancreatitis. Although individuals with more body fat and higher serum cytokines and lipase are more likely to experience problems, the roles that these characteristics play are not clear. We used severe acute pancreatitis as a rep...

Neutrophils and their chemoattractants, the CXC-ELR chemokines keratinocyte cytokine (KC) and macrophage inflammatory protein-2 (MIP-2), play a critical role in pancreatitis. While acute pancreatitis is initiated in acinar cells, it is unclear if these are a source of CXC-ELR chemokines. KC and MIP-2 have NF-κB, activator protein-1 (AP-1) sites in...

There is no clinical treatment that reduces acinar injury during pancreatitis. Human immunodeficiency virus (HIV) protease inhibitors (PI), including nelfinavir (NFV) and ritonavir (RTV), may reduce the rate of pancreatitis in HIV-infected patients. Since permeability transition pore (PTPC)-mediated mitochondrial dysfunction occurs during pancreati...

IntroductionModels of acute pancreatitisPathogenesis of pancreatic injuryMechanisms of cell death in pancreatitisSummaryReferences

Heat shock proteins (HSPs), induced by a variety of stresses, are known to protect against cellular injury. Recent studies have demonstrated that prior beta-adrenergic stimulation as well as thermal or culture stress induces HSP70 expression and protects against cerulein-induced pancreatitis. The goal of our current studies was to determine whether...

Protease-activated receptor-2 (PAR-2) is present in the pancreas, where it has been shown to play a protective role during pancreatitis. However, the mechanism by which it protects against pancreatitis still remains to be elucidated. Acute pancreatitis is associated with premature zymogen activation and a blockage in digestive enzyme secretion. To...

Cyclooxygenase-2 (COX-2), a widely distributed enzyme, plays an important role in inflammation. We have studied the role of COX-2 in acute pancreatitis and pancreatitis-associated lung injury using both the pharmacological inhibition of COX-2 and genetic deletion of COX-2. Pancreatitis was induced in mice by 12 hourly injections of cerulein. The se...

Intrapancreatic activation of trypsinogen is believed to play a critical role in the initiation of acute pancreatitis, but mechanisms responsible for intrapancreatic trypsinogen activation during pancreatitis have not been clearly defined. In previous in vitro studies, we have shown that intra-acinar cell activation of trypsinogen and acinar cell i...

Prior thermal stress induces heat shock protein 70 (HSP70) expression in the pancreas and protects against secretagogue-induced pancreatitis, but it is not clear that this thermal stress-induced protection is actually mediated by HSP70 since thermal stress may have other, non-HSP related, effects. In the present study, we have administered antisens...

Intra-acinar cell activation of digestive enzyme zymogens including trypsinogen is generally believed to be an early and critical event in acute pancreatitis. We have found that the phosphatidylinositol 3-kinase inhibitor wortmannin can reduce the intrapancreatic activation of trypsinogen that occurs during two dissimilar experimental models of rod...

The present study was undertaken to evaluate the role of serine proteases in regulating digestive enzyme secretion in pancreatic acinar cells. Isolated acini were stimulated by various secretagogues in the presence or absence of cell-permeant serine protease inhibitors 4-(2-aminoethyl)-benzenesulfonyl fluoride and N(alpha)-p-tosyl-L-phenylalanine c...

Intra-acinar cell nuclear factor-κB (NF-κB) and trypsinogen activation are early events in secretagogue-induced acute pancreatitis. We have studied the relationship between NF-κB and trypsinogen activation in rat pancreas. CCK analogue caerulein induces early (within 15 min) parallel activation of both NF-κB and trypsinogen in pancreas in vivo as w...