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In Alzheimer's disease (AD), fatal neuronal cell loss occurs long before relevant evidence can lead to a reliable diagnosis. If characteristic pathological alterations take place in the enteric nervous system (ENS), it could be one of the most promising targets for an early diagnosis, using submucosal biopsies from the gut. We therefore investigated time- and spatial-dependent changes in an amyloid-β protein precursor (AβPP) overexpressing transgenic mouse model to examine early changes within the ENS. Wholemount preparations and paraffin sections were analyzed for the expression of neuronal, glial, and innate immunity markers. Isolated myenteric networks were screened for differences in overall protein expression, and a motility analysis delivered functional data. The level of AβPP in the gut was significantly higher in the AD mouse model than in wild-type mice and also higher in the gut than in the brain at all ages investigated. The transcriptional level of Nestin, GFAP, and TLR4 increased with age with a peak at 3 months. At the protein level, human amyloid-β was located in myenteric neurons. Myenteric networks showed a reduction of the neuronal density in AβPP compared to wild-type mice, which was functionally relevant as revealed by motility analysis. The ENS undergoes significant changes during the early onset of AβPP expression in AD mouse models that appear before those seen in the brain as demonstrated in this study. Thus, there is a chance of determining similar alterations in the human gut of AD patients, which could be used to develop early diagnostic approaches.

Background: Gastric slow waves propagate aborally as rings of excitation. Circumferential propagation does not normally occur, except at the pacemaker region. We hypothesized that (i) the unexplained high-velocity, high-amplitude activity associated with the pacemaker region is a consequence of circumferential propagation; (ii) rapid, high-amplitude circumferential propagation emerges during gastric dysrhythmias; (iii) the driving network conductance might switch between interstitial cells of Cajal myenteric plexus (ICC-MP) and circular interstitial cells of Cajal intramuscular (ICC-IM) during circumferential propagation; and (iv) extracellular amplitudes and velocities are correlated., Methods: An experimental-theoretical study was performed. High-resolution gastric mapping was performed in pigs during normal activation, pacing, and dysrhythmia. Activation profiles, velocities, and amplitudes were quantified. ICC pathways were theoretically evaluated in a bidomain model. Extracellular potentials were modeled as a function of membrane potentials., Key Results: High-velocity, high-amplitude activation was only recorded in the pacemaker region when circumferential conduction occurred. Circumferential propagation accompanied dysrhythmia in 8/8 experiments was faster than longitudinal propagation (8.9 vs 6.9 mm s(-1) ; P = 0.004) and of higher amplitude (739 vs 528 μV; P = 0.007). Simulations predicted that ICC-MP could be the driving network during longitudinal propagation, whereas during ectopic pacemaking, ICC-IM could outpace and activate ICC-MP in the circumferential axis. Experimental and modeling data demonstrated a linear relationship between velocities and amplitudes (P < 0.001)., Conclusions & Inferences: The high-velocity and high-amplitude profile of the normal pacemaker region is due to localized circumferential propagation. Rapid circumferential propagation also emerges during a range of gastric dysrhythmias, elevating extracellular amplitudes and organizing transverse wavefronts. One possible explanation for these findings is bidirectional coupling between ICC-MP and circular ICC-IM networks., (© 2012 Blackwell Publishing Ltd.)

Mutations in SCN5A, the gene encoding the pore-forming subunit of cardiac Na(+) channels, cause a spectrum of arrhythmic syndromes. Of these, sinoatrial node (SAN) dysfunction occurs in patients with both loss- and gain-of-function SCN5A mutations. We explored for corresponding alterations in SAN function and intracardiac conduction and clarified possible mechanisms underlying these in an established mouse long QT syndrome type 3 model carrying a mutation equivalent to human SCN5A-ΔKPQ. Electrophysiological characterizations of SAN function in living animals and in vitro sinoatrial preparations were compared with cellular SAN and two-dimensional tissue models exploring the consequences of Scn5a+/ΔKPQ mutations. Scn5a+/ΔKPQ mice showed prolonged electrocardiographic QT and corrected QT intervals confirming long QT phenotypes. They showed frequent episodes of sinus bradycardia, sinus pause/arrest, and significantly longer sinus node recovery times, suggesting compromised pacemaker activity compared with wild-type mice. Electrocardiographic waveforms suggested depressed intra-atrial, atrioventricular node, and intraventricular conduction in Scn5a+/ΔKPQ mice. Isolated Scn5a+/ΔKPQ sinoatrial preparations similarly showed lower mean intrinsic heart rates and overall slower conduction through the SAN to the surrounding atrium than did wild-type preparations. Computer simulations of both single SAN cells as well as two-dimensional SAN-atrial models could reproduce the experimental observations of impaired pacemaker and sinoatrial conduction in terms of changes produced by both augmented tail and reduced total Na(+) currents, respectively. In conclusion, the gain-of-function long QT syndrome type 3 murine Scn5a+/ΔKPQ cardiac system, in overlap with corresponding features reported in loss-of-function Na(+) channel mutations, shows compromised SAN pacemaker and conduction function explicable in modeling studies through a combination of augmented tail and reduced peak Na(+) currents.

In a few recent studies, the presence of arrhythmias based on reentry and circus movement of the slow wave have been shown to occur in normal and diseased stomachs. To date, however, reentry has not been demonstrated before in any other part of the gastrointestinal system. No animals had to be killed for this study. Use was made of materials obtained during the course of another study in which 11 rats were treated with streptozotocin and housed with age-matched controls. After 3 and 7 mo, segments of duodenum, jejunum, and ileum were isolated and positioned in a tissue bath. Slow wave propagation was recorded with 121 extracellular electrodes. After the experiment, the propagation of the slow waves was reconstructed. In 10 of a total of 66 intestinal segments (15%), a circus movement of the slow wave was detected. These reentries were seen in control (n = 2) as well as in 3-mo (n = 2) and 7-mo (n = 6) diabetic rats. Local conduction velocities and beat-to-beat intervals during the reentries were measured (0.42 ± 0.15 and 3.03 ± 0.67 cm/s, respectively) leading to a wavelength of 1.3 ± 0.5 cm and a circuit diameter of 4.1 ± 1.5 mm. This is the first demonstration of a reentrant arrhythmia in the small intestine of control and diabetic rats. Calculations of the size of the circuits indicate that they are small enough to fit inside the intestinal wall. Extrapolation based on measured velocities and rates indicate that reentrant arrhythmias are also possible in the distal small intestine of larger animals including humans.

The number of myenteric interstitial cells of Cajal (ICC-MY), responsible for the generation and propagation of the slow wave in the small intestine, has been shown to decrease in diabetes, suggesting impairment of slow-wave (SW) propagation and related motility. To date, however, this expected decrease in SW propagation has neither been recorded nor analysed. Eleven rats were treated with streptozotocin and housed in pairs with 11 age-matched control animals. After 3 or 7 months, segments of duodenum, jejunum and ileum were isolated and divided into two parts. One part was processed for immediate freezing, cryosectioning and immunoprobing using anti-c-Kit antibody to quantify ICC-MY. The second part was superfused in a tissue bath, and SW propagation was recorded with 121 extracellular electrodes. In addition, a cellular automaton was developed to study the effects of increasing the number of inactive cells on overall propagation. The number of ICC-MY was significantly reduced after 3 months of diabetes, but rebounded to control levels after 7 months of diabetes. Slow-wave frequencies, velocities and extracellular amplitudes were unchanged at any stage of diabetes. The cellular automaton showed that SW velocity was not linearly related to the number of inactive cells. The depletion of ICC-MY is not as severe as is often assumed and in fact may rebound after some time. In addition, at least in the streptozotocin model, the initial reduction in ICC-MY is not enough to affect SW propagation. Diabetic intestinal dysfunction may therefore be more affected by impairments of other systems, such as the enteric system or the muscle cells.

Background: The significance of gastric dysrhythmias remains uncertain. Progress requires a better understanding of dysrhythmic behaviors, including the slow wave patterns that accompany or promote them. The aim of this study was to use high-resolution spatiotemporal mapping to characterize and quantify the initiation and conduction of porcine gastric dysrhythmias., Methods: High-resolution mapping was performed on healthy fasted weaner pigs under general anesthesia. Recordings were made from the gastric serosa using flexible arrays (160-192 electrodes; 7.6mm spacing). Dysrhythmias were observed to occur in 14 of 97 individual recordings (from 8 of 16 pigs), and these events were characterized, quantified and classified using isochronal mapping and animation., Key Results: All observed dysrhythmias originated in the corpus and fundus. The range of dysrhythmias included incomplete conduction block (n=3 pigs; 3.9±0.5cpm; normal range: 3.2±0.2cpm) complete conduction block (n=3; 3.7±0.4cpm), escape rhythm (n=5; 2.0±0.3cpm), competing ectopic pacemakers (n=5, 3.7±0.1cpm) and functional re-entry (n=3, 4.1±0.4cpm). Incomplete conduction block was observed to self-perpetuate due to retrograde propagation of wave fragments. Functional re-entry occurred in the corpus around a line of unidirectional block. 'Double potentials' were observed in electrograms at sites of re-entry and at wave collisions., Conclusions & Inferences: Intraoperative multi-electrode mapping of fasted weaner healthy pigs detected dysrhythmias in 15% of recordings (from 50% of animals), including patterns not previously reported. The techniques and findings described here offer new opportunities to understand the nature of human gastric dysrhythmias., (© 2011 Blackwell Publishing Ltd.)

Objective: To investigate the propagation of the electrical impulses in a unilateral ureteric obstruction model using a high-resolution technique in vivo., Materials and Methods: In Wistar rats (n= 15), the left mid-ureter was occluded and the electrical activity was recorded from the proximal and distal part of the obstructed ureter and from the right ureter at different times up to 2 weeks post-obstruction using 64 extracellular electrodes., Results: In the left ureter, impulses propagated in an antegrade direction at a frequency of 15.5 ± 1.3/min and a velocity of 1.6 ± 0.1 cm/s. Immediately post-obstruction, the proximal part showed an increase in frequency (19.1 ± 2.5/min; P < 0.05) followed by a gradual decrease (at 2 weeks: 2.5 ± 1.2/min; P < 0.001). The velocity of these impulses decreased gradually (at 2 weeks: 0.5 ± 0.1 cm/s; P < 0.05). Distally, the antegrade propagations gradually disappeared and, at 1 week, 33% of ureters showed retrograde impulses and 67% displayed no electrical activity. The frequency of both antegrade and retrograde impulses distal to the obstruction dropped immediately after obstruction so that, at 1 day, it was 1.0 ± 0.3 and 1.5 ± 0.2/min, respectively (P < 0.01 for both). The velocity of these antegrade and retrograde impulses showed a significant rise throughout the post-obstruction period. The right ureter showed only a transient increase in frequency from 18.7 ± 2.7 to 30.3 ± 6.1/min (P < 0.05)., Conclusions: Using this high-resolution technique, it is concluded that, after ureteric obstruction, there were immediate and significant changes in the propagation of electrical impulses in the proximal and distal left ureter and in the right ureter, all of which behaved differently. This data may provide a better insight into the electrophysiological function of the normal and obstructed ureter., (© 2010 THE AUTHORS. BJU INTERNATIONAL © 2010 BJU INTERNATIONAL.)

Purpose: We investigated the propagation of electrical impulses in a reversible, complete or partial unilateral ureteral obstruction model in vivo., Materials and Methods: In Wistar rats the left mid ureter was completely (8) or partially (7) occluded and released after 24 hours. We recorded electrical activity of the left and right ureter before, during and after obstruction at different stages up to 2 weeks after obstruction using a high resolution, 64 extracellular electrode probe., Results: Complete obstruction in the left proximal ureter caused an immediate increase in frequency from a mean ± SEM of 14.8 ± 1.3 to 18.6 ± 1.7 per minute (p <0.05), followed by a 1.4 ± 0.9 per minute decrease (p <0.001). Within the first 2 days after reversal velocity gradually decreased from 1.82 ± 0.12 to 0.79 ± 0.17 cm per second (p <0.001). Release of obstruction gradually restored frequency and velocity, which returned to baseline at 2 weeks. Generally the alterations in rats with complete and partial obstruction were similar but they were less marked in those with partial obstruction. Distal to the obstruction site the impulses disappeared (38%) or propagated retrograde (43%) at some stage in the post-obstruction period. These abnormal impulse propagations also gradually disappeared in the post-obstruction stage., Conclusions: After complete or partial ureteral obstruction there were immediate, significant changes in the propagation of electrical impulses in the proximal and distal left ureter, which were generally less marked after partial than after complete obstruction. Reversal of obstruction resulted in the gradual disappearance of this abnormality in 2 weeks., (Copyright © 2011 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Background: The pig is a popular model for gastric electrophysiology studies. However, its normal baseline gastric activity has not been well characterized. High-resolution (HR) mapping has recently enabled an accurate description of human and canine gastric slow wave activity, and was employed here to define porcine gastric slow wave activity., Methods: Fasted pigs underwent HR mapping following anesthesia and laparotomy. Flexible printed-circuit-board arrays were used (160-192 electrodes; spacing 7.62 mm). Anterior and posterior surfaces were mapped simultaneously. Activation times, velocities, amplitudes and frequencies were calculated, and regional differences evaluated., Key Results: Mean slow wave frequency was 3.22 ± 0.23 cpm. Slow waves propagated isotropically from the pacemaker site (greater curvature, mid-fundus). Pacemaker activity was of higher velocity (13.3 ± 1.0 mm s(-1)) and greater amplitude (1.3 ± 0.2 mV) than distal fundal activity (9.0 ± 0.6 mm s(-1), 0.9 ± 0.1 mV; P < 0.05). Velocities and amplitudes were similar in the distal fundus, proximal corpus (8.4 ± 0.8 mm s(-1), 1.0 ± 0.1 mV), distal corpus (8.3 ± 0.8 mm s(-1), 0.9 ± 0.2 mV) and antrum (6.8 ± 0.6 mm s(-1), 1.1 ± 0.2 mV). Activity was continuous across the anterior and posterior gastric surfaces., Conclusions & Inferences: This study has quantified normal porcine gastric slow wave activity at HR during anesthesia and laparotomy. The pacemaker region was associated with high-amplitude, high-velocity slow wave activity compared to the activity in the rest of the stomach. The increase in distal antral slow wave velocity and amplitude previously described in canines and humans is not observed in the pig. Investigators should be aware of these inter-species differences.

The hypothesis was put forward by Thuneberg that rhythmically contracting interstitial cells of Cajal (ICC) were sensing stretch of the musculature and that this information was transmitted to smooth muscle cells via peg and socket contacts. The present study provides the evidence for the contractile nature of ICC as perceived by Thuneberg. The contractile activity is shown by video frame subtraction and by tracking areas of interest in sequential video frames. Thuneberg used neonatal ICC in culture maintained between two coverslips thereby allowing growth factors to quickly reach optimal concentrations. Contractions of ICC were seen to precede smooth muscle contractions. In addition, strong contractions were observed solely in branches of ICC. It is hoped that this communication will stimulate discussion about the contractile nature of ICC and that this phenomenon will eventually find its place amongst the physiological properties of the ICC networks of the gut musculature., (2010. © 2010 Wiley-Liss, Inc.)

Slow waves coordinate gastric motility, and abnormal slow-wave activity is thought to contribute to motility disorders. The current understanding of normal human gastric slow-wave activity is based on extrapolation from data derived from sparse electrode recordings and is therefore potentially incomplete. This study employed high-resolution (HR) mapping to reevaluate human gastric slow-wave activity. HR mapping was performed in 12 patients with normal stomachs undergoing upper abdominal surgery, using flexible printed circuit board (PCB) arrays (interelectrode distance 7.6 mm). Up to six PCBs (192 electrodes; 93 cm(2)) were used simultaneously. Slow-wave activity was characterized by spatiotemporal mapping, and regional frequencies, amplitudes, and velocities were defined and compared. Slow-wave activity in the pacemaker region (mid to upper corpus, greater curvature) was of greater amplitude (mean 0.57 mV) and higher velocity (8.0 mm/s) than the corpus (0.25 mV, 3.0 mm/s) (P < 0.001) and displayed isotropic propagation. A marked transition to higher amplitude and velocity activity occurred in the antrum (0.52 mV, 5.9 mm/s) (P < 0.001). Multiple (3-4) wavefronts were found to propagate simultaneously in the organoaxial direction. Frequencies were consistent between regions (2.83 +/- 0.35 cycles per min). HR mapping has provided a more complete understanding of normal human gastric slow-wave activity. The pacemaker region is associated with high-amplitude, high-velocity activity, and multiple wavefronts propagate simultaneously. These data provide a baseline for future HR mapping studies in disease states and will inform noninvasive diagnostic strategies.

Gastric pacing has been investigated as a potential treatment for gastroparesis. New pacing protocols are required to improve symptom and motility outcomes; however, research progress has been constrained by a limited understanding of the effects of electrical stimulation on slow-wave activity. This study introduces high-resolution (HR) "entrainment mapping" for the analysis of gastric pacing and presents four demonstrations. Gastric pacing was initiated in a porcine model (typical amplitude 4 mA, pulse width 400 ms, period 17 s). Entrainment mapping was performed using flexible multielectrode arrays (

Background: A periodic electrical activity, termed "slow waves", coordinates gastrointestinal contractions. Slow-wave dysrhythmias are thought to contribute to dysmotility syndromes such as postoperative gastroparesis, but the clinical significance of these dysrhythmias remains poorly defined. Electrogastrography (EGG) has been unable to characterize dsyrhythmic activity reliably, and the most accurate method for evaluating slow waves is to record directly from the surface of the target organ. This study presents a novel laparoscopic device for recording serosal slow-wave activity, together with its validation., Methods: The novel device consists of a shaft (diameter, 4 mm; length, 300 mm) and a flexible connecting cable. It contains four individual electrodes and is fully shielded. Validation was performed by comparing slow-wave recordings from the laparoscopic device with those from a standard electrode platform in an open-abdomen porcine model. An intraoperative human trial of the device also was performed by recording activity from the gastric antrum of a patient undergoing a laparoscopic cholecystectomy., Results: Slow-wave amplitudes were similar between the laparoscopic device and the standard recording platform (mean 0.38 ± 0.03 mV vs range 0.36-0.38 ± 0.03 mV) (p = 0.94). The signal-to-noise ratio (SNR) also was similar between the two types of electrodes (13.7 dB vs 12.6 dB). High-quality antral slow-wave recordings were achieved in the intraoperative human trial (amplitude, 0.41 ± 0.04 mV; SNR, 12.6 dB), and an activation map was constructed showing normal aboral slow-wave propagation at a velocity of 6.3 ± 0.9 mm/s., Conclusions: The novel laparoscopic device achieves high-quality serosal slow-wave recordings. It is easily deployable and atraumatic. It is anticipated that this device will aid in the clinical investigation of normal and dsyrhythmic slow-wave activity. In particular, it offers new potential for investigating the effect of surgical procedures on slow-wave activity.

Slow waves are known to originate orally in the stomach and to propagate toward the antrum, but the exact location of the pacemaker and the precise pattern of propagation have not yet been studied. Using assemblies of 240 extracellular electrodes, simultaneous recordings of electrical activity were made on the fundus, corpus, and antrum in open abdominal anesthetized dogs. The signals were analyzed off-line, pathways of slow wave propagation were reconstructed, and slow wave velocities and amplitudes were measured. The gastric pacemaker is located in the upper part of the fundus, along the greater curvature. Extracellularly recorded slow waves in the pacemaker area exhibited large amplitudes (1.8 +/- 1.0 mV) and rapid velocities (1.5 +/- 0.9 cm/s), whereas propagation in the remainder of the fundus and in the corpus was slow (0.5 +/- 0.2 cm/s) with low-amplitude waveforms (0.8 +/- 0.5 mV). In the antrum, slow wave propagation was fast (1.5 +/- 0.6 cm/s) with large amplitude deflections (2.0 +/- 1.3 mV). Two areas were identified where slow waves did not propagate, the first in the oral medial fundus and the second distal in the antrum. Finally, recordings from the entire ventral surface revealed the presence of three to five simultaneously propagating slow waves. High resolution mapping of the origin and propagation of the slow wave in the canine stomach revealed areas of high amplitude and rapid velocity, areas with fractionated low amplitude and low velocity, and areas with no propagation; all these components together constitute the elements of a gastric conduction system.

High-resolution, multi-electrode mapping is providing valuable new insights into the origin, propagation, and abnormalities of gastrointestinal (GI) slow wave activity. Construction of high-resolution mapping arrays has previously been a costly and time-consuming endeavor, and existing arrays are not well suited for human research as they cannot be reliably and repeatedly sterilized. The design and fabrication of a new flexible printed circuit board (PCB) multi-electrode array that is suitable for GI mapping is presented, together with its in vivo validation in a porcine model. A modified methodology for characterizing slow waves and forming spatiotemporal activation maps showing slow waves propagation is also demonstrated. The validation study found that flexible PCB electrode arrays are able to reliably record gastric slow wave activity with signal quality near that achieved by traditional epoxy resin-embedded silver electrode arrays. Flexible PCB electrode arrays provide a clinically viable alternative to previously published devices for the high-resolution mapping of GI slow wave activity. PCBs may be mass-produced at low cost, and are easily sterilized and potentially disposable, making them ideally suited to intra-operative human use.

Peristaltic motor activity of the gut is an essential activity to sustain life. In each gut organ, a multitude of overlapping mechanisms has developed to acquire the ability of coordinated contractile activity under a variety of circumstances and in response to a variety of stimuli. The presence of several simultaneously operating control systems is a challenge for investigators who focus on the role of one particular control activity since it is often not possible to decipher which control systems are operating or dominant in a particular situation. A crucial advantage of multiple control systems is that gut motility control can withstand injury to one or more of its components. Our efforts to increase understanding of control mechanism are not helped by recent attempts to eliminate proven control systems such as interstitial cells of Cajal (ICC) as pacemaker cells, or intrinsic sensory neurons, nor does it help to view peristalsis as a simple reflex. This review focuses on the role of ICC as slow-wave pacemaker cells and places ICC into the context of other control mechanisms, including control systems intrinsic to smooth muscle cells. It also addresses some areas of controversy related to the origin and propagation of pacemaker activity. The urge to simplify may have its roots in the wish to see the gut as a consequence of a single perfect design experiment whereas in reality the control mechanisms of the gut are the messy result of adaptive changes over millions of years that have created complementary and overlapping control systems. All these systems together reliably perform the task of moving and mixing gut content to provide us with essential nutrients.

Background & Aims: Gastric arrhythmias occur in humans and experimental animals either spontaneously or induced by drugs or diseases. However, there is no information regarding the origin or the propagation patterns of the slow waves that underlie such arrhythmias., Methods: To elucidate this, simultaneous recordings were made on the antrum and the distal corpus during tachygastrias in open abdominal anesthetized dogs using a 240 extracellular electrode assembly. After the recordings, the signals were analyzed, and the origin and path of slow wave propagations were reconstructed., Results: Several types of arrhythmias could be distinguished, including (1) premature slow waves (25% of the arrhythmias), (2) single aberrant slow waves (4%), (3) bursts (18%), (4) regular tachygastria (11%), and (5) irregular tachygastria (10%). During regular tachygastria, rapid, regular slow waves emerged from the distal antrum or the greater curvature, whereas, during irregular tachygastria, numerous variations occurred in the direction of propagation, conduction blocks, focal activity, and re-entry. In 12 cases, the arrhythmia was initiated in the recorded area. In each case, after a normal propagating slow wave, a local premature slow wave occurred in the antrum. These premature slow waves propagated in various directions, often describing a single or a double loop that re-entered several times, thereby initiating additional slow waves., Conclusions: Gastric arrhythmias resemble those in the heart and share many common features such as focal origin, re-entry, circular propagation, conduction blocks, and fibrillation-like behavior.

The aim of this study was to characterize the role of the late Na+ current (I(Na,L)) as a mechanism for induction of both tachy and bradyarrhythmias in murine heart and sino-atrial node tissue. The sea anemone toxin ATX-II and ranolazine were used to increase and inhibit, respectively, I(Na,L). In sixteen hearts studied, exposure to 1-10nM ATX-II caused a slowing of intrinsic heart rate and prolongations of the P-R and QT intervals, the duration of the monophasic action potential, and the sinus node recovery time, accompanied by frequent occurrences of early after depolarisations, delayed after depolarisations and rapid, repetitive ventricular tachy and sino-atrial bradyarrhythmias. ATX-II also slowed sinus node pacemaking, and induced bradycardic arrhythmias in isolated sino-atrial preparations (n=5). The ATX-II-induced alteration of electrophysiological properties and occurrence of arrhythmic events were significantly attenuated by 10 microM ranolazine in intact hearts (n=11) and isolated sino-atrial preparations (n=5). In conclusion, the I(Na,L) enhancer ATX-II causes both tachy and bradyarrhythmias in the murine heart, and these arrhythmias are markedly attenuated by the I(Na,L) blocker, ranolazine (10 microM). The results suggest that I(Na,L) blockade may be the mechanism underlying the reductions of both brady and tachyarrhythmias by ranolazine that were observed during the MERLIN-TIMI clinical outcomes trial.

Previous studies have reported on propagation of individual spikes in isolated segments of the pregnant uterus, but there is no information on patterns of spike propagation in the intact organ. There is also no information on propagation of myometrial burst. The aim of this study was to record, at high resolution, patterns of propagation of electrical activities in the pregnant uterus. Sixteen timed-pregnant guinea pigs were euthanized at term, and their uteruses isolated. Fetuses were removed and replaced by an equal amount of Tyrode. A 240-electrode array was positioned at various locations along the organ, all signals were recorded simultaneously, and the electrical propagations were reconstructed. In the intact pregnant uterus at term, spikes propagated with high velocity in longitudinal (6.8 +/- 2.4 cm/s) and slower velocity in circular direction (2.8 +/- 1.0 cm/s; P < 0.01). Direction of propagation and frequency of activity were highly variable but showed similar patterns at the ovary or cervical end and along the anterior, posterior, and antimesometrial borders. Along mesometrium, spike propagation was sparse and fractionated. Migration of burst (0.6 +/- 0.4 cm/s) was significantly much slower than that of individual spikes (P < 0.001). Initial burst activity was located at variable locations along the ovarial end of the antimesometrial border, while the latest excitation occurred at the cervical end (1.2 +/- 0.9 min). In conclusion, high resolution electrical mapping of the intact pregnant uterus reveals fundamental properties in spatial and temporal patterns of spike and burst propagation that determine the contraction of the organ.

The pattern of propagation of slow waves in the small intestine is not clear. Specifically, it is not known whether propagation is determined by a single dominant ICC-MP (Interstitial cells of Cajal located in the Myenteric Plexus) pacemaker unit or whether there are multiple active pacemakers. To determine this pattern of propagation, waveforms were recorded simultaneously from 240 electrodes distributed along the whole length of the intact isolated feline small intestine. After the experiments, the propagation patterns of successive individual slow waves were analysed. In the intact small intestine, there was only a single slow wave pacemaker unit active, and this was located at or 6-10 cm from the pyloric junction. From this site, slow waves propagated in the aboral direction at gradually decreasing velocities. The majority of slow waves (73%) reached the ileocaecal junction while the remaining waves were blocked. Ligation of the intestine at one to four locations led to: (a) decrease in the distal frequencies; (b) disappearance of distal propagation blocks; (c) increase in velocities; (d) emergence of multiple and unstable pacemaker sites; and (e) propagation from these sites in the aboral and oral directions. In conclusion, in the quiescent feline small intestine a single pacemaker unit dominates the organ, with occasional propagation blocks of the slow waves, thereby producing the well-known frequency gradient.

Myoelectric recordings from the gastrointestinal (GI) tract in conscious animals have been limited in duration and site. Recently, we have implanted 24 electrodes and obtained electrograms from these sites simultaneously (200 Hz sampling rate; 1.1 MB/min data stream). An automated electrogram analysis was developed to process this large amount of data. Myoelectrical recordings from the GI tract often consist of slow wave deflections followed by one or more action potentials (=spike deflections) in the same traces. To analyze these signals, a first module separates the signal into one containing only slow waves and a second one containing only spikes. The timings of these waveforms were then detected, in real time, for all 24 electrograms, in a separate slow wave detection module and a separate spike-detection module. Basic statistics such as timing and amplitudes and the number of spikes per slow wave were performed and displayed on-line. In summary, with this online analysis, it is possible to study for long periods of time and under various experimental conditions major components of gastrointestinal motility.

Background: Spatio-temporal (ST) maps provide a method for visualizing a temporally evolving and spatially varying field, which can also be used in the analysis of gastrointestinal motility. However, it is not always clear what the underlying contractions are that are represented in ST maps and whether some types of contractions are poorly represented or possibly not at all., Methods: To analyze the translation from stationary or propagating rhythmic contractions of the intestine to ST maps, a simulation program was used to represent different patterns of intestinal contraction and to construct their corresponding ST maps. A number of different types of contractions were simulated and their ST maps analyzed., Results: Circular strong contractions were well represented in ST maps as well as their frequency and velocity. Longitudinal contractions were not detected at all. Combinations of circular and longitudinal contractions were, to a limited extent detectable at a point in space and time. The method also enabled the construction of specific ST-patterns to mimic real-life ST maps and the analysis of the corresponding contraction patterns., Conclusion: Spatio-temporal simulations provide a method to understand, teach and analyze ST maps. This approach could be useful to determine characteristics of contractions under a variety of circumstances.

Muscarinic agonists are known to enhance small intestinal contractions. A similar effect was also seen in pilot experiments with a nucleoside transport inhibitor. However, there is no information on their effects on the spatial pattern of action potential propagation. In an anesthetized, open-abdomen, canine (n=8) model, the propagation patterns of the slow wave and the ensuing action potentials (= spikes) were recorded before and during the i.v. administration of bethanechol or nucleoside transport inhibitor. Vehicle injections in 8 dogs served as controls. Electrical recordings were made using a 240-electrode array positioned on a 5-cm segment of the jejunum in situ. The incidence and the propagation of the action potentials were analyzed. Bethanechol dose-dependently increased the number of both longitudinally and circumferentially propagating spikes per slow wave. As during control, spikes in bethanechol propagated for a limited distance before terminating spontaneously, thereby exciting only a limited area (= patch). However, bethanechol did not change the size of the longitudinal spike patches (18.8+/-6.9 mm(2) at baseline and 25.0+/-18.6 mm(2) at 0.5 mg/kg) nor of the circular spike patches (90.0+/-41.2 mm(2) at baseline and 95.4+/-36.5 mm(2) at 0.5 mg/kg). The nucleoside transport inhibitor increased the occurrence of circular spikes in a step-wise fashion (>or=0.5 mg/kg). The size of the nucleoside transport inhibitor-induced circular spike patches (136.6+/-46.8 mm(2)) was larger than those during baseline or muscarinic stimulation. Muscarinic agonists stimulate small intestinal contractility by inducing more action potentials, which in turn would trigger increased calcium release from intracellular stores. On the other hand, nucleoside transport inhibition enhances contractility by increasing both the number and the size of the circular spike patches.

Objectives: The United Arab Emirates is witnessing a rapid development in population and infrastructure, leading to an expansion in the educational field and the health care system, including universities, hospitals and research institutes. One potential outcome of this development is an increase in biomedical research publications. This was examined in this study., Method: Searches were made of three databases; PubMed, Current Contents and embase. All records from these databases related to the Emirates were downloaded and cross-referenced. Duplications were removed as well as erroneous records. A total of 1369 publications during 1998-2004 were obtained., Results: Analysis of these records revealed that the Faculty of Medicine and Health Sciences, located at the federal University, was responsible for 48% of all biomedical publications. All hospitals together accounted for 24%, while other universities and other research institutes accounted for 13 and 14% respectively. Further analysis revealed that there had been no further growth in the number of publications since 1998. This is in contrast to the increasing number of institutions that have been set up in the 1998-2004 period; from 29 to 112., Conclusion: The Emirates are witnessing a rapid development in universities, colleges, hospitals and research centres. The ratio of publications, as yet, has not kept up with this development. The enormous growth in institutes, however, may, in time, herald an Arabian renaissance in scientific activity and related publications.

There is limited data available on the electrical activity of the rectum. An in vivo canine model was developed to record 240 extracellular electrograms simultaneously from the serosal surface of the rectum thereby enabling an off-line reconstruction of the behaviour of the electrical signals. Serosal rectal electrical activity is characterized by brief bursts of action potentials (=spikes) with a frequency of 22 cycles min(-1). High-resolution mapping of these signals revealed predominant propagation of these spikes in the longitudinal direction, originating from any site and conducted for a limited time and length before stopping spontaneously, thereby describing a patch of activity. The dimension of the patches in the longitudinal direction was significantly longer than the transversal width (13.6 vs 2.4 mm; P < 0.001). Spike propagation could occur in the aboral (46% of cases), in the oral (34%) or in both directions (20%). A bolus of betanechol (i.v., 0.5 mg kg(-1)) increased the frequency of the spikes without affecting size, shape or orientation of the patches. As in other parts of the gastrointestinal system, individual spike propagation in the rectum is limited to small areas or patches. The contractile activity of the organ could possibly reflect this underlying pattern of electrical behaviour.

Myoelectric recordings from the intestines in conscious animals have been limited to a few electrode sites with relatively large inter-electrode distances. The aim of this project was to increase the number of recording sites to allow high-resolution reconstruction of the propagation of myoelectrical signals. Sets of six unipolar electrodes, positioned in a 3x2 array, were constructed. A silver ring close to each set served as the reference electrodes. Inter-electrode distances varied from 4 to 8 mm. Electrode sets, to a maximum of 4, were implanted in various configurations allowing recording from 24 sites simultaneously. Four sets of 6 electrodes each were implanted successfully in 11 female Beagles. Implantation sites evaluated were the upper small intestine (n=10), the lower small intestine (n=4) and the stomach (n=3). The implants remained functional for 7.2 months (median; range 1.4-27.3 months). Recorded signals showed slow waves at regular intervals and spike potentials. In addition, when the sets were positioned close together, it was possible to re-construct the propagation of individual slow waves, to determine their direction of propagation and to calculate their propagation velocity. No signs or symptoms of interference with normal GI-function were observed in the tested animals. With this approach, it is possible to implant 24 extracellular electrodes on the serosal surface of the intestines without interfering with its normal physiology. This approach makes it possible to study the electrical activities of the GI system at high resolution in vivo in the conscious animal.

Since the development of knockout animals, the mouse has become an important model to study gastrointestinal motility. However, little information is available on the electrical and contractile activities induced by distension in the murine small intestine. Spatiotemporal electrical mapping and mechanical recordings were made from isolated intestinal segments from different regions of the murine small intestine during distension. The electrical activity was recorded with 16 extracellular electrodes while motility was assessed simultaneously by tracking the border movements with a digital camera. Distension induced propagating oscillatory contractions in isolated intestinal segments. These propagating contractions were dictated by the underlying propagating slow wave with superimposed spikes. The frequencies, velocities, and direction of the propagating oscillations strongly correlated with the frequencies (r = 0.86), velocities (r = 0.84), and direction (r = 1) of the electrical slow waves. N(omega)-nitro-L-arginine methyl ester decreased the maximal diameter of the segment and reduced the peak contraction amplitude of the propagating oscillatory contractions, whereas atropine and verapamil blocked the propagating oscillations. Tetrodotoxin had little effect on the maximal diameter and peak contraction amplitude. In conclusion, distension in the murine small intestine does not initiate peristaltic reflexes but induces a propagating oscillatory motor pattern that is determined by propagating slow waves with superimposed spikes. These spikes are cholinergic and calcium dependent.

In an anesthetized, open-abdomen, canine model, the propagation pattern of the slow wave and its direction, velocity, amplitude, and frequency were investigated in the small intestine of 8 dogs. Electrical recordings were made using a 240-electrode array from 5 different sites, spanning the length of the small intestine. The majority of slow waves propagated uniformly and aborally (84%). In several cases, however, other patterns were found including propagation in the oral direction (11%) and propagation block (2%). In addition, in 69 cases (3%), a slow wave was initiated at a local site beneath the electrode array. Such peripheral pacemakers were found throughout the entire intestine. The frequency, velocity, and amplitude of slow waves were highest in the duodenum and gradually declined along the intestine reaching lowest values in the distal ileum (from 17.4+/-1.7 c/min to 12.2+/-0.7 c/min; 10.5+/-2.4 cm/s to 0.8+/-0.2 cm/s, and 1.20+/-0.35 mV to 0.31+/-0.10 mV, respectively; all p<0.001). Consequently, the wavelength of the slow wave was strongly reduced from 36.4+/-0.8 cm to 3.7 +/- 0.1 cm (p<0.001). We conclude that the patterns of slow wave propagation are usually, though not always, uniform in the canine small intestine and that the gradient in the wavelength will influence the patterns of local contractions.

In contrast to the mechanisms of segmental and peristaltic contractions in the small intestine, not much is known about the mechanism of pendular contractions. High-resolution electrical and mechanical recordings were performed from isolated segments of the rabbit ileum during pendular contractions. The electrical activities were recorded with 32 extracellular electrodes while motility was assessed simultaneously by video tracking the displacements of 20-40 serosal markers. The electrical activities consisted of slow waves, followed by spikes, that propagated in either the aboral or oral direction. The mechanical activity always followed the initial electrical activity, describing a contraction phase in one direction followed by a relaxation phase in the opposite direction. Pendular displacements were always in rhythm with the slow wave, whereas the direction of the displacements was dictated by the origin of the slow wave. If the slow wave propagated aborally, then the pendular displacement occurred in the oral direction, whereas if the slow wave propagated in the oral direction, then the displacement occurred in the aboral direction. In the case of more complex propagation patterns, such as in the area of pacemaking or collision, direction of displacements remained always opposite to the direction of the slow wave. In summary, the direction and pattern of propagation of the slow wave determine the rhythm and the direction of the pendular motility. The well-known variability in pendular movements is caused by the variability in the propagation of the underlying slow wave.

The frequency and propagation velocity of distension-induced peristaltic contractions in the antrum and duodenum are distinctly different and depend on activation of intrinsic excitatory motoneurons as well as pacemaker cells, the interstitial cells of Cajal associated with Auerbach's plexus (ICC-AP). Because ICC are critical for coordination of motor activities along the long axis of many regions in the gut, the role of ICC in antroduodenal coordination was investigated. We used immunohistochemistry, electron microscopy, simultaneous multiple electrical recordings in vitro, and videofluoroscopy in vivo in mice and rats. A strongly reduced number of ICC-AP with loss of network characteristics was observed in a 4-mm area in the rat and a 1-mm area in the mouse pyloric region. The pyloric region showed a slow wave-free gap of 4.1 mm in rats and 1.3 mm in mice. Between antrum and duodenum, there was no interaction of electrical activities and in the absence of gastric emptying, there was no coordination of motor activities. When the pyloric sphincter opened, 2.4 s before the front of the antral wave reached the pylorus, the duodenum distended after receiving gastric content and aboral duodenal peristalsis was initiated, often disrupting other motor patterns. The absence of ICC-AP and slow wave activity in the pyloric region allows the antrum and duodenum to have distinct uncoordinated motor activities. Coordination of aborally propagating peristaltic antral and duodenal activity is initiated by opening of the pylorus, which is followed by distention-induced duodenal peristalsis. Throughout this coordinated motor activity, the pacemaker systems in antrum and duodenum remain independent.

In seven isolated segments of the feline duodenum, the timings of all spikes and the locations of all spike patches that occurred after 12-16 successive slow waves were analysed. Simultaneous recordings were performed during 1-min periods using 240 extracellular electrodes (24 x 10 array; interelectrode distance 2 mm) positioned onto the serosal surface. In all seven preparations, spikes always occurred during the first half of the slow wave cycle. From preparation to preparation, and within 1-min periods in each preparation, there was limited variation in the spike-spike intervals, in the times between the spikes and the preceding slow wave and in the number of spikes at each electrode site. In contrast, the number of electrode sites that recorded spikes and the number of spike patches both showed great variability between preparations and sometimes within a single preparation. In addition, the location of spikes and spike patches was not random but was significantly concentrated in certain areas, often located along the anti-mesenteric border, while other sites showed little or no spike activity. In conclusion, spikes and spike patches tend to occur significantly in some areas and not in others. This spatial heterogeneity will play a role in intestinal motility.

In an open-abdominal anesthetized and fasted canine model of the intact small intestine, the presence, location, shape, and frequency of spike patches were investigated. Recordings were performed with a 240-electrode array (24 x 10, 2-mm interelectrode distance) from several sites sequentially, spanning the whole length of the small intestine. All 240 electrograms were recorded simultaneously during periods of 5 min and were analyzed to reconstruct the origin and propagation of individual spikes. At every level in the small intestine, spikes propagated in all directions before stopping abruptly, thereby activating a circumscribed area termed a "patch." Two types of spikes were found: longitudinal spikes, which propagated predominantly in the longitudinal direction and occurred most often in the duodenum, and a second type, circumferential spikes, which propagated predominantly in the circular direction and occurred much more frequently in the jejunum and ileum. Circumferential spikes conducted faster than longitudinal spikes (17 +/- 6 and 7 +/- 2 cm/s, respectively; P < 0.001). Circumferential spikes originated in >90% of all cases from the antimesenteric border, whereas longitudinal spikes were initiated all around the circumference of the intestinal tube. Finally, the spatial sequence of spike patches after the slow wave was very irregular in the upper part of the intestine but much more regular in the lower part. In conclusion, spikes and spike patches occur throughout the small intestine, whereas their type, sites of origin, extent of propagation, and frequencies of occurrence differ along the length of the small intestine, suggesting differences in local patterns of motility.

The relationship between slow waves and peristaltic reflexes has not been well analyzed. In this study, we have recorded the electrical activity of slow waves together with that generated by spontaneous peristaltic contractions at 240 extracellular sites simultaneously. Recordings were made from five isolated tubular and six sheet segments of feline duodenum superfused in vitro. In all preparations, slow waves propagated as broad wave fronts along the longitudinal axis of the preparation in either the aborad or the orad direction. Electrical potentials recorded during peristalsis (peristaltic waves) also propagated as broad wave fronts in either directions. Peristaltic waves often spontaneously stopped conducting (46%), in contrast to slow waves that never did. Peristaltic waves propagated at a lower velocity than the slow waves (0.98 +/- 0.25 and 1.29 +/- 0.28 cm/s, respectively; P < 0.001; n = 24) and in a direction independent of the preceding slow wave direction (64% in the same direction, 46% in the opposite direction). In conclusion, slow waves and peristaltic waves in the isolated feline duodenum seem to constitute two separate electrical events that may drive two different mechanisms of contraction in the small intestine.

Abstract Measuring propagation anisotropy may help in determining the tissue layers involved in the propagation of electrical impulses in the intestine. We used 240 extracellular electrograms recorded from the isolated feline duodenum. The conduction velocities of slow waves and of individual spikes were measured from their site of origin into all directions. Both slow waves and spikes propagate anisotropically in the small intestine but in different directions and to a different degree. Slow waves propagated anisotropically faster in the circumferential (1.7 +/- 0.8 cm s(-1)) than in the axial direction (1.3 +/- 0.5 cm s(-1); P < 0.001). Spikes, on the other hand, propagated faster in the longitudinal direction (7.8 +/- 4.5 cm s(-1)) than in the circumferential direction (3.3 +/- 4.3 cm s(-1); P < 0.001). Furthermore, the average conduction velocity of spikes (6.3 +/- 4.5 cm s(-1)) was significantly higher than that of slow waves (1.5 +/- 1.1 cm s(-1); P < 0.001). The anisotropic propagation of spikes supports the argument that these propagate in the longitudinal muscle layer. The anisotropic propagation of slow waves may be the result of the interaction between the myenteric layer of interstitial cells of Cajal and their electrotonic connection to both the longitudinal and the circular muscle layer.

Several types of electrical events occur in the small intestine but their spatial and temporal contributions to overall motility are not clear. In order to quantify local motility in greater detail, a new technique of recording and analysing movements at multiple sites was developed. Use was made of isolated segments of feline duodenum superfused in a tissue bath. Multiple marker dots (20-75) were placed on the serosal surface by applying fine spots of candle soot in rectangular arrays (1-2 mm dot separation). A digital video camera was used to record spontaneous movements of the dots for periods of 10-30 min. After each experiment, 4-6 periods (10-60 s each) of video frames were transferred to a computer (25 fps, 720 x 576 pixels) and the movements of the dots was tracked every 40 ms using custom-made software. Initial results (eight experiments) show that spontaneous motility is remarkably variable, both in space and time. Three types of movement could be discerned: (i) periodic, rolling or pendular movements, with a frequency of approximately 15 min-1 occurring predominantly in the longitudinal direction; (ii) twitches, wherein a subset of dots were suddenly displaced longitudinally; and (iii) drifts of most of the dots in a circular or oblique direction. All three types of movement occurred throughout every recording session although their relative magnitudes differed greatly from moment to moment. Occasionally, it was possible to detect propagated 'contractions' with an apparent velocity of 10 mm s(-1). Immobilizing the preparation at one point by inserting a needle through the middle of the array of markers had a negligible effect on the displacements, whereas application of verapamil (10(-5) mol L(-1)) reduced or abolished motility. In summary, we present a new technique to map in detail two-dimensional motility at the surface of the intestine. Initial results seem to suggest that motility at the serosal surface is not uniform and highly anisotropic.

In the small intestines, the major task of the slow wave is to induce mechanical movements in the intestinal wall by generating local calcium spikes. High resolution electrical mapping reveals fundamental differences in propagation between slow waves and calcium spikes. These differences suggest that slow waves and spikes are propagated by different mechanisms through different cell networks.

In the isolated feline gastroduodenal region, the spatial propagation of slow waves and of individual spikes was reconstructed. Recordings were performed simultaneously from 240 extracellular electrodes positioned on the serosal surface across the junction. Results from nine experiments (22 slow waves) showed that the slow wave never propagated across the gastroduodenal region and that this block was due to the presence of a zone of quiescence caudal to the pylorus. In contrast, spikes (n=155) were able to propagate into the quiescent zone, either from the antrum (15.4%) or from the duodenum (34.0%) and occasionally, were able to propagate from one organ to the other (10.9%). However, in all cases, spike conduction was self-limited and activated a local area termed a 'patch'. The length of the patches located in the gastroduodenal region was significantly longer than in the rest of the duodenum (20.2 mm +/- 9. 7 vs. 9.5 mm +/- 3.2; P < 0.001) indicating a possible enhancement of spike propagation in this region. In conclusion, in spite of the total conduction block for slow waves, individual spikes are able to propagate across the gastroduodenal region, albeit in self-limited areas or 'patches'. These spike patches could form the building blocks for gastroduodenal coordination.

Asynchrony of spikes has made it difficult to study the spatial and temporal behavior of spikes in the gastrointestinal system. By simultaneously recording from a large number of closely spaced electrodes, we investigated the propagation of individual spikes. Recordings were performed from the serosal surface of the isolated feline duodenum at 240 sites simultaneously. Analysis of the tracings made it possible to reconstruct the propagation of individual spikes. Spikes propagate in the longitudinal and circumferential directions in self-limiting areas or "patches." Conduction within patches may occur in the orad or aborad direction irrespective of the direction of the slow wave. Most of the patches are smaller (<40 mm(2)), although inhomogeneous activation by the preceding slow wave may increase their size. Stimulation by ACh, TTX, or tetraethylammonium does not affect the average patch size but does increase significantly their number and distribution in the duodenum [from 26% (control) to 56%, 61%, and 72%, respectively]. In conclusion, individual spikes activate limited areas or patches in the small intestine, and pharmacological stimulation increases the number and distribution of these patches. In the small intestine, this pattern of activation would induce localized contractions. Contraction could be modulated by the size, number, and distribution of spike patches.

In the isolated pregnant myometrium of the rat, the pattern of propagation was investigated by recording simultaneously from 240 different extracellular sites while the contraction of the tissue was recorded isometrically. Analysis of all recorded electrograms allowed the two-dimensional spread of activity in the myometrium to be reconstructed. From these activation maps, the conduction velocities were measured in the longitudinal, oblique and transversal directions. At low concentrations (10(-9 )and 5x10(-9) M), oxytocin significantly increased the frequency and duration of electrical bursts and the average spike intervals, without affecting the homogeneity of action potential propagation, concomitant with a significant increase in the amplitude of contractions. At high concentrations (10(-8) and 5x10(-8) M), oxytocin induced conduction blocks and the size of inexcitable areas was increased, concomitantly with an increase in muscle contractures. In contrast, the conduction velocities in the longitudinal, oblique and circular directions were not influenced by oxytocin at any concentrations.

Objectives: The objectives of this study were to determine the mechanisms responsible for the initiation and the termination of episodes of circus movements and to describe the characteristics of these circuits in rat myometrium., Study Design: By means of simultaneous recordings from 240 sites in Wistar rats at 17, 19, or 21 days' gestation, a spatial and temporal analysis was performed on the electrical activation from the beginning until the end of 22 episodes of circus movements., Results: The initiation of reentry was caused by (1) transient unexcitable areas at the beginning of the burst or (2) lines of conduction blocks. Circus movements were terminated by (1) reversal of recruitment (decruitment) at the end of the burst, (2) occurrence of lines of conduction blocks, or (3) interruption of the circuit. On average circuits rotated for 6 revolutions during 2 seconds. In most cases circuits remained stable; sometimes circuits drifted along the tissue and occasionally multiple wavelets were seen instead of a single circuit., Conclusions: Spatial nonhomogeneities in conduction caused by transient unexcitable areas play a major role in both the initiation and the termination of episodes of circus movements in the pregnant rat myo-metrium. In addition, most circuits remained in a single location, although sometimes meandering or even fibrillatory activity was seen.

Detailed spatial analysis of the propagation of individual slow waves was performed in the isolated gastroduodenal preparation of the cat. Use was made of a system that allowed the simultaneous recordings from 240 extracellular electrodes, which were positioned across the gastroduodenal region. Reconstructions of the spread of propagation (n = 31) revealed that (a) the antral slow wave never propagated into the duodenum but was blocked at the pyloric ring, (b) the duodenal slow wave did not activate the antral tissue, and (c) a quiescent zone in which no slow waves could be recorded was always present at the most proximal part of the duodenum immediately distal to the pyloric ring. Furthermore, phase density distributions of duodenal cycles revealed that antral activity had no influence on the rate of discharge of duodenal pacemakers. Light microscopic study of sections of the duodenum close to the pyloric ring and further away did not show any structural differences between the quiescent zone and the active areas. In conclusion, slow waves do not propagate across the gastroduodenal junction in the isolated feline preparation and therefore do not seem to play a role in the electro-mechanical integration between the stomach and the duodenum.

Objective and Design: The normal aborad propagation of the slow wave in the small intestine is easily distorted by pacing, hypoxia or transection. We studied whether acute local ischaemia would also induce serious conduction disturbances and ectopic pacemaking., Methods: After general anaesthesia and a mid-abdominal incision, a multi-electrode array of 240 extracellular electrodes was positioned on the serosal surface of an exteriorized intestinal loop. Simultaneous recordings of all 240 surface electrodes was performed during a control period and for 5-10 min following local acute arterial occlusion. After the experiments activation maps were constructed describing the pattern of propagation of the slow waves., Results: During control periods, the activation maps showed homogeneous aborad conduction of the slow wave. During acute ischaemia, local areas of inexcitability developed rapidly, merging together to form lines of conduction block. This in turn often provoked the appearance of subsidiary ectopic pacemakers. The location of the conduction blocks as well as that of ectopic pacemakers was highly variable and could disappear and reappear at other sites., Conclusion: Within minutes, acute ischaemia disturbed the organized homogeneous aborad propagation of the slow wave leading to pronounced inhomogeneous depression of conduction, local inexcitability, conduction block and the appearance of subsidiary pacemakers.

The propagation of individual action potentials during spontaneous bursts of activity in isolated pregnant rat myometrium in the final stage of pregnancy was analyzed. Simultaneous recordings from 240 extracellular recording sites (inter-electrode distance 1 mm) made it possible to reconstruct, in spatial and temporal details, the conduction of the electrical impulse. On several occasions, the impulse was seen to be conducted in a circular fashion whereby the impulse repeatedly re-excited the myometrium. No evidence was found of circuits rotating around an area of depressed excitability or anatomical obstacle, suggesting that these circuits are similar to those proposed to occur in cardiac muscle by the "leading circuit" model. Because of the anisotropic conduction properties of the myometrium, several circuits revolved in an ellipse with the long axis parallel to the longitudinal fiber direction, similar to functional re-entry in the anisotropic ventricle. Of a total of 46 bursts analyzed, myometrial re-entry occurred in 10 of the bursts. Furthermore, re-entries were found at day 17, day 19 and day 21 ( = term) stages of pregnancy suggesting that re-entry may occur throughout the final stage of gestation. In conclusion, functional re-entry, previously shown in the myocardium, may also occur in the pregnant myometrium. The presence of re-entry in the uterus could underlie the mechanism for uterine tachysystole, leading to dysfunctional labor.

Using the CD-ROM system of MEDLINE, which contains the origins of articles that are published in about 3500 international medical journals, a survey was performed on the medical publications from the six countries in the Gulf Cooperating Council (GCC) over a period of five years (1990-1994). The Kingdom of Saudi Arabia was the largest producer of publications, with approximately 400 papers each year. In the same period the output from Kuwait declined from about 200 to a lower number, an effect probably caused by the invasion. In contrast, the United Arab Emirates, and to a lesser extent the Sultanate of Oman, have shown a growth in their publication record due to the initiation of new medical schools in these two countries. In the six GCC countries, all the colleges of medicine together were responsible for 34% of the total number of publications, hospitals and health centers published 45% of all papers, while non-medical colleges and other institutions published smaller amounts (10% and 11% respectively).

High resolution electrical mapping in the gastrointestinal system entails recording from a large number of extracellular electrodes simultaneously. It allows the collection of signals from 240 individual sites which are then amplified, filtered, digitized, multiplexed and stored on tape. After recording, periods of interest can be analysed and the original sequence of activity reconstructed. This technology, originally developed to study normal rhythms and abnormal dysrhythmias in the heart, has been modified to allow recordings from the gastrointestinal tract. In this report, initial results are presented describing the origin and propagation of the slow wave in the isolated stomach and the isolated duodenum in the cat. These results show that in both organs it not uncommon to have more than one focus active during a single cycle. The conduction of slow waves from such a multiple pacemaker environment can become quite complex, and this may play a role in determining the contractile pattern in these organs.

In renal pelvis preparations isolated from the sheep, the location of the pacemaker and the pathway of conduction of the electrical impulse in the pelvis were analyzed in detail. An electrophysiological acquisition system was used allowing simultaneous recordings from 240 extracellular electrodes. Reconstruction of the spread of activity showed that the site of the pelvis pacemaker was, in virtually all cases, located at the pelvicalyceal border and never in the body of the pelvis or in the area of the pelviureteric junction. One single pacemaker was responsible for a particular spread of activation, and fusion of activity originating from two or more pacemakers did not place. Furthermore, spontaneous shifts of the pacemaker could occur from one site to another along the pelvicalyceal border. Conduction from the site of the current pacemaker to the pelviureteric junction and the ureter was slow, inhomogeneous, and contorted. Multiple instances of partial or total conduction block were seen at all levels in the pelvis and were not restricted to the pelviureteric junction. The occurrence of the conduction block did not seem to be related to the length of the preceding interval, implying that the refractory period did not play a major role in the genesis of intrapelvic conduction block. In conclusion, high-resolution mapping of the renal pelvis is possible and reveals location and behavior of the pacemaker and documents inhomogeneities in conduction and conduction block.

High-resolution mapping makes it possible to reconstruct and display the conduction pattern of the action potential as it propagates through cardiac or smooth muscles. During slow and regular activity, time mapping of the spread of activation muscles. During slow and regular activity, time mapping of the spread of activation is relatively simple and straightforward. However, when frequencies are high or conduction is slow, such as seen during atrial fibrillation or found in the pregnant uterus, the tracking of individual waves may become more difficult and uncertain. In order to reconstruct the pathway of a single wave, a search and sorting routine was developed which makes it possible to distinguish, track and display individual wavelets. The algorithm is able to detect variations in conduction block, spontaneous shifts in the location of the pacemaker and changes in the direction of conduction. It is less sensitive when two or more wavefronts intermingle in space and time, such as during collision or fusion. Wave mapping is especially useful, in addition to current time mapping, in sorting quickly through the large amount of data produced by high-resolution mapping of electrical activities in cardiac and smooth muscle.

Detailed spatial analysis of propagation of individual action potential was performed during spontaneous bursts of activity in the isolated 17-day pregnant rat myometrium. Use was made of high-resolution mapping with simultaneous recordings from 240 extracellular electrodes. Positioning of the electrode assembly by itself did not have any adverse effects, and no differences were found in the period or duration of spontaneous bursts recorded with and without the electrode assembly touching the tissue. The spread of propagation of individual action potentials was reconstructed at several moments during myometrial spike bursts. Both the direction and the sequence of activation of the myometrium were found to be highly variable and depended on 1) the level and spatial dispersion of excitability and 2) whether conduction occurred predominantly in the longitudinal or the circumferential direction. Furthermore, conduction was frequently complicated by the spontaneous occurrence of 1) lines of conduction block, 2) focal sites of pacemaking, or 3) merging of two or more wavelets into a single wave. In contrast, when the myometrium was divided into small segments, activity became much more regular, and both the location of the pacemaker and the direction of propagation were much more stable than in the whole myometrium. In conclusion, spontaneous spatial variations in local spike propagation at the preterm stage could provide for the necessary asynchrony in activation and play a role in the prevention of forceful contractions and premature labor.