High Prevalence of Slow Transit Constipation in Patients With Gastroparesis
JOURNAL OF NEUROGASTROENTEROLOGY AND MOTILITY
2019; 25 (2): 267?75
High Prevalence of Slow Transit Constipation in Patients With Gastroparesis.
Journal of neurogastroenterology and motility
Neural control properties of the external anal sphincter in young and elderly women.
Neurourology and urodynamics
Background/Aims: Current evidence suggests the presence of motility or functional abnormalities in one area of the gastrointestinal tract increases the likelihood of abnormalities in others. However, the relationship of gastroparesis to chronic constipation (slow transit constipation and dyssynergic defecation) has been incompletely evaluated.Methods: We retrospectively reviewed the records of all patients with chronic dyspeptic symptoms and constipation who underwent both a solid gastric emptying scintigraphy and a highresolution anorectal manometry at our institution since January 2012. When available, Xray defecography and radiopaque marker colonic transit studies were also reviewed. Based on the gastric emptying results, patients were classified as gastroparesis or dyspepsia with normal gastric emptying (control group). Differences in anorectal and colonic findings were then compared between groups.Results: Two hundred and six patients met the inclusion criteria. Patients with gastroparesis had higher prevalence of slow transit constipation by radiopaque marker study compared to those with normal emptying (64.7% vs 28.1%, P = 0.013). Additionally, patients with gastroparesis had higher rates of rectocele (88.9% vs 60.0%, P = 0.008) and intussusception (44.4% vs 12.0%, P = 0.001) compared to patients with normal emptying. There was no difference in the rate of dyssynergic defecation between those with gastroparesis vs normal emptying (41.1% vs 42.1%, P = 0.880), and no differences in anorectal manometry findings.Conclusions: Patients with gastroparesis had a higher rate of slow transit constipation, but equal rates of dyssynergic defecation compared to patients with normal gastric emptying. These findings argue for investigation of possible delayed colonic transit in patients with gastroparesis and vice versa.
View details for PubMedID 30870880
The assessment and management of defecatory dysfunction: a critical appraisal.
Current opinion in gastroenterology
The prevalence of fecal incontinence (FI) increases with age and affects more than 15% of the elderly population. Sarcopenia, skeletal muscle structural, and functional decline with aging, is known to be caused by neuromuscular dysfunction. However, age-related alterations of the neuromuscular function of the external anal sphincter (EAS) have not been studied. This study aims to quantitatively characterize the effect of aging on the EAS by assessing the firing patterns and size of motor unit action potential (MUAP) using high-density surface electromyography (HD-sEMG) recording and analysis techniques.Thirteen young (31.0?▒?3.6 years) and 14 elderly (64.3?▒?6.2 years) healthy women were recruited for this study. EMG activity of the EAS during maximal voluntary contraction was recorded by a 64-Channel, HD-sEMG intra-rectal probe. HD-sEMG signals were decomposed into MUAP spike trains to extract the firing rate and amplitudes thereof.HD-sEMG decomposition was successfully performed. For the young and elderly groups, mean motor unit (MU) firing rates of 11.4?▒?2.1 pulses per second (PPS) and 9.6?▒?2.3 PPS, and mean MUAP amplitudes of 45.2?▒?14.3?ÁV and 61.9?▒?21.2?ÁV were respectively obtained. Both the MU firing rate and MUAP amplitude were significantly different between two groups (P?.05). Moreover, the MUAP firing rate and amplitude correlated with age with a linear regression model (P?.05).This study represents the first effort to examine the effect of aging on the neuromuscular function of EAS. Results suggest an age-related impairment of lower motor neuron descending excitation to the EAS with a compensatory increase in mean MU size.
View details for DOI 10.1002/nau.24108
View details for PubMedID 31321803
Irritable bowel syndrome (IBS) patients have SCN5A channelopathies that lead to decreased NaV1.5 current and mechanosensitivity.
American journal of physiology. Gastrointestinal and liver physiology
To summarize the advances in diagnostic modalities and management options for defecatory dysfunction and highlight the areas in need of further research.The diagnostic utility of high-resolution anorectal manometry (ARM), which has emerged as a promising tool for the diagnosis of defecatory dysfunction, appears to be questionable in differentiating disease from normal physiology. There also seems to be discrepancy between results of various tests of anorectal function in the diagnosis of defecatory dysfunction. New revisions in diagnostic criteria for defecatory dysfunction by Rome IV consortium, may enhance its diagnostic yield. Biofeedback remains to be the most effective evidence-based treatment option for patients with defecatory dysfunction. Anorectal pressure profile cannot predict or mediate the success of biofeedback. Biofeedback may improve the symptoms through central effects.Despite the advances in the ARM and defecography techniques, no one test has been able to be considered as the 'gold standard' for diagnosis of defecatory dysfunction. The mechanism of action of biofeedback in defecatory dysfunction remains poorly understood.
View details for PubMedID 29064840
A rare cause of an upper gastrointestinal bleed.
Long-term Follow-up Study of Fecal Microbiota Transplantation for Severe and/or Complicated Clostridium difficile Infection A Multicenter Experience
JOURNAL OF CLINICAL GASTROENTEROLOGY
2016; 50 (5): 398-402
The SCN5A-encoded voltage-gated mechanosensitive sodium (Na+) channel NaV1.5 is expressed in human GI smooth muscle cells and interstitial cells of Cajal. NaV1.5 contributes to smooth muscle electrical slow waves and mechanical sensitivity. In predominately Caucasian IBS patient cohorts, 2-3% have SCN5A missense mutations which alter NaV1.5 function and may contribute to IBS pathophysiology. In this study examined a racially and ethnically diverse cohort of IBS patients for SCN5A missense mutations, and compared them to IBS negative controls, and determined the resulting NaV1.5 voltage-dependent and mechanosensitive properties. All SCN5A exons were sequenced from somatic DNA of 252 Rome III IBS patients with diverse ethnic and racial backgrounds. Missense mutations were introduced into wild-type SCN5A by site-directed mutagenesis and co-transfected with GFP into HEK-293 cells. NaV1.5 voltage-dependent and mechanosensitive functions were studied by whole cell electrophysiology with and without shear force. Five of 252 IBS patients (2.0%) had six rare SCN5A mutations, which were absent in 377 IBS-negative controls. All (6/6, 100%) IBS-associated NaV1.5 mutations had voltage-dependent gating abnormalities: current density reduction (R225W, R433C, R986Q, F1293S) and altered voltage dependence (R225W, R433C, R986Q, G1037V, F1293S) and at least one kinetic parameter was altered in all mutations. Four IBS-associated SCN5A mutations (4/6, 67%) resulted in altered NaV1.5 mechanosensitivity (R225W, R433C, R986Q, F1293S). In this racially and ethnically diverse cohort of IBS patients we show that 2% of IBS patients harbor SCN5A mutations that are absent in IBS-negative controls and result in NaV1.5 channels with abnormal voltage-dependent and mechanosensitive function.
View details for DOI 10.1152/ajpgi.00016.2017
View details for PubMedID 29167113
Advancing treatment options for chronic idiopathic constipation
EXPERT OPINION ON PHARMACOTHERAPY
2016; 17 (4): 501-511
Our aim was to investigate fecal microbiota transplantation (FMT) efficacy in patients with severe and/or complicated Clostridium difficile infection (CDI).FMT is successful for recurrent CDI, although its benefit in severe or complicated CDI has not specifically been evaluated.A multicenter long-term follow-up study was performed in patients who received FMT for severe and/or complicated CDI (diagnosed using standard criteria). Pre-FMT and post-FMT questionnaires were completed. Study outcomes included cure rates and time to resolution of symptoms.A total of 17 patients (82% inpatients, 18% outpatients) were included (76.4% women; mean age, 66.4 y; mean follow-up, 11.4 mo). Patients had severe and complicated (76.4%) or either severe or complicated (23.6%) CDI. Sixteen patients (94.1%) had diarrhea, which resolved in 12 (75%; mean time to resolution, 5.7 d) and improved in 4 (25%) after FMT. Eleven patients (64.7%) had abdominal pain, which resolved in 8 (72.7%; mean time to resolution, 9.6 d) and improved in 3 (27.3%) after FMT. Two of 17 patients experienced early CDI recurrence (?90 d) after FMT (primary cure rate, 88.2%); and in 1 patient, a second FMT resulted in cure (secondary cure rate, 94.1%). Late CDI recurrence (?90 d) was seen in 1 of 17 patients (5.9%) in association with antibiotics and was successfully treated with a repeat FMT. No adverse effects directly related to FMT occurred.FMT was successful and safe in this cohort of patients with severe or complicated CDI. Primary and secondary cure rates were 88.2% and 94.1%, respectively.
View details for Web of Science ID 000375032900010
View details for PubMedID 26125460
Neurogenic Bowel Dysfunction in Patients with Neurogenic Bladder.
Current bladder dysfunction reports
2016; 11 (4): 334?40
Chronic constipation is a global problem affecting all ages and associated with considerable morbidity and significant financial burden for society. Though formerly defined on the basis of a single symptom, infrequent defecation; constipation is now viewed as a syndrome encompassing several complaints such as difficulty with defecation, a sense of incomplete evacuation, hard stools, abdominal discomfort and bloating.The expanded concept of constipation has inevitably led to a significant change in outcomes in clinical trials, as well as in patient expectations from new therapeutic interventions. The past decades have also witnessed a proliferation in therapeutic targets for new agents. Foremost among these have been novel prokinetics, a new category, prosecretory agents and innovative approaches such as inhibitors of bile salt transport. In contrast, relatively few effective therapies exist for the management of those anorectal and pelvic floor problems that result in difficult defecation.Though constipation is a common and often troublesome disorder, many of those affected can resolve their symptoms with relatively simple measures. For those with more resistant symptoms a number of novel, effective and safe options now exist. Those with defecatory difficulty (anismus, pelvic floor dysfunction) continue to represent a significant management challenge.
View details for DOI 10.1517/14656566.2016.1127356
View details for Web of Science ID 000370759000001
View details for PubMedID 26630260
Ranolazine inhibits voltage-gated mechanosensitive sodium channels in human colon circular smooth muscle cells
AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY
2015; 309 (6): G506-G512
Patients with primary neurologic conditions often experience urinary and bowel dysfunction due to loss of sensory and/or motor control. Neurogenic bowel dysfunction is frequently characterized by both constipation and fecal incontinence. In general, the management of neurogenic bowel dysfunction has been less well studied than bladder dysfunction despite their close association.. It is widely accepted that establishment of a multifaceted bowel regimen is the cornerstone of conservative management. Continuing assessment is necessary to determine need for more invasive interventions. In the clinical setting, the Urologist may be the principle provider addressing bowel concerns in addition to bladder dysfunction, and furthermore, treatment of one often impacts the other. Future directions should include development of follow up and management guidelines that address the comprehensive care of this patient population.
View details for PubMedID 28717406
A Hidden Cause of Dysphagia. Primary Esophageal Lymphoma.
2015; 149 (3): 549-550
Abdominal Pain and Bloating in an Auto Mechanic
2014; 146 (7): 1610-1611
Distinct modulation of K-v1.2 channel gating by wild type, but not open form, of syntaxin-1A
AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY
2007; 292 (5): G1233-G1242
Human jejunum smooth muscle cells (SMCs) and interstitial cells of Cajal (ICCs) express the SCN5A-encoded voltage-gated, mechanosensitive sodium channel NaV1.5. NaV1.5 contributes to small bowel excitability, and NaV1.5 inhibitor ranolazine produces constipation by an unknown mechanism. We aimed to determine the presence and molecular identity of Na(+) current in the human colon smooth muscle and to examine the effects of ranolazine on Na(+) current, mechanosensitivity, and smooth muscle contractility. Inward currents were recorded by whole cell voltage clamp from freshly dissociated human colon SMCs at rest and with shear stress. SCN5A mRNA and NaV1.5 protein were examined by RT-PCR and Western blots, respectively. Ascending human colon strip contractility was examined in a muscle bath preparation. SCN5A mRNA and NaV1.5 protein were identified in human colon circular muscle. Freshly dissociated human colon SMCs had Na(+) currents (-1.36 ▒ 0.36 pA/pF), shear stress increased Na(+) peaks by 17.8 ▒ 1.8% and accelerated the time to peak activation by 0.7 ▒ 0.3 ms. Ranolazine (50 ?M) blocked peak Na(+) current by 43.2 ▒ 9.3% and inhibited shear sensitivity by 25.2 ▒ 3.2%. In human ascending colon strips, ranolazine decreased resting tension (31%), reduced the frequency of spontaneous events (68%), and decreased the response to smooth muscle electrical field stimulation (61%). In conclusion, SCN5A-encoded NaV1.5 is found in human colonic circular smooth muscle. Ranolazine blocks both peak amplitude and mechanosensitivity of Na(+) current in human colon SMCs and decreases contractility of human colon muscle strips. Our data provide a likely mechanistic explanation for constipation induced by ranolazine.
View details for DOI 10.1152/ajpgi.00051.2015
View details for Web of Science ID 000361817700011
View details for PubMedID 26185330
View details for PubMedCentralID PMC4572410
Calcium source diversity in feline lower esophageal sphincter circular and sling muscle
AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY
2004; 286 (2): G271-G277
SNARE proteins, syntaxin-1A (Syn-1A) and SNAP-25, inhibit delayed rectifier K(+) channels, K(v)1.1 and K(v)2.1, in secretory cells. We showed previously that the mutant open conformation of Syn-1A (Syn-1A L165A/E166A) inhibits K(v)2.1 channels more optimally than wild-type Syn-1A. In this report we examined whether Syn-1A in its wild-type and open conformations would exhibit similar differential actions on the gating of K(v)1.2, a major delayed rectifier K(+) channel in nonsecretory smooth muscle cells and some neuronal tissues. In coexpression and acute dialysis studies, wild-type Syn-1A inhibited K(v)1.2 current magnitude. Of interest, wild-type Syn-1A caused a right shift in the activation curves of K(v)1.2 without affecting its steady-state availability, an inhibition profile opposite to its effects on K(v)2.1 (steady-state availability reduction without changes in voltage dependence of activation). Also, although both wild-type and open-form Syn-1A bound equally well to K(v)1.2 in an expression system, open-form Syn-1A failed to reduce K(v)1.2 current magnitude or affect its gating. This is in contrast to the reported more potent effect of open-form Syn-1A on K(v)2.1 channels in secretory cells. This finding together with the absence of Munc18 and/or 13-1 in smooth muscles suggested that a change to an open conformation Syn-1A, normally facilitated by Munc18/13-1, is not required in nonsecretory smooth muscle cells. Taken together with previous reports, our results demonstrate the multiplicity of gating inhibition of different K(v) channels by Syn-1A and is compatible with versatility of Syn-1A modulation of repolarization in various secretory and nonsecretory (smooth muscle) cell types.
View details for DOI 10.1152/ajpgi.00473.2006
View details for Web of Science ID 000247935800007
View details for PubMedID 17234891
Within muscular equivalents of cat lower esophageal sphincter (LES), the circular muscle develops greater spontaneous tone, whereas the sling muscle is more responsive to cholinergic stimulation. Smooth muscle contraction involves a combination of calcium release from stores and of calcium entry via several pathways. We hypothesized that there are differences in the sources of Ca(2+) used for contraction in sling and circular muscles and that these differences could contribute to functional asymmetry observed within LES. Contraction of muscle strips from circular and sling regions of LES was assessed in the presence of TTX. In Ca(2+)-free Krebs, tone was inhibited to a greater degree in circular than sling muscle. L-type Ca(2+) channel blockade with nifedipine or verapamil inhibited tone in LES circular but not sling muscle. Sarcoplasmic reticulum (SR) Ca(2+)-ATPase inhibitor cyclopiazonic acid (CPA) caused greater increase in tone in sling than in circular muscle. The phospholipase C inhibitor U-73122 and the SR inositol 1,4,5-trisphosphate [Ins(1,4,5)P(3)] receptor blocker 2-aminoethoxydiphenyl borate (2-APB) inhibited tone in circular and sling muscles, demonstrating that continuous release of Ca(2+) from Ins(1,4,5)P(3)-sensitive stores is important in tone generation in both muscles. In Ca(2+)-free Krebs, ACh-induced contractions (AChC) were inhibited to a greater degree in sling than circular muscles. However, nifedipine and verapamil greatly inhibited AChC in the circular but not sling muscle. Depletion of SR Ca(2+) stores with CPA or inhibition of Ins(1,4,5)P(3)-mediated store release with either U-73122 or 2-APB inhibited AChC in both muscles. We demonstrate that LES circular and sling muscles 1) use intracellular and extracellular Ca(2+) sources to different degrees in the generation of spontaneous tone and AChC and 2) use different Ca(2+) entry pathways. These differences hold the potential for selective modulation of LES tone in health and disease.
View details for DOI 10.1152/ajpgi.00291.2003
View details for Web of Science ID 000188002500011
View details for PubMedID 14563670