Greg O'Grady

Postoperative ileus: mechanisms and future directions for research

Postoperative ileus (POI) is an abnormal pattern of gastrointestinal motility characterized by nausea, vomiting, abdominal distension and/or delayed passage of flatus or stool, which may occur following surgery. Postoperative ileus slows recovery, increases the risk of developing postoperative complications and confers a significant financial load on healthcare institutions. The aim of the present review is to provide a succinct overview of the clinical features and pathophysiological mechanisms of POI, with final comment on selected directions for future research.Terminology used when describing POI is inconsistent, with little differentiation made between the obligatory period of gut dysfunction seen after surgery (‘normal POI’) and the more clinically and pathologically significant entity of a ‘prolonged POI’. Both normal and prolonged POI represent a fundamentally similar pathophysiological phenomenon. The aetiology of POI is postulated to be multifactorial, with principal mediators being inflammatory cell activation, autonomic dysfunction (both primarily and as part of the surgical stress response), agonism at gut opioid receptors, modulation of gastrointestinal hormone activity and electrolyte derangements. A final common pathway for these effectors is impaired contractility and motility and gut wall oedema. There are many potential directions for future research. In particular, there remains scope to accurately characterize the gastrointestinal dysfunction that underscores an ileus, development of an accurate risk stratification tool will facilitate early implementation of preventive measures and clinical appraisal of novel therapeutic strategies that target individual pathways in the pathogenesis of ileus warrant further investigation.

Tissue-Specific Mathematical Models of Slow Wave Entrainment in Wild-Type and 5-HT2B Knockout Mice with Altered Interstitial Cells of Cajal Networks

Gastrointestinal slow waves are generated within networks of interstitial cells of Cajal (ICCs). In the intact tissue, slow waves are entrained to neighboring ICCs with higher intrinsic frequencies, leading to active propagation of slow waves. Degradation of ICC networks in humans is associated with motility disorders; however, the pathophysiological mechanisms of this relationship are uncertain. A recently developed biophysically based mathematical model of ICC was adopted and updated to simulate entrainment of slow waves. Simulated slow wave propagation was successfully entrained in a one-dimensional model, which contained a gradient of intrinsic frequencies. Slow wave propagation was then simulated in tissue models which contained a realistic two-dimensional microstructure of the myenteric ICC networks translated from wild-type (WT) and 5-HT(2B) knockout (degraded) mouse jejunum. The results showed that the peak current density in the WT model was 0.49 muA mm(-2) higher than the 5-HT(2B) knockout model, and the intracellular Ca(2+) density after 400 ms was 0.26 mM mm(-2) higher in the WT model. In conclusion, tissue-specific models of slow waves are presented, and simulations quantitatively demonstrated physiological differences between WT and 5-HT(2B) knockout models. This study provides a framework for evaluating how ICC network degradation may impair slow wave propagation and ultimately motility and transit.

A Tissue Framework for Simulating the Effects of Gastric Electrical Stimulation and In Vivo Validation

Gastric pacing is used to modulate normal or abnormal gastric slow-wave activity for therapeutic purposes. New protocols are required that are optimized for motility outcomes and energy efficiency. A computational tissue model was developed, incorporating smooth muscle and interstitial cell of Cajal layers, to enable predictive simulations of slow-wave entrainment efficacy under different pacing frequencies. Concurrent experimental validation was performed via high-resolution entrainment mapping in a porcine model (bipolar pacing protocol: 2 mA amplitude; 400 ms pulsewidth; 17-s period; midcorpus). Entrained gastric slow-wave activity was found to be anisotropic (circular direction: 8.51 mmmiddots-1; longitudinal: 4.58 mmmiddots -1), and the simulation velocities were specified accordingly. Simulated and experimental slow-wave activities demonstrated satisfactory agreement, showing similar propagation patterns and frequencies (3.5-3.6 cycles per minute), and comparable zones of entrainment (ZOEs; 64 cm 2). The area of ZOE achieved was found to depend on the phase interactions between the native and entrained activities. This model allows the predictions of phase interactions between native and entrained activities, and will be useful for determining optimal frequencies for gastric pacing, including multichannel pacing studies. The model provides a framework for the development of more sophisticated predictive gastric pacing simulations in future.

Numerical metrics for automated quantification of interstitial cell of Cajal network structural properties

Depletion of interstitial cells of Cajal (ICC) networks is known to occur in several gastrointestinal motility disorders. Although confocal microscopy can effectively image and visualize the spatial distribution of ICC networks, current descriptors of ICC depletion are limited to cell numbers and volume computations. Spatial changes in ICC network structural properties have not been quantified. Given that ICC generate electrical signals, the organization of a network may also affect physiology. In this study, six numerical metrics were formulated to automatically determine complex ICC network structural properties from confocal images: density, thickness, hole size, contact ratio, connectivity and anisotropy. These metrics were validated and applied in proof-of-concept studies to quantitatively determine jejunal ICC network changes in mouse models with decreased (5-HT2B receptor knockout (KO)) and normal (Ano1 KO) ICC numbers, and during post-natal network maturation. Results revealed a novel remodelling phenomenon occurring during ICC depletion, namely a spatial rearrangement of ICC and the preferential longitudinal alignment. In the post-natal networks, an apparent pruning of the ICC network was demonstrated. The metrics developed here enabled the first detailed quantitative analyses of structural changes that may occur in ICC networks during depletion and development.

A framework for the online analysis of multi-electrode gastric slow wave recordings

High resolution mapping of electrical activity is becoming an important technique for analysing normal and dysrhythmic gastrointestinal (GI) slow wave activity. Several methods are used to extract meaningful information from the large quantities of data obtained, however, at present these methods can only be used offline. Thus, all analysis currently performed is retrospective and done after the recordings have finished. Limited information about the quality or characteristics of the data is therefore known while the experiments take place. Building on these offline analysis methods, an online implementation has been developed that identifies and displays slow wave activations working alongside an existing recording system. This online system was developed by adapting existing and novel signal processing techniques and linking these to a new user interface to present the extracted information. The system was tested using high resolution porcine data, and will be applied in future high resolution mapping studies allowing researchers to respond in real time to experimental observations.

A Theoretical Analysis of Electrogastrography (EGG) Signatures Associated With Gastric Dysrhythmias

Routine screening and accurate diagnosis of chronic gastrointestinal motility disorders represent a significant problem in current clinical practice. The electrogastrography (EGG) provides a noninvasive option for assessing gastric slow waves, as a means of diagnosing gastric dysrhythmias, but its uptake in motility practice has been limited partly due to an incomplete sensitivity and specificity. This paper presents the development of a human whole-organ gastric model to enable virtual (in silico) testing of gastric electrophysiological dispersion in order to improve the diagnostic accuracy of EGG. The model was developed to simulate normal gastric slow wave conduction as well as three types of dysrhythmias identified in recent high-resolution gastric mapping studies: conduction block, re-entry, and ectopic pacemaking. The stomach simulations were then applied in a torso model to identify predicted EGG signatures of normal and dysrhythmic slow wave profiles. The resulting EGG data were compared using percentage differences and correlation coefficients. Virtual EGG channels that demonstrated a percentage difference over 100% and a correlation coefficient less than

Automated detection of gastric slow wave events and estimation of propagation velocity vector fields from serosal high-resolution mapping

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Systematic review of peri-operative prognostic biomarkers in pancreatic ductal adenocarcinoma

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Cellular automaton model for simulating tissue-specific intestinal electrophysiological activity

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A miniature power-efficient bidirectional telemetric platform for in-vivo acquisition of electrophysiological signals

0.5 for the ectopic pacemaker case) were further investigated for their specific distinguishing features. In particular, anatomical locations from the epigastric region and specific channel configurations were identified that could be used to clinically diagnose the three classes of human gastric dysrhythmia. These locations and channels predicted by simulations present a promising methodology for improving the clinical reliability and applications of EGG.