Anatomical registration and three‐dimensional visualization of low and high‐resolution pan‐colonic manometry recordings

Background Colonic propagating sequences (PS) are important for the movement of colonic content and defecation, and aberrant PS patterning has been associated with slow transit constipation. However, because these motor patterns are typically recorded over long periods (24 h +), the visualization of PS spatiotemporal patterning is difficult. Here, we develop a novel method for displaying pan‐colonic motility patterns. Methods A 3D mesh representing the geometry of the human colon was created as follows: (i) Human colon images from the Visible Human Dataset were digitized to create a 3D data cloud, and (ii) A surface mesh was fitted to the cloud using a least‐squares minimization technique. Colonic manometry catheters were placed in the ascending colon of healthy controls and patients with slow transit constipation (STC), with the aid of a colonoscope. The colonic manometry data were interpolated and mapped to the model according to the following anatomical landmarks: cecum, hepatic flexure, splenic flexure, sigmoid‐descending junction, and anus. Key Results These 3D images clearly and intuitively communicate characteristics of normal and abnormal colonic motility. Specifically we have shown the reduced amplitude of the antegrade propagating pressure waves (PPW) throughout the colon and reduced frequency of PPWs at the mid‐colon in patients with STC. Conclusions and Inferences A novel method for the 3D visualization of PS is presented, providing an intuitive method for representing a large volume of physiological data. These techniques can be used to display frequency, amplitude or velocity data, and will help to convey regions of abnormally in patient populations.     

Bowel preparation affects the amplitude and spatiotemporal organization of colonic propagating sequences

Background Colonic manometry is performed using either colonoscopically assisted catheter placement, after bowel preparation, or nasocolonic intubation of the unprepared bowel. There has been little systematic evaluation of the effects of bowel cleansing upon colonic propagating pressure wave sequences. Methods Eight healthy volunteers underwent nasocolonic placement of a water‐perfused silicone catheter which recorded pressures at 16 recording sites each spaced 7.5 cm apart in the unprepared colon for 24 h. These measures were compared with those obtained in another eight healthy volunteers in whom the catheter was placed to the caecum at colonoscopy in the prepared colon. Key Results The colonic motor responses to meals and morning waking, and the normal nocturnal suppression did not differ between the two groups, nor were the overall frequency, regional dependence nor extent of propagating sequences (PS) influenced by bowel preparation. Bowel preparation did result in a significant increase in the frequency of high amplitude PS (22 ± 7 vs 8 ± 4 HAPS/24 h; P = 0.003). Additionally, a number of the measures of spatiotemporal organization among consecutive PS (linkage among sequences and predefecatory stereotypical patterning) were significantly altered by bowel preparation. Conclusions & Inferences The overall frequency of PSs, the colonic responses to physiological stimuli such a meal and morning waking and nocturnal suppression, are not influenced by prior bowel preparation. However, investigators wishing to study HAPS frequency, or the more complex spatiotemporal relationships among consecutive PSs, should control for bowel preparation when making comparisons among study groups.     

High‐resolution colonic manometry accurately predicts colonic neuromuscular pathological phenotype in pediatric slow transit constipation

Background Severe pediatric slow transit constipation (STC) is commonly due to intrinsic colonic neuromuscular disease. We sought to correlate neuromuscular histological phenotypes in pediatric STC with colonic manometric phenotypes using high‐resolution manometry (HRM). We tested the hypothesis that failure of motor quiescence (FQ) between bisacodyl‐induced high amplitude propagating sequences (HAPSs) might predict neuromuscular pathology. Methods Eighteen children (10 males, median age: 7.5 years) with refractory STC underwent stationary colonic HRM before segmental colonic resection. Six age‐matched constipated children with normal colonic transit served as controls. Colonic resection specimens underwent histopathological analysis. Conventional manometric parameters and area under the curve (AUC) during a 1‐min period following bisacodyl‐induced HAPSs [PBAUC₁], as measure of FQ, were calculated. Key Results Numbers of postbisacodyl HAPSs in descending and sigmoid segments were lower in patients than controls (P < 0.01, respectively). Low amplitude propagating sequences (LAPSs) were common prebisacodyl in controls and rare in STC (P < 0.001), whereas postbisacodyl LAPS were more common in STC (P < 0.001). Postbisacodyl, both retrograde propagating contractions and bursts of contractions were present in STC patients only (P < 0.001 and P < 0.01). Postbisacodyl simultaneous pressurization was seen only in STC (P < 0.05 and P < 0.001, in descending and rectosigmoid segments). Histological abnormalities were present in 17/18. Fourteen were neurogenic, one neuro‐myogenic, and two myogenic. In segments with HAPS, PBAUC₁ was predictive of colonic neuropathy using a cutoff of 205 mmHg.s^‐1 (Sensitivity 100%, specificity 86%, PPV92%, NPV100%). Conclusions & Inferences PBAUC₁ is increased in multiple colonic segments in neuropathic pediatric STC and constitutes a sensitive and specific biomarker of neuropathy.     

Substance P and vasoactive intestinal peptide are reduced in right transverse colon in pediatric slow‐transit constipation

Background Slow‐transit constipation (STC) is recognized in children but the etiology is unknown. Abnormalities in substance P (SP), vasoactive intestinal peptide (VIP) and nitric oxide (NO) have been implicated. The density of nerve fibers in circular muscle containing these transmitters was examined in colon from children with STC and compared to other pediatric and adult samples. Methods Fluorescence immunohistochemistry using antibodies to NO synthase (NOS), VIP and SP was performed on colonic biopsies (transverse and sigmoid colon) from 33 adults with colorectal cancer, 11 children with normal colonic transit and anorectal retention (NAR) and 51 with chronic constipation and slow motility in the proximal colon (STC). The percentage area of nerve fibers in circular muscle containing each transmitter was quantified in confocal images. Key Results In colon circular muscle, the percentage area of nerve fibers containing NOS > VIP > SP (6 : 2 : 1). Pediatric groups had a higher density of nerve fibers than adults. In pediatric samples, there were no regional differences in NOS and VIP, while SP nerve fiber density was higher in sigmoid than proximal colon. STC children had lower SP and VIP nerve fiber density in the proximal colon than NAR children. Twenty‐three percent of STC children had low SP nerve fiber density. Conclusions & Inferences There are age‐related reductions in nerve fiber density in human colon circular muscle. NOS and VIP do not show regional variations, while SP nerve fiber density is higher in distal colon. 1/3 of pediatric STC patients have low SP or VIP nerve fiber density in proximal colon.     

Twenty-four hour spatiotemporal mapping of colonic propagating sequences provides pathophysiological insight into constipation

Abstract  Colonic propagating sequences (PS)s are a major determinant of luminal propulsion. A global appreciation of spatiotemporal patterning of PSs requires evaluation of 24 h pan-colonic recordings, a difficult task given that PSs are relatively infrequent events that are not uniformly distributed throughout the colon. Here we developed a means of space-time-pressure 'mapping' in a condensed format, 24 h of colonic recording in such a manner that readily permits an overall view of colonic antegrade and retrograde colonic PSs within a single figure. Such graphical representation readily permits appreciation and identification of aberrant patterns in severe constipation and may be an important clinical and research tool in the assessment of colonic motor disorders.     

Lower functional gastrointestinal disorders: evidence of abnormal colonic transit in a 287 patient cohort

Background Abnormalities of colonic motility were reported in relatively small studies of patients with lower functional gastrointestinal disorders (FGID) including irritable bowel syndrome (IBS). The influence of gender and body mass on the observed motor pathophysiology is unclear. We sought to compare colonic transit in patients within different lower FGID subgroups and healthy controls, controlling for gender and BMI, and to determine whether BMI independently influences colonic motility. Methods We evaluated a scintigraphic gastrointestinal and colonic transit database of 287 lower FGID patients associated with constipation (IBS‐C, or functional constipation, n = 118), diarrhoea (IBS‐D or functional diarrhoea, n = 139) or mixed bowel function (IBS‐M, n = 30) and 170 healthy controls. We measured colon filling at 6 h (CF 6 h), and overall colonic transit at 8, 24 and 48 h. Key Results Colon filling at 6 h did not differentiate health from FGID. Colonic transit was abnormal at 24 h (GC24 of <1.50 or >3.86) in 29.7% of all lower FGID patients. There was a significant overall association between colonic transit and subject group (healthy controls and FGID subgroups) at 8 (P = 0.01), 24 (P < 0.001) and 48 h (P < 0.001) in particular for those with diarrhoea or constipation at 24 and 48 h (P < 0.05), even after adjusting for age, gender and BMI. In addition, BMI was associated with colonic transit after adjusting for age, gender and subject group. Conclusions & Inferences Abnormal transit is documented non‐invasively with scintigraphy in 30% of lower FGID patients; transit measurement may help document pathophysiology and inform selection of therapy in lower FGID.     

The effects of methane and hydrogen gases produced by enteric bacteria on ileal motility and colonic transit time

Background Gases produced by intestinal flora may modulate intestinal motor function in healthy individuals as well as those with functional bowel disease. Methane, produced by enteric bacteria in the human gut, is associated with slowed intestinal transit and constipation. The effects of hydrogen, another main gas produced by bacterial fermentation in the gut, on small bowel and colonic motor function remains unrecognized. Therefore, we set out to investigate whether intestinal gases including methane and hydrogen could influence the small bowel motility and colonic transit. Methods Guinea pig ileum was placed in the peristaltic bath with tension transducers attached to measure velocity and amplitude of peristaltic contraction before and after the infusion of control, hydrogen, and methane gases. Also, changes in the intraluminal pressures were monitored before and after the gas infusions. Key Results Methane decreased peristaltic velocity and increased contraction amplitude significantly of guinea pig ileum (P < 0.05). The AUC of intraluminal pressure was significantly increased with methane in guinea pig ileum (P < 0.05). In a second experiment, guinea pig colon was placed in the peristaltic bath to measure transit time before and after control, hydrogen, methane, and methane‐hydrogen mixture gas infusions. Hydrogen shortened colonic transit time by 47% in the proximal colon, and by 10% in the distal colon, when compared with baselines (P < 0.05). Conclusions & Inferences Methane delayed ileal peristaltic conduction velocity by augmenting contractility. Hydrogen shortened colonic transit, and that effect was more prominent in the proximal colon than distal colon.     

Altered periodic rectal motor activity: a mechanism for slow transit constipation

The pathophysiology of slow transit constipation is poorly understood. Both decreased and increased distal colonic motility have been reported. In healthy humans, a 3 cycles per minute (cpm), periodic rectal motor activity (PRMA) has been described. Our aim was to investigate the characteristics of PRMA and to assess its role in the pathogenesis of constipation. A six-sensor solid-state probe was placed with the tip sensor in the mid-transverse colon, without sedation, and prolonged colonic motility was recorded in nine patients with slow transit constipation (1M, 8F) and in 11 healthy subjects (3M, 8F). Subjects were free to ambulate. We examined the frequency, nocturnal vs. diurnal variation, and characteristics of PRMA, and its relationship to proximal colonic motility. All subjects showed PRMA. The rhythm was similar (2.5-4 cpm) in both groups. However, constipated patients exhibited a greater (P < 0.001) number of PRMA cycles than controls. The duration of each cycle and amplitude of pressure waves during PRMA were also greater (P < 0.05) at night in patients compared with controls. In patients, 40% of PRMA cycles were associated with a proximal colonic motor event compared with 81% in controls (P < 0.02). The area under the curve of all colonic pressure waves and incidence of specialized propagating pressure waves was lower (P < 0.05) in patients during daytime. When compared with controls, constipated patients exhibited reduced daytime colonic pressure waves and a higher frequency of PRMA. Most of the PRMA was unrelated to proximal colonic activity in constipated patients in contrast with findings in control patients. In addition to decreased colonic motility, this excessive and unco-ordinated phasic rectal activity may further impede stool transport and contribute to the pathogenesis of slow transit constipation.     

Association of bile acid receptor TGR5 variation and transit in health and lower functional gastrointestinal disorders

Background The membrane bound bile acid (BA) receptor, TGR5, is located on myenteric, cholinergic and nitrergic neurons in colon and proximal small intestine. Our aim was to assess the association of genetic variation in TGR5 and small bowel transit (SBT) and colonic transit. Methods In 230 healthy controls and 414 patients with lower functional GI disorders [FGID: irritable bowel syndrome (IBS)‐alternators (Alt) 84, IBS‐constipation (IBS‐C) 157, IBS‐diarrhea (IBS‐D) 173], we tested the association between TGR5 SNP rs11554825 (minor allele frequency 41%) with symptom phenotype (total cohort) and intermediate phenotype (SBT or colonic transit by radioscintigraphy) which was available in 213 people in this cohort. The association with symptom phenotype was assessed using logistic regression, while the association with colonic filling at 6 h (CF6), and colonic transit [geometric center (GC) at 24 h] was assessed using ancova , in each instance assuming a dominant genetic model. Key Results There was no significant association with symptom phenotype. We observed a potential association of SNP rs11554825 with overall transit: CF6 (P = 0.061) and GC24 (P = 0.083). The association of the SNP with CF6 in the IBS‐D subgroup (P = 0.017) indicated the TC/CC subgroup had an average 50% faster SBT compared with the TT subgroup. In IBS‐D patients, GC24 was not significantly associated with rs11554825 (TC/CC vs TT). Conclusions & Inferences Variation in TGR5 may contribute to altered SBT and colonic transit in lower FGID. Further studies are required to characterize the potential role of BA receptor, TGR5, in the mechanism and treatment of bowel dysfunction in lower FGID.     

Spatio-temporal analysis reveals aberrant linkage among sequential propagating pressure wave sequences in patients with symptomatically defined obstructed defecation

Abstract  Available evidence implicates abnormal colonic contractility in patients suffering from constipation. Traditional analysis of colonic manometry focuses on the frequency, extent and amplitude of propagating sequences (PS). We tested the hypotheses that the spatio-temporal linkage among sequential PSs exists throughout the healthy human colon and is disrupted during constipation. In eight patients with severe constipation and eight healthy volunteers, we recorded colonic pressures from 16 regions (caecum–rectum) for 24 h. Sequential PSs were regionally linked if the two PSs originated from different colonic regions but the segments of colon traversed by each PS overlapped. In order to determine whether this linkage occurred by chance, a computer program was used to randomly rearrange all PSs in time. Data were re-analysed to compare regional linkage between randomly re-ordered PSs (expected) and the natural distribution of PSs (observed). In controls the observed regional linkage (82.5 ± 9.0%) was significantly greater than the expected value (60.5 ± 4.3%; P  = 0.0001). In patients the observed and expected regional linkage did not differ. The (observed − expected) delta value of regional linkage in controls was significantly greater than in patients (21.7 ± 8.5% vs −2.3 ± 7.0%; P  = 0.01). Regional linkage among sequential PSs in the healthy colon appears to be a real phenomenon and this linkage is lost in patients with constipation. Regional linkage may be important for normal colonic transit and loss of linkage might have pathophysiological relevance to and provide a useful biomarker of severe constipation.     

Results of 24-h manometric recording of colonic motor activity with endoluminal instillation of bisacodyl in patients with severe chronic slow transit constipation

The aims of this study were to assess the prevalence of manometric colonic abnormalities and to evaluate the motor effect of intraluminal bisacodyl in a cohort of refractory constipated patients. Twenty-four hour colonic motility recordings were performed in 40 patients referred for a severe intractable chronic constipation. At the end of each recording session the motor effects of the endoluminal instillation of 10 mg bisacodyl were assessed. These patients were compared with 20 healthy subjects. The number of high-amplitude propagating contractions (HAPC) was significantly decreased in patients with slow transit constipation (12 +/- 11.6 vs 1 +/- 8.6, P < 0.001). Based on manometric patterns four groups of patients were isolated. Ten patients had no spontaneous HAPC, no food-induced colonic motor response and significantly lower colonic activity in transverse colon (374 +/- 1220 vs 3249 +/- 3458, P < 0.05). Five patients had significantly increased sigmoid segmental motility (20298 +/- 6364 vs 88780 +/- 3643, P < 0.001) and eight patients had significantly lower number of HAPC without other manometric abnormalities while 17 patients had normal colonic motility recordings. Endoluminal bisacodyl was able to induce HAPCs in all groups of patients. Patients with severe slow transit refractory constipation represented a heterogeneous group and endoluminal bisacodyl was able to promote a propagated motor activity in a majority of patients even in those suspected of having an inert colon.     

Proximal colonic propagating pressure waves sequences and their relationship with movements of content in the proximal human colon

Abstract  Abnormal colonic motor patterns have been implicated in the pathogenesis of severe constipation. Yet in health, the mechanical link between movement of colonic content and regional pressures have only been partially defined. This is largely due to current methodological limitations. Utilizing a combination of simultaneous colonic manometry, high-resolution scintigraphy and a quantitative technique for detecting discrete episodic flow, our aim was to examine the propulsive properties of colonic propagating sequences (PS) in the healthy colon. In six healthy volunteers a nasocolonic manometry catheter was positioned to record colonic pressures at 7.5 cm intervals from terminal ileum to the splenic flexure. With subjects positioned under a gamma camera, 30 MBq of ^99mTc sulfur colloid was instilled into the terminal ileum, 22.5 cm proximal to the ileocolonic junction. Isotopic images were recorded (10 s/frame) and synchronized with the manometric trace. In the proximal colon we identified 137 antegrade PSs, of which 93% were deemed to be associated temporally with movements of luminal content. Low amplitude PSs, with component pressure waves between 2 mmHg and 5 mmHg, were as likely to be associated with colonic movements as higher amplitude PSs. As such there was no correlation between the amplitude of the PS and the temporal relationship with colonic movements. Within the proximal colon, 24 retrograde PSs were identified, 23 of which were associated with retrograde movements of colonic content. We conclude that proximal colonic PSs are highly propulsive and are a major determinant of proximal colonic flow.     

High amplitude propagated contractions

While most colonic motor activity is segmental and non‐propulsive, colonic high amplitude propagated contractions (HAPC) can transfer colonic contents over long distances and often precede defecation. High amplitude propagated contractions occur spontaneously, in response to pharmacological agents or colonic distention. A subset of patients with slow transit constipation have fewer HAPC. In this issue of Neurogastroenterology and Motility, Rodriguez et al. report that anal relaxation during spontaneous and bisacodyl‐induced HAPC exceeds anal relaxation during rectal distention in constipated children undergoing colonic manometry. Moreover, and consistent with a neural mechanism, anal relaxation often precedes arrival of HAPC in the left colon. High amplitude propagated contractions are also used to evaluate the motor response to a meal and pharmacological stimuli (e.g., bisacodyl, neostigmine) and to identify colonic inertia during colonic motility testing in chronic constipation. This editorial comprehensively reviews the characteristics, physiology and pharmacology of HAPC, their assessment by manometry, and relevance to constipation and diarrhea.     

Regional variation in the neurochemical coding of the myenteric plexus of the human colon and changes in patients with slow transit constipation

Abstract There are differences in the structure and function between regions of the colon. In patients with slow transit constipation the activity of all regions is markedly slowed. Counts of colonic neurones in slow transit constipation have been semiquantitative and led to varying results. We have applied new methods of quantification of markers in whole mounts of the colonic myenteric plexus to compare density of innervation between regions and between normal patients and those undergoing resection for severe constipation. Whole mounts of colonic myenteric plexus were made from specimens removed for cancer treatment (controls) and cases of severe constipation. All neurones were labelled by anti‐human neuronal protein antibodies. Neurones synthesizing acetyl choline were labelled for choline acetyltransferase (ChAT) and those for nitric oxide by antisera to nitric oxide synthase (NOS). Four populations of neurones were distinguished and quantified according to the two selective markers, ChAT and NOS. In the normal major populations were NOS alone (51% of ascending colon neurones and 44% of descending colon neurones) and ChAT alone (41% ascending colon, 48% descending colon). Nitric oxide synthase/ChAT and NOS‐/ChAT‐comprised only small populations. In all regions in severe constipation, the percentage of NOS‐only colonic myenteric neurones was raised (54% ascending colon, 49% descending colon) and ChAT only was reduced (36% ascending colon, 42% descending colon). The other populations were not changed. Accurate quantification of neuronal populations in whole mounts of human colon reveals inter‐regional differences in innervation and marked changes in innervation in cases of very severe constipation.     

Removal of tonic nitrergic inhibition is a potent stimulus for human proximal colonic propagating sequences

Propagating sequences (PS) are important in colonic propulsion and defecation, yet the triggers of these motor patterns are not understood. Nonadrenergic noncholinergic neurones are believed to modulate smooth muscle in the gastrointestinal tract via the ubiquitous inhibitory neurotransmitter nitric oxide (NO). In the mouse colon periods of quiescence correlate with an increase in the release of NO. We investigated the colonic response to NO synthase inhibition in the conscious human subject. Intravenous infusion of saline or N(G)-monomethyl-L-arginine (L-NMMA; 3 or 6 mg kg(-1) h(-1)) occurred in random order in six healthy volunteers in whom a 5 m long nasocolonic manometry catheter was positioned such that 16 recording sites, at 7.5-cm intervals, spanned the terminal ileum and colon. L-NMMA infusion at 3 mg kg(-1) h(-1), but not 6 mg kg(-1) h(-1) significantly (P = 0.02) increased proximal colonic PS frequency (2.0 +/- 1.9 vs 11.7 +/- 7.0 PS h(-1)) and non-propagating motor activity (5,296 +/- 2,750 vs 6,362 +/- 1,275 mmHg s). We conclude that blockade of NO synthesis has a stimulatory effect on the frequency of proximal colonic PS. This suggests removal of tonic nitrergic inhibition of the colon might be a physiological stimulus for propagating activity.     

Classification of normal and abnormal colonic motility based on cross‐correlations of pancolonic manometry data

Background Manual analysis of data acquired from manometric studies of colonic motility is laborious, subject to laboratory bias and not specific enough to differentiate all patients from control subjects. Utilizing a cross‐correlation technique, we have developed an automated analysis technique that can reliably differentiate the motor patterns of patients with slow transit constipation (STC) from those recorded in healthy controls. Methods Pancolonic manometric data were recorded from 17 patients with STC and 14 healthy controls. The automated analysis involved calculation of an indicator value derived from cross‐correlations calculated between adjacent recording sites in a manometric trace. The automated technique was conducted on blinded real data sets (observed) and then to determine the likelihood of positive indicator values occurring by chance, the channel number within each individual data set were randomized (expected) and reanalyzed. Key Results In controls, the observed indicator value (3.2 ± 1.4) was significantly greater than that predicted by chance (0.8 ± 1.5; P < 0.0001). In patients, the observed indicator value (?2.7 ± 1.8) did not differ from that predicted by chance (?3.5 ± 1.6; P = 0.1). The indicator value for controls differed significantly from that of patients (P < 0.0001), with all individual patients falling outside of the range of indicator values for controls. Conclusions & Inferences Automated analysis of colonic manometry data using cross‐correlation separated all patients from controls. This automated technique indicates that the contractile motor patterns in STC patients differ from those recorded in healthy controls. The analytical technique may represent a means for defining subtypes of constipation.     

Impaired propulsive motility in the distal but not proximal colon of BK channel β1‐subunit knockout mice

Background Large‐conductance Ca²⁺‐activated K⁺ (BK) channels regulate smooth muscle tone. The BK channel β1‐subunit increases Ca²⁺ sensitivity of the α‐subunit in smooth muscle. We studied β1‐subunit knockout (KO) mice to determine if gastrointestinal (GI) motility was altered. Methods Colonic and intestinal longitudinal muscle reactivity to bethanechol and colonic migrating motor complexes (CMMCs) were measured in vitro. Gastric emptying and small intestinal transit were measured in vivo. Colonic motility was assessed in vivo by measuring fecal output and glass bead expulsion time. Myoelectric activity of distal colon smooth muscle was measured in vitro using intracellular microelectrodes. Key Results Bethanechol‐induced contractions were larger in the distal colon of β1‐subunit KO compared to wild type (WT) mice; there were no differences in bethanechol reactivity in the duodenum, ileum, or proximal colon of WT vsβ1‐subunit KO mice. There were more retrogradely propagated CMMCs in the distal colon of β1‐subunit KO compared to WT mice. Gastrointestinal transit was unaffected by β1‐subunit KO. Fecal output was decreased and glass bead expulsion times were increased in β1‐subunit KO mice. Membrane potential of distal colon smooth muscle cells from β1‐subunit KO mice was depolarized with higher action potential frequency compared to WT mice. Paxilline (BK channel blocker) depolarized smooth muscle cells and increased action potential frequency in WT distal colon. Conclusions & Inferences BK channels play a prominent role in smooth muscle function only in the distal colon of mice. Defects in smooth muscle BK channel function disrupt colonic motility causing constipation.     

Progesterone receptors and serotonin levels in colon epithelial cells from females with slow transit constipation

Background Females with slow transit constipation (STC) exhibit progesterone receptor (P4R) overexpression in colon muscle that impair their contractility. These studies examined whether these patients have an overexpression of P4R in epithelial cells and whether P4 affects the SERT‐5‐HT pathway. Methods Tissues were obtained from surgical specimens of seven females with STC and six controls. Feasibility studies were performed in biopsies from six patients with STC and three controls. P4R, SERT and TPH‐1 mRNA and protein expression and 5‐HT by ELISA were determined. Contraction was studied in normal muscle cells pretreated with P4 or buffer. Progesterone effects on SERT and 5‐HT levels were studied in normal human mucosa in vitro and in wild and SERT knockout mice in vivo. Key Results P4R was overexpressed in epithelial cells in STC compared with controls. The levels of SERT were lower and 5‐HT higher in STC. In epithelial cells P4 treatment decreased SERT and increased mucosal 5‐HT without affecting TPH‐1. Progesterone impaired the contraction of normal muscle cells induced by Ach and 5‐HT. Progesterone decreased SERT and increased 5‐HT levels in the colon of wild mice in vivo but had no effect on the high basal levels of 5‐HT in SERT knockout mice. Conclusions & Inferences P4R are present in colon epithelial cells and are overexpressed in females with STC. These cells have reduced SERT and high 5‐HT levels and normal TPH‐1. These 5‐HT signaling abnormalities are related to overexpression of P4R since they are reproduced in human epithelial cells in vitro and in mice in vivo.     

Performance characteristics of scintigraphic colon transit measurement in health and irritable bowel syndrome and relationship to bowel functions

Background The inter‐ and intra‐subject variations of scintigraphy, which are used to identify colonic transit disturbances in irritable bowel syndrome (IBS), are unclear. The relationship between colonic transit and bowel functions is incompletely understood. To assess inter‐ and intra‐subject variations of scintigraphic colonic transit measurements in 86 IBS patients and 17 healthy subjects and to quantify the relationship between colonic transit and bowel symptoms in 147 IBS patients and 46 healthy subjects. Methods Data from participants with multiple colonic transit measurements were analysed. Primary end points were colonic filling at 6 h (CF6h) and geometric center (GC) at 24 and 48 h for colonic transit. Bowel functions were assessed by daily stool diaries. Key Results Inter‐ and intra‐subject variations were greater for small intestinal than colonic transit. Overall, inter‐ and intra‐subject variations were relatively narrow for colonic transit (both GC24h and GC48h, with lower COV at 48 h); there was little intra‐subject variation in health and IBS‐constipation over a period of ≤3 weeks and over 2.0 years (median, range 0.1, 11.0 years). Significant intra‐individual differences in GC24h were observed only in IBS‐D patients. Colonic transit was significantly associated with stool form (accounting for 19–27% of the variance), frequency (19%), and ease of stool passage (12%). Conclusions & Inferences Despite inter‐subject variation in scintigraphic colonic transit results, the intra‐subject measurements are reproducible over time in healthy volunteers and patients with IBS; significant changes in colonic transit at 24 h were observed only in IBS‐D. Colonic transit is associated with stool form, frequency and ease of passage.     

Pilot study of pyridostigmine in constipated patients with autonomic neuropathy

BACKGROUND: The effects of cholinesterase inhibitors, which increase colonic motility in health, on chronic constipation are unknown. Our aims were to evaluate the efficacy of cholinesterase inhibitors for dysautonomia and chronic constipation and to assess whether acute effects could predict the long term response. METHODS: In this single-blind study, 10 patients with autonomic neuropathy and constipation were treated with placebo (2 weeks), followed by an escalating dose of pyridostigmine to the maximum tolerated dose (i.e., 180-540 mg daily) for 6 weeks. Symptoms and gastrointestinal transit were assessed at 2 and 8 weeks. The acute effects of neostigmine on colonic transit and motility were also assessed. RESULTS: At baseline, 4, 6, and 3 patients had delayed gastric, small intestinal, and colonic transit respectively. Pyridostigmine was well tolerated in most patients, improved symptoms in 4 patients, and accelerated the geometric center for colonic transit at 24 h by > or =0.7 unit in 3 patients. The effects of i.v. neostigmine on colonic transit and compliance predicted (P < 0.05) the effects of pyridostigmine on colonic transit. CONCLUSIONS: Pyridostigmine improves colonic transit and symptoms in some patients with autonomic neuropathy and constipation. The motor response to neostigmine predicted the response to oral pyridostigmine.