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AIM: Elevated plasma C-reactive protein (CRP) is regarded as a risk predictor for cardiovascular diseases. This systematic review explored the robustness of observations that CRP is elevated in periodontitis. Similarly, the effect of periodontal therapy on CRP levels was investigated. MATERIAL AND METHODS: Selection of publications was based on: (1) cross-sectional (case-control) studies; (2) longitudinal (treatment) studies; (3) high-sensitivity CRP measurement; (4) median and/or mean (+/-SD) values presented; and (5) subjects with no systemic disorders. RESULTS: Screening of the initially 448 identified studies and reference checking resulted in 18 suitable papers. The majority of the studies showed that CRP levels are higher in patients than in controls. Often, studies showed that patients had CRP levels >2.1 mg/l. A meta-analysis of 10 cross-sectional studies showed that the weighted mean difference (WMD) of CRP between patients and controls was 1.56 mg/l (p<0.00001). Evidence from available treatment studies (n=6) showed lower levels of CRP after periodontal therapy. Eligible treatment studies in a meta-analysis demonstrated a WMD of reductions of CRP after therapy of 0.50 mg/L (95% CI 0.08-0.93) (p=0.02). CONCLUSIONS: There is strong evidence from cross-sectional studies that plasma CRP in periodontitis is elevated compared with controls. There is modest evidence on the effect of periodontal therapy in lowering the levels of CRP. [ABSTRACT FROM AUTHOR]

Fermented foods play a significant role in the human diet for their natural, highly nutritious and healthy attributes. Our aim was to study the effect of yeast extract, a fermented substance extracted from natural yeast, on colonic motility to better understand its potential therapeutic role. A yeast extract was given to rats by gavage for 3 days, and myogenic and neurogenic components of colonic motility were studied using spatiotemporal maps made from video recordings of the whole colon ex vivo. A control group received saline gavages. The yeast extract caused excitation of the musculature by increasing the propagation length and duration of long-distance contractions, the major propulsive activity of the rat colon. The yeast extract also evoked rhythmic propulsive motor complexes (RPMCs) which were antegrade in the proximal and mid-colon and retrograde in the distal colon. RPMC activity was evoked by distention-induced neural activity, but it was myogenic in nature since we showed it to be generated by bethanechol in the presence of tetrodotoxin. In conclusion, ingestion of yeast extract stimulates rat colon motility by exciting neurogenic and myogenic control mechanisms., (© 2024 The Author(s). Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Effective and widely available strategies are needed to diagnose colonic motility dysfunction. We investigated whether ultrasonography could generate spatiotemporal maps combined with motor pattern frequency analysis, to become a noninvasive method to characterize human colon motor patterns. Abdominal colonic ultrasonography was performed on healthy subjects (N = 7), focusing on the detailed recording of spontaneous haustral activities. We developed image segmentation and frequency analysis software to analyze the motor patterns captured. Ultrasonography recordings of the ascending, transverse, and descending colon identified three distinct rhythmic motor patterns: the 1 cycle/min and the 3 cycles/min cyclic motor pattern were seen throughout the whole colon, whereas the 12 cycles/min cyclic motor pattern was identified in the ascending colon. The rhythmic motor patterns of the human colon that are associated with interstitial cells of Cajal-associated pacemaking activity can be accurately identified and quantified using ultrasound. NEW & NOTEWORTHY Ultrasonography in the clinical field is an underutilized tool for assessing colonic motility; however, with the addition of frequency analysis techniques, it provides a method to identify human colonic motor patterns. Here we report on the 1, 3, and 12 cpm rhythmic motor patterns. Ultrasound has the potential to become a bedside assessment for colonic dysmotility and may reveal the health of interstitial cells of Cajal (ICC) pacemaker activities.

Deep breathing exercises are the second most used complementary health approach in the United States. Two heart rate variability (HRV) parameters, the root mean square of successive differences (RMSSD) and the respiratory sinus arrhythmia (RSA), are used to assess parasympathetic reactivity to deep breathing, but they are often not in agreement. Our purpose was to determine the cause of the disagreement. We investigated HRV parameters in 38 subjects during baseline, deep breathing, and recovery. Here we show that RMSSD as a measure of parasympathetic reactivity is unreliable; it does not reflect the increase in HRV during deep breathing as determined by RSA. We observed a decrease in RMSSD values despite a marked increase in HRV as determined by RSA and the standard deviation of normal heartbeat interval (SDNN) in healthy subjects and patients with functional bowel disorders. We show that RSA captures all aspects of HRV, whereas successive differences in heart rate intervals are only a small part of HRV, with decreasing variability during deep breathing in most subjects. We present a new measure of calculating RSA during deep breathing that may become an essential tool for researchers and clinicians. We also provide a unique visualization of the increased heart rate variability during deep breathing. Hence, RMSSD cannot be used to assess parasympathetic reactivity during deep breathing; using RSA is recommended. The use of RMSSD in previous influential studies may have led to erroneous conclusions about parasympathetic reactivity during deep breathing. Its continued use may undervalue the effects of the autonomic nervous system in slow deep breathing.

The machinery maintaining fecal continence prevents involuntary loss of stool and is based on the synchronized interplay of multiple voluntary and involuntary mechanisms, dependent on cooperation between motor responses of the musculature of the colon, pelvic floor, and anorectum, and sensory and motor neural pathways. Knowledge of the physiology of fecal continence is key toward understanding the pathophysiology of fecal incontinence. The idea that involuntary contraction of the internal anal sphincter is the primary mechanism of continence and that the external anal sphincter supports continence only by voluntary contraction is outdated. Other mechanisms have come to the forefront, and they have significantly changed viewpoints on the mechanisms of continence and incontinence. For instance, involuntary contractions of the external anal sphincter, the puborectal muscle, and the sphincter of O'Beirne have been proven to play a role in fecal continence. Also, retrograde propagating cyclic motor patterns in the sigmoid and rectum promote retrograde transit to prevent the continuous flow of content into the anal canal. With this review, we aim to give an overview of primary and secondary mechanisms controlling fecal continence and evaluate the strength of evidence.

Patients with a defecation disorder may not evoke a normal defecation reflex, or the reflex may be excessive, as a dysfunction of the spinal autonomic nervous system. Treatment with various forms of lumbar and sacral neuromodulation have shown symptom improvement, but potential changes in autonomic functioning are rarely studied. Here we evaluate the effects on autonomic function of a single session of low-level laser therapy (LLLT) on the lumbar and sacral spine in 41 patients with chronic gastrointestinal motor dysfunction. The LLLT protocol used red LED light at a wavelength of 660 nm for 10 min and infrared LED light at a wavelength of 840 nm for 10 min, followed by infrared laser light at a wavelength of 825 nm for 10 min. Effects on the autonomic nervous system were assessed by measuring heart rate variability (HRV) changes. Respiratory Sinus Arrhythmia (RSA) and Root Mean Square of Successive Differences (RMSSD) were used to quantify parasympathetic reactivity; the Baevsky's Stress Index (SI) reflected sympathetic activity while the ratios SI/RSA and SI/RMSSD were used to show shifts in autonomic dominance. The results indicate that lumbar and sacral neuromodulation using light arrays reduced, whereas stimulation by the laser probes significantly increased parasympathetic activity. The light arrays increased whereas the laser probes significantly decreased sympathetic activity (SI). The entire protocol shifted the autonomic balance toward parasympathetic activity. The comparison of actual vs. sham neuromodulation proved that the change in HRV parameters was due to actual light stimulation and not due to the arrays and probe touching the skin. In conclusion, a single session of LLLT markedly affects autonomic nervous system activity reflected in changes in HRV which is only possible by generating activity in the spinal autonomic nerves. These results warrant a study into the effects of LLLT on restoring autonomic dysfunction in chronic refractory colonic motility disorders., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Ali, Saha, Milkova, Liu, Sharma, Huizinga and Chen.)

We report the first study assessing human colon manometric features and their correlations with changes in autonomic functioning in patients with refractory chronic constipation prior to consideration of surgical intervention. High-resolution colonic manometry (HRCM) with simultaneous heart rate variability (HRV) was performed in 14 patients, and the resulting features were compared to healthy subjects. Patients were categorized into three groups that had normal, weak, or no high amplitude propagating pressure waves (HAPWs) to any intervention. We found mild vagal pathway impairment presented as lower HAPW amplitude in the proximal colon in response to proximal colon balloon distention. Left colon dysmotility was observed in 71% of patients, with features of (1) less left colon HAPWs, (2) lower left colon HAPW amplitudes (69.8 vs 102.3 mmHg), (3) impaired coloanal coordination, (4) left colon hypertonicity in patients with coccyx injury. Patients showed the following autonomic dysfunction: (1) high sympathetic tone at baseline, (2) high sympathetic reactivity to active standing and meal, (3) correlation of low parasympathetic reactivity to the meal with absence of the coloanal reflex, (4) lower parasympathetic and higher sympathetic activity during occurrence of HAPWs. In conclusion, left colon dysmotility and high sympathetic tone and reactivity, more so than vagal pathway impairment, play important roles in refractory chronic constipation and suggests sacral neuromodulation as a possible treatment., (© 2022. The Author(s).)

The quest to understand the pathophysiology of autism spectrum disorder (ASD) has led to extensive literature that purports to provide evidence for autonomic dysfunction based on heart rate and heart rate variability (HRV), in particular respiratory sinus arrhythmia (RSA), a measure of parasympathetic functioning. Many studies conclude that autism is associated with vagal withdrawal and sympathetic hyperactivation based on HRV and electrodermal analyses. We will argue that a critical analysis of the data leads to the hypothesis that autonomic nervous system dysfunction is not a dominant feature of autism. Most children with ASD have normal parasympathetic baseline values and normal autonomic responses to social stimuli. The existing HRV and electrodermal data cannot lead to the conclusion of an over-excitation of the sympathetic nervous system. A small subgroup of ASD children in experimental settings has relatively low RSA values and relatively high heart rates. The data suggest that this is likely associated with a relatively high level of anxiety during study conditions, associated with co-morbidities such as constipation, or due to the use of psychoactive medication. Many studies interpret their data to conform with a preferred hypothesis of autonomic dysfunction as a trait of autism, related to the polyvagal theory, but the HRV evidence is to the contrary. HRV analysis may identify children with ASD having autonomic dysfunction due to co-morbidities., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Barbier, Chen and Huizinga.)

The musculature of the gastrointestinal tract is a vast network of collaborating excitable cell types. Embedded throughout are the interstitial cells of Cajal (ICC) intertwined with enteric nerves. ICC sense external stimuli such as distention, mediate nerve impulses to smooth muscle cells, and provide rhythmic excitation of the musculature. Neural circuitry involving both the intrinsic and extrinsic autonomic nervous systems, in collaboration with the ICC, orchestrate an array of motor patterns that serve to provide mixing of content to optimize digestion and absorption, microbiome homeostasis, storage, transit, and expulsion. ICC are specialized smooth muscle cells that generate rhythmic depolarization to the musculature and so provide the means for peristaltic and segmenting contractions. Some motor patterns are purely myogenic, but a neural stimulus initiates most, further depolarizing the primary pacemaker cells and the musculature and/or initiating transient pacemaker activity in stimulus-dependent secondary ICC pacemaker cells. From stomach to rectum, ICC networks rhythmically provide tracks along which contractions advance., (© 2022. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Gastric peristalsis is critically dependent on an underlying electrical conduction system. Recent years have witnessed substantial progress in clarifying the operations of this system, including its pacemaking units, its cellular architecture, and slow-wave propagation patterns. Advanced techniques have been developed for assessing its functions at high spatiotemporal resolutions. This review synthesizes and evaluates this progress, with a focus on human and translational physiology. A current conception of the initiation and conduction of slow-wave activity in the human stomach is provided first, followed by a detailed discussion of its organization at the cellular and tissue level. Particular emphasis is then given to how gastric electrical disorders may contribute to disease states. Gastric dysfunction continues to grow in their prevalence and impact, and while gastric dysrhythmia is established as a clear and pervasive feature in several major gastric disorders, its role in explaining pathophysiology and informing therapy is still emerging. New insights from high-resolution gastric mapping are evaluated, together with historical data from electrogastrography, and the physiological relevance of emerging biomarkers from body surface mapping such as retrograde propagating slow waves. Knowledge gaps requiring further physiological research are highlighted.

Our understanding of human colonic motility, and autonomic reflexes that generate motor patterns, has increased markedly through high-resolution manometry. Details of the motor patterns are emerging related to frequency and propagation characteristics that allow linkage to interstitial cells of Cajal (ICC) networks. In studies on colonic motor dysfunction requiring surgery, ICC are almost always abnormal or significantly reduced. However, there are still gaps in our knowledge about the role of ICC in the control of colonic motility and there is little understanding of a mechanistic link between ICC abnormalities and colonic motor dysfunction. This review will outline the various ICC networks in the human colon and their proven and likely associations with the enteric and extrinsic autonomic nervous systems. Based on our extensive knowledge of the role of ICC in the control of gastrointestinal motility of animal models and the human stomach and small intestine, we propose how ICC networks are underlying the motor patterns of the human colon. The role of ICC will be reviewed in the autonomic neural reflexes that evoke essential motor patterns for transit and defecation. Mechanisms underlying ICC injury, maintenance, and repair will be discussed. Hypotheses are formulated as to how ICC dysfunction can lead to motor abnormalities in slow transit constipation, chronic idiopathic pseudo-obstruction, Hirschsprung's disease, fecal incontinence, diverticular disease, and inflammatory conditions. Recent studies on ICC repair after injury hold promise for future therapies.

Background: Gastroenterologists have ignored or emphasized the importance of the rectosigmoid junction in continence or constipation on and off for 200 years. Here, we revisit its significance using high-resolution colonic manometry., Methods: Manometry, using an 84-channel water-perfused catheter, was performed in 18 healthy volunteers., Results: The rectosigmoid junction registers as an intermittent pressure band of 26.2 ± 7.2 mmHg, or intermittent phasic transient pressure increases at a dominant frequency of 3 cpm and an amplitude of 28.6 ± 8.6 mmHg; or a combination of tone and transient pressures, at a single sensor, 10-17 cm above the anal verge. Features are its relaxation or contraction in concert with relaxation or contraction of the anal sphincters when a motor pattern such as a high-amplitude propagating pressure wave or a simultaneous pressure wave comes down, indicating that such pressure increases or decreases at the rectosigmoid junction are part of neurally driven programs. We show that the junction is a site where motor patterns end, or where they start; e.g. retrogradely propagating cyclic motor patterns emerge from the junction., Conclusions: The rectosigmoid junction is a functional sphincter that should be referred to as the sphincter of O'Beirne; it is part of the "braking mechanism," contributing to continence by keeping content away from the rectum. In an accompanying case report, we show that its excessive presence in a patient with severe constipation can be a primary pathophysiology., (© 2021. Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Chronic constipation can have one or more of many etiologies, and a diagnosis based on symptoms is not sufficient as a basis for treatment, in particular surgery., Aim: To investigate the cause of chronic constipation in a patient with complete absence of spontaneous bowel movements., Methods: High-resolution colonic manometry was performed to assess motor functions of the colon, rectum, the sphincter of O'Beirne and the anal sphincters., Results: Normal colonic motor patterns were observed, even at baseline, but a prominent high-pressure zone at the rectosigmoid junction, the sphincter of O'Beirne, was consistently present. In response to high-amplitude propagating pressure waves (HAPWs) that were not consciously perceived, the sphincter and the anal sphincters would not relax and paradoxically contract, identified as autonomous dyssynergia. Rectal bisacodyl evoked marked HAPW activity with complete relaxation of the sphincter of O'Beirne and the anal sphincters, indicating that all neural pathways to generate the coloanal reflex were intact but had low sensitivity to physiological stimuli. A retrograde propagating cyclic motor pattern initiated at the sphincter of O'Beirne, likely contributing to failure of content to move into the rectum., Conclusions: Chronic constipation without the presence of spontaneous bowel movements can be associated with normal colonic motor patterns but a highly exaggerated pressure at the rectosigmoid junction: the sphincter of O'Beirne, and failure of this sphincter and the anal sphincters to relax associated with propulsive motor patterns. The sphincter of O'Beirne can be an important part of the pathophysiology of chronic constipation., (© 2021. Springer Science+Business Media, LLC, part of Springer Nature.)

Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

The parameters of heart rate variability (HRV) can non-invasively assess some autonomic activities, and HRV is influenced by many bodily actions. Although parasympathetic activity is the primary driver of colonic propulsive activity, and sympathetic activity a major inhibitor of colonic motility, they are rarely measured and almost play no role in diagnosis of colon motor dysfunction or in standard treatments. Here we set out to optimize HRV analysis of autonomic nervous system changes related to human colon motility. The electrocardiogram and impedance were recorded in synchrony with colonic motor patterns by high-resolution manometry. Respiratory sinus arrhythmia (RSA), root mean square of successive differences of beat-to-beat intervals (RMSSD), the Baevsky Index or Sympathetic Index (SI), and the ratios of SI/RSA and SI/RMSSD were shown to indicate a marked increase in parasympathetic and withdrawal of sympathetic activity during the high-amplitude propagating pressure waves (HAPWs). Strong associations were seen with HAPWs evoked by a meal and rectal bisacodyl indicating a marked increase in parasympathetic and withdrawal of sympathetic activity during the gastrocolic reflex and the defecation reflex. When HAPWs occurred in quick succession, parasympathetic activation (RSA and RMSSD) occurred in a rhythmic fashion. Hence, during propulsive motor patterns, an overall shift in autonomic activity toward increased parasympathetic control was shown to be reflected in HRV. HRV assessment may therefore be valuable in the assessment of autonomic dysfunction related to colonic dysmotility., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Ali, Liu, Chen and Huizinga.)

Contraction patterns of the human colon are rarely discussed from the perspective of its haustra. Colonic motility was analyzed in 21 healthy subjects using 84-sensor manometry catheters with 1-cm sensor spacing. Capsule endoscopy and manometry showed evidence of narrow rhythmic circular muscle contractions. X-ray images of haustra and sensor locations allowed us to identify manometry motor activity as intrahaustral activity. Two common motor patterns were observed that we infer to be associated with individual haustra: rhythmic pressure activity confined to a single sensor, and activity confined to a section of the colon of 3-6 cm length. Intrahaustral activity was observed by 3-4 sensors. Approximately 50% of the haustra were intermittently active for ∼30% of the time; 2,402 periods of haustral activity were analyzed. Intrahaustral activity showed rhythmic pressure waves, propagating in mixed direction, 5-30 mmHg in amplitude at a frequency of ∼3 cpm (range 2-6) or ∼12 cpm (range 7-15), or exhibiting a checkerboard segmentation pattern. Boundaries of the haustra showed rhythmic pressure activity with or without elevated baseline pressure. Active haustra often showed no boundary activity probably allowing transit to neighboring haustra. Haustral boundaries were seen at the same sensor for the 6- to 8-h study duration, indicating that they did not propagate, thereby likely contributing to continence. The present study elucidates the motility characteristics of haustral boundaries and the nature of intrahaustral motor patterns and paves the way for investigating their possible role in pathophysiology of defecation disorders. NEW & NOTEWORTHY Here, we present the first full characterization and quantification of motor patterns that we infer to be confined to single haustra, both intrahaustral activity and haustral boundary activity, in the human colon using high-resolution manometry. Haustral activity is intermittent but consistently present in about half of the haustra. Intrahaustral activity presents as a cyclic motor pattern of mixed propagation direction dominated by simultaneous pressure waves that can resolve into checkerboard segmentation, allowing for mixing, absorption, and stool formation.

Functional intestinal imaging holds importance for the diagnosis and evaluation of treatment of gastrointestinal diseases. Currently, preclinical imaging of intestinal motility in animal models is performed either invasively with excised intestines or noninvasively under anesthesia, and cannot reveal intestinal dynamics in the awake condition. Capitalizing on near-infrared optics and a high-absorbing contrast agent, we report the Trans-illumination Intestine Projection (TIP) imaging system for free-moving mice. After a complete system evaluation, we performed in vivo studies, and obtained peristalsis and segmentation motor patterns of free-moving mice. We show the in vivo typical segmentation motor pattern, that was previously shown in ex vivo studies to be controlled by intestinal pacemaker cells. We also show the effects of anesthesia on motor patterns, highlighting the possibility to study the role of the extrinsic nervous system in controlling motor patterns, which requires unanesthetized live animals. Combining with light-field technologies, we further demonstrated 3D imaging of intestine in vivo (3D-TIP). Importantly, the added depth information allows us to extract intestines located away from the abdominal wall, and to quantify intestinal motor patterns along different directions. The TIP system should open up avenues for functional imaging of the GI tract in conscious animals in natural physiological states.

Nitrergic nerves have been proposed to play a critical role in the orchestration of peristaltic activities throughout the gastrointestinal tract. In the present study, we investigated the role of nitric oxide, using spatiotemporal mapping, in peristaltic activity of the whole ex vivo mouse intestine. We identified a propulsive motor pattern in the form of propagating myogenic contractions, that are clustered by the enteric nervous system into a minute rhythm that is dependent on nitric oxide. The cluster formation was abolished by TTX, lidocaine and nitric oxide synthesis inhibition, whereas the myogenic contractions, occurring at the ICC-MP initiated slow wave frequency, remained undisturbed. Cluster formation, inhibited by block of nitric oxide synthesis, was fully restored in a highly regular rhythmic fashion by a constant level of nitric oxide generated by sodium nitroprusside; but the action of sodium nitroprusside was inhibited by lidocaine indicating that it was relying on neural activity, but not rhythmic nitrergic nerve activity. Hence, distention-induced activity of cholinergic nerves and/or a co-factor within nitrergic nerves such as ATP is also a requirement for the minute rhythm. Cluster formation was dependent on distention but was not evoked by a distention reflex. Block of gap junction conductance by carbenoxolone, dose dependently inhibited, and eventually abolished clusters and contraction waves, likely associated, not with inhibition of nitrergic innervation, but by abolishing ICC network synchronization. An intriguing feature of the clusters was the presence of bands of rhythmic inhibitions at 4-8 cycles/min; these inhibitory patches occurred in the presence of tetrodotoxin or lidocaine and hence were not dependent on nitrergic nerves. We propose that the minute rhythm is generated by nitric oxide-induced rhythmic depolarization of the musculature via ICC-DMP., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Parsons and Huizinga.)

The small intestine is covered by a network of coupled oscillators, the interstitial cells of Cajal (ICC). These oscillators synchronize to generate rhythmic phase waves of contraction. At points of low coupling, oscillations desynchronise, frequency steps occur and every few waves terminates as a dislocation. The amplitude of contractions is modulated at frequency steps. The phase difference between contractions at a frequency step and a proximal reference point increased slowly at first and then, just at the dislocation, increased rapidly. Simultaneous frequency and amplitude modulation (AM/FM) results in a Fourier frequency spectrum with a lower sideband, a so called Lashinsky spectrum, and this was also seen in the small intestine. A model of the small intestine consisting of a chain of coupled Van der Pol oscillators, also demonstrated simultaneous AM/FM at frequency steps along with a Lashinsky spectrum. Simultaneous AM/FM, together with a Lashinsky spectrum, are predicted to occur when periodically-forced or mutually-coupled oscillators desynchronise via a supercritical Andronov-Hopf bifurcation and have been observed before in other physical systems of forced or coupled oscillators in plasma physics and electrical engineering. Thus motility patterns in the intestine can be understood from the viewpoint of very general dynamical principles.

Background: High-resolution colonic manometry gives an unprecedented window into motor patterns of the human colon. Our objective was to characterize motor activities throughout the entire colon that possessed persistent rhythmicity and spanning at least 5 cm., Methods: High-resolution colonic manometry using an 84-channel water-perfused catheter was performed in 19 healthy volunteers. Rhythmic activity was assessed during baseline, proximal balloon distention, meal, and bisacodyl administration., Key Results: Throughout the entire colon, a cyclic motor pattern occurred either in isolation or following a high-amplitude propagating pressure wave (HAPW), consisting of clusters of pressure waves at a frequency centered on 11-13 cycles/min, unrelated to breathing. The cluster duration was 1-6 minutes; the pressure waves traveled for 8-27 cm, lasting 5-8 seconds. The clusters itself could be rhythmic at 0.5-2 cpm. The propagation direction of the individual pressure waves was mixed with >50% occurring simultaneous. This high-frequency cyclic motor pattern co-existed with the well-known low-frequency cyclic motor pattern centered on 3-4 cpm. In the rectum, the low-frequency cyclic motor pattern dominated, propagating predominantly in retrograde direction. Proximal balloon distention, a meal and bisacodyl administration induced HAPWs followed by cyclic motor patterns., Conclusions and Inferences: Within cyclic motor patterns, retrograde propagating, low-frequency pressure waves dominate in the rectum, likely keeping the rectum empty; and mixed propagation, high-frequency pressure waves dominate in the colon, likely promoting absorption and storage, hence contributing to continence. Propagation and frequency characteristics are likely determined by network properties of the interstitial cells of Cajal., (© 2020 John Wiley & Sons Ltd.)

Characterization of high-amplitude propagating pressure waves (HAPWs or HAPCs) plays a key role in diagnosis of colon dysmotility using any type of colonic manometry. With the introduction of high-resolution manometry, more insight is gained into this most prominent propulsive motor pattern. Here, we use a water-perfused catheter with 84 sensors with intervals between measuring points of 1 cm throughout the colon, for 6-8 h, in 19 healthy subjects. The catheter contained a balloon to evoke distention. We explored as stimuli a meal, balloon distention, oral prucalopride, and bisacodyl injection, with a goal to optimally evoke HAPWs. We developed a quantitative measure of HAPW activity, the "HAPW Index." Our protocol elicited 290 HAPWs. 21% of HAPWs were confined to the proximal colon with an average amplitude of 75.3 ± 3.3 mmHg and an average HAPW Index of 440 ± 58 mmHg·m·s. 29% of HAPWs started in the proximal colon and ended in the transverse or descending colon, with an average amplitude of 87.9 ± 3.1 mmHg and an average HAPW Index of 3,344 ± 356 mmHg·m·s. Forty-nine percent of HAPWs started and ended in the transverse or descending colon with an average amplitude of 109.3 ± 3.3 mmHg and an average HAPW Index of 2,071 ± 195 mmHg·m·s. HAPWs with and without simultaneous pressure waves (SPWs) initiated the colo-anal reflex, often abolishing 100% of anal sphincter pressure. Rectal bisacodyl and proximal balloon distention were the most optimal stimuli to evoke HAPWs. These measures now allow for a confident diagnosis of abnormal motility in patients with colonic motor dysfunction. NEW & NOTEWORTHY High-amplitude propagating pressure waves (HAPWs) were characterized using 84 sensors throughout the entire colon in healthy subjects, taking note of site of origin, site of termination, amplitude, and velocity, and to identify optimal stimuli to evoke HAPWs. Three categories of HAPWs were identified, including the associated colo-anal reflex. Proximal balloon distention and rectal bisacodyl were recognized as reliable stimuli for evoking HAPWs, and a HAPW Index was devised to quantify this essential colonic motor pattern.

Background/aims: Luminal factors such as short-chain fatty acids are increasingly recognized for playing a regulatory role in peristaltic activity. Our objective was to understand the roles of butyrate and propionate in regulating peristaltic activity in relation to distention-induced activities., Methods: Butyrate and propionate were perfused intraluminally under varying intraluminal pressures in murine colons bathed in Krebs solution. We used video recording and spatiotemporal maps to examine peristalsis induced by the intrinsic rhythmic colonic motor complex (CMC) as well as pellet-induced peristaltic reflex movements., Results: The CMC showed several configurations at different levels of excitation, culminating in long distance contractions (LDCs) which possess a triangular shape in murine colon spatiotemporal maps. Butyrate increased the frequency of CMCs but was a much weaker stimulus than distention and only contributed to significant changes under low distention. Propionate inhibited CMCs by decreasing either their amplitudes or frequencies, but only in low distention conditions. Butyrate did not consistently counteract propionate-induced inhibition likely due to the multiple and distinct mechanisms of action for these signaling molecules in the lumen. Pellet movement occurred through ongoing CMCs as well as pellet induced peristaltic reflex movements and butyrate augmented both types of peristaltic motor patterns to decrease the amount of time required to expel each pellet., Conclusions: Butyrate is effective in promoting peristalsis, but only when the level of colonic activity is low such as under conditions of low intraluminal pressure. This suggests that it may play a significant role in patients with poor fiber intake, where there is low mechanical stimulation in the lumen., (Copyright © 2020 Tan, Lee, Chen and Huizinga.)

The interstitial cells of Cajal associated with the myenteric plexus (ICC-MP) are a network of coupled oscillators in the small intestine that generate rhythmic electrical phase waves leading to corresponding waves of contraction, yet rhythmic action potentials and intercellular calcium waves have been recorded from c-kit-mutant mice that lack the ICC-MP, suggesting that there may be a second pacemaker network. The gap junction blocker carbenoxolone induced a "pinstripe" motor pattern consisting of rhythmic "stripes" of contraction that appeared simultaneously across the intestine with a period of ~4 s. The infinite velocity of these stripes suggested they were generated by a coupled oscillator network, which we call X. In c-kit mutants rhythmic contraction waves with the period of X traveled the length of the intestine, before the induction of the pinstripe pattern by carbenoxolone. Thus X is not the ICC-MP and appears to operate under physiological conditions, a fact that could explain the viability of these mice. Individual stripes consisted of a complex pattern of bands of contraction and distension, and between stripes there could be slide waves and v waves of contraction. We hypothesized that these phenomena result from an interaction between X and the circular muscle that acts as a damped oscillator. A mathematical model of two chains of coupled Fitzhugh-Nagumo systems, representing X and circular muscle, supported this hypothesis. The presence of a second coupled oscillator network in the small intestine underlines the complexity of motor pattern generation in the gut. NEW & NOTEWORTHY Physiological experiments and a mathematical model indicate a coupled oscillator network in the small intestine in addition to the c-kit-expressing myenteric interstitial cells of Cajal. This network interacts with the circular muscle, which itself acts as a system of damped oscillators, to generate physiological contraction waves in c-kit (W) mutant mice.

Abnormal colonic motility may be associated with dysfunction of the autonomic nervous system (ANS). Our aim was to evaluate if associations between colonic motor patterns and autonomic neural activity could be demonstrated by assessing changes in heart rate variability (HRV) in healthy volunteers. A total of 145 colonic motor patterns were assessed in 11 healthy volunteers by High-Resolution Colonic Manometry (HRCM) using an 84-channel water-perfused catheter. Motor patterns were evoked by balloon distention, a meal and luminal bisacodyl. The electrocardiogram (ECG) and cardiac impedance were assessed during colonic manometry. Respiratory sinus arrhythmia (RSA) and root mean square of successive differences of beat-to-beat intervals (RMSSD) served as measures of parasympathetic reactivity while the Baevsky's Stress Index (SI) and the pre-ejection period (PEP) were used as measures of sympathetic reactivity. Taking all motor patterns into account, our data show that colonic motor patterns are accompanied by increased parasympathetic activity and decreased sympathetic activity that may occur without eliciting a significant change in heart rate. Motor Complexes (more than one motor pattern occurring in close proximity), High-Amplitude Propagating Pressure Waves followed by Simultaneous Pressure Waves (HAPW-SPWs) and HAPWs without SPWs are all associated with an increase in RSA and a decrease in SI. Hence RSA and SI may best reflect autonomic activity in the colon during these motor patterns as compared to RMSSD and PEP. SI and PEP do not measure identical sympathetic reactivity. The SPW, which is a very low amplitude pressure wave, did not significantly change the autonomic measures employed here. In conclusion, colonic motor patterns are associated with activity in the ANS which is reflected in autonomic measures of heart rate variability. These autonomic measures may serve as proxies for autonomic neural dysfunction in patients with colonic dysmotility., (Copyright © 2020 Yuan, Ali, Mathewson, Sharma, Faiyaz, Tan, Parsons, Zhang, Milkova, Liu, Ratcliffe, Armstrong, Schmidt, Chen and Huizinga.)

Background: Activating luminal 5-HT 4 receptors results in the release of 5-HT from enterochromaffin cells into the lamina propria to modulate colonic motility. Our aim was to evaluate characteristics of colonic motor patterns involved in the prokinetic effects of intraluminal prucalopride in the rabbit colon., Methods: Colonic motor patterns were studied ex vivo using simultaneous spatiotemporal diameter mapping and pressure sensing., Key Results: Intraluminal prucalopride and intraluminal exogenous 5-HT strongly evoked or enhanced the colonic motor complex at all levels of excitation beginning with generation of clusters of fast propagating contractions (FPCs), then development of long-distance contractions (LDCs) within the clusters, and finally forceful LDCs as the highest level of excitation. Intraluminal prucalopride and intraluminal exogenous 5-HT stimulated propulsive motor activity in a dose-dependent and antagonist-sensitive manner by increasing the contraction amplitude, intraluminal pressure, frequency, velocity, and degree of propagation of the colonic motor complex., Conclusions and Inferences: Activating mucosal 5-HT 4 receptors via intraluminal prucalopride or 5-HT increases propulsive motor activity in a graded manner; that is, depending on starting conditions, amplitudes or frequencies of an activity may increase or a new pattern may be initiated. Our data support further studies into delivering 5-HT 4 receptor agonists via colon-targeted drug delivery systems and studies into the role of luminal 5-HT as an essential requirement for normal colon motor pattern generation., (© 2019 John Wiley & Sons Ltd.)

Alterations in colonic motility are implicated in the pathophysiology of bowel disorders, but high-resolution manometry of human colonic motor function has revealed that our knowledge of normal motor patterns is limited. Furthermore, various terminologies and definitions have been used to describe colonic motor patterns in children, adults and animals. An example is the distinction between the high-amplitude propagating contractions in humans and giant contractions in animals. Harmonized terminology and definitions are required that are applicable to the study of colonic motility performed by basic scientists and clinicians, as well as adult and paediatric gastroenterologists. As clinical studies increasingly require adequate animal models to develop and test new therapies, there is a need for rational use of terminology to describe those motor patterns that are equivalent between animals and humans. This Consensus Statement provides the first harmonized interpretation of commonly used terminology to describe colonic motor function and delineates possible similarities between motor patterns observed in animal models and humans in vitro (ex vivo) and in vivo. The consolidated terminology can be an impetus for new research that will considerably improve our understanding of colonic motor function and will facilitate the development and testing of new therapies for colonic motility disorders.

Background: Nitric oxide (NO) mediates inhibitory neurotransmission and is a critical component of neuronal programs that generate propulsive contractions. NO acts via its receptor NO-sensitive guanylyl cyclase (NO-GC) which is expressed in smooth muscle cells (SMC) and interstitial cells of Cajal (ICC). Organ bath studies with colonic rings from NO-GC knockout mice (GCKO) have indicated NO-GC to modulate spontaneous contractions. The cell-specific effects of NO-GC on the dominant pan-colonic propulsive contraction, the long distance contractions (LDCs), of whole colon preparations have not yet been described., Methods: Contractions of whole colon preparations from wild type (WT), global, and cell-specific GCKO were recorded. After transformation into spatiotemporal maps, motility patterns were analyzed. Simultaneous perfusion of the colon enabled the correlation of outflow with LDCs to analyze contraction efficiency., Key Results: Deletion of NO-GC in both ICC and SMC (ie, in GCKO and SMC/ICC-GCKO) caused loss of typical LDC activity and instead generated high-frequency LDC-like contractions with inefficient propulsive activity. Frequency was also increased in WT, SMC-GCKO, and ICC-GCKO colon in the presence of L-NAME to block neuronal NO synthase. LDC efficiency was dependent on NO-GC in SMC as it was reduced in GCKO, SMC-GCKO, and ICC/SMC-GCKO colon; LDC efficiency was decreased in all genotypes in the presence of L-NAME., Conclusions and Inferences: NO/cGMP signaling is critical for normal peristaltic movements; as NO-GC in both SMC and ICC is essential, both cell types appear to work in synchrony. The efficiency of contractions to expel fluid is particularly influenced by NO-GC in SMC., (© 2019 John Wiley & Sons Ltd.)

Background: Excessive sympathetic inhibition may be a cause of colon motor dysfunction. Our aim was to better understand the mechanisms of sympathetic inhibition on colonic motor patterns using the rabbit colon, hypothesizing that noradrenaline selectively inhibits propulsive motor patterns., Methods: Changes in motor patterns of the rabbit colon were studied ex vivo using noradrenaline and adrenoceptor antagonists and analyzed using spatiotemporal diameter maps., Key Results: Noradrenaline abolished propulsive contractions: it abolished the long-distance contractions (LDCs) from a baseline frequency of 0.8 ± 0.3 and the clusters of fast propagating contractions (FPCs) at a frequency of 14.4 ± 2.8 cpm. Both motor patterns recovered after addition of the α 2 -adrenoceptor antagonist yohimbine to a frequency of 0.5 ± 0.2  and 9.9 ± 3.3 cpm, respectively. The β-adrenoceptor antagonist propranolol did not prevent the loss of propulsive motor patterns with noradrenaline. Noradrenaline did not inhibit haustral boundary contractions and increased the frequency of the myogenic ripples from 8.3 ± 1.4 to 10.5 ± 1.3 cpm which was not affected by yohimbine, propranolol nor the α 1 -adrenoceptor blocker prazosin., Conclusions and Inferences: Noradrenergic inhibition of propulsive motor patterns is mediated by the α 2 -adrenoceptor to inhibit the neurogenic LDCs and the neurogenic clustering of FPCs. The neurogenic haustral boundary contractions are not affected, suggesting that α 2- receptors are on selective neural circuits. The excitatory effect of noradrenaline on ripples may be due to the activation of adrenoceptors on interstitial cells of Cajal, but action on α 1- receptors was excluded. No role for the β-adrenoceptor was found., (© 2019 John Wiley & Sons Ltd.)

Gastrointestinal smooth muscle research has evolved from studies on muscle strips to spatiotemporal mapping of whole organ motor and electrical activities. Decades of research on single muscle cells and small sections of isolated musculature from animal models has given us the groundwork for interpretation of human in vivo studies. Human gut motility studies have dramatically improved by high-resolution manometry and high-resolution electrophysiology. The details that emerge from spatiotemporal mapping of high-resolution data are now of such quality that hypotheses can be generated as to the physiology (in healthy subjects) and pathophysiology (in patients) of gastrointestinal (dys) motility. Such interpretation demands understanding of the musculature as a super-network of excitable cells (neurons, smooth muscle cells, other accessory cells) and oscillatory cells (the pacemaker interstitial cells of Cajal), for which mathematical modeling becomes essential. The developing deeper understanding of gastrointestinal motility will bring us soon to a level of precision in diagnosis of dysfunction that is far beyond what is currently available.

The role of short-chain fatty acids (SCFAs) in the control of colonic motility is controversial. Germ-free (GF) mice are unable to produce these metabolites and serve as a model to study how their absence affects colonic motility. GF transit is slower than controls, and colonization of these mice improves transit and serotonin [5-hydroxytryptamine (5-HT)] levels. Our aim was to determine the role SCFAs play in improving transit and whether this is dependent on mucosal 5-HT signaling. Motility was assessed in GF mice via spatiotemporal mapping. First, motor patterns in the whole colon were measured ex vivo with or without luminal SCFA, and outflow from the colon was recorded to quantify outflow caused by individual propulsive contractions. Second, artificial fecal pellet propulsion was measured. Motility was then assessed in tryptophan hydroxylase-1 (TPH1) knockout (KO) mice, devoid of mucosal 5-HT, with phosphate buffer, butyrate, or propionate intraluminal perfusion. GF mice exhibited a lower proportion of propulsive contractions, lower volume of outflow/contraction, slower velocity of contractions, and slower propulsion of fecal pellets compared with controls. SCFAs changed motility patterns to that of controls in all parameters. Butyrate administration increased the proportion of propulsive contractions in controls yet failed to in TPH1 KO mice. Propionate inhibited propulsive contractions in all mice. Our results reveal significant abnormalities in the propulsive nature of colonic motor patterns in GF mice, explaining the decreased transit time in in vivo studies. We show that butyrate but not propionate activates propulsive motility and that this may require mucosal 5-HT. NEW & NOTEWORTHY Understanding the role that the microbiota play in governing the physiology of colonic motility is lacking. Here, we offer for the first time, to our knowledge, a detailed analysis of colonic motor patterns and pellet propulsion using spatiotemporal mapping in the absence of microbiota. We show a striking difference in germ-free and control phenotypes and attribute this to a lack of fermentation-produced short-chain fatty acid. We then show that butyrate but not propionate can restore motility and that the butyrate effect likely requires mucosal 5-hydroxytryptamine.

The gut is enmeshed by a number of cellular networks, but there is only a limited understanding of how these networks generate the complex patterns of activity that drive gut contractile functions. Here we review two fundamental types of cell behaviour, excitable and oscillating, and the patterns that networks of such cells generate, trigger waves and phase waves, respectively. We use both the language of biophysics and the theory of nonlinear dynamics to define these behaviours and understand how they generate patterns. Based on this we look for evidence of trigger and phase waves in the gut, including some of our recent work on the small intestine., (© 2018 The Authors. The Journal of Physiology © 2018 The Physiological Society.)

Simultaneous pressure waves (SPWs) in manometry recordings of the human colon have been associated with gas expulsion. Our hypothesis was that the SPW might be a critical component of most colonic motor functions, and hence might act as a biomarker for healthy colon motility. To that end, we performed high-resolution colonic manometry (HRCM), for the first time using an 84-sensor (1 cm spaced) water-perfused catheter, in 17 healthy volunteers. Intraluminal pressure patterns were recorded during baseline, proximal and rectal balloon distention, after a meal and following proximal and rectal luminal bisacodyl administration. Quantification was performed using software, based on Image J, developed during this study. Gas expulsion was always associated with SPWs, furthermore, SPWs were associated with water or balloon expulsion. SPWs were prominently emerging at the termination of proximal high amplitude propagating pressure waves (HAPWs); we termed this motor pattern HAPW-SPWs; hence, SPWs were often not a pan-colonic event. SPWs and HAPW-SPWs were observed at baseline with SPW amplitudes of 12.0 ± 8.5 mmHg and 20.2 ± 7.2 mmHg respectively. The SPW occurrence and amplitude significantly increased in response to meal, balloon distention and luminal bisacodyl, associated with 50.3% anal sphincter relaxation at baseline, which significantly increased to 59.0% after a meal, and 69.1% after bisacodyl. Often, full relaxation was achieved. The SPWs associated with gas expulsion had a significantly higher amplitude compared to SPWs without gas expulsion. SPWs could be seen to consist of clusters of high frequency pressure waves, likely associated with a cluster of fast propagating, circular muscle contractions. SPWs were occasionally observed in a highly rhythmic pattern at 1.8 ± 1.2 cycles/min. Unlike HAPWs, the SPWs did not obliterate haustral boundaries thereby explaining how gas can be expelled while solid content can remain restrained by the haustral boundaries. In conclusion, the SPW may become a biomarker for normal gas transit, the gastrocolonic reflex and extrinsic neural reflexes. The SPW assessment reveals coordination of activities in the colon, rectum and anal sphincters. SPWs may become of diagnostic value in patients with colonic dysmotility.

New Findings: What is the central question of this study? What is the nature of slow wave-driven contraction frequency gradients in the small intestine? What is the main finding and its importance? Frequency plateaux are composed of discrete waves of increased interval, each wave associated with a contraction dislocation. Smooth frequency gradients are generated by localized neural modulation of wave frequency, leading to functionally important wave turbulence. Both patterns are emergent properties of a network of coupled oscillators, the interstitial cells of Cajal., Abstract: A gut-wide network of interstitial cells of Cajal generates electrical oscillations (slow waves) that orchestrate waves of muscle contraction. In the small intestine there is a gradient in slow wave frequency from high at the duodenum to low at the terminal ileum. Time-averaged measurements of frequency have suggested either a smooth or a stepped (plateaued) gradient. We measured individual contraction intervals from diameter maps of the mouse small intestine to create interval maps (IMaps). The IMaps showed that each frequency plateau was composed of discrete waves of increased interval. Each interval wave originated at a terminating contraction wave, a 'dislocation', at the proximal boundary of the plateau. In a model chain of coupled phase oscillators, interval wave frequency increased as coupling decreased or as the natural frequency gradient or noise increased. Injuring the intestine at a proximal point, to destroy coupling, suppressed distal steps, which then reappeared with gap junction block by carbenoxolone. This lent further support to our previous hypothesis that lines of dislocations were fixed by points of low coupling strength. Dislocations, induced by electrical field pulses in the intestine and by equivalent phase shift in the model, were associated with interval waves. When the enteric nervous system was active, IMaps showed a chaotic, turbulent pattern of interval change, with no frequency steps or plateaux. This probably resulted from local, stochastic release of neurotransmitters. Plateaux, dislocations, interval waves and wave turbulence arise from a dynamic interplay between natural frequency and coupling in the network of interstitial cells of Cajal., (© 2018 The Authors. Experimental Physiology © 2018 The Physiological Society.)

Evidence suggests that there are both nociceptive and neuropathic components of cancer-induced pain. We have observed that changes in intrinsic membrane properties and excitability of normally non-nociceptive Aβ sensory neurons are consistent in rat models of peripheral neuropathic pain and cancer-induced pain. This has prompted a comparative investigation of the intracellular electrophysiological characteristics of sensory neurons and of the ultrastructural morphology of the dorsal horn in rat models of neuropathic pain and cancer-induced pain. Neuropathic pain model rats were induced with a polyethylene cuff implanted around a sciatic nerve. Cancer-induced pain model rats were induced with mammary rat metastasis tumour-1 rat breast cancer or MATLyLu rat prostate cancer cells implanted into the distal epiphysis of a femur. Behavioural evidence of nociception was detected using von Frey tactile assessment. Aβ-fibre low threshold mechanoreceptor neurons in both cancer-induced pain and neuropathic pain models exhibited slower dynamics of action potential genesis, including a wider action potential duration and lower action potential amplitude compared to those in control animals. Enhanced excitability of Aβ-fibre low threshold mechanoreceptor neurons was also observed in cancer-induced pain and neuropathic pain models. Furthermore, both cancer-induced pain and neuropathic pain models showed abundant abnormal axonal sprouting in bundles of myelinated axons in the ipsilateral spinal laminae IV and V. The patterns of changes show consistency between rat models of cancer-induced pain and neuropathic pain. These findings add to the body of evidence that animal models of cancer-induced pain and neuropathic pain share features that may contribute to the peripheral and central sensitization and tactile hypersensitivity in both pain states.

New Findings: What is the central question of this study? What are the dynamical rules governing interstitial cell of Cajal (ICC)-generated slow wave contractions in the small intestine, as reflected in their phase response curve and state space? What is the main finding and its importance? The phase response curve has a region of phase advance surrounding a phase delay peak. This pattern is important in generating a stable synchrony within the ICC network and is related to the state space of the ICC; in particular, the phase delay peak corresponds to the unstable equilibrium point that threads the ICC's limit cycle. Interstitial cells of Cajal (ICCs) generate electrical oscillations in the gut. Synchronization of the ICC population is required for generation of coherent electrical waves ('slow waves') that cause muscular contraction and thereby move gut content. The phase response curve (PRC) is an experimental measure of the dynamical rules governing a population of oscillators that determine their synchrony and gives an experimental window onto the state space of the oscillator, its dynamical landscape. We measured the PRC of slow wave contractions in the mouse small intestine by the novel combination of diameter mapping and single pulse electrical field stimulation. Phase change (τ) was measured as a function of old phase (ϕ) and distance from the stimulation electrode (d). Plots of τ(ϕ, d) showed an arrowhead-shaped region of phase advance enclosing at its base a phase delay peak. The phase change mirrored the perturbed pattern of contraction waves in response to a pulse. The (ϕ, d) plane is the surface of a displacement tube extending from the limit cycle through state space. To visualize the state space vector field on this tube, latent phase (ϕ lat ) was calculated from τ. At the transition from advance to delay, isochrons made boomerang turns before tightening and winding around the phase delay peak corresponding to the unstable equilibrium point that threads the limit cycle. This isochron foliation had previously been observed in oscillator models such as the Fitzhugh-Nagumo but has not been demonstrated experimentally. The spatial extension of the PRC afforded by diameter mapping allows a better understanding of the dynamical properties of ICCs and how they synchronize as a population., (© 2017 The Authors. Experimental Physiology © 2017 The Physiological Society.)

Introduction: Clinical data on cancer-induced bone pain (CIBP) suggest extensive changes in sensory function. In a previous investigation of an animal model of CIBP, we have observed that changes in intrinsic membrane properties and excitability of dorsal root ganglion (DRG) nociceptive neurons correspond to mechanical allodynia and hyperalgesia., Objectives: To investigate the mechanisms underlying changes in nonnociceptive sensory neurons in this model, we have compared the electrophysiological properties of primary nonnociceptive sensory neurons at <1 and >2 weeks after CIBP model induction with properties in sham control animals., Methods: Copenhagen rats were injected with 10 6 MAT-LyLu rat prostate cancer cells into the distal femur epiphysis to generate a model of CIBP. After von Frey tactile measurement of mechanical withdrawal thresholds, the animals were prepared for acute electrophysiological recordings of mechanically sensitive neurons in the DRG in vivo., Results: The mechanical withdrawal threshold progressively decreased in CIBP model rats. At <1 week after model induction, there were no changes observed in nonnociceptive Aβ-fiber DRG neurons between CIBP model rats and sham rats. However, at >2 weeks, the Aβ-fiber low-threshold mechanoreceptors (LTMs) in CIBP model rats exhibited a slowing of the dynamics of action potential (AP) genesis, including wider AP duration and lower AP amplitude compared with sham rats. Furthermore, enhanced excitability of Aβ-fiber LTM neurons was observed as an excitatory discharge in response to intracellular injection of depolarizing current into the soma., Conclusion: After induction of the CIBP model, Aβ-fiber LTMs at >2 weeks but not <1 week had undergone changes in electrophysiological properties. Importantly, changes observed are consistent with observations in models of peripheral neuropathy. Thus, Aβ-fiber nonnociceptive primary sensory neurons might be involved in the peripheral sensitization and tumor-induced tactile hypersensitivity in CIBP., Competing Interests: Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Small intestinal muscularis externa macrophages have been associated with interstitial cells of Cajal. They have been proposed to play various roles in motility disorders and to take part in a microbiota-driven regulation of gastrointestinal motility. Our objective was to understand the reaction of resident macrophages of the musculature to a pro-inflammatory stimulator, lipopolysaccharide (LPS). Mice were injected with LPS or saline and sacrificed after 6 hr. Whole mounts were stained with antibodies toward CD169, ionized calcium-binding adaptor molecule 1 (iba1) (microglial/macrophage marker) and heme oxygenase-1 (HO-1). Cell densities were measured using unbiased stereology., Results: iba1 pos cells showed an overall higher density than CD169 pos and HO-1 pos cells. Most HO-1 pos and iba1 pos cells were positive for CD 169 in serosa and at Auerbach's plexus (AP). At the deep muscular plexus, mainly iba1 pos cells were present, and were mostly CD169 neg ; a few HO-1 pos cells were present., Conclusions: A new subset of resident macrophages in the intestinal muscularis externa was discovered, identified as iba1 pos CD169 neg . HO-1 is constitutively present in most macrophages in serosa and at AP, suggesting a M2 phenotype. LPS-treatment results in an up-regulation of HO-1 pos /CD169 neg cells in serosa and at AP. Anat Rec, 300:1114-1122, 2017. © 2016 The Authors. The Anatomical Record published by Wiley Periodicals, Inc. on behalf of American Association of Anatomists., (© 2016 The Authors. The Anatomical Record published by Wiley Periodicals, Inc. on behalf of American Association of Anatomists.)