Peristaltic Contraction Waves Research Articles

On a coupled electro-chemomechanical model of gastric smooth muscle contraction

The stomach is a central organ in the gastrointestinal tract that performs a variety of functions, in which the spatio-temporal organisation of active smooth muscle contraction in the stomach wall (SW) is highly regulated. In the present study, a three-dimensional model of the gastric smooth muscle contraction is presented, including the mechanical contribution of the mucosal and muscular layer of the SW. Layer-specific and direction-dependent model parameters for the active and passive stress-stretch characteristics of the SW were determined experimentally using porcine smooth muscle strips. The electrical activation of the smooth muscle cells (SMC) due to the pacemaker activity of the interstitial cells of Cajal (ICC) is modelled by using FitzHugh-Nagumo-type equations, which simulate the typical ICC and SMC slow wave behaviour. The calcium dynamic in the SMC depends on the SMC membrane potential via a gaussian function, while the chemo-mechanical coupling in the SMC is modelled via an extended Hai-Murphy model. This cascade is coupled with an additional mechano-electrical feedback-mechanism, taking into account the mechanical response of the ICC and SMC due to stretch of the SW. In this way the relaxation responses of the fundus to accommodate incoming food, as well as the typical peristaltic contraction waves in the antrum for mixing and transport of the chyme, have been well replicated in simulations performed at the whole organ level. Statement of SignificanceIn this article, a novel three-dimensional electro-chemomechanical model of the gastric smooth muscle contraction is presented. The propagating waves of electrical membrane potential in the network ofinterstitial cells of Cajal (ICC) and smooth muscle cells (SMC) lead to a global pattern of change in the calciumdynamics inside the SMC. Taking additionally into account the mechanical response of the ICC and SMC due to stretch of the stomach wall, also referred to as mechanical feedback-mechanism, the result is a complex spatio-temporal regulation of the active contraction and relaxation of the gastric smooth muscle tissue. Being a firstapproach, in future view such a three-dimensional model can give an insight into the complexload transferring system of the stomach wall, as well as into the electro-chemomechanicalcoupling process underlying smooth muscle contraction in health and disease.

Spectral moment measures for the analysis of acoustic swallowing evaluation

During pharyngeal phase of swallowing, related muscles work together to produce wave-like contractions and to move food into esophageal phase. How the peristaltic contraction of muscles and movement of bolus coordinate can significantly strengthen or weaken one’s swallowing functions. This study uses the spectral moment analysis to investigate the acoustic effects of the peristaltic contraction wave during pharyngeal phase of swallowing. Four spectral moments describe features of the energy spectrum: the first moment (mean, centre of gravity) and the second moment (standard deviation) represent the spectrum's central tendency and dispersion respectively. Skewness and kurtosis (moment 3 and 4 ) represent spectrum's tilt and peak in relation to the central tendency. Results indicate that spectral moment measures may be one acoustic index sensitive to peristaltic contraction properties of swallowing. The statistical interpretation in accord with swallowing evaluation will be discussed.

Endoscopic Variceal Sequential Ligation Does Not Increase Risk of Gastroesophageal Reflux Disease in Cirrhosis Patients

BackgroundEndoscopic variceal sequential ligation (EVSL) is currently endorsed in our hospital, as the preferred endoscopic treatment for prevention of variceal rebleeding and achieving adequate hemostasis. There is currently a lack of consensus surrounding EVSL-induced changes in esophageal motor function and abnormal reflux.AimsTo explore alterations in esophageal motor function and risk of abnormal gastroesophageal reflux in liver cirrhosis patients with esophageal varices, after EVSL.MethodsTwenty-one liver cirrhosis patients with esophageal varices were studied using manometry and 24-h pH monitoring 1 day prior to and 1 month following EVSL. The EVSL consisted of performing esophageal variceal ligation using a multi-band ligator, which was repeated every 4 weeks until the varices were eradicated.ResultsThe amplitude and duration of peristaltic contraction waves and the percentage of abnormal esophageal contraction waveforms were unaltered in both the proximal (P > 0.05) and the distal (P > 0.05) esophagus after EVSL. However, the lower esophageal sphincter pressure was decreased following EVSL (16.1 ± 7.9 mmHg vs 21.1 ± 6.3 mmHg (P < 0.05)). Various quantitative parameters including percentage of total monitoring time with pH < 4.0, total number of reflux episodes, number of reflux episodes > 5 min, and DeMeester scores were not increased in post-EVSL patients. Abnormal reflux monitored by 24-h pH monitoring occurred in ten (47.6%) pre-EVSL patients and 11 (52.4%) post-EVSL patients.ConclusionsAlthough EVSL affects esophageal motility by relatively decreasing LES pressure, it does not induce substantial motor abnormalities nor increase risk of abnormal gastroesophageal reflux disease in cirrhosis patients.

Effect of Laparoscopic Antireflux Surgery on Esophageal Motility

Background/Aims: The effect of laparoscopic antireflux surgery on esophageal motility is incompletely understood, and any indication for this procedure in patients with motility disorder is disputed in literature. We evaluated the influence of laparoscopic Nissen fundoplication on impaired esophageal motility. Methods: In this pathological manometric study, we divided the patients into two groups preoperatively: the hypomotility group (mean amplitude of esophageal contraction wave <40 mm Hg; HYPO group, n = 11) and the normal group (mean amplitude of esophageal contraction wave >40 mm Hg; NORM group, n = 43). The amplitudes of esophageal contraction waves 3 and 8 cm above the lower esophageal sphincter and the percentage of peristaltic contraction waves of the tubular esophagus were analyzed pre- and postoperatively. Results: In total, 54 patients with GERD underwent esophageal manometry before and 6 months after Nissen fundoplication. The length and pressure of the lower esophageal sphincter were increased in both groups postoperatively (p < 0.01). Patients in the HYPO group (n = 11) showed a statistically significant increase of mean amplitude of esophageal contraction (32.8 vs. 57.3 mm Hg; p < 0.01), while no change was found in the NORM group (n = 43). A total of 72% of patients with preoperative motility disorder showed normal postoperative manometry. Conclusion: Nissen fundoplication normalizes esophageal motility, especially in patients with preoperative hypomotility. Patients with impaired esophageal motility should not per se be excluded from antireflux surgery.

Deletion ofGpr128results in weight loss and increased intestinal contraction frequency

To generate a Gpr128 gene knockout mouse model and to investigate its phenotypes and the biological function of the Gpr128 gene. Bacterial artificial chromosome-retrieval methods were used for constructing the targeting vector. Using homologous recombination and microinjection technology, a Gpr128 knockout mouse model on a mixed 129/BL6 background was generated. The mice were genotyped by polymerase chain reaction (PCR) analysis of tail DNA and fed a standard laboratory chow diet. Animals of both sexes were used, and the phenotypes were assessed by histological, biochemical, molecular and physiological analyses. Semi-quantitative reverse transcription-PCR and Northern blotting were used to determine the tissue distribution of Gpr128 mRNA. Beginning at the age of 4 wk, body weights were recorded every 4 wk. Food, feces, blood and organ samples were collected to analyze food consumption, fecal quantity, organ weight and constituents of the blood and plasma. A Trendelenburg preparation was utilized to examine intestinal motility in wild-type (WT) and Gpr128(-/-) mice at the age of 8 and 32 wk. Gpr128 mRNA was highly and exclusively detected in the intestinal tissues. Targeted deletion of Gpr128 in adult mice resulted in reduced body weight gain, and mutant mice exhibited an increased frequency of peristaltic contraction and slow wave potential of the small intestine. The Gpr128(+/+) mice gained more weight on average than the Gpr128(-/-) mice since 24 wk, being 30.81 ± 2.84 g and 25.74 ± 4.50 g, respectively (n = 10, P < 0.01). The frequency of small intestinal peristaltic contraction was increased in Gpr128(-/-) mice. At the age of 8 wk, the frequency of peristalsis with an intraluminal pressure of 3 cmH2O was 6.6 ± 2.3 peristalsis/15 min in Gpr128(-/-) intestine (n = 5) vs 2.6 ± 1.7 peristalsis/15 min in WT intestine (n = 5, P < 0.05). At the age of 32 wk, the frequency of peristaltic contraction with an intraluminal pressure of 2 and 3 cmH2O was 4.6 ± 2.3 and 3.1 ± 0.8 peristalsis/15 min in WT mice (n = 8), whereas in Gpr128(-/-) mice (n = 8) the frequency of contraction was 8.3 ± 3.0 and 7.4 ± 3.1 peristalsis/15 min, respectively (2 cmH2O: P < 0.05 vs WT; 3 cmH2O: P < 0.01 vs WT). The frequency of slow wave potential in Gpr128(-/-) intestine (35.8 ± 4.3, 36.4 ± 4.2 and 37.1 ± 4.8/min with an intraluminal pressure of 1, 2 and 3 cmH2O, n = 8) was also higher than in WT intestine (30.6 ± 4.2, 31.4 ± 3.9 and 31.9 ± 4.5/min, n = 8, P < 0.05). We have generated a mouse model with a targeted deletion of Gpr128 and found reduced body weight and increased intestinal contraction frequency in this animal model.

An Uncommon Cause of Food Impaction

Purpose: Esophageal food impaction is usually secondary to structural abnormalities of the esophagus such as Schatzki's ring, eosinophilic esophagitis or strictures. Nutcracker esophagus (NE) is an esophageal motility disorder characterized by the presence of hypertensive but peristaltic contraction waves, making food impactions rare. We describe a patient with meat impaction associated with NE. A 66-year-old male presented with chest pain and dysphagia 3 hours after ingesting a large meal. His pain was located in the mid chest associated with difficulty swallowing his own saliva. He denied any history of dysphagia, chest pain or heartburn. Physical exam revealed an alert man in mild distress with pooling of saliva in his mouth. Cardiac, pulmonary and abdominal exams were unremarkable. An EKG and three sets of cardiac enzymes ruled out cardiac causes of chest pain. All the initial laboratory results were normal except for a WBC 11,950; with a normal eosinophil count. A CT of the chest revealed foreign material in the esophagus, consistent with undigested food. Prior to endoscopic evaluation, the patient's symptoms spontaneously subsided. Endoscopy revealed mildly hemorrhagic mucosa in the mid esophagus with no strictures, concentric rings or esophageal furrows. Biopsies of the esophagus were normal, with no evidence of eosinophilic esophagitis. A single contrast esophagram revealed tertiary contractions of the esophagus. High resolution manometry (HRM) (Figure 1) revealed normal peristaltic wet swallows with normal contraction amplitudes at 7 and 11 cm above the LES. At 3 cm above the LES, however, the amplitudes ranged from 196-386 mmHg, consistent with NE. The patient was discharged the day after the procedure and returded 1 month later for follow-up. He remained asymptomatic and no treatment was required. Nutcracker esophagus can be diffuse or segmental. The manometry findings in our patient were consistent with a segmental nutcracker esophagus. Only 4 cases have reported of nutcracker esophagus and food impaction, but ours is the first one diagnosed with high resolution manometry. Although rare, nutcracker esophagus can cause esophageal food impaction and HRM is of paramount importance in diagnosing this entity in minimally symptomatic patients.Figure: [573] High resolution manometry showing hypertensive peristaltic waves in the distal esophagus.

A new look at the comparative physiology of insect and human hearts

Recent electrocardiographic (ECG) studies of insect hearts revealed the presence of human-like, involuntary and purely myogenic hearts. Certain insects, like a small light-weight species of hoverfly (Episyrphus balteatus), have evolved a very efficient cardiac system comprised of a compact heart ventricle and a narrow tube of aorta, which evolved as an adaptation to sustained hovering flights. Application of thermocardiographic and optocardiographic ECG methods revealed that adult flies of this species use the compact muscular heart chamber (heart ventricle) for intensive pumping of insect “blood“ (haemolymph) into the head and thorax which is ringed all over with indirect flight musculature. The recordings of these hearts revealed extremely high, record rates of forward-directed, anterograde heartbeat (up to 10Hz), associated with extremely enhanced synchronic (not peristaltic) propagation of systolic myocardial contractions (32.2mm/s at room temperature). The relatively slow, backward-directed or retrograde cardiac contractions occurred only sporadically in the form of individual or twinned pulses replacing occasionally the resting periods. The compact heart ventricle contained bi-directional lateral apertures, whose opening and closure diverted the intracardiac anterograde “blood” streams between the abdominal haemocoelic cavity and the aortan artery, respectively. The visceral organs of this flying machine (crop, midgut) exhibited myogenic, extracardiac peristaltic pulsations similar to heartbeat, including the periodically reversed forward and backward direction of the peristaltic waves. The tubular crop contracted with a periodicity of 1Hz, both forwards and backwards, with propagation of the peristaltic waves at 4.4mm/s. The air-inflated and blindly ended midgut contracted at 0.2Hz, with a 0.9mm/s propagation of the peristaltic contraction waves. The neurogenic system of extracardiac haemocoelic pulsations, widely engaged in the regulation of circulatory and respiratory functions in other insect species, has been replaced here by a more economic, myogenic pulsation of the visceral organs as a light-weight evolutionary adaptation to prolonged hovering flight. Striking structural, functional and even genetic similarities found between the hearts of Episyrphus, Drosophila and human hearts, have been practically utilised for inexpensive testing of new cardioactive or cardioinhibitory drugs on insect heart.

Deglutitive Inhibition, Latency Between Swallow and Esophageal Contractions and Primary Esophageal Motor Disorders

Swallowing induces an inhibitory wave that is followed by a contractile wave along the esophageal body. Deglutitive inhibition in the skeletal muscle of the esophagus is controlled in the brain stem whilst in the smooth muscle, an intrinsic peripheral control mechanism is critical. The latency between swallow and contractions is determined by the pattern of activation of the inhibitory and excitatory vagal pathways, the regional gradients of inhibitory and excitatory myenteric nerves, and the intrinsic properties of the smooth muscle. A wave of inhibition precedes a swallow-induced peristaltic contraction in the smooth muscle part of the human oesophagus involving both circular and longitudinal muscles in a peristaltic fashion. Deglutitive inhibition is necessary for drinking liquids which requires multiple rapid swallows (MRS). During MRS the esophageal body remains inhibited until the last of the series of swallows and then a peristaltic contraction wave follows. A normal response to MRS requires indemnity of both inhibitory and excitatory mechanisms and esophageal muscle. MRS has recently been used to assess deglutitive inhibition in patients with esophageal motor disorders. Examples with impairment of deglutitive inhibition are achalasia of the LES and diffuse esophageal spasm.

Effect of aging on esophageal motility in patients with and without GERD.

Background/Aims: The impact of aging on esophageal motility is not completely understood. This study aims at assessing 1) whether degeneration of esophageal body motility occurs with age and 2) whether this development is influenced by gastroesophageal reflux disease (GERD).Methods: 326 consecutive patients with symptoms of GERD underwent a diagnostic work-up including a water-perfused esophageal manometry. Patients were divided by age: 17–39 years (group 1, n=75), 40–49 years (group 2, n=79), 50–59 years (group 3, n=64), 60–69 years (group 4, n=74), and >70 years (group 5, n=34). GERD was diagnosed if patients had erosive esophagitis at endoscopy, a positive pH-metry, or both. The amplitude of esophageal contraction waves 3 cm and 8 cm above the lower esophageal sphincter and the percentage of peristaltic contraction waves of the tubular esophagus were analyzed and correlated to GERD.Results: A normal esophageal manometry was found in 86.7%, 73.4%, 67.2%, 58.1%, and 55.9% (p<0.01) in groups 1–5, respectively. Esophageal contraction wave amplitudes were affected by age in patients positive for GERD only (p<0.01). Esophageal body peristalsis was affected by age (p<0.01) independent of the diagnosis of GERD. Conclusion: Aging is correlated to esophageal motor abnormalities. GERD has a significant impact on esophageal contraction wave amplitude, but not on peristalsis.

A Mathematical Simulation of the Ureter: Effects of the Model Parameters on Ureteral Pressure/Flow Relations

Ureteral peristaltic mechanism facilitates urine transport from the kidney to the bladder. Numerical analysis of the peristaltic flow in the ureter aims to further our understanding of the reflux phenomenon and other ureteral abnormalities. Fluid-structure interaction (FSI) plays an important role in accuracy of this approach and the arbitrary Lagrangian-Eulerian (ALE) formulation is a strong method to analyze the coupled fluid-structure interaction between the compliant wall and the surrounding fluid. This formulation, however, was not used in previous studies of peristalsis in living organisms. In the present investigation, a numerical simulation is introduced and solved through ALE formulation to perform the ureteral flow and stress analysis. The incompressible Navier-Stokes equations are used as the governing equations for the fluid, and a linear elastic model is utilized for the compliant wall. The wall stimulation is modeled by nonlinear contact analysis using a rigid contact surface since an appropriate model for simulation of ureteral peristalsis needs to contain cell-to-cell wall stimulation. In contrast to previous studies, the wall displacements are not predetermined in the presented model of this finite-length compliant tube, neither the peristalsis needs to be periodic. Moreover, the temporal changes of ureteral wall intraluminal shear stress during peristalsis are included in our study. Iterative computing of two-way coupling is used to solve the governing equations. Two phases of nonperistaltic and peristaltic transport of urine in the ureter are discussed. Results are obtained following an analysis of the effects of the ureteral wall compliance, the pressure difference between the ureteral inlet and outlet, the maximum height of the contraction wave, the contraction wave velocity, and the number of contraction waves on the ureteral outlet flow. The results indicate that the proximal part of the ureter is prone to a higher shear stress during peristalsis compared with its middle and distal parts. It is also shown that the peristalsis is more efficient as the maximum height of the contraction wave increases. Finally, it is concluded that improper function of ureteropelvic junction results in the passage of part of urine back flow even in the case of slow start-up of the peristaltic contraction wave.

775 Influence of the Cannabinoid Type 1 Receptor Antagonist Rimonabant On Esophageal Function in Man

Background: Cannabinoid type 1 (CB1) receptors have been implicated in the control of transient lower esophageal sphincter (LES) relaxations (TLESRs) in animals. In man, nonscpecific cannabinoid receptor agonism was found to inhibit TLESRS, but it is unclear whether CB1 receptors are involved in the control of esophageal function. Aim: To study the effects of the CB1 receptor antagonist rimonabant on fasting and postprandial LES function in healthy subjects. Methods: Eleven healthy volunteers underwent two esophageal sleeve manometry studies after 3 days premedication with placebo or rimonabant 20 mg/ day. Drug was administered after 30 minutes and a standardized meal was administered after 90 minutes, with measurements continuing to 120 minutes postprandially. Throughout the study, 10 wet swallows were administered at 30-minute intervals. Results: Intragastric pressure was significantly enhanced by pretreatment with rimonabant (24.5±1.5 vs. 20.4±1.7 mmHg, p=0.01). Rimonabant did not significantly alter preprandial LES pressure (20.3±4.0 vs. 17.3±3.0 mmHg, NS), but postprandial LES pressures were significantly enhanced (ANOVA p<0.01), with post-hoc significant differences at 30, 60, 90, and 120 minutes after the end of the meal (respectively 17.1±2.7 vs. 10.0±1.7; 17.8±3.3 vs. 10.2±1.6; 19.3±3.6 vs. 10.4±1.3 mmHg and 19.6±3.1 vs. 8.6±3.0; all p<0.05). Swallow-induced relaxations (97±1 vs. 97±1%, NS) and amplitude of peristaltic contractions were not altered, but rimonabant significantly increased the duration of peristaltic contraction waves at all time points (e.g. 5.0±0.3 vs. 8.0±0.3 sec preprandially and 5.0±0.2 vs. 8.2±0.3 sec at 30 min postprandially, both p<0.01). The tendency of a decreased number of TLESRs after rimonabant did not reach statistical significance (TLESRs total 2.3±0.8 vs. 3.3±0.5, p=0.08; preprandially 0.6±0.2 vs.1.3±0.3, p=0.14; postprandially 1.6±0.8 vs. 2.0±0.4, p=0.10). Conclusion: The CB1 receptor antagonist rimonabant enhances postprandial LES pressure and tends to decrease TLESRs in healthy subjects.

778 Cytokeratin Assisted Laser Scanning Cytometry (LSC) Permits Fully Automated Detection of Aneuploidy in Fixed Barrett's Biopsies

Background: Cannabinoid type 1 (CB1) receptors have been implicated in the control of transient lower esophageal sphincter (LES) relaxations (TLESRs) in animals. In man, nonscpecific cannabinoid receptor agonism was found to inhibit TLESRS, but it is unclear whether CB1 receptors are involved in the control of esophageal function. Aim: To study the effects of the CB1 receptor antagonist rimonabant on fasting and postprandial LES function in healthy subjects. Methods: Eleven healthy volunteers underwent two esophageal sleeve manometry studies after 3 days premedication with placebo or rimonabant 20 mg/ day. Drug was administered after 30 minutes and a standardized meal was administered after 90 minutes, with measurements continuing to 120 minutes postprandially. Throughout the study, 10 wet swallows were administered at 30-minute intervals. Results: Intragastric pressure was significantly enhanced by pretreatment with rimonabant (24.5±1.5 vs. 20.4±1.7 mmHg, p=0.01). Rimonabant did not significantly alter preprandial LES pressure (20.3±4.0 vs. 17.3±3.0 mmHg, NS), but postprandial LES pressures were significantly enhanced (ANOVA p<0.01), with post-hoc significant differences at 30, 60, 90, and 120 minutes after the end of the meal (respectively 17.1±2.7 vs. 10.0±1.7; 17.8±3.3 vs. 10.2±1.6; 19.3±3.6 vs. 10.4±1.3 mmHg and 19.6±3.1 vs. 8.6±3.0; all p<0.05). Swallow-induced relaxations (97±1 vs. 97±1%, NS) and amplitude of peristaltic contractions were not altered, but rimonabant significantly increased the duration of peristaltic contraction waves at all time points (e.g. 5.0±0.3 vs. 8.0±0.3 sec preprandially and 5.0±0.2 vs. 8.2±0.3 sec at 30 min postprandially, both p<0.01). The tendency of a decreased number of TLESRs after rimonabant did not reach statistical significance (TLESRs total 2.3±0.8 vs. 3.3±0.5, p=0.08; preprandially 0.6±0.2 vs.1.3±0.3, p=0.14; postprandially 1.6±0.8 vs. 2.0±0.4, p=0.10). Conclusion: The CB1 receptor antagonist rimonabant enhances postprandial LES pressure and tends to decrease TLESRs in healthy subjects.

776 Novel Fluorescence-Labeled Peptide for Targeting Intra-Epithelial Neoplasia in Barrett's Esophagus

Background: Cannabinoid type 1 (CB1) receptors have been implicated in the control of transient lower esophageal sphincter (LES) relaxations (TLESRs) in animals. In man, nonscpecific cannabinoid receptor agonism was found to inhibit TLESRS, but it is unclear whether CB1 receptors are involved in the control of esophageal function. Aim: To study the effects of the CB1 receptor antagonist rimonabant on fasting and postprandial LES function in healthy subjects. Methods: Eleven healthy volunteers underwent two esophageal sleeve manometry studies after 3 days premedication with placebo or rimonabant 20 mg/ day. Drug was administered after 30 minutes and a standardized meal was administered after 90 minutes, with measurements continuing to 120 minutes postprandially. Throughout the study, 10 wet swallows were administered at 30-minute intervals. Results: Intragastric pressure was significantly enhanced by pretreatment with rimonabant (24.5±1.5 vs. 20.4±1.7 mmHg, p=0.01). Rimonabant did not significantly alter preprandial LES pressure (20.3±4.0 vs. 17.3±3.0 mmHg, NS), but postprandial LES pressures were significantly enhanced (ANOVA p<0.01), with post-hoc significant differences at 30, 60, 90, and 120 minutes after the end of the meal (respectively 17.1±2.7 vs. 10.0±1.7; 17.8±3.3 vs. 10.2±1.6; 19.3±3.6 vs. 10.4±1.3 mmHg and 19.6±3.1 vs. 8.6±3.0; all p<0.05). Swallow-induced relaxations (97±1 vs. 97±1%, NS) and amplitude of peristaltic contractions were not altered, but rimonabant significantly increased the duration of peristaltic contraction waves at all time points (e.g. 5.0±0.3 vs. 8.0±0.3 sec preprandially and 5.0±0.2 vs. 8.2±0.3 sec at 30 min postprandially, both p<0.01). The tendency of a decreased number of TLESRs after rimonabant did not reach statistical significance (TLESRs total 2.3±0.8 vs. 3.3±0.5, p=0.08; preprandially 0.6±0.2 vs.1.3±0.3, p=0.14; postprandially 1.6±0.8 vs. 2.0±0.4, p=0.10). Conclusion: The CB1 receptor antagonist rimonabant enhances postprandial LES pressure and tends to decrease TLESRs in healthy subjects.

A stomach road or “Magenstrasse” for gastric emptying

Gastric muscle contractions grind and mix solid/liquid meal within the stomach, and move it into the bowels at a controlled rate. Contractions are of two types: slow volume-reducing contractions of the proximal stomach (the fundus), and peristaltic contraction waves in the distal stomach (the antrum). Fundic squeeze maintains gastro-duodenal pressure difference to drive gastric emptying. Emptying is generally assumed to proceed from the antrum to the fundus, so that ingested drugs can take hours to enter the small intestines and activate. Antral contraction waves (ACW), in contrast, generate fluid motions that break down and mix gastric content. Using a computer model of the human stomach, we discover a new function of these contraction waves apart from grinding and mixing. In coordination with fundic contraction, antral contraction waves move liquid content from the fundus along a very narrow path to the duodenum through the center of the antrum. Using physiological data, we show that this gastric emptying “Magenstrasse” (stomach road) can funnel liquid gastric content from the farthest reaches of the fundus directly to the intestines within 10 min. Consequently, whereas drugs (tablets, capsules, liquid) released off the Magenstrasse may require hours to enter the duodenum, at low concentration, when released on the Magenstrasse the drug can enter the duodenum and activate within 10 min—at high concentration. This discovery might explain observed high variability in drug initiation time, and may have important implications to both drug delivery and digestion, as well as to other wall-driven emptying of elastic containers.

Gastric flow and mixing studied using computer simulation

The fed human stomach displays regular peristaltic contraction waves that originate in the proximal antrum and propagate to the pylorus. High-resolution concurrent manometry and magnetic resonance imaging (MRI) studies of the stomach suggest a primary function of antral contraction wave (ACW) activity unrelated to gastric emptying. Detailed evaluation is difficult, however, in vivo. Here we analyse the role of ACW activity on intragastric fluid motions, pressure, and mixing with computer simulation. A two-dimensional computer model of the stomach was developed with the 'lattice-Boltzmann' numerical method from the laws of physics, and stomach geometry modelled from MRI. Time changes in gastric volume were specified to match global physiological rates of nutrient liquid emptying. The simulations predicted two basic fluid motions: retrograde 'jets' through ACWs, and circulatory flow between ACWs, both of which contribute to mixing. A well-defined 'zone of mixing', confined to the antrum, was created by the ACWs, with mixing motions enhanced by multiple and narrower ACWs. The simulations also predicted contraction-induced peristaltic pressure waves in the distal antrum consistent with manometric measurements, but with a much lower pressure amplitude than manometric data, indicating that manometric pressure amplitudes reflect direct contact of the catheter with the gastric wall. We conclude that the ACWs are central to gastric mixing, and may also play an indirect role in gastric emptying through local alterations in common cavity pressure.

Cardiac chamber formation: development, genes, and evolution.

Concepts of cardiac development have greatly influenced the description of the formation of the four-chambered vertebrate heart. Traditionally, the embryonic tubular heart is considered to be a composite of serially arranged segments representing adult cardiac compartments. Conversion of such a serial arrangement into the parallel arrangement of the mammalian heart is difficult to understand. Logical integration of the development of the cardiac conduction system into the serial concept has remained puzzling as well. Therefore, the current description needed reconsideration, and we decided to evaluate the essentialities of cardiac design, its evolutionary and embryonic development, and the molecular pathways recruited to make the four-chambered mammalian heart. The three principal notions taken into consideration are as follows. 1) Both the ancestor chordate heart and the embryonic tubular heart of higher vertebrates consist of poorly developed and poorly coupled "pacemaker-like" cardiac muscle cells with the highest pacemaker activity at the venous pole, causing unidirectional peristaltic contraction waves. 2) From this heart tube, ventricular chambers differentiate ventrally and atrial chambers dorsally. The developing chambers display high proliferative activity and consist of structurally well-developed and well-coupled muscle cells with low pacemaker activity, which permits fast conduction of the impulse and efficacious contraction. The forming chambers remain flanked by slowly proliferating pacemaker-like myocardium that is temporally prevented from differentiating into chamber myocardium. 3) The trabecular myocardium proliferates slowly, consists of structurally poorly developed, but well-coupled, cells and contributes to the ventricular conduction system. The atrial and ventricular chambers of the formed heart are activated and interconnected by derivatives of embryonic myocardium. The topographical arrangement of the distinct cardiac muscle cells in the forming heart explains the embryonic electrocardiogram (ECG), does not require the invention of nodes, and allows a logical transition from a peristaltic tubular heart to a synchronously contracting four-chambered heart. This view on the development of cardiac design unfolds fascinating possibilities for future research.

Enhanced Locomotion Caused by Loss of the Drosophila DEG/ENaC Protein Pickpocket1

Coordination of rhythmic locomotion depends upon a precisely balanced interplay between central and peripheral control mechanisms [1]. Although poorly understood, peripheral proprioceptive mechanosensory input is thought to provide information about body position for moment-to-moment modifications of central mechanisms mediating rhythmic motor output [2]. Pickpocket1 (PPK1) is a Drosophila subunit of the epithelial sodium channel (ENaC) family displaying limited expression in multiple dendritic (md) sensory neurons tiling the larval body wall and a small number of bipolar neurons in the upper brain [3]. ppk1 null mutant larvae had normal external touch sensation and md neuron morphology but displayed striking alterations in crawling behavior. Loss of PPK1 function caused an increase in crawling speed and an unusual straight path with decreased stops and turns relative to wild-type. This enhanced locomotion resulted from sustained peristaltic contraction wave cycling at higher frequency with a significant decrease in pause period between contraction cycles. The mutant phenotype was rescued by a wild-type PPK1 transgene and duplicated by expressing a ppk1RNAi transgene or a dominant-negative PPK1 isoform. These results demonstrate that the PPK1 channel plays an essential role in controlling rhythmic locomotion and provide a powerful genetic model system for further analysis of central and peripheral control mechanisms and their role in movement disorders.

Intraluminal pressure changes in vivo in the middle and distal pig ureter during propagation of a peristaltic wave

Objectives. To establish the characteristics of mechanical activity during ureteral peristalsis and unidirectional bolus transport, pressure changes in the middle and distal (juxtavesical and ureterovesical junction) porcine ureter were quantified in vivo. Methods. Five female New Yorkshire pigs (50 to 60 kg) were studied under halothane anesthesia. The endoscopic approach was used to position an 8-channel 6F perfusion catheter under direct vision into the distal ureter by way of the orifice. Ureteral activity was studied in two separate sessions at 1-week intervals. The pressure, propagation velocity, and length of the peristaltic waves were analyzed. Results. The average maximal pressure in a not previously instrumented ureter amounted to 35.7 ± 1.2 cm H 2O in the mid-ureter, and decreased to 19.4 ± 1.3 cm H 2O in the juxtavesical ureter ( P <0.001) and further to 7.2 ± 1.0 cm H 2O ( P <0.001) in the submucosal segment. The propagation velocity of the peristaltic wave through the ureter was 2.1 ± 1.3 cm/s. The length of the pressure peak was 5.9 ± 1.6 cm. Conclusions. A ureteral peristaltic contraction wave travels at approximately 2 cm/s and is approximately 6 cm long. It is responsible for the unidirectional transport of a urinary bolus and itself acts as an “active” antireflux mechanism. The maximal pressure in the lumen of the ureter decreased from proximally to distally, but remains sufficiently high at the ureterovesical junction to prevent retrograde urine leakage when the ureter empties its urinary bolus into the bladder and the orifice is open.

Effect of bethanechol on esophageal function using multichannel intraluminal impedance (MII)

Background: Toward more understanding esophageal motility disorders it is important to have data about bolus movement together with associated peristalsis. In previous studies we have shown, that impedancometry is a reliable technique for recording intestinal chyme transport (1, 2), as well as for studying the dynamics of esophageal bolus transport (3). Now, we performed synchronous manometry and impedancometry in healthy subjects and patients with achalasia using a single catheter in order to test the applicability of this combination for the study of esophageal motility. Materials and Methods: Studies were performed in 8 healthy volunteers and 8 patients with achalasia. A custom-made combine catheter consisting of II impedance segments (each 2cm long) and 4 semiconductor pressure transducers was used. The pressure transducers were located between the impedance channels 1-2, 4-5, 7-8 and 10-11 (intertransducer distance 6 ern). The catheter was passed through the nose into the esophagus as previously described (3). Studies were performed using liquid (10 ml Osmolite) and semisolid boluses (10 ml Yogurt) at supine and upright position. Data were visually analyzed. Results: (a) In healthy subjects bolus transport and associated primary peristalsis with lower sphincter relaxation could be recorded reliably. The patterns were highly unique independent of bolus viscosity and body position. A detailed analysis of the correlation between peristalsis and bolus transit is possible. The propagation of the bolus is significantly faster than the propagation of the associated peristaltic contraction wave. (b) Patients with achalasia featured unique manometry tracings but quite variable impedance tracings, showing that different phenomena can be recorded by the 2 techniques. The spatial and temporal analysis the manometry and impedance tracings indicates that esophageal aperistalsis with simultaneous pressure elevation in achalasia seems to result from a common cavity phenomen. Summary: Simultaneous manometry and impedancometry to study esophageal motility are feasible. Bolus transport and associated peristalsis can be well studied. Both techniques provide different but complementary data on esophageal motility. The combination of both techniques opens new horizons for studying esophageal motility disorders.

Effect of intraluminal temperature on human oesophageal motor function.

Oesophageal motor activity is altered by bolus temperature. The effects of sustained cold or warm intraluminal temperature on oesophageal motility have not been documented in detail. Oesophageal manometry was performed in 11 normal subjects after intraluminal room, cold- and warm-water treatments. The intraluminal temperatures were 34.2 +/- 0.8, 30.6 +/- 1.7 and 39.7 +/- 0.9 degrees C respectively during room temperature, cold and warm applications. Low-temperature treatment prolonged the duration of lower oesophageal sphincter relaxation and the duration of oesophageal peristaltic contraction wave compared with the room temperature and warm treatments. Low temperature also attenuated the mean pressure slope of oesophageal contraction waves and resulted in an increased percentage of non-transmitted and simultaneous contractions. The effects of low-temperature application remained constant and there was no adaptation. Cooling oesophageal lumen temperature alters oesophageal motor activity, and this effect is not adaptive.