Maria Schipper

Randomized controlled trials of antibiotic prophylaxis in severe acute pancreatitis: Relationship between methodological quality and outcome

Aim: To evaluate the methodological quality of randomized controlled trials (RCTs) of systemic antibiotic prophylaxis in severe acute pancreatitis in relation to outcome. Methods: The MEDLINE, EMBASE and Cochrane databases were searched for RCTs that studied the effectiveness of systemic antibiotic prophylaxis in severe acute pancreatitis. A meta-analysis was performed with a random effects model. Methodological quality was quantified by a previously published scoring system (range 0–17 points). Results: Six studies, with a total of 397 participants, obtained a methodological score of at least 5 points and were included. Systemic antibiotic prophylaxis had no significant effect on infection of pancreatic necrosis (absolute risk reduction (ARR) 0.055; 95% CI –0.084 to 0.194) and mortality (ARR 0.058, 95% CI –0.017 to 0.134). Spearman correlation showed an inverse association between methodological quality and ARR for mortality (correlation coefficient –0.841, p = 0.036). Conclusions: The inverse relationship between methodological quality and impact of antibiotic prophylaxis on mortality emphasizes the importance of high-quality RCTs. At present, adequate evidence for the routine use of antibiotic prophylaxis in severe acute pancreatitis is lacking.

Candidate genotypes associated with functional dyspepsia

Abstract  There is accumulating evidence of a genetic predisposition for developing a functional gastrointestinal (GI) disorder. Identification of the genetic factors may improve understanding of underlying pathophysiological mechanisms. We aimed to test the association of functional polymorphisms in genes involved in serotonergic signalling and G‐protein‐mediated signal transduction, both affecting gastroduodenal sensory and motor function, with functional dyspepsia (FD). FD patients, send to our tertiary referral centre, were studied (n = 112). Healthy controls (n = 336) free of GI symptoms were matched 1 : 3 for age and gender. Polymorphisms in genes encoding the serotonin receptor type three A subunit (HTR3A), the serotonin transporter (SERT) and the G‐protein β3 subunit (GNB3) were analysed. The FD patients displayed a higher prevalence of the T allele of the GNB3 C825T polymorphism compared to healthy controls (OR = 1.60, 95% CI: 1.03–2.49, P = 0.038). No association between FD and the genotype of the insertion/deletion polymorphism in the promoter of SERT (SERT‐P) or HTR3A C178T polymorphism was observed. Tertiary referral FD is associated with the 825T allele of the GNB3 gene. The increased signal transduction associated with this allele may contribute to the abnormalities in gastroduodenal sensory and motor function observed in FD.

Regional differences in expression of TPH‐1, SERT, 5‐HT3 and 5‐HT4 receptors in the human stomach and duodenum

Abstract  The aim of this study was to increase the understanding of the role of serotonergic signalling in normal gastroduodenal function at a molecular level.

The complex of the insect LDL receptor homolog, lipophorin receptor, LpR, and its lipoprotein ligand does not dissociate under endosomal conditions

The insect low‐density lipoprotein (LDL) receptor (LDLR) homolog, lipophorin receptor (LpR), mediates endocytic uptake of the single insect lipoprotein, high‐density lipophorin (HDLp), which is structurally related to LDL. However, in contrast to the fate of LDL, which is endocytosed by LDLR, we previously demonstrated that after endocytosis, HDLp is sorted to the endocytic recycling compartment and recycled for resecretion in a transferrin‐like manner. This means that the integrity of the complex between HDLp and LpR is retained under endosomal conditions. Therefore, in this study, the ligand‐binding and ligand‐dissociation capacities of LpR were investigated by employing a new flow cytometric assay, using LDLR as a control. At pH 5.4, the LpR–HDLp complex remained stable, whereas that of LDLR and LDL dissociated. Hybrid HDLp‐binding receptors, containing either the β‐propeller or both the β‐propeller and the hinge region of LDLR, appeared to be unable to release ligand at endosomal pH, revealing that the stability of the complex is imparted by the ligand‐binding domain of LpR. The LpR–HDLp complex additionally appeared to be EDTA‐resistant, excluding a low Ca2+ concentration in the endosome as an alternative trigger for complex dissociation. From binding of HDLp to the above hybrid receptors, it was inferred that the stability upon EDTA treatment is confined to LDLR type A (LA) ligand‐binding repeats 1–7. Additional (competition) binding experiments indicated that the binding site of LpR for HDLp most likely involves LA‐2–7. It is therefore proposed that the remarkable stability of the LpR–HDLp complex is attributable to this binding site. Together, these data indicate that LpR and HDLp travel in complex to the endocytic recycling compartment, which constitutes a key determinant for ligand recycling by LpR.

Inflammatory Gene Haplotype-Interaction Networks Involved in Coronary Collateral Formation

Objectives: Formation of collateral circulation is an endogenous response to atherosclerosis, and is a natural escape mechanism by re-routing blood. Inflammatory response- related genes underlie the formation of coronary collaterals. We explored the genetic basis of collateral formation in man postulating interaction networks between functional Single Nucleotide Polymorphisms (SNPs) in these inflammatory gene candidates. Methods: The contribution of 41 genes as well as the interactions among them was examined in a cohort of 226 coronary artery disease patients, genotyped for 54 candidate SNPs. Patients were classified to the extent of collateral circulation. Stepwise logistic regression analysis and a haplotype entropy procedure were applied to search for haplotype interactions among all 54 polymorphisms. Multiple testing was addressed by using the false discovery rate (FDR) method. Results: The population comprised 84 patients with and 142 without visible collaterals. Among the 41 genes, 16 pairs of SNPs were implicated in the development of collaterals with the FDR of 0.19. Nine SNPs were found to potentially have main effects on collateral formation. Two sets of coupling haplotypes that predispose to collateral formation were suggested. Conclusions: These findings suggest that collateral formation may arise from the interactions between several SNPs in inflammatory response related genes, which may represent targets in future studies of collateral formation. This may enhance developing strategies for risk stratification and therapeutic stimulation of arteriogenesis.

Serotonergic signalling in the stomach and duodenum of patients with gastroparesis

Abstract  Serotonin (5‐HT) is involved in the regulation of motoric and sensory functions of the upper gastrointestinal tract. The aim of the current study was to determine whether serotonergic signalling is altered in patients with idiopathic gastroparesis. Mucosal biopsy specimens were collected from the duodenum, antrum and fundus of 11 patients with idiopathic gastroparesis and 11 healthy controls. Neuroendocrine cells, specifically 5‐HT producing cells, were counted after immunohistochemistry, and non‐neuronal mRNA expression levels of tryptophan hydroxylase (TPH)‐1, 5‐HT transport protein (SERT), 5‐HT3 and 5‐HT4 receptor were quantified by real time RT‐PCR. The number of 5‐HT producing cells was comparable between patients and controls. No difference in expression of TPH‐1 (rate limiting enzyme in 5‐HT biosynthetic pathway) and SERT (responsible for 5‐HT uptake) was found between patients and controls (P > 0.05). In the duodenum, the expression of the 5‐HT3 receptor subunits and the 5‐HT4 receptor was comparable between both groups. However, the 5‐HT4(c) splice variant was expressed more abundantly in healthy controls compared to patients (P = 0.015). This study suggests that the delayed gastric emptying and upper abdominal symptoms in idiopathic gastroparesis do not result from altered mucosal 5‐HT biosynthetic and uptake capacity.

SEQUENTIAL ANALYSIS OF ENVIRONMENTAL MONITORING DATA: OPTIMAL SPRTs

Data provided by an environmental monitoring system are sampled successively. We propose to analyse such data by means of the sequential probability ratio test (SPRT) which is especially designed to analyse data which are sampled consecutively. We present a method, the minimax method, that can be used to select an SPRT which is optimal in testing the null hypothesis θ = θ0 against the composite alternative hypothesis θ ≠ θ0 for three monitoring systems, namely a system consisting of one sampling location with known mean and variance, a system consisting of one sampling location with unknown mean and variance and a system consisting of two sampling locations with unknown mean and covariance matrix. The latter test is applied to field data of the mallard.

Sequential Analysis of Environmental Monitoring Data: Refined SPRT's for Testing against a Minimal Relevant Trend

Environmental monitoring data are collected successively in time. Therefore, it is self evident to think about analyzing the data sequentially. We propose the use of a sequential probability ratio test (SPRT), developed to test against a simple hypothesis, to test against a minimal relevant trend 01 (i.e., a composite hypothesis). Three refinements are introduced: the boundaries An and Bn are made funnel shaped, 01 is replaced by 0 if the norm of 0 exceeds the norm of 01, and observation is stopped as soon as a predescribed accuracy is attained. Simulation studies show that these refinements generalize the SPRT for testing against a composite hypothesis and improve the performance in terms of power and expected sample size of the test. The robustness of the adjusted SPRT against spatial and serial correlation is studied. We demonstrate that the test is robust against serial correlation between -.5 and +.5 and spatial correlation between -.5 and +.2. The use of the SPRT is illustrated with filed data on three Tern species-the Sandwich Tern, the Arctic Tern, and the Common Tern.

Making sequential analysis of environmental monitoring data feasible by simplifying the covariance matrix structure

As environmental monitoring data are collected successively in time, the data are suitable for sequential analysis. An earlier article proposed a refined sequential probability ratio test (SPRT) to test against a minimal relevanttrend, assuming no serial correlations and without modeling the spatial covariance matrix. As the model parameters are unknown in advance, a minimal number of observations(nmin) is required for estimation prior to analysis. Leaving the spatial covariance matrix unstructured, nmin increases if the number of sampling locations increases. Therefore, assumptions on the spatial covariance matrix are proposed, thereby reducing the number of nuisance parameters, thus reducingnmin. This article studies. three simple types of spatial covariance matrix structures and derives an adjusted SPRT for each of these types. Furthermore, we examine the robustness against deviations from the assumed spatial covariance matrix structure. Simulation studies show that adjusted SPRTs can be derived rather easily and that they are in general robust against deviations from the assumed type of spatial covariance matrix. Sequential analysis of simulated data, which are based on monitoring data of bats in the Netherlands, illustrates the use of one of the derived SPRTs.