Rod Smallwood

Electrical arrhythmias in the human stomach.

Myoelectrical activity was recorded from the human antrum on 136 occasions using a monopolar mucosal electrode in preoperative and post-vagotomy patients, and bipolar serosal electrodes in post-cholecystectomy patients, and the incidence of antral arrhythmias observed. Arrhythmias of long duration were observed in five out of 62 patients after vagotomy and one out of 10 patients after cholecystectomy, but not in preoperative patients. They were characterised by slow waves with increased frequency, variable period, amplitude, and wave shape and were associated with periods of slow wave inhibition. None of the patients with an arrhythmia had any symptoms of disordered gastric motility. Antral arrhythmias could also be induced in some patients by the administration of insulin, secretin, cholecystokinin-pancreozymin, glucagon, and pentagastrin. The appearance of antral arrhythmias is probably due to a relative increase of sympathetic over parasympathetic activity. The maximal slow wave frequency observed was 8.3 cycles per minute and it is probable that in vivo human antral smooth muscle has a maximum frequency above which it cannot be driven.

Control of defecation in patients with spinal injuries by stimulation of sacral anterior nerve roots.

OBJECTIVE--To observe the effects of stimulation of the sacral anterior roots on anorectal and low colonic pressures and to programme implanted stimulators to produce defecation. DESIGN--Prospective study of 12 consecutive patients. SETTING--Spinal injuries unit and university gastrointestinal physiology department. PATIENTS--12 Patients with complete supraconal spinal cord lesions. Their injuries had been sustained at least two years before the study. INTERVENTIONS--A Brindley-Finetech intradural sacral anterior root stimulator was implanted in all patients. Three months postoperatively the stimulator settings were adjusted after measurement of simultaneous anorectal and low colonic pressures. MAIN OUTCOME MEASURES--Full defecation. RESULTS--Six patients achieved complete rectal evacuation of faeces using the implant and subsequently did not require manual help for defecation. For all but one of the patients the total time taken to complete defecation was reduced, and all were free from constipation, the most prevalent gastrointestinal symptom in patients with spinal injuries. CONCLUSIONS--Sacral anterior root stimulators can be programmed to achieve complete unassisted defecation and can considerably improve the quality of life of patients with spinal injuries.

The application of multiscale modelling to the process of development and prevention of stenosis in a stented coronary artery

The inherent complexity of biomedical systems is well recognized; they are multiscale, multiscience systems, bridging a wide range of temporal and spatial scales. While the importance of multiscale modelling in this context is increasingly recognized, there is little underpinning literature on the methodology and generic description of the process. The COAST (complex autonoma simulation technique) project aims to address this by developing a multiscale, multiscience framework, coined complex autonoma (CxA), based on a hierarchical aggregation of coupled cellular automata (CA) and agent-based models (ABMs). The key tenet of COAST is that a multiscale system can be decomposed into N single-scale CA or ABMs that mutually interact across the scales. Decomposition is facilitated by building a scale separation map on which each single-scale system is represented according to its spatial and temporal characteristics. Processes having well-separated scales are thus easily identified as the components of the multiscale model. This paper focuses on methodology, introduces the concept of the CxA and demonstrates its use in the generation of a multiscale model of the physical and biological processes implicated in a challenging and clinically relevant problem, namely coronary artery in-stent restenosis.

Multi-frequency imaging and modelling of respiratory related electrical impedance changes

Two studies concerning multi-frequency impedance measurements are presented. The first uses tetrapolar measurements made on the thorax and the second electrical impedance tomography images, also made from the thorax. The way in which the impedance and the changes in impedance with ventilation depend upon frequency are investigated using Cole-Cole modelling and also a physiological model of lung tissue. There is an excellent fit to the Cole-Cole model, and the results show that it should be possible to identify tissue on the basis of the impedance spectrum and the spectrum of the changes in impedance during breathing.

Development of a three dimensional multiscale computational model of the human epidermis.

Transforming Growth Factor (TGF-β1) is a member of the TGF-beta superfamily ligand-receptor network. and plays a crucial role in tissue regeneration. The extensive in vitro and in vivo experimental literature describing its actions nevertheless describe an apparent paradox in that during re-epithelialisation it acts as proliferation inhibitor for keratinocytes. The majority of biological models focus on certain aspects of TGF-β1 behaviour and no one model provides a comprehensive story of this regulatory factors action. Accordingly our aim was to develop a computational model to act as a complementary approach to improve our understanding of TGF-β1. In our previous study, an agent-based model of keratinocyte colony formation in 2D culture was developed. In this study this model was extensively developed into a three dimensional multiscale model of the human epidermis which is comprised of three interacting and integrated layers: (1) an agent-based model which captures the biological rules governing the cells in the human epidermis at the cellular level and includes the rules for injury induced emergent behaviours, (2) a COmplex PAthway SImulator (COPASI) model which simulates the expression and signalling of TGF-β1 at the sub-cellular level and (3) a mechanical layer embodied by a numerical physical solver responsible for resolving the forces exerted between cells at the multi-cellular level. The integrated model was initially validated by using it to grow a piece of virtual epidermis in 3D and comparing the in virtuo simulations of keratinocyte behaviour and of TGF-β1 signalling with the extensive research literature describing this key regulatory protein. This research reinforces the idea that computational modelling can be an effective additional tool to aid our understanding of complex systems. In the accompanying paper the model is used to explore hypotheses of the functions of TGF-β1 at the cellular and subcellular level on different keratinocyte populations during epidermal wound healing.

Large bowel myoelectrical activity in man.

The myoelectrical activity of human colon and rectum has been studied by three types of electrode in man--intraluminal (suction), serosal and cutaneous. The patterns obtained indicate a high degree of consistency between the methods and the value of surface electrodes is emphasized. Gradient along the large bowel of both frequency and percentage electrical activity have been observed and possible physiological roles are postulated for them. By correlating the features of regular electrical and corresponding regular motor waves an alteration in the myoelectrical pattern is observed in the region of the rectosigmoid junction.

The effect of stimulation on the myoelectrical activity of the rectosigmoid in man

The myoelectrical activity of the rectosigmoid has been studied in 66 subjects at rest and after stimulation with either pentagastrin 6·0 μg/kg hr intravenously in 21 cases, neostigmine 0·5 mg intramuscularly in 20 cases, or two bisacodyl suppositories in 19 cases. Two electrical rhythms were present at rest. A faster rhythm (frequency 6-9 cycles/min) predominated and its incidence was significantly increased by neostigmine at all levels in the rectosigmoid and by bisacodyl in the rectum only. The incidence of the slower rhythm (frequency 2·5-4·0 cycles/min) was significantly increased by pentagastrin which had no effect on the faster rhythm. The amplitude of each basic electrical rhythm rose when its incidence was increased. Motor waves were augmented corresponding to which of the two electrical rhythms was increased after stimulation.

A Comparison of Imaging Methodologies for 3D Tissue Engineering

Imaging of cells in two dimensions is routinely performed within cell biology and tissue engineering laboratories. When biology moves into three dimensions imaging becomes more challenging, especially when multiple cell types are used. This review compares imaging techniques used regularly in our laboratory in the culture of cells in both two and three dimensions. The techniques reviewed include phase contrast microscopy, fluorescent microscopy, confocal laser scanning microscopy, electron microscopy, and optical coherence tomography. We compare these techniques to the current “gold standard” for imaging three‐dimensional tissue engineered constructs, histology. Microsc. Res. Tech. 73:1123–1133, 2010.

An integrated systems biology approach to understanding the rules of keratinocyte colony formation

Closely coupled in vitro and in virtuo models have been used to explore the self-organization of normal human keratinocytes (NHK). Although it can be observed experimentally, we lack the tools to explore many biological rules that govern NHK self-organization. An agent-based computational model was developed, based on rules derived from literature, which predicts the dynamic multicellular morphogenesis of NHK and of a keratinocyte cell line (HaCat cells) under varying extracellular Ca++ concentrations. The model enables in virtuo exploration of the relative importance of biological rules and was used to test hypotheses in virtuo which were subsequently examined in vitro. Results indicated that cell–cell and cell–substrate adhesions were critically important to NHK self-organization. In contrast, cell cycle length and the number of divisions that transit-amplifying cells could undergo proved non-critical to the final organization. Two further hypotheses, to explain the growth behaviour of HaCat cells, were explored in virtuo—an inability to differentiate and a differing sensitivity to extracellular calcium. In vitro experimentation provided some support for both hypotheses. For NHKs, the prediction was made that the position of stem cells would influence the pattern of cell migration post-wounding. This was then confirmed experimentally using a scratch wound model.

A Complex Automata approach for in-stent restenosis: two-dimensional multiscale modelling and simulations

In-stent restenosis, the maladaptive response of a blood vessel to injury caused by the deployment of a stent, is a multiscale system involving a large number of biological and physical processes. We describe a Complex Automata model for in-stent restenosis, coupling bulk flow, drug diffusion, and smooth muscle cell models, all operating on different time scales. Details of the single scale models and of the coupling interfaces are described, together with first simulation results, obtained with a dedicated software environment for Complex Automata simulations. Preliminary results show that the model can reproduce growth trends observed in experimental studies and facilitate testing of hypotheses concerning the interaction of key factors.