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Biomedical subjects

Michael G T Raraty

Publications and source records attributed to Michael G T Raraty.

9 recordsLinked to original sources
PubMed2006

Trypsinogen mutations in pancreatic disorders.

There are multiple PRSS1 mutations described in hereditary pancreatitis but only a minority of these are clinically relevant. The two most frequent point mutations are in exon 2 (N29I) and exon3 (R122H), found in diverse racial populations. Both mutations result in early onset pancreatitis but the mechanism underlying this phenotype is unclear. The frequency of these mutations in such diverse populations suggests they have spontaneously occurred many times. The origin of the major mutations may be explained by gene conversions, accounting for multiple founders. The implications are discussed in terms of mechanism of action of the mutations and clinical presentation.

Gene Conversion↗
PubMed2004

Ethanol toxicity in pancreatic acinar cells: mediation by nonoxidative fatty acid metabolites.

Ethanol causes pancreatic damage by an unknown mechanism. Previously, we demonstrated that a sustained rise of the cytosolic Ca(2+) concentration ([Ca(2+)](i)) causes pancreatic acinar cell injury. Here we have investigated the effects of ethanol and its metabolites on Ca(2+) signaling in pancreatic acinar cells. Most cells exposed to ethanol (up to 850 mM) showed little or no increase in [Ca(2+)](i) (and never at concentrations <50 mM). During sustained exposure to 850 mM ethanol, acetylcholine (ACh) evoked a normal [Ca(2+)](i) elevation and following ACh removal there was a normal and rapid recovery to a low resting level. The oxidative metabolite acetaldehyde (up to 5 mM) had no effect, whereas the nonoxidative unsaturated metabolite palmitoleic acid ethyl ester (10-100 microM, added on top of 850 mM ethanol) induced sustained, concentration-dependent increases in [Ca(2+)](i) that were acutely dependent on external Ca(2+) and caused cell death. These actions were shared by the unsaturated metabolite arachidonic acid ethyl ester, the saturated equivalents palmitic and arachidic acid ethyl esters, and the fatty acid palmitoleic acid. In the absence of external Ca(2+), releasing all Ca(2+) from the endoplasmic reticulum by ACh (10 microM) or the specific Ca(2+) pump inhibitor thapsigargin (2 microM) prevented such Ca(2+) signal generation. We conclude that nonoxidative fatty acid metabolites, rather than ethanol itself, are responsible for the marked elevations of [Ca(2+)](i) that mediate toxicity in the pancreatic acinar cell and that these compounds act primarily by releasing Ca(2+) from the endoplasmic reticulum.

Acetylcholine↗
PubMed2004

Acute pancreatitis and organ failure: pathophysiology, natural history, and management strategies.

Acute pancreatitis is a common condition that carries a significant risk of morbidity and mortality. It is characterized by intra-acinar cell activation of digestive enzymes and a subsequent systemic inflammatory response governed by the release of proinflammatory cytokines. In 80% of patients the disease runs a self-limiting course, but in the rest, pancreatic necrosis and systemic organ failure carry a mortality rate of up to 40%. The key to management is early identification of the patients liable to have a severe attack and require treatment in a high-dependency or critical-care setting by a specialist team. In gallstone-induced pancreatitis, early removal of ductal calculi by endoscopic sphincterotomy is indicated. The use of prophylactic antibiotics to prevent the infection of pancreatic necrosis remains controversial, but once established, infected necrosis must be removed. Although a number of techniques to accomplish this end have been described, minimally invasive techniques are gaining in popularity.

Acute Disease↗
PubMed2004

Cancer in the elderly: pancreatic cancer.

Pancreatic cancer remains a devastating and difficult disease to diagnose and successfully treat. Its incidence increases with age, with 60% of patients being over the age of 65 at presentation. Due to the insidious nature and asymptomatic onset of pancreatic cancer approximately 85% of patients present with disseminated or locally advanced disease resulting in a very poor prognosis. In the past the elderly patient, who may be felt to be too frail for operative procedures or further therapy, may have missed out on optimal treatment. In this article we review the investigation and treatment of pancreatic cancer and examine current evidence with regard to pancreatic cancer in the elderly. The evidence suggests that surgical resection can be performed safely in patients who are fit for surgery in specialist centres but may require more intensive post-operative rehabilitation.

Age Factors↗
PubMed2003

Signal transduction, calcium and acute pancreatitis.

Evidence consistently suggests that the earliest changes of acute pancreatitis are intracellular, the hallmark of which is premature intracellular activation of digestive zymogens, accompanied by disruption of normal signal transduction and secretion. Principal components of physiological signal transduction include secretagogue-induced activation of G-protein-linked receptors, followed by generation of inositol 1,4,5-trisphosphate, nicotinic acid adenine dinucleotide phosphate and cyclic ADP-ribose. In response, calcium is released from endoplasmic reticulum terminals within the apical, granular pole of the cell, where calcium signals are usually contained by perigranular mitochondria, in turn responding by increased metabolism. When all three intracellular messengers are administered together, even at threshold concentrations, dramatic potentiation results in sustained, global, cytosolic calcium elevation. Prolonged, global elevation of cytosolic calcium is also induced by hyperstimulation, bile salts, alcohol and fatty acid ethyl esters, and depends on continued calcium entry into the cell. Such abnormal calcium signals induce intracellular activation of digestive enzymes, and of nuclear factor kappaB, as well as the morphological changes of acute pancreatitis. Depletion of endoplasmic reticulum calcium and mitochondrial membrane potential may contribute to further cell injury. This review outlines current understanding of signal transduction in the pancreas, and its application to the pathophysiology of acute pancreatitis.

Acute Disease↗
PubMed2002

New techniques and agents in the adjuvant therapy of pancreatic cancer.

Pancreatic ductal adenocarcinoma represents a major oncological challenge. Despite improvements in surgical techniques, long-term survival after resection is poor, with few patients surviving after 5 years. Until recently, there have been no large randomized trials of adjuvant therapy in pancreatic ductal adenocarcinoma. However, major trials such as the European Study Group for Pancreatic Cancer (ESPAC-1) and ESPAC-3 trials have set new standards for patient recruitment and development in this field. Adjuvant therapy has the potential to improve both patient survival and quality of life after curative resection. Currently, the best treatment is with 5-fluorouracil with folinic acid, but in the light of ongoing clinical trials, this may be supplanted by gemcitabine as the treatment of choice. Chemoradiotherapy does not appear to be beneficial in the adjuvant setting, but trials of a wide variety of other techniques and agents in the treatment of advanced disease are being undertaken and some of these will almost certainly be extended into the adjuvant setting in time. Great progress has been made in the adjuvant treatment of pancreatic cancer in the past 10 years and similar advances are likely over the next decade.

Adenocarcinoma↗