Michael Larvin

APACHE-II SCORE FOR ASSESSMENT AND MONITORING OF ACUTE PANCREATITIS

The value of the Acute Physiology and Chronic Health Enquiry (APACHE-II) score, the Simplified Acute Physiology score, and the Medical Research Council (MRC) sepsis score were compared with clinical assessment and Ranson and Imrie scores in the evaluation and monitoring of acute pancreatitis in 290 attacks. Attacks were graded mild (231) if uncomplicated, or severe (59) when major organ failure or a pancreatic collection occurred. Only APACHE-II scores were available at the time of admission; they correctly predicted outcome in 77% of attacks and identified 63% of severe attacks, compared with 44% achieved by clinical assessment. After 48 h, APACHE-II was most accurate, and correctly predicted outcome in 88% of attacks, compared with 69% for Ranson and 84% for Imrie scores. APACHE-II predicted 73% of pancreatic collections at 48 h, compared with 65% for Ranson and 58% for Imrie scores. In acute pancreatitis, APACHE-II may facilitate rapid selection of patients for intensive therapy or clinical trials, improve comparison between groups of patients, and indicate that a pancreatic collection is probable.

Sarcopenia, dynapenia, and the impact of advancing age on human skeletal muscle size and strength; a quantitative review.

Changing demographics make it ever more important to understand the modifiable risk factors for disability and loss of independence with advancing age. For more than two decades there has been increasing interest in the role of sarcopenia, the age-related loss of muscle or lean mass, in curtailing active and healthy aging. There is now evidence to suggest that lack of strength, or dynapenia, is a more constant factor in compromised wellbeing in old age and it is apparent that the decline in muscle mass and the decline in strength can take quite different trajectories. This demands recognition of the concept of muscle quality; that is the force generating per capacity per unit cross-sectional area (CSA). An understanding of the impact of aging on skeletal muscle will require attention to both the changes in muscle size and the changes in muscle quality. The aim of this review is to present current knowledge of the decline in human muscle mass and strength with advancing age and the associated risk to health and survival and to review the underlying changes in muscle characteristics and the etiology of sarcopenia. Cross-sectional studies comparing young (18–45 years) and old (>65 years) samples show dramatic variation based on the technique used and population studied. The median of values of rate of loss reported across studies is 0.47% per year in men and 0.37% per year in women. Longitudinal studies show that in people aged 75 years, muscle mass is lost at a rate of 0.64–0.70% per year in women and 0.80–00.98% per year in men. Strength is lost more rapidly. Longitudinal studies show that at age 75 years, strength is lost at a rate of 3–4% per year in men and 2.5–3% per year in women. Studies that assessed changes in mass and strength in the same sample report a loss of strength 2–5 times faster than loss of mass. Loss of strength is a more consistent risk for disability and death than is loss of muscle mass.

Preoperative hematologic markers as independent predictors of prognosis in resected pancreatic ductal adenocarcinoma: neutrophil-lymphocyte versus platelet-lymphocyte ratio

BACKGROUND The objective of this study was to investigate whether the preoperative hematologic markers, the platelet-lymphocyte ratio (PLR), or the neutrophil-lymphocyte ratio (NLR) ratio are significant prognostic indicators in resected pancreatic ductal adenocarcinoma. METHODS A total of 84 patients undergoing pancreatoduodenectomy for pancreatic ductal adenocarcinoma over a 10-year period were identified from a retrospectively maintained database. RESULTS The preoperative NLR was found to be a significant prognostic marker (P = .023), whereas PLR had no significant relationship with survival (P = .642) using univariate Cox survival analysis. The median overall survival in patients with an NLR of < or =3.0 (n = 55) was 13.7, 17.0 months in those with an NLR of 3.0 to 4.0 (n = 17) and 5.9 months in patients with a value of >4.0 (n = 12) (log rank, P = .016). The NLR retained its significance on multivariate analysis (P = .039) along with resection margin status (P = .001). CONCLUSION The preoperative NLR represents a significant independent prognostic indicator in patients with resected pancreatic ductal adenocarcinoma, whereas PLR does not.

Intestinal hypoperfusion contributes to gut barrier failure in severe acute pancreatitis.

Intestinal barrier failure and subsequent bacterial translocation have been implicated in the development of organ dysfunction and septic complications associated with severe acute pancreatitis. Splanchnic hypoperfusion and ischemia/reperfusion injury have been postulated as a cause of increased intestinal permeability. The urinary concentration of intestinal fatty acid binding protein (IFABP) has been shown to be a sensitive marker of intestinal ischemia, with increased levels being associated with ischemia/reperfusion. The aim of the current study was to assess the relationship between excretion of IFABP in urine, gut mucosal barrier failure (intestinal hyperpermeability and systemic exposure to endotoxemia), and clinical severity. Patients with a clinical and biochemical diagnosis of acute pancreatitis were studied within 72 hours of onset of pain. Polyethylene glycol probes of 3350 kDa and 400 kDa were administered enterally, and the ratio of the percentage of retrieval of each probe after renal excretion was used as a measure of intestinal macromolecular permeability. Collected urine was also used to determine the IFABP concentration (IFABP-c) and total IFABP (IFABP-t) excreted over the 24-hour period, using an enzyme-linked immun-osorbent assay technique. The systemic inflammatory response was estimated from peak 0 to 72-hour plasma C-reactive protein levels, and systemic exposure to endotoxins was measured using serum IgM en-dotoxin cytoplasmic antibody (EndoCAb) levels. The severity of the attack was assessed on the basis of the Atlanta criteria. Sixty-one patients with acute pancreatitis (severe in 19) and 12 healthy control subjects were studied. Compared to mild attacks, severe attacks were associated with significantly higher urinary IFABP-c (median 1092 pg/ml vs. 84 pg/ml; P < 0.001) and IFABP-t (median 1.14 μg vs. 0.21 |μg; P = 0.003). Furthermore, the control group had significantly lower IFABP-c (median 37 pg/ml; P = 0.029) and IFABP-t (median 0.06 μg; P = 0.005) than patients with mild attacks. IFABP correlated positively with the polyethylene glycol 3350 percentage retrieval (r = 0.50; P < 0.001), CRP (r = 0.51; P < 0.001), and inversely with serum IgM EndoCAb levels (r = —0.32; P = 0.02). The results of this study support the hypothesis that splanchnic hypoperfusion contributes to the loss of intestinal mucosal integrity associated with a severe attack of pancreatitis.

Knockdown of microRNA-21 Inhibits Proliferation and Increases Cell Death by Targeting Programmed Cell Death 4 (PDCD4) in Pancreatic Ductal Adenocarcinoma

ObjectiveThis study aims to examine the expression of a panel of five microRNAs (miRNA) in pancreatic ductal adenocarcinoma (PDAC) and the functional effect of miR-21 inhibition in PDAC cell lines.BackgroundmiRNA are short, non-coding RNA molecules, which play important roles in several cellular processes by silencing expression of their target genes through translational repression or mRNA degradation. They are often aberrantly expressed in cancer, and this dysregulation can promote carcinogenesis by altering the expression of tumour suppressor or oncogenes.MethodsmiRNA expression levels were measured in 24 PDAC tumour/matched adjacent normal tissue samples and three PDAC cell lines using reverse transcription polymerase chain reaction. Levels of cell proliferation and death and expression of programmed cell death 4 (PDCD4; tumour suppressor) were studied in PDAC cells (MIA-Pa-Ca-2) in the absence or presence of a miR-21 inhibitor.ResultsPDAC primary tissues and cell lines displayed a consistent upregulation of miR-21 (P < 0.0001) and downregulation of both miR-148a (P < 0.0001) and miR-375 (P < 0.0001) relative to adjacent normal tissue. Furthermore, miR-21 levels in the primary tumours correlated with disease stage (P < 0.0001). Inhibition of miR-21 in MIA-Pa-Ca-2 PDAC cells led to reduced cell proliferation (P < 0.01) and increased cell death (P < 0.01), with simultaneous increase in levels of the tumour suppressor, PDCD4 (P < 0.01).ConclusionmiRNA expression profiles may be used as biomarkers for detecting pancreatic cancer. Moreover, miR-21 could be a predictor of disease progression and a possible therapeutic target in part by upregulating PDCD4 in pancreatic cancer.

Cannabinoids mediate opposing effects on inflammation‐induced intestinal permeability

BACKGROUND AND PURPOSE Activation of cannabinoid receptors decreases emesis, inflammation, gastric acid secretion and intestinal motility. The ability to modulate intestinal permeability in inflammation may be important in therapy aimed at maintaining epithelial barrier integrity. The aim of the present study was to determine whether cannabinoids modulate the increased permeability associated with inflammation in vitro.

Small RNA: A Large Contributor to Carcinogenesis?

IntroductionHomeostasis in normal tissue includes balancing cell proliferation and apoptosis (programmed cell death). Mutations in proto-oncogenes or tumor suppressor genes may lead to disruption of normal cellular function, uncontrolled cell proliferation, and subsequent carcinogenesis.DiscussionMicro-RNAs (miRNAs) are short (19–24 nucleotide) noncoding RNA sequences that inhibit protein translation and can cause the degradation of subsequent messenger RNA, thus playing an important role in the regulation of gene expression. Aberrant expression of miRNAs has been shown to inhibit tumor suppressor genes or inappropriately activate oncogenes initiating the cancer process. Unique miRNA expression profiles have been found in different cancer types at different stages, suggesting a possible diagnostic application. This review summarizes the current evidence supporting a link between aberrant miRNA expression and carcinogenesis and its possible role in improving diagnosis and treatment of cancers, particularly of gastrointestinal origin.

Genetic Polymorphisms of GSTT1, GSTM1, GSTP1, MnSOD, and Catalase in Nonhereditary Chronic Pancreatitis: Evidence of Xenobiotic Stress and Impaired Antioxidant Capacity

Epidemiological studies have demonstrated a variety of potential environmental factors that may alter susceptibility to chronic pancreatitis (CP) through oxidative/xenobiotic stress; however, a direct causal and mechanistic role has not been established. We aimed (1) to determine the prevalence of functional genetic polymorphisms in the antioxidant enzymes, glutathione S-transferase GSTM-1, GSTP-1, and GSTT-1, manganese superoxide dismutase, and catalase in CP and (2) to reveal evidence of oxidative stress in patients with CP by measuring whole-blood glutathione redox status. In total, 122 patients with CP (75 alcohol-induced [AlCP], 33 idiopathic [ICP], and 13 hereditary) and 245 age- and sex-matched controls were recruited. The prevalence of the functional GSTT-1 genotype (GSTT-1*A) was significantly higher in CP (88.5%) compared to healthy controls (76%; χ2 = 7.26, P = 0.007). Stratification to disease etiology demonstrated that the GSTT-1*A genotype was also significantly more prevalent among patients with ICP (94%; P = 0.02; 95% CI, 0.04–9.16) but not in those with AlCP. In 22 patients with stable CP, the whole-blood glutathione concentration (median [IQR]: 72 μmol/L [21–181 μmol/L]) and the glutathione redox ratio (GSH/GSSG) (median [IQR]: 9 (3–77]) were significantly reduced compared to those in 20 healthy volunteers (median [IQR]: 815 μmol/L [679–1148 μmol/L], P < 0.001, and 96 [52–347], P = 0.005, respectively). We conclude that the GSTT-1 functional genotype is associated with ICP. Evidence of altered glutathione redox status suggests that this disease modification may be a consequence of oxidative stress or the bioactivation of xenobiotics.

The SPINK1 N34S variant is associated with acute pancreatitis

Objective Acute pancreatitis (AP) is a disease whose pathogenesis remains largely obscure. Genetic research has focussed attention upon the role of the pancreatic protease/protease inhibitor system. The aim of this study was to investigate the prevalence of genetic variants of the trypsin inhibitor, SPINK1, in acute pancreatitis. Methods We genotyped 468 patients with AP and 1117 healthy controls for SPINK1 alterations by single-strand conformation polymorphism analysis and by melting curve analysis using fluorescence resonance energy transfer probes. Results The c.101A>G (p.N34S) variant was detected in 24/936 alleles of patients and in 18/2234 alleles of healthy controls (odds ratio=3.240; 95% confidence interval: 1.766–5.945; P<0.001). In the UK patients, the mean age of patients with N34S was 11.9 years younger compared with N34S negative patients (P=0.023), but this was not apparent in the German patients. Allele frequencies for the c.163C>T (p.P55S) variant did not differ between patients and controls. Conclusion The SPINK1 N34S variant is associated with acute pancreatitis. This supports the importance of premature protease activation in the pathogenesis of AP and suggests that mutated SPINK1 may predispose certain individuals to develop this disease.

Clinical Presentation and Delayed Treatment of Cholangitis in Older People

Acute cholangitis is more common in older people, and increasing age is a determinant of morbidity and mortality, as is early biliary decompression by ERCP. This study aims to identify factors that may contribute to delays in the diagnosis and treatment of older people with acute cholangitis. Case notes of 122 patients (45 aged < 75 years, 77 > 75 years) with a final diagnosis of acute cholangitis who underwent ERCP were reviewed for presenting clinical features (pain, jaundice, rigors, fever, falls, incontinence, confusion), liver function tests, blood count, and the interval from admission to diagnosis, ultrasonography, and ERCP. The most common symptom at presentation was abdominal pain (81%), followed by jaundice (55%). These symptoms were no less common in older patients. Charcots triad was present in only 15.6% of young and 18.8% of older patients. Jaundice was not detected in 16% of significantly hyperbilirubinemic older patients, but only the presence of functional symptoms was associated with significant diagnostic delay (median, 1 day [range: 0–11] vs. 9.5 days [3–25]; P< 0.001) and delay in performing ERCP (median: 4 days [0–24] vs. 16.5 days [2–29], P< 0.001). Overall mortality was 10%, and the incidence of septic shock was similar in both groups. Charcots classical triad is infrequent in patients suffering from acute cholangitis. Given the greater difficulty assessing jaundice in older people and the confounding effect of falls, incontinence, and confusion, a routine policy of liver function tests, with further investigation of abnormal results in such presentations, may reduce delays in diagnosing and treating acute cholangitis.