Anthony R. J. Phillips

Organ failure and infection of pancreatic necrosis as determinants of mortality in patients with acute pancreatitis.

BACKGROUND & AIMS There is no consistency between the individual studies in the literature on whether organ failure (OF) or infected pancreatic necrosis (IPN) is the main determinant of severity in acute pancreatitis. We aimed to statistically aggregate the available data and determine the pooled influence of OF and IPN on mortality in patients with acute pancreatitis. METHODS The search for relevant observational studies was undertaken in the MEDLINE, EMBASE, and Scopus electronic databases, as well as in the proceedings of major gastroenterology meetings. The summary estimates are presented as relative risk (RR) and 95% confidence interval (CI). RESULTS Fourteen studies comprising 1478 patients with acute pancreatitis were meta-analyzed. A total of 600 patients developed OF and 179 of them died (mortality, 30%); 314 patients developed IPN and 102 of them died (mortality, 32%). In a stratified analysis, patients with OF and IPN had a significantly higher risk of death in comparison with patients with OF and no IPN (RR = 1.94; 95% CI: 1.32-2.85; P = .0007) and in comparison with patients with IPN and no OF (RR = 2.65; 95% CI: 1.30-5.40; P = .0007). CONCLUSIONS In patients with acute pancreatitis, the absolute influence of OF and IPN on mortality is comparable and thus the presence of either indicates severe disease. The relative risk of mortality doubles when OF and IPN are both present and indicates extremely severe disease or critical acute pancreatitis.

Regeneration of the Heart in Diabetes by Selective Copper Chelation

Heart disease is the major cause of death in diabetes, a disorder characterized by chronic hyperglycemia and cardiovascular complications. Although altered systemic regulation of transition metals in diabetes has been the subject of previous investigation, it is not known whether changed transition metal metabolism results in heart disease in common forms of diabetes and whether metal chelation can reverse the condition. We found that administration of the Cu-selective transition metal chelator trientine to rats with streptozotocin-induced diabetes caused increased urinary Cu excretion compared with matched controls. A Cu(II)-trientine complex was demonstrated in the urine of treated rats. In diabetic animals with established heart failure, we show here for the first time that 7 weeks of oral trientine therapy significantly alleviated heart failure without lowering blood glucose, substantially improved cardiomyocyte structure, and reversed elevations in left ventricular collagen and beta(1) integrin. Oral trientine treatment also caused elevated Cu excretion in humans with type 2 diabetes, in whom 6 months of treatment caused elevated left ventricular mass to decline significantly toward normal. These data implicate accumulation of elevated loosely bound Cu in the mechanism of cardiac damage in diabetes and support the use of selective Cu chelation in the treatment of this condition.

Systematic review and meta‐analysis of enteral nutrition formulations in acute pancreatitis

Although the benefits of enteral nutrition in acute pancreatitis are well established, the optimal composition of enteral feeding is largely unknown. The aim of the study was to compare the tolerance and safety of enteral nutrition formulations in patients with acute pancreatitis.

A systematic review of experimental treatments for mitochondrial dysfunction in sepsis and multiple organ dysfunction syndrome

Sepsis and multiple organ dysfunction syndrome (MODS) are major causes of morbidity and mortality in the intensive care unit. Recently mitochondrial dysfunction has been proposed as a key early cellular event in critical illness. A growing body of experimental evidence suggests that mitochondrial therapies are effective in sepsis and MODS. The aim of this article is to undertake a systematic review of the current experimental evidence for the use of therapies for mitochondrial dysfunction during sepsis and MODS and to classify these mitochondrial therapies. A search of the MEDLINE and PubMed databases (1950 to July 2009) and a manual review of reference lists were conducted to find experimental studies containing data on the efficacy of mitochondrial therapies in sepsis and sepsis-related MODS. Fifty-one studies were included in this review. Five categories of mitochondrial therapies were defined-substrate provision, cofactor provision, mitochondrial antioxidants, mitochondrial reactive oxygen species scavengers, and membrane stabilizers. Administration of mitochondrial therapies during sepsis was associated with improvements in mitochondrial electron transport system function, oxidative phosphorylation, and ATP production and a reduction in cellular markers of oxidative stress. Amelioration of proinflammatory cytokines, caspase activation, and prevention of the membrane permeability transition were reported. Restoration of mitochondrial bioenergetics was associated with improvements in hemodynamic parameters, organ function, and overall survival. A substantial body of evidence from experimental studies at both the cellular and the organ level suggests a beneficial role for the administration of mitochondrial therapies in sepsis and MODS. We expect that mitochondrial therapies will have an increasingly important role in the management of sepsis and MODS. Clinical trials are now required.

Newly diagnosed diabetes mellitus after acute pancreatitis: a systematic review and meta-analysis

Background Diabetes mellitus (DM) is common in the general population and it poses a heavy burden to society in the form of long-term disability, healthcare use and costs. The pancreas is a key player in glucose homeostasis, but the occurrence of newly diagnosed DM after acute pancreatitis (AP), the most frequent disease of the pancreas, has never been assessed systematically. The aim of this study was to conduct a systematic literature review to determine the prevalence and time course of DM and related conditions after the first attack of AP as well as the impact of covariates. Methods Relevant literature cited in three electronic databases (Scopus, EMBASE and MEDLINE) was reviewed independently by two authors. The main outcome measures studied were newly diagnosed prediabetes, DM, or DM treated with insulin. Pooled prevalence and 95% CIs were calculated for all outcomes. Results A total of 24 prospective clinical studies, involving 1102 patients with first episode of AP, met all the eligibility criteria. Prediabetes and/or DM was observed in 37% (95% CI 30% to 45%) individuals after AP. The pooled prevalence of prediabetes, DM and treatment with insulin after AP was 16% (95% CI 9% to 24%), 23% (95% CI 16% to 31%), and 15% (95% CI 9% to 21%), respectively. Newly diagnosed DM developed in 15% of individuals within 12 months after first episode of AP and the risk increased significantly at 5 years (relative risk 2.7 (95% CI 1.9 to 3.8)). A similar trend was observed with regard to treatment with insulin. The severity of AP, its aetiology, individuals’ age and gender had minimal effect on the studied outcomes. Conclusions Patients with AP often develop prediabetes and/or DM after discharge from hospital, and have a greater than twofold increased risk of DM over 5 years. Further studies are warranted to determine the optimal strategy for its detection and whether the risk of developing DM after AP can be reduced.

Systematic review of oxidative stress associated with pneumoperitoneum

There have been several reports of ischaemic complications after routine laparoscopy. The aim of this review was to investigate the relationship between this oxidative stress and pneumoperitoneum.

Connexins in wound healing; perspectives in diabetic patients.

Skin lesions are common events and we have evolved to rapidly heal them in order to maintain homeostasis and prevent infection and sepsis. Most acute wounds heal without issue, but as we get older our bodies become compromised by poor blood circulation and conditions such as diabetes, leading to slower healing. This can result in stalled or hard-to-heal chronic wounds. Currently about 2% of the Western population develop a chronic wound and this figure will rise as the population ages and diabetes becomes more prevalent [1]. Patient morbidity and quality of life are profoundly altered by chronic wounds [2]. Unfortunately a significant proportion of these chronic wounds fail to respond to conventional treatment and can result in amputation of the lower limb. Life quality and expectancy following amputation is severely reduced. These hard to heal wounds also represent a growing economic burden on Western society with published estimates of costs to healthcare services in the region of

Fluid therapy in acute pancreatitis: anybody's guess.

25B annually [3]. There exists a growing need for specific and effective therapeutic agents to improve healing in these wounds. In recent years the gap junction protein Cx43 has been shown to play a pivotal role early on in the acute wound healing process at a number of different levels [4-7]. Conversely, abnormal expression of Cx43 in wound edge keratinocytes was shown to underlie the poor rate of healing in diabetic rats, and targeting its expression with an antisense gel restored normal healing rates [8]. The presence of Cx43 in the wound edge keratinocytes of human chronic wounds has also been reported [9]. Abnormal Cx43 biology may underlie the poor healing of human chronic wounds and be amenable therapeutic intervention [7]. This article is part of a Special Issue entitled: The Communicating junctions, composition, structure and characteristics.

Three-colour fluorescence immunohistochemistry reveals the diversity of cells staining for macrophage markers in murine spleen and liver

Objective: The aim of this study was to systematically review and evaluate the quality of current evidence about fluid therapy (FT) in acute pancreatitis (AP). Background: Intravenous FT is thought to be important in the early management of patients with AP. Clinically relevant questions remain regarding the type of fluid, the rate of administration, and the goal of FT. Methods: A comprehensive literature search for human studies was performed using online databases (MEDLINE, EMBASE, PubMed, and the Cochrane Library). The quality of the entire body of evidence was then graded according to the Grading of Recommendations Assessment, Development and Evaluation Working Group guidelines in relation to 3 key areas: type of fluid, rate of fluid administration, and goal-directed FT. Results: The initial search yielded 410 studies, of which 15 met the inclusion criteria. Only 2 randomized studies compared types of fluids. Nine studies looked at aggressive versus nonaggressive resuscitation protocols, of which 4 concluded that an aggressive approach yielded better outcomes and 5 concluded that a nonaggressive approach was better. Two studies investigated goal-directed FT, using different goals; one demonstrating benefit and the other none. Analysis of the body of evidence as per the Grading of Recommendations Assessment, Development and Evaluation Working Group revealed that the majority of evidence was of low or very low quality. Conclusions: FT is considered a cornerstone of the early management of patients with AP and yet the evidence on which it is based remains paltry and of poor quality. This systematic review has demonstrated the equipoise necessary for the design of randomized controlled trials to answer pressing questions relating to the type of fluid, the rate of administration, and how FT should be guided.

Early nasogastric tube feeding versus nil per os in mild to moderate acute pancreatitis: A randomized controlled trial

Macrophages have traditionally been identified in murine tissues using a small range of markers, typically F4/80, CD68 and CD11b. However many studies have suggested that substantial heterogeneity exists in macrophage populations, and no single marker, nor even pair of markers, can necessarily identify all the populations. Further, many of the key monoclonal antibodies have been raised in the same species, making it difficult to combine them in histochemical studies. Here we have optimised a triple colour immunofluorescent staining protocol, utilising an anti-FITC technique, to allow antibodies to macrophage markers to be used simultaneously. We highlight the substantial heterogeneity of cells in both normal liver and spleen that stain for F4/80, CD68, CD11b, and CD11c. Using diet-induced steatohepatitis as a model of liver inflammation, we show that CD11b is expressed by newly migrating macrophage precursors, but is an unreliable marker for macrophage precursors when used alone because it is also expressed by migrating neutrophils. In healthy livers CD11c expression is a unique feature of a population of cells immediately surrounding the sinusoids. However, during hepatic inflammation CD11c can also be co-expressed by other cells, including both infiltrating cells and F4/80+ cells within the liver parenchyma. While no one marker alone is sufficient to account for all macrophage populations, we confirm that F4/80 marks the majority of the tissue-resident macrophages in both the liver and the spleen, although F4/80- populations that are positive for CD68, CD11b, or CD11c also exist. Distinguishing between tissue macrophages and dendritic cells with these markers remains problematic.