The association between bacterobilia and the risk of postoperative complications following pancreaticoduodenectomy.

BACKGROUND: Pre-operative biliary bacterial colonisation (bacterobilia) is considered a risk factor for infectious complications after pancreaticoduodenectomy (PD). This study aimed to investigate the role of the PD biliary microbiome grown in the development of post-PD complications. METHODS: In a retrospective study of 162 consecutive patients undergoing PD (2008-2018), intra-operative bile cultures were analyzed and sensitivities compared to pre-anesthetic antibiotics and thirty-day post-surgery complications. RESULTS: Bacterobilia was present in 136 patients (84%). Most bile cultures grew bacteria resistant to pre-operative antibiotics (n = 112, 82%). Patients with bacterobilia had significantly higher rates of major complication than patients without (P = 0.017), as well as higher rates of surgical-site infections (SSI) (P = 0.010). Patients with negative bile cultures (n = 26) had significantly lower rates of major complication and SSI than those growing sensitive (n = 24) or non-sensitive (n = 112) bacteria (major complication P = 0.029 and SSI P = 0.011). CONCLUSION: Positive bile cultures were associated with a higher incidence of major complications and SSI. Patients with sterile bile cultures had the lowest risk of post-operative complications and efforts to reduce rates of bacterobilia, such as limitation of biliary instrumentation, should be considered. Sensitivity to antibiotics had no effect upon the rate of post-operative complications, but this may reflect low cohort numbers.

The effect of renin angiotensin system genetic variants in acute pancreatitis.

OBJECTIVES: We sought association of genetic variants in the renin-angiotensin system (RAS) and vitamin D system with acute pancreatitis (AP) development and severity. BACKGROUND: The endocrine RAS is involved in circulatory homeostasis through the pressor action of angiotensin II at its AT1 receptor. However, local RAS regulate growth and inflammation in diverse cells and tissues, and their activity may be suppressed by vitamin D. Intrapancreatic angiotensin II generation has been implicated in the development of AP. METHODS: Five hundred forty-four white patients with AP from 3 countries (United Kingdom, 22; Germany, 136; and The Netherlands 386) and 8487 control subjects (United Kingdom 7833, The Netherlands 717) were genotyped for 8 polymorphisms of the RAS/vitamin D systems, chosen on the basis of likely functionality. RESULTS: The angiotensin-converting enzyme I (rather than D) allele was significantly associated with alcohol-related AP when all cohorts were combined (P = 0.03). The renin rs5707 G (rather than A) allele was associated with AP (P = 0.002), infected necrosis (P = 0.025) and mortality (P = 0.046). CONCLUSIONS: The association of 2 RAS polymorphisms with AP suggests the need for further detailed analysis of the role of RAS/vitamin D in the genesis or severity of AP, particularly given the ready potential for pharmacological manipulation of this system using existing marketed agents. However, further replication studies will be required before any such association is considered robust, particularly given the significant heterogeneity of AP causation and clinical course.

An observational study to determine the effect of delayed admission to the intensive care unit on patient outcome.

INTRODUCTION: Delayed patient admission to the intensive care unit (ICU) due to lack of bed availability is a common problem, but the effect on patient outcome is not fully known. METHODS: A retrospective study was performed using departmental computerised records to determine the effect of delayed ICU admission and temporary management within the operating theatre suite on patient outcome. Emergency surgical and medical patients admitted to the ICU (2003 to 2007) were divided into delay (more than three hours from referral to admission) and no-delay (three or fewer hours from referral to admission) groups. Our primary outcome measure was length of ICU stay. Secondary outcome measures were mortality rates and duration of organ support. RESULTS: A total of 1,609 eligible patients were included and 149 (9.3%) had a delayed admission. The delay and no-delay groups had similar baseline characteristics. Median ICU stay was 5.1 days (delay) and 4.5 days (no-delay) (P = 0.55) and ICU mortality was 26.8% (delay) and 24.2% (no-delay) (P = 0.47). Following adjustment for demographic and baseline characteristics there was no difference in either length of ICU stay or mortality rates between groups. ICU admission delay was associated with both an increased requirement for advanced respiratory support (92.3% delay vs. 76.4% no-delay, P <0.01) and a longer time spent ventilated (median four days delay vs. three days no-delay, P = 0.04). CONCLUSIONS: No significant difference in length of ICU stay or mortality rate was demonstrated between the delay and no-delay cohorts. Patients within the delay group had a significantly greater requirement for advanced respiratory support and spent a longer time ventilated.

Rare presentation of Brunner's gland adenoma: another differentiation in patients with recurrent "idiopathic" pancreatitis.

BACKGROUND: Brunner's gland adenoma (BGA) is an unusual benign neoplasm arising from Brunner's glands in the duodenum. When symptomatic it presents either with duodenal obstruction or bleeding. However, pancreatitis secondary to ampullary obstruction from a BGA is very rare. METHODS: A 23-year-old female presented with recurrent episodes of "idiopathic" pancreatitis. She was extensively investigated and was found to have a large polypoid BGA, intermittently obstructing the ampulla. This created a ball-valve effect causing secondary intermittent obstruction of the pancreatic duct resulting in pancreatitis. The condition was cured surgically, through transduodenal excision of the BGA. We reviewed the surgical literature pertaining to these unusual and similar causes of obstructive pancreatitis, not related to gallstones. RESULTS: BGA of the duodenum is a rare cause of pancreatitis. Extensive investigations should be carried out in all cases of unexplained pancreatitis before classifying the condition as "idiopathic". Discovery of a lesion of this nature gives an opportunity to provide a permanent surgical cure. CONCLUSIONS: BGA adds an unusual etiology for pancreatitis. All patients with pancreatitis should undergo extensive investigations before being termed "idiopathic". Surgical excision of the BGA provides a definitive curative treatment for the adenoma and pancreatitis.

The role of 18FDG PET/CT in the management of colorectal liver metastases.

INTRODUCTION: Surgical resection remains the only potentially curative treatment for colorectal liver metastases (CLM). However, involvement of both the hepatic lobes or extrahepatic disease (EHD) can be a contra-indication for resection. The aim of the present study was to examine the addition of combined positron emission and computed tomography (PET/CT) to CLM staging to assess the effects upon staging and management. METHODS: All CLM patients referred to a single centre between January 2005 and January 2009 were prospectively included. All underwent routine staging (clinical examination and computed tomography), followed by a whole body (18) fluoro-deoxy-glucose ((18)FDG)-PET/CT scan and Fong clinical risk score calculation. RESULTS: Sixty-four patients were included [63% male with a median age of 63 years (age range 32-79 years)]. The addition of PET/CT led to disease upstaging in 20 patients (31%) and downstaging in two patients (3%). EHD was found in 24% of low-risk patients (Fong score 0-2) as compared with 44% of high-risk patients (Fong score 3-5) (P= 0.133). There was a trend towards a greater influence upon management in patients with a low score (44% vs. 17%; P= 0.080). CONCLUSION: The addition of PET/CT led to management changes in over one-third of patients but there was no correlation between alterations in staging or management and the Fong clinical risk score; suggesting that PET/CT should be utilized, where available, in the pre-operative staging of CLM patients.

Pancreaticoduodenectomy for advanced duodenal and ampullary adenomatosis in familial adenomatous polyposis.

BACKGROUND: Patients with familial adenomatous polyposis (FAP) develop duodenal and ampullary polyps that may progress to malignancy via the adenoma-carcinoma sequence. OBJECTIVE: The aim of this study was to review a large series of FAP patients undergoing pancreaticoduodenectomy for advanced duodenal and ampullary polyposis. METHODS: A retrospective case notes review of all FAP patients undergoing pancreaticoduodenectomy for advanced duodenal and ampullary adenomatosis was performed. RESULTS: Between October 1993 and January 2010, 38 FAP patients underwent pancreaticoduodenectomy for advanced duodenal and ampullary polyps. Complications occurred in 29 patients and perioperative mortality in two. Postoperative histology revealed five patients to have preoperatively undetected cancer (R = 0.518, P < 0.001). CONCLUSIONS: Pancreaticoduodenectomy in FAP is associated with significant morbidity, but low mortality. All patients under consideration for operative intervention require careful preoperative counselling and optimization.

Managing acute and chronic pancreatitis.

Pancreatitis may be acute or chronic. Although both can be caused by similar aetiologies, they tend to follow distinct natural histories. Around 80% of acute pancreatitis (AP) diagnoses occur secondary to gallstone disease and alcohol misuse. AP is commonly associated with sudden onset of upper abdominal pain radiating to the back that is usually severe enough to warrant the patient seeking urgent medical attention. Onset of pain may be related to a recent alcohol binge or rich, fatty meal. The patient may appear unwell, be tachycardic and have exquisite tenderness in the upper abdomen. Overall, 10-25% of AP episodes are classified as severe, leading to an associated mortality rate of 7.5%. Disease severity is best predicted from a number of clinical scoring systems which can be applied at diagnosis in association with repeated clinical assessment, measurement of acute inflammatory markers, and CT. All patients with suspected AP should be referred urgently. Chronic pancreatitis (CP) follows continued, repetitive or sustained injury to the pancreas and 70% of diagnoses occur secondary to alcohol abuse. The characteristic presenting feature of CP is insidious progression of chronic, severe, upper abdominal pain, radiating to the back, caused by a combination of progressive pancreatic destruction, inflammation and duct obstruction. Signs and symptoms include weight loss and steatorrhoea and later on diabetes. CP patients may also present with recurrent episodes mimicking AP, both symptomatically and metabolically. Diagnosis of CP should be based on symptom profile, imaging and assessment of exocrine and endocrine pancreatic function. CT should be the first-line imaging investigation.

Management of Slipped Gastric Bands via Creation of a De Novo Tunnel and Band Replacement: a Single-Centre Experience.

BACKGROUND: A lack of clarity remains over the optimal strategy for the management of laparoscopic adjustable gastric band (LAGB) slippage, which, although rare (around 3% in our experience), can when acute result in obstruction, gastric erosion or ischaemia. Typically, slipped bands are removed acutely. The aim of this study was to explore outcomes following immediate or delayed resiting of slipped LAGBs in a single centre, comparing simple repositioning with retunnelling and replacement. METHODS: A retrospective analysis of computerised records, notes and prospectively maintained bariatric databases was undertaken to identify all patients with a slipped LAGB in a single centre. RESULTS: Thirty-two patients required operative intervention following a diagnosis of slipped LAGB (median time from initial LAGB insertion to slippage 2.9 years). Two (6%) patients underwent band removal and 30 (94%), band revision surgery (25 immediately and five at a planned but expedited procedure).Twenty-four (77%) patients underwent insertion of a new LAGB via a de novo retrogastric tunnel, five (21%) of which required further future operative intervention; whereas, six (23%) patients underwent repositioning of the existing LAGB within the same tunnel, five (83%) of which underwent further operative intervention (log-rank test p = 0.0001). Following LAGB revision, there was no significant further change in BMI (median + 1 kg/m2; range - 13 to + 10 kg/m2). CONCLUSION: Resiting of slipped LAGBs is safe and maintains weight loss. Although a significant risk of future operative intervention remains, this can be reduced via the creation of a de novo retrogastric tunnel for band resiting.

ACE and response to pulmonary rehabilitation in COPD: two observational studies.

INTRODUCTION: Skeletal muscle impairment is an important feature of chronic obstructive pulmonary disease (COPD). Renin-angiotensin system activity influences muscle phenotype, so we wished to investigate whether it affects the response to pulmonary rehabilitation. METHODS: Two studies are described; in the first, the response of 168 COPD patients (mean forced expiratory volume in one second 51.9% predicted) to pulmonary rehabilitation was compared between different ACE insertion/deletion polymorphism genotypes. In a second, independent COPD cohort (n=373), baseline characteristics and response to pulmonary rehabilitation were compared between COPD patients who were or were not taking ACE inhibitors or angiotensin receptor antagonists (ARB). RESULTS: In study 1, the incremental shuttle walk distance improved to a similar extent in all three genotypes; DD/ID/II (n=48/91/29) 69(67)m, 61 (76)m and 78 (78)m, respectively, (p>0.05). In study 2, fat free mass index was higher in those on ACE-I/ARB (n=130) than those who were not (n=243), 17.8 (16.0, 19.8) kg m-2 vs 16.5 (14.9, 18.4) kg/m2 (p<0.001). However change in fat free mass, walking distance or quality of life in response to pulmonary rehabilitation did not differ between groups. CONCLUSIONS: While these data support a positive association of ACE-I/ARB treatment and body composition in COPD, neither treatment to reduce ACE activity nor ACE (I/D) genotype influence response to pulmonary rehabilitation.

Novel diagnostic and prognostic biomarkers in biliary tract cancer.

INTRODUCTION: The worldwide incidence of biliary tract carcinoma (BTC, tumours of the bile ducts and gall-bladder) continues to rise, with the only potentially curative treatment remaining surgical resection or transplantation, possible in only a minority of patients. Late presentation and a paucity of effective treatments mandate the development of techniques for early lesion detection. AREAS COVERED: This article reviews currently available biomarkers for the diagnosis and prognosis of BTC, as well as recently published studies describing novel serum, bile and urinary biomarkers. EXPERT OPINION: The incorporation of novel analysis techniques, such as digital image analysis and fluorescence in situ hybridization, into existing management algorithms enhances the accuracy of brush cytology taken at the time of therapeutic endoscopy. However, a key goal is the discovery of reliable non-invasive biomarkers with high sensitivity and specificity. Recent advances in gene sequencing and expression, clonal evolution and tumour heterogeneity in other cancers should advance understanding of BTC tumour biology and facilitate biomarker discovery.

No evidence for a local renin-angiotensin system in liver mitochondria.

The circulating, endocrine renin-angiotensin system (RAS) is important to circulatory homeostasis, while ubiquitous tissue and cellular RAS play diverse roles, including metabolic regulation. Indeed, inhibition of RAS is associated with improved cellular oxidative capacity. Recently it has been suggested that an intra-mitochondrial RAS directly impacts on metabolism. Here we sought to rigorously explore this hypothesis. Radiolabelled ligand-binding and unbiased proteomic approaches were applied to purified mitochondrial sub-fractions from rat liver, and the impact of AngII on mitochondrial function assessed. Whilst high-affinity AngII binding sites were found in the mitochondria-associated membrane (MAM) fraction, no RAS components could be detected in purified mitochondria. Moreover, AngII had no effect on the function of isolated mitochondria at physiologically relevant concentrations. We thus found no evidence of endogenous mitochondrial AngII production, and conclude that the effects of AngII on cellular energy metabolism are not mediated through its direct binding to mitochondrial targets.

Duration of preceding hypertension is associated with prolonged length of ICU stay.

BACKGROUND: A substantial proportion of patients suffer prolonged length of intensive care unit stay (PLOS) or prolonged mechanical ventilation (PMV) following coronary artery bypass grafting (CABG). Identifying factors associated with PLOS and PMV would aid in patient risk stratification. We sought to identify the factors associated with PLOS and PMV following CABG. METHODS: Participants were patients undergoing first-time elective CABG. All were observed until discharge and clinical data were collected on a standardized proforma. PLOS and PMV were defined a priori as >2 days and >12 h respectively, based on centre norms. RESULTS: Of the 439 patients in the study, 105 (23.9%) had PLOS and 111 (25.2%) had PMV. Independent predictors of PMV were age, diabetes, previous myocardial infarction (MI), New York Heart Association (NYHA) class and statin use. The only independent predictor of PLOS was the duration of preceding hypertension. CONCLUSION: The factors associated with PMV and PLOS in our study are easily attainable, routine clinical details and may be built into bed management algorithms. Confirmation of the association of preceding hypertension and subsequent investigation of the possible mechanism mediating this association, is suggested.

The ACE gene and human performance: 12 years on.

Some 12 years ago, a polymorphism of the angiotensin I-converting enzyme (ACE) gene became the first genetic element shown to impact substantially on human physical performance. The renin-angiotensin system (RAS) exists not just as an endocrine regulator, but also within local tissue and cells, where it serves a variety of functions. Functional genetic polymorphic variants have been identified for most components of RAS, of which the best known and studied is a polymorphism of the ACE gene. The ACE insertion/deletion (I/D) polymorphism has been associated with improvements in performance and exercise duration in a variety of populations. The I allele has been consistently demonstrated to be associated with endurance-orientated events, notably, in triathlons. Meanwhile, the D allele is associated with strength- and power-orientated performance, and has been found in significant excess among elite swimmers. Exceptions to these associations do exist, and are discussed. In theory, associations with ACE genotype may be due to functional variants in nearby loci, and/or related genetic polymorphism such as the angiotensin receptor, growth hormone and bradykinin genes. Studies of growth hormone gene variants have not shown significant associations with performance in studies involving both triathletes and military recruits. The angiotensin type-1 receptor has two functional polymorphisms that have not been shown to be associated with performance, although studies of hypoxic ascent have yielded conflicting results. ACE genotype influences bradykinin levels, and a common gene variant in the bradykinin 2 receptor exists. The high kinin activity haplotye has been associated with increased endurance performance at an Olympic level, and similar results of metabolic efficiency have been demonstrated in triathletes. Whilst the ACE genotype is associated with overall performance ability, at a single organ level, the ACE genotype and related polymorphism have significant associations. In cardiac muscle, ACE genotype has associations with left ventricular mass changes in response to stimulus, in both the health and diseased states. The D allele is associated with an exaggerated response to training, and the I allele with the lowest cardiac growth response. In light of the I-allele association with endurance performance, it seems likely that other regulatory mechanisms exist. Similarly in skeletal muscle, the D allele is associated with greater strength gains in response to training, in both healthy individuals and chronic disease states. As in overall performance, those genetic polymorphisms related to the ACE genotype, such as the bradykinin 2 gene, also influence skeletal muscle strength. Finally, the ACE genotype may influence metabolic efficiency, and elite mountaineers have demonstrated an excess of I alleles and I/I genotype frequency in comparison to controls. Interestingly, this was not seen in amateur climbers. Corroboratory evidence exists among high-altitude settlements in both South America and India, where the I allele exists in greater frequency in those who migrated from the lowlands. Unfortunately, if the ACE genotype does influence metabolic efficiency, associations with peak maximal oxygen consumption have yet to be rigorously demonstrated. The ACE genotype is an important but single factor in the determinant of sporting phenotype. Much of the mechanisms underlying this remain unexplored despite 12 years of research.

Genetic influences in sport and physical performance.

The common inheritance of approximately 20 000 genes defines each of us as human. However, substantial variation exists between individual human genomes, including 'replication' of gene sequences (copy number variation, tandem repeats), or changes in individual base pairs (mutations if <1% frequency and single nucleotide polymorphisms if >1% frequency). A vast array of human phenotypes (e.g. muscle strength, skeletal structure, tendon elasticity, and heart and lung size) influences sports performance, each itself the result of a complex interaction between a myriad of anatomical, biochemical and physiological systems. This article discusses the role for genetic influences in influencing sporting performance and injury, offering specific exemplars where these are known. Many of these preferable genotypes are uncommon, and their combination even rarer. In theory, the chances of an individual having a perfect sporting genotype are much lower than 1 in 20 million - as the number of associated polymorphisms increase, the odds decrease correspondingly. Many recently discovered polymorphisms that may affect sports performance have been described in animal or other human based models, and have been included in this review if they may apply to athletic populations. Muscle performance is heavily influenced by basal muscle mass and its dynamic response to training. Genetic factors account for approximately 50-80% of inter-individual variation in lean body mass, with impacts detected on both 'training-naive' muscle mass and its growth response. Several cytokines such as interleukin-6 and -15, cilliary neurotrophic factor and insulin-like growth factor (IGF) have myoanabolic effects. Genotype-associated differences in endocrine function, necessary for normal skeletal muscle growth and function, may also be of significance, with complex interactions existing between thyroxine, growth hormone and the downstream regulators of the anabolic pathways (such as IGF-1 and IGF-2). Almost 200 polymorphisms are known to exist in the vitamin D receptor (VDR) gene. VDR genotype is associated with differences in strength in premenopausal women. VDR expression decreases with age and VDR genotype is associated with fat-free mass and strength in elderly men and women. Muscle fibre type determination is complex. Whilst initial composition is likely to be strongly influenced by genetic factors, training has significant effects on fibre shifts. Polymorphisms of the peroxisome proliferator-activated receptor α (PPARα) gene and R577x polymorphism of the ACTN3 gene are both associated with specific fibre compositions. Alterations in cardiac size have been associated with both increased performance and excess cardiovascular mortality. PPARα is a ligand-activated transcription factor that regulates genes involved in fatty acid uptake and oxidation, lipid metabolism and inflammation. Psychology plays an important role in training, competition, tolerance of pain and motivation. However, the role of genetic variation in determining psychological state and responses remains poorly understood; only recently have specific genes been implicated in motivational behaviour and maintenance of exercise. Thyroid hormone receptors exist within the brain and influence both neurogenesis and behaviour. With the current state of knowledge, the field of genetic influences on sports performance remains in its infancy, despite over a decade of research.

Acute pancreatitis.

PURPOSE OF REVIEW: To review advances over the last year in the prevention, diagnosis and management of acute pancreatitis. RECENT FINDINGS: Obesity is an independent risk factor for severity in acute pancreatitis, and heavy alcohol consumption for the development of necrosis in severe acute pancreatitis. Biochemical markers have been further tested, including carbohydrate-deficient transferrin for the diagnosis of alcohol-induced acute pancreatitis, urinary trypsinogen-2 as a diagnostic marker for acute pancreatitis, and interleukin-6 and procalcitonin as markers of disease severity. A new, simple stratification system, the 'panc 3 score', has been described. There are conflicting data on the use of antibiotic prophylaxis in acute necrotizing pancreatitis, and on the chemoprevention of postendoscopic retrograde cholangiopancreatography pancreatitis. Enteral feeding is established as standard practice early in the management of acute pancreatitis of all aetiologies; probiotics and other compounds may also play a role. SUMMARY: Over the last year, there have been further innovations in the risk stratification and management of acute pancreatitis. Unresolved issues include chemoprevention of endoscopic retrograde cholangiopancreatography-induced acute pancreatitis, the indications for antibiotic prophylaxis in severe acute pancreatitis and nutritional supplementation with probiotics and synbiotics.