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Background: Percutaneous tibial nerve stimulation (PTNS) is a new ambulatory therapy for faecal incontinence. Data from case series suggest it has beneficial outcomes in 50-80% patients; however its effectiveness against sham electrical stimulation has not been investigated. We therefore aimed to assess the short-term efficacy of PTNS against sham electrical stimulation in adults with faecal incontinence.Methods: We did a double-blind, multicentre, pragmatic, parallel-group, randomised controlled trial (CONtrol of Faecal Incontinence using Distal NeuromodulaTion [CONFIDeNT]) in 17 specialist hospital units in the UK that had the skills to manage patients with faecal incontinence. Eligible participants aged 18 years or older with substantial faecal incontinence for whom conservative treatments (such as dietary changes and pelvic floor exercises) had not worked, were randomly assigned (1:1) to receive either PTNS (via the Urgent PC neuromodulation system) or sham stimulation (via a transcutaneous electrical nerve stimulation machine to the lateral forefoot) once per week for 12 weeks. Randomisation was done with permuted block sizes of two, four, and six, and was stratified by sex and then by centre for women. Patients and outcome assessors were both masked to treatment allocation for the 14-week duration of the trial (but investigators giving the treatment were not masked). The primary outcome was a clinical response to treatment, which we defined as a 50% or greater reduction in episodes of faecal incontinence per week. We assessed this outcome after 12 treatment sessions, using data from patients' bowel diaries. Analysis was by intention to treat, and missing data were multiply imputed. This trial is registered with the ISRCTN registry, number 88559475, and is closed to new participants.Findings: Between Jan 23, 2012, and Oct 31, 2013, we randomly assigned 227 eligible patients (of 373 screened) to receive either PTNS (n=115) or sham stimulation (n=112). 12 patients withdrew from the trial: seven from the PTNS group and five from the sham group (mainly because they could not commit to receiving treatment every week). Two patients (one in each group) withdrew because of an adverse event that was unrelated to treatment (exacerbation of fibromyalgia and rectal bleeding). 39 (38%) of 103 patients with full data from bowel diaries in the PTNS group had a 50% or greater reduction in the number of episodes of faecal incontinence per week compared with 32 (31%) of 102 patients in the sham group (adjusted odds ratio 1·28, 95% CI 0·72-2·28; p=0·396). No serious adverse events related to treatment were reported in the trial. Seven mild, related adverse events were reported in each treatment group, mainly pain at the needle site (four in PTNS, three in sham).Interpretation: PTNS given for 12 weeks did not confer significant clinical benefit over sham electrical stimulation in the treatment of adults with faecal incontinence. Further studies are warranted to determine its efficacy in the long term, and in patient subgroups (ie, those with urgency).Funding: National Institute for Health Research. [ABSTRACT FROM AUTHOR]

Objectives Autonomic nervous system dysfunction has been implicated in visceral hypersensitivity. However, the specific contribution of the parasympathetic nervous system (PNS) is unclear. We aimed to determine whether physiological and pharmacological manipulation of parasympathetic tone influences the development of hypersensitivity in a validated model of acid-induced oesophageal pain. Design Prior to, and following, a 30-min distal oesophageal infusion of 0.15 M hydrochloric acid, pain thresholds to electrical stimulation were determined in the proximal non-acid exposed oesophagus in healthy subjects. Validated sympathetic (skin conductance response) and parasympathetic (cardiac vagal tone) parameters were measured at baseline and continuously thereafter. In study 1, 55 subjects were randomised in a pragmatic blinded crossover design to receive deep breathing or un-paced breathing during acid infusion. In study 2, 32 subjects were randomised in a blinded, crossover design to receive intravenous atropine or placebo (saline) with deep breathing during acid infusion. Results Study 1: Deep breathing increased cardiac vagal tone (2.1±2.3 vs -0.3±2.3, p=0.0006) with concomitant withdrawal of skin conductance response (-0.6 ± 4.9 vs 3±4.8, p=0.03) in comparison with un-paced breathing. Deep breathing prevented the development of acid-induced oesophageal hypersensitivity in comparison with sham breathing (p=0.0001). Study 2: Atropine, in comparison with placebo, blocked the attenuating effect of deep breathing on the development of acid-induced oesophageal hypersensitivity (p=0.046). Conclusions The development of oesophageal hyperalgesia is prevented by physiologically increasing parasympathetic tone. This effect is pharmacologically blocked with atropine, providing evidence that the PNS influences the development of oesophageal pain hypersensitivity. [ABSTRACT FROM AUTHOR]

Objective: Current diagnostic methods for gastro-oesophageal reflux disease (GORD) have moderate sensitivity/specificity and can be invasive and expensive. Pepsin detection in saliva has been proposed as an 'office-based' method for GORD diagnosis. The aims of this study were to establish normal values of salivary pepsin in healthy asymptomatic subjects and to determine its value to discriminate patients with reflux-related symptoms (GORD, hypersensitive oesophagus (HO)) from functional heartburn (FH). Design: 100 asymptomatic controls and 111 patients with heartburn underwent MII-pH monitoring and simultaneous salivary pepsin determination on waking, after lunch and dinner. Cut-off value for pepsin positivity was 16 ng/mL. Patients were divided into GORD (increased acid exposure time (AET), n=58); HO (normal AET and + Symptom Association Probability (SAP), n=26) and FH (normal AET and--SAP, n=27). Results: 1/3 of asymptomatic subjects had pepsin in saliva at low concentration (0(0-59)ng/mL). Patients with GORD and HO had higher prevalence and pepsin concentration than controls (HO, 237(52-311)ng/mL and GORD, 121(29-252)ng/mL)(p<0.05). Patients with FH had low prevalence and concentration of pepsin in saliva (0(0-40) ng/mL). A positive test had 78.6% sensitivity and 64.9% specificity for diagnosis of GORD+HO (likelihood ratio: 2.23). However, one positive sample with >210 ng/mL pepsin suggested presence of GORD+HO with 98.2% specificity (likelihood ratio: 25.1). Only 18/84 (21.4%) of GORD+HO patients had 3 negative samples. Conclusion In patients with symptoms suggestive of GORD, salivary pepsin testing may complement questionnaires to assist office-based diagnosis. This may lessen the use of unnecessary antireflux therapy and the need for further invasive and expensive diagnostic methods. [ABSTRACT FROM AUTHOR]

The article discusses the use of anorectal manometry in diagnosing dyssynergic defecation, highlighting the challenges and complexities involved in accurately identifying and understanding such conditions. The study compares the Endocuff with artificial intelligence-assisted colonoscopy in detecting colorectal adenoma, emphasizing the importance of statistical methodology in interpreting study findings. The authors acknowledge the need for longitudinal studies to assess the impact of enduring straining on anorectal function and structural pathologies in cases of dyssynergic defecation. [Extracted from the article]

Objectives: To present methods and baseline results for an online screening tool to identify increased risk for Parkinson's disease (PD) in the UK population. Methods: Risk estimates for future PD were derived from the results of a systematic review of risk factors and early features of PD. Participants aged 60-80 years without PD were recruited by self-referral. They completed an online survey (including family history, non-motor symptoms and lifestyle factors), a keyboardtapping task and the University of Pennsylvania Smell Identification Test. Risk scores were calculated based on survey answers. Preliminary support for the validity of this algorithm was assessed by comparing those estimated to be higher risk for PD with those at lower risk using proxies, including smell loss, REM-sleep behaviour disorder and reduced tapping speed, and by assessing associations in the whole group. Results: 1324 eligible participants completed the survey and 1146 undertook the keyboard-tapping task. Smell tests were sent to 1065 participants. Comparing the 100 highest-risk participants and 100 lowest-risk participants, median University of Pennsylvania Smell Identification Test scores were 30/40 versus 33/40 (p<0.001), mean number of key taps in 30 s were 55 versus 58 (p=0.045), and 24% versus 10% scored above cut-off for REM-sleep behaviour disorder ( p=0.008). Regression analyses showed increasing risk scores were associated with worse scores in the three proxies across the whole group (p=0.001). Conclusions: PREDICT-PD is the first study to systematically combine risk factors for PD in the general population. Validity to predict risk of PD will be tested through longitudinal follow-up of incident PD diagnosis. [ABSTRACT FROM AUTHOR]

Prostaglandin E2 (PGE2) plays a major role in pain processing and hypersensitivity. This study investigated whether PGE2 levels are increased in the esophageal mucosa after acid infusion and whether increases in PGE2 are associated with heartburn. Furthermore, expression of the PGE2 receptor EP1 was investigated in human esophageal mucosa. Fourteen healthy male volunteers were randomized to 30-min lower esophageal acid (1% HCl) or saline perfusion. Before and after acid perfusion, endoscopic biopsies were taken from the distal esophagus. PGE2 concentration (pg/mg protein) and EP1 mRNA and protein in biopsy samples were measured by ELISA, RT-PCR, and Western blotting. Symptom status of heartburn was evaluated with a validated categorical rating scale with a higher values corresponding to increasing intensity. PGE2 levels in the esophageal mucosa significantly increased after acid infusion (before vs. after acid infusion: 23.2 ± 8.6 vs. 68.6 ± 18.3, P < 0.05), but not after saline infusion (before vs. after saline infusion: 9.3 ± 2.5 vs. 9.0 ± 3.2, NS). Time to first sensation (min) after acid infusion was less than after saline (saline vs. acid infusion: 22.1 ± 4.1 vs. 5.4 ± 1.5, P < 0.05). Intensity of heartburn in the acid-infusion group was also significantly greater compared with saline (saline vs. acid infusion: 54.3 ± 13.1 vs. 178.5 ± 22.8, P < 0.01). Changes in PGE2 levels in the esophagus correlated with symptom intensity score (r = 0.80, P = 0.029). EP1 mRNA and protein expression were observed in the normal human esophageal mucosa. Esophageal PGE2 expression is associated with mucosal acid exposure and heartburn. [ABSTRACT FROM AUTHOR]

Abstract: Knowledge of molecular mechanisms that underlie development of the enteric nervous system has greatly expanded in recent decades. Enteric neuropathies related to aberrant genetic development are thus becoming increasingly recognized. There has been no recent review of these often highly morbid disorders. This review highlights advances in knowledge of the molecular pathogenesis of these disorders from a clinical perspective. It includes diseases characterized by an infantile aganglionic Hirschsprung phenotype and those in which structural abnormalities are less pronounced. The implications for diagnosis, screening and possible reparative approaches are presented. [Copyright &y& Elsevier]

Some patients with chronic constipation may undergo colectomy yielding tissue appropriate to diagnosis of underlying neuromuscular pathology. The analysis of such tissue has, over the past 40 years, fuelled research that has explored the presence of neuropathy, myopathy and more recently changes in interstitial cells of Cajal (ICC). In this chapter, the data from these studies have been critically reviewed in the context of the significant methodological and interpretative issues that beset the field of gastrointestinal neuromuscular pathology. On this basis, reductions in ICC appear to a consistent finding but one whose role as a primary cause of slow-transit constipation requires further evaluation. Findings indicative of significant neuropathy or myopathy are variable and in many studies subject to considerable methodological bias. Methods with practical diagnostic utility in the individual patient have rarely been employed and require further validation in respect of normative data. [Copyright &y& Elsevier]

Objective Guidelines on histopathological techniques and reporting for adult and paediatric gastrointestinal neuromuscular pathology have been produced recently by an international working group (IWG). These addressed the important but relatively neglected areas of histopathological practice of the general pathologist, including suction rectal biopsy and full-thickness intestinal tissue. Recommendations were presented for the indications, safe acquisition of tissue, histological techniques, reporting and referral of such histological material. Design Consensual processes undertaken by the IWG and following established guideline decision group methodologies. Results and conclusion This report presents a contemporary and structured classification of gastrointestinal neuromuscular pathology based on defined histopathological criteria derived from the existing guidelines. In recognition of its origins and first presentation in London at the World Congress of Gastroenterology 2009, this has been named 'The London Classification⇔tm). The implementation of this classification should allow some diagnostic standardisation, but should necessarily be viewed as a starting point for future modification as new data become available. [ABSTRACT FROM AUTHOR]

The term gastrointestinal neuromuscular disease describes a clinically heterogeneous group of disorders of children and adults in which symptoms are presumed or proven to arise as a result of neuromuscular, including interstitial cell of Cajal, dysfunction. Such disorders commonly have impaired motor activity, i.e. slowed or obstructed transit with radiological evidence of transient or persistent visceral dilatation. Whilst sensorimotor abnormalities have been demonstrated by a variety of methods in these conditions, standards for histopathological reporting remain relatively neglected. Significant differences in methodologies and expertise continue to confound the reliable delineation of normality and specificity of particular pathological changes for disease. Such issues require urgent clarification to standardize acquisition and handling of tissue specimens, interpretation of findings and make informed decisions on risk-benefit of full-thickness tissue biopsy of bowel or other diagnostic procedures. Such information will also allow increased certainty of diagnosis, facilitating factual discussion between patients and caregivers, as well as giving prognostic and therapeutic information. The following report, produced by an international working group, using established consensus methodology, presents proposed guidelines on histological techniques and reporting for adult and paediatric gastrointestinal neuromuscular pathology. The report addresses the main areas of histopathological practice as confronted by the pathologist, including suction rectal biopsy and full-thickness tissue obtained with diagnostic or therapeutic intent. For each, indications, safe acquisition of tissue, histological techniques, reporting and referral recommendations are presented. [ABSTRACT FROM AUTHOR]

Abstract: The gastrointestinal (GI) tract is a system of organs within multicellular animals which facilitates the ingestion, digestion, and absorption of food with subsequent defecation of waste. A complex arrangement of nerves and ancillary cells contributes to the sensorimotor apparatus required to subserve such essential functions that are with the exception of the extreme upper and lower ends of the GI tract normally subconscious. However, it also has the potential to provide conscious awareness of injury. Although this function can be protective, when dysregulated, particularly on a chronic basis, the same system can lead to considerable morbidity. The anatomical and molecular basis of gastrointestinal nociception, conditions associated with chronic unexplained visceral pain, and developments in treatment are presented in this review. [Copyright &y& Elsevier]

Previous studies have demonstrated that a single 30-mm distal esophageal infusion of concentrated (0.15 M, pH 0.8) hydrochloric acid (HCl) induces hyperalgesia to an electrical stimulus in a human model. The aim of this study was to refine this model using physiological acid concentrations (pH 1.8-4) in repeated short exposures. Two different cohorts of 10 volunteers underwent two studies. Study 1: randomization to four 5-mm distal esophageal infusions of acid (0.15 M) or saline, 1 h apart. Double-blind measurements of baseline and postexposure proximal esophageal and chest wall pain thresholds (PTs) were performed to electrical stimulation at 30-mm intervals throughout the study. Study 2: randomization to four 15-mm infusions of 0.15, 0.075, and 0.01 M HCI and saline. En study 1, with multiple acid infusions, a significant progressive drop in PTs was observed in both areas tested (P ≤ 0.0001). In study 2, increasing acid concentrations had a significant effect over multiple time points, P ≤ 0.0001. Similar initial reductions in PT's were observed for all acid concentrations compared with saline; however, hypersensitivity was shorter lasting with 0.01 M acid. In healthy subjects, esophageal hypersensitivity can be induced and maintained up to 4 h by repeated short-duration acid infusion and at physiological pH levels. This has implications for future model design and pathophysiological understanding of acid-related esophageal hypersensitivity. [ABSTRACT FROM AUTHOR]

PURPOSE: Currently, rectal sensation may be measured by balloon distention or mucosal electrostimulation. This study investigated the application of a graded heat stimulus to the rectum using a novel thermal probe as a further method of evaluating rectal sensory afferent mechanisms. METHODS: A thermal probe specially designed in our institution was used to test rectal heat sensitivity in 31 healthy subjects. This was compared with all other standard anorectal physiologic measurements. Repeatability studies were also performed. RESULTS: Heat stimulation of the mid rectum elicited sensory responses in all subjects. The most common reported response was not heat but a sharp or prickling sensation. The median rectal heat threshold was similar in males (median, 47°C; range, 44–50°C) compared with females (median, 45°C; range, 43–50°C; P > 0.05). There was a high degree of repeatability with rectal heat and balloon distention thresholds, but not electrostimulation thresholds. A strong correlation was found between rectal heat thresholds and defecatory desire (r = 0.71; P < 0.001) and maximum tolerable volumes (r = 0.8; P < 0.001) measured with balloon distention. CONCLUSION: This is the first demonstration of a repeatable sensory response to heat stimulation in the rectum of normal subjects. Strong correlation between heat thresholds and balloon distention to maximum tolerable volumes and defecatory desire suggest common sensory afferent pathway excitation. Heat stimulation is a simple technique that has a high degree of repeatability and may be an objective assessment of polymodal nociceptor function in the rectum. [ABSTRACT FROM AUTHOR]

Skeletal muscle-derived cells (SMDC) hold tremendous potential for replenishing dysfunctional muscle lost due to disease or trauma. Current therapeutic usage of SMDC relies on harvesting autologous cells from muscle biopsies that are subsequently expanded in vitro before re-implantation into the patient. Heterogeneity can arise from multiple factors including quality of the starting biopsy, age and comorbidity affecting the processed SMDC. Quality attributes intended for clinical use often focus on minimum levels of myogenic cell marker expression. Such approaches do not evaluate the likelihood of SMDC to differentiate and form myofibres when implanted in vivo, which ultimately determines the likelihood of muscle regeneration. Predicting the therapeutic potency of SMDC in vitro prior to implantation is key to developing successful therapeutics in regenerative medicine and reducing implementation costs. Here, we report on the development of a novel SMDC profiling tool to examine populations of cells in vitro derived from different donors. We developed an image-based pipeline to quantify morphological features and extracted cell shape descriptors. We investigated whether these could predict heterogeneity in the formation of myotubes and correlate with the myogenic fusion index. Several of the early cell shape characteristics were found to negatively correlate with the fusion index. These included total area occupied by cells, area shape, bounding box area, compactness, equivalent diameter, minimum ferret diameter, minor axis length and perimeter of SMDC at 24 h after initiating culture. The information extracted with our approach indicates live cell imaging can detect a range of cell phenotypes based on cell-shape alone and preserving cell integrity could be used to predict propensity to form myotubes in vitro and functional tissue in vivo. [ABSTRACT FROM AUTHOR]

Objectives: Anastomotic leakage (AL) is one of the most devastating complications after colorectal surgery. The verification of the adequate perfusion of the anastomosis is essential to ensuring anastomosis integrity following colonic resections. This study aimed to evaluate the efficacy of measuring the electrical activity of the colonic muscularis externa at an anastomosis site for perfusion analysis following colorectal surgery. Methods: Strips of human isolated colon were maintained in a horizontal tissue bath to record spontaneous contractions and myoelectric activity and spike potentials (using a bipolar electrode array for the wireless transmission of myoelectric data—the xBar system) from the circular muscle. Intraoperative myoelectric signal assessment was performed by placing the electrode array on the colon prior to and following mesenteric artery ligation, just prior to colonic resection. Results: In human isolated colon, the amplitude, duration, and frequency of contractions were inhibited during hypoxia by >80% for each measurement, compared to control values and time-matched oxygenated muscle. Intraoperative (N = 5; mean age, 64.8 years; range, 54–74 years; 60% females) myoelectric signal assessment revealed a decline in spike rate following arterial ligation, with a mean reduction of 112.64 to 51.13 spikes/min (p < 0.0008). No adverse events were observed during the study, and the device did not substantially alter the surgical procedure. Conclusions: The electrical and contraction force of the human colon was reduced by ischemia, both in vitro and in vivo. These preliminary findings also suggest the potential of the xBar system to measure such changes during intraoperative and possibly postoperative periods to predict the risk of anastomotic viability as a surrogate of evolving dehiscence. [ABSTRACT FROM AUTHOR]