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(2008)Journal ArticleBackground and Purpose: Anticoagulation reduces the risk of stroke in nonvalvular atrial fibrillation yet remains underused. We explored barriers to the use of anticoagulants among Australian family physicians. Methods: The authors conducted a representative, national survey. Results: Of the 596 (64.4%) eligible family physicians who participated, 15.8% reported having a patient with nonvalvular atrial fibrillation experience an intracranial hemorrhage with anticoagulation and 45.8% had a patient with known nonvalvular atrial fibrillation experience a stroke without anticoagulation. When presented with a patient at `very high risk` of stroke, only 45.6% of family physicians selected warfarin in the presence of a minor falls risk and 17.1% would anticoagulate if the patient had a treated peptic ulcer. Family physicians with less decisional conflict and longer-standing practices were more likely to endorse anticoagulation. Conclusion: Strategies to optimize the management of nonvalvular atrial fibrillation should address psychological barriers to using anticoagulation.
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(2006)Conference PaperBackground: Warfarin reduces stroke risk associated with non-valvular atrial fibrillation (NVAF) yet is underutilised. Wider use of warfarin is advocated to reduce the risk of mortality and disability. Aims: We have funding to: 1) develop an innovative intervention (Stop-Stroke) to optimise General Practitioners' (GPs) management of NVAF; 2) evaluate Stop-Stroke using a rigorous, clustered RCT; 3) determine the incremental cost per life year saved due to Stop-Stroke. Methods: Random allocation of 110 GPs from across Australia to control or the Stop-Stroke intervention. Stop-Stroke will comprise patient identification and recall, management plans, peer coaching, specialist support and decision tools. Data will be collected from over 2500 patients. Primary Outcome: The proportion of patients with NVAF over 65 who are on 'appropriate' antithrombotic treatment (judged against standardised criteria) will be compared. 'Appropriate treatment' will be determined using standardised medical record audits and blinded expert review. Results and Analysis: Outcomes will be compared, adjusting for clustered randomisation. Analysis will be by intention to treat. Implications: There is no proven implementation strategy for enhancing the prevention of stroke in patients with NVAF. If effective, Stop-Stroke will bridge evidence-practice gaps in managing NVAF and reduce the risk of stroke and disability in the Australian community.
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(2007)Conference PaperBackground: Optimising the management of NVAF is proving difficult and the potential to reduce stroke risk is yet to be fully realised. Barriers to using anticoagulants need to be addressed. Aims: To describe GP management of NVAF and barriers to the use of warfarin. Methods: Representative survey of Australian GPs. b: Of the 593 GP participants (response = 64.3%), 46.2% reported the experience of an ischaemic stroke in their NVAF patients without anticoagulation. When asked to select treatment for a hypothetical NVAF patient at 'high' risk of stroke, 71.0% appropriately selected warfarin. In the presence of a minor falls risk, 45.4% of GPs selected warfarin. Only 28.8% would anticoagulate the patient at high risk of stroke with a history of recurrent nosebleeds and 16.9% would anti-coagulate such a patient with a treated peptic ulcer bleed. 37.9% agreed that 'it is hard to decide whether the benefits of warfarin outweigh the risks', while only 54.3% agreed they fully understood their patients' views on both the benefits and risks of warfarin. Conclusion: Any strategy to improve the evidence based management of NVAF must address the excessive concerns clinicians have about anticoagulation. We need to reduce anxiety about 'acts of commission' in the management of NVAF.
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(2006)Journal ArticleBackground and Purpose: Anticoagulation reduces the risk of stroke in nonvalvular atrial fibrillation yet remains underused. We explored barriers to the use of anticoagulants among Australian family physicians. Methods: The authors conducted a representative, national survey. Results: Of the 596 (64.4%) eligible family physicians who participated, 15.8% reported having a patient with nonvalvular atrial fibrillation experience an intracranial hemorrhage with anticoagulation and 45.8% had a patient with known nonvalvular atrial fibrillation experience a stroke without anticoagulation. When presented with a patient at "very high risk" of stroke, only 45.6% of family physicians selected warfarin in the presence of a minor falls risk and 17.1% would anticoagulate if the patient had a treated peptic ulcer. Family physicians with less decisional conflict and longer-standing practices were more likely to endorse anticoagulation. Conclusion: Strategies to optimize the management of nonvalvular atrial fibrillation should address psychological barriers to using anticoagulation.
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(2011)Journal ArticleSignificance : Prominent fibrosis is a major histological feature of chronic pancreatitis, a progressive necroinflammatory condition of the pancreas, most commonly associated with alcohol abuse. Patients with this disease often develop exocrine and endocrine insufficiency characterised by maldigestion and diabetes. Up until just over a decade ago, there was little understanding of the pathogenesis of pancreatic fibrosis in chronic pancreatitis. Recent Studies : In recent times, significant progress has been made in this area, mostly due to the identification, isolation and characterisation of the cells, namely pancreatic stellate cells (PSCs) that are now established as key players in pancreatic fibrogenesis. In health, PSCs maintain normal tissue architecture via regulation of the synthesis and degradation of extracellular matrix (ECM) proteins. During pancreatic injury, PSCs transform into an activated phenotype that secretes excessive amounts of the ECM proteins that comprise fibrous tissue. Critical Issues : This Review summarises current knowledge and critical aspects of PSC biology which have been increasingly well characterised over the past few years, particularly with respect to the response of PSCs to factors that stimulate or inhibit their activation and the intracellular signalling pathways governing these processes. Based on this knowledge, several therapeutic strategies have been examined in experimental models of pancreatic fibrosis, demonstrating that pancreatic fibrosis is a potentially reversible condition, at least in early stages. Future Directions : These will involve translation of the laboratory findings into effective clinical approaches to prevent/inhibit PSC activation so as to prevent, retard or reverse the fibrotic process in pancreatitis.
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(2013)Journal ArticleActivated pancreatic stellate cells (PSCs) are responsible for the fibrotic matrix of chronic pancreatitis and pancreatic cancer. In vitro protocols examining PSC biology have usually involved PSCs cultured on plastic, a non-physiological surface. However, PSCs cultured on physiological matrices e.g. MatrigelTM (normal basement membrane) and collagen (fibrotic pancreas), may have distinctly different behaviours compared to cells cultured on plastic. Therefore, we aimed to i) compare PSC gene expression after culture on plastic, MatrigelTM and collagen I; ii) validate the gene array data for transgelin, the most highly dysregulated gene in PSCs grown on activating versus non-activating matrices, at mRNA and protein levels; iii) examine the role of transgelin in PSC function; and iv) assess transgelin expression in human chronic pancreatitis sections. Culture of PSCs on different matrices significantly affected their gene expression pattern. 146, 619 and 432 genes respectively were differentially expressed (p < 0.001) in PSCs cultured on collagen I vs MatrigelTM, MatrigelTM vs plastic and collagen I vs plastic. The highest fold change (12.5 fold upregulation) in gene expression in cells on collagen I vs MatrigelTM, was observed for transgelin (an actin stress fibre associated protein). Transgelin was significantly increased in activated PSCs versus quiescent PSCs. Silencing transgelin expression decreased PSC proliferation and also reduced platelet derived growth factor (PDGF)-induced PSC migration. Notably, transgelin was highly expressed in chronic pancreatitis in stromal areas and peri-acinar spaces but was absent in acinar cells. These findings suggest that transgelin is a potentially useful target protein to modulate PSC function so as to ameliorate pancreatic fibrosis.
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(2012)Journal ArticleWhile the morphology and function of cells of the exocrine and endocrine pancreas have been studied over several centuries, one important cell type in the gland, the pancreatic stellate cell (PSC), had remained undiscovered until as recently as twenty years ago. Even after its first description in 1982, it was to be another 16 years before its biology could begin to be studied, because it was only in 1998 that methods were developed to isolate and culture PSCs from rodent and human pancreas. PSCs are now known to play a critical role in pancreatic fibrosis, a consistent histological feature of two major diseases of the pancreas - chronic pancreatitis and pancreatic cancer. In health, PSCs maintain normal tissue architecture via regulation of the synthesis and degradation of extracellular matrix (ECM) proteins. Recent studies have also implied other additional functions for PSCs as progenitor cells, immune cells or intermediaries in exocrine pancreatic secretion in humans. During pancreatic injury, PSCs transform from their quiescent phase into an activated, myofibroblast-like phenotype that secretes excessive amounts of ECM proteins leading to the fibrosis of chronic pancreatitis and pancreatic cancer. An ever increasing number of factors that stimulate and/or inhibit PSC activation via paracrine and autocrine pathways are being identified and characterized. It is also now established that PSCs interact closely with pancreatic cancer cells to facilitate cancer progression. Based on these findings, several therapeutic strategies have been examined in experimental models of chronic pancreatitis as well as pancreatic cancer, in a bid to inhibit/retard PSC activation and thereby alleviate chronic pancreatitis or reduce tumour growth in pancreatic cancer. The challenge that remains is to translate these pre-clinical developments into clinically applicable treatments for patients with chronic pancreatitis and pancreatic cancer.
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(2012)Book ChapterThe past decade has seen rapid advances in our understanding of the fibrogenic process in the pancreas mainly due to the elucidation of the biology of the cells that are critical to this process. However, it is also becoming increasingly clear that PSCs do not merely exist to regulate ECM turnover in health and disease, but may also have other important roles in the normal pancreas as immune cells and/or progenitor cells. In vitro and in vivo experimental studies have provided encouraging results in terms of developing therapeutic strategies to target PSCs in chronic pancreatitis and pancreatic cancer. The challenge that remains is to translate these findings to the clinical situation so as to improve the outcome for patients afflicted with these diseases.
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(2012)Journal ArticleThe field of pancreatic stellate cell (PSC) biology is very young, as the essential in-vitro tools to study these cells (ie, methods to isolate and culture PSC) were only developed as recently as in 1998. Nonetheless, there has been an exponential increase in research output in this field over the past decade, with numerous research groups around the world focusing their energies into elucidating the biology and function of these cells. It is now well established that PSC are responsible for producing the stromal reaction (fibrosis) of two major diseases of the pancreas—chronic pancreatitis and pancreatic cancer. Despite exponentially increasing data, the methods for studying PSC remain variable. Although within individual laboratories methods are consistent, different methodologies used by various research groups make it difficult to compare results and conclusions. This article is not a review article on the functions of PSC. Instead, members of the Pancreatic Star Alliance (http://www.pancreaticstaralliance.com) discuss here and consolidate current knowledge, to outline and delineate areas of consensus or otherwise (eg, with regard to methodological approaches) and, more importantly, to identify essential directions for future research.
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(2011)Journal ArticleBackground and aims Administration of repeated lipopolysaccharide (LPS) injections in alcohol-fed rats leads to significant pancreatic injury including fibrosis. However, it remains unknown whether alcoholic (chronic) pancreatitis has the potential to regress when alcohol is withdrawn. The aims of the study were (1) to compare the effect of alcohol withdrawal/continuation on pancreatic acute injury and fibrosis; and (2) to assess the effects of alcohol 6 LPS on pancreatic stellate cell (PSC) apoptosis in vivo and in vitro. Methods Rats fed isocaloric LiebereDeCarli liquid diets 6 alcohol for 10 weeks were challenged with LPS (3 mg/kg/week for 3 weeks) and then either switched to control diet or maintained on an alcohol diet for 3 days, 7 days or 3 weeks. Pancreatic sections were assessed for acute tissue injury, fibrosis, PSC apoptosis and activation. Cultured rat PSCs were exposed to 10 mM ethanol 6 1 mg/ml LPS for 48 or 72 h and apoptosis was assessed (Annexin V, caspase-3 and terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL)). Results Withdrawal of alcohol led to resolution of pancreatic lesions including fibrosis and to increased PSC apoptosis. Continued alcohol administration perpetuated pancreatic injury and prevented PSC apoptosis. Alcohol and LPS significantly inhibited PSC apoptosis in vitro, and the effect of LPS on PSC apoptosis could be blocked by Toll-like receptor 4 small interfering RNA. Conclusions Induction of PSC apoptosis upon alcohol withdrawal is a key mechanism mediating the resolution of pancreatic fibrosis. Conversely, continued alcohol intake perpetuates pancreatic injury by inhibiting apoptosis and promoting activation of PSCs. Characterisation of the pathways mediating PSC apoptosis has the potential to yield novel therapeutic strategies for chronic pancreatitis.