Charles H Knowles

Queen Mary, University of London, Londinium, England, United Kingdom

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Publications (148)920.96 Total impact

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    Annals of surgery 09/2014; · 7.19 Impact Factor
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    Neurogastroenterology and Motility 09/2014; 26(9). · 2.94 Impact Factor
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    ABSTRACT: Background Sacral nerve stimulation (SNS) is now well established as a treatment for fecal incontinence (FI) resistant to conservative measures and may also have utility in the management of chronic constipation; however, mechanism of action is not fully understood. End organ effects of SNS have been studied in both clinical and experimental settings, but interpretation is difficult due to the multitude of techniques used and heterogeneity of reported findings. The aim of this study was to systematically review available evidence on the mechanisms of SNS in the treatment of FI and constipation.Methods Two systematic reviews of the literature (performed in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses framework) were performed to identify manuscripts pertaining to (a) clinical and (b) physiological effects of SNS during the management of hindgut dysfunction.Key ResultsThe clinical literature search revealed 161 articles, of which 53 were deemed suitable for analysis. The experimental literature search revealed 43 articles, of which nine were deemed suitable for analysis. These studies reported results of investigative techniques examining changes in cortical, gastrointestinal, colonic, rectal, and anal function.Conclusions & InferencesThe initial hypothesis that the mechanism of SNS was primarily peripheral motor neurostimulation is not supported by the majority of recent studies. Due to the large body of evidence demonstrating effects outside of the anorectum, it appears likely that the influence of SNS on anorectal function occurs at a pelvic afferent or central level.
    Neurogastroenterology and Motility 09/2014; 26(9). · 2.94 Impact Factor
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    ABSTRACT: IntroductionAlthough sacral neuromodulation (SNM) is an established treatment for faecal incontinence, stimulation parameters have been derived empirically and only one frequency (14 Hz) is employed clinically. The aim of this study was to test a range of stimulation frequencies to establish an optimal frequency of SNM for maximum augmentation of anal canal cortical evoked potentials (EPs) in an animal model.Methods In female Wistar rats, anal canal EPs were recorded over the primary somatosensory cortex using a flexible multielectrode array, and the effect of SNM was studied. SNM was applied at 0·1–100 Hz and a frequency response curve plotted. The data were fitted to a quadratic equation.ResultsThe magnitude of potentiation of anal canal EPs caused by SNM depended significantly on stimulation frequency (P < 0·001). The frequency–potentiation relationship was parabolic in form, with a clear optimum at 2 Hz. The SNM must be applied for at least 3 min. The theoretical maximal potentiation predicted by the model was not found to be statistically different to actual data recorded (P = 0·514–0·814). The response depended on stimulation amplitude in an ‘all-or-nothing’ fashion. EPs were augmented when the SNM intensity was 0·5 times the motor threshold to tail twitch or greater, but values below this intensity failed to affect the EPs.Conclusion The effect of SNM in this animal model is governed principally by frequency, with an optimum of 2 Hz. If animal data can be translated to humans, optimization of SNM frequency may offer a clinically relevant improvement in the efficacy of SNM.Surgical relevanceSacral neuromodulation (SNM) for faecal incontinence currently employs stimulation parameters that have been derived empirically and may not be optimal. This study used an animal model of SNM and focused on its acute effect on anal canal cortical evoked potentials (EPs). It was found that SNM potentiated EPs, with a clear optimum at a frequency of 2 Hz. If this finding is applicable to the mechanism of action of human SNM, this suggests that there may be a clinically relevant improvement by reducing stimulus frequency from its typical value of 14 Hz to 2 Hz.
    British Journal of Surgery 07/2014; · 4.84 Impact Factor
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    ABSTRACT: Chronic visceral pain affects millions of individuals worldwide and remains poorly understood, with current therapeutic options constrained by gastrointestinal (GI) side effects. Visceral pain is strongly associated with inflammation and distension of the gut. Here we report that the voltage-gated sodium channel subtype NaV1.9 is expressed in half of gut-projecting rodent dorsal root ganglia sensory neurons. We show that NaV1.9 is required for normal mechanosensation, for direct excitation and for sensitisation of mouse colonic afferents by mediators from inflammatory bowel disease tissues, and by noxious inflammatory mediators individually. Excitatory responses to ATP or PGE2 were substantially reduced in NaV1.9-/- mice. Deletion of NaV1.9 substantially attenuates excitation, and subsequent mechanical hypersensitivity, following application of inflammatory soup (bradykinin, ATP, histamine, PGE2 and 5HT) to visceral nociceptors located in the serosa and mesentery. Responses to mechanical stimulation of mesenteric afferents were also reduced by loss of NaV1.9 and there was a rightward shift in stimulus-response function to ramp colonic distension. By contrast, responses to rapid, high-intensity phasic distension of the colon are initially unaffected; however run-down of responses to repeat phasic distension were exacerbated in NaV1.9-/- afferents. Finally colonic afferent activation by supernatants derived from inflamed human tissue was greatly reduced in NaV1.9-/- mice. These results demonstrate that NaV1.9 is required for persistence of responses to intense mechanical stimulation, contributes to inflammatory mechanical hypersensitivity and is essential for activation by noxious inflammatory mediators including those from diseased human bowel. These observations indicate that NaV1.9 represents a high-value target for development of visceral analgesics.
    Pain 06/2014; · 5.64 Impact Factor
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    ABSTRACT: The Joint hypermobility syndrome (JHS) is a non-inflammatory connective tissue disorder with a prevalence of 20%. It is characterised by joint hypermobility,chronic pain, fibromyalgia (FM) and dysautonomia. Gastrointestinal (GI) symptoms e.g., dyspepsia, reflux, bloating and constipation are present in up to 80% of affected individuals. Small studies suggest that FGID are common in these patients yet no controlled studies have systematically investigated if JHS is associated with particular GI diagnoses nor explored the effect of JHS on non-GI symptom presentation and quality of life (QOL).
    Gut 06/2014; 63(Suppl 1):A194-A195. · 13.32 Impact Factor
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    ABSTRACT: 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.
    Gut 05/2014; · 13.32 Impact Factor
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    ABSTRACT: 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). 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). 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 77.6% sensitivity and 63.2% specificity for diagnosis of GORD+HO (likelihood ratio: 2.2). However, one positive sample with >210 ng/mL pepsin suggested presence of GORD+HO with 96% specificity (likelihood ratio: 24.4). Only 18/84 (21.4%) of GORD+HO patients had 3 negative samples. 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.
    Gut 05/2014; · 13.32 Impact Factor
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    ABSTRACT: Two types of neuromodulation are currently practised for the treatment of fecal incontinence (FI): sacral nerve stimulation (SNS) and percutaneous tibial nerve stimulation (PTNS). This study compares these therapies, as no data exist to prospectively assess their relative efficacy and costs. The subjects of this study were two distinct cohorts undergoing SNS (between 2003 and 2008) or PTNS (2008-onwards) for FI. Clinical outcomes assessed at 3 months included incontinence scores and the number of weekly incontinence episodes. The direct medical costs for each procedure were calculated from the audited expenditure of our unit. Thirty-seven patients (94.6 % women) underwent permanent SNS and 146 (87.7 % women) underwent PTNS. The mean pre-treatment incontinence score (±SD) was greater in the SNS cohort (14 ± 4 vs. 12 ± 4) and the mean post-treatment incontinence scores were similar for the two therapies (9 ± 5 vs. 10 ± 4), with a greater effect size evident in the SNS patients. In a 'pseudo case-control' analysis with 37 "matched" patients, the effect of both treatments was similar. The cost of treating a patient for 1 year was £11 374 ($18 223) for permanent SNS vs. £1740 ($2784) for PTNS. Given the lesser cost and invasive nature of PTNS, where both techniques are available, a trial of PTNS could be considered for all patients.
    Surgery Today 05/2014; · 1.21 Impact Factor
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    ABSTRACT: RPMC) in the distal colon. The 5-HT3 agonist m-CPBG and 5-HT exerted strong inhibitory effects, suggesting that the 5-HT3 antagonists have effects in addition to blocking effects of endogenous 5-HT. The fact that antagonists and agonists are all inhibitory to the most prominent propulsive activity of the colon, the neurogenic LDC, suggests a complicated receptor repertoire on inhibitory and excitatory neurons making the pharmacological applica-tion of 5-HT related compounds affecting all receptors within the whole colon difficult to interpret. Pancolonic Long Distance Contractions (LDCs; left) are inhibited and Rhythmic Propulsive Motor Complexes (RPMCs; bottom right) markedly increased in the distal colon by addition of the 5HT3 antagonist palonosetron. A similar effect is seen with 5HT4 receptor stimulation. Chronic constipation is associated with advanced age. The causes are not always clear, but reductions in human enteric nerve density with age have been observed [1]. Due to extensive enteric nerve reserve the functional significance of this observation is unknown. We report the largest recorded functional study of neuromuscular activities in human isolated colon over a wide range of ages, and compare with similar studies in mice. Macroscopically-normal colon was obtained at surgery for bowel cancer, following informed consent. Mucosa-free strips were cut parallel to circular muscles and suspended in Krebs solution for isometric recording. Electrical field stimulation (EFS) was applied at 5Hz for 10s every 1min as previously described [2]. Colonic loops (3mm wide) were prepared from female C57BL/6 mice (3 & 24 months) with 5Hz EFS applied for 30s every 2min. N=patients/mice. Tissue was obtained from 132 patients (1118 strips; 30-90 years). Strips contracted (787 strips, 70%) or relaxed during EFS (331; 30%), and a contraction on termination of EFS often followed (899 strips, 80%). Responses were abolished by tetrodotoxin 1μM (n=12). Contrac-tions during EFS were abolished (n=16), and after-contractions decreased (by 48±5%; n= 18) by atropine 1μM. These were decreased further by NK1-3 receptor antagonists (31±7%; n=11). Relaxations were abolished by the NO synthase inhibitor L-NAME 300μM (n=53). The contractions during EFS decreased with age (by 57±22 mg/g tissue/year; P=0.013; r 2 = 0.13; n=47). Similarly the % of strips which relaxed in response to EFS (≥3 strips/patient) increased with age (P=0.004; r 2 =0.08; n=132), e.g. 40% of strips >79 years of age relaxed. When separated for region and gender, the latter change was statistically significant only in the ascending colon of females (P=0.003; r 2 =0.28; n=30), although a similar trend was observed in males (P=0.06; r 2 =0.19; n=19). There were no changes in the contractions to carbachol 10μM with age (P=0.08; r 2 =0.07; n=47). In mice, EFS induced relaxations followed by after-contractions (50 proximal, 32 distal loops; n=10 3 months; n=11 24 months). In proximal colon, 5Hz EFS evoked larger responses in 3 month than 24 month old mice (31±8 g/g tissue and 16±3 g/g tissue; P<0.05; 2-way ANOVA; Bonferroni post-test; n=10, 11). This age-related effect is seen only in proximal and not distal colon. Responses to carbachol 10μM (n=10, 11) were unchanged with age in both regions. We have demonstrated that advanced age is associated with changes in the neuromuscular function of human colon. This change was only detected in the ascending colon, was more prominent in females, and is supported by findings in mice. Further studies are now required to investigate age-related structural changes. 1. Bernard CE et al.
    DDW- Digestive disease week, USA; 05/2014
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    ABSTRACT: Background: Nitric oxide (NO) is elaborated in huge amounts in acute illness and exacerbations of inflammatory bowel disease. NO acts as an inhibitory neurotransmitter by relaxation of smooth muscle cells and suggested to be of major importance in acute colonic dilatation in ulcerative colitis. The migrating motor complex (MMC) is a cyclic motility pattern aiding absorption of nutrients and propulsion of intestinal contents. When MMC is dysregulated, it constitutes a cornerstone in the diagnosis of enteric dysmotility, which can promote development of small intestinal bacterial overgrowth. Little is known on how NO works in conjunction with other neurotransmitters to regulate the motor activity of the MMC during fasting. Methods: Twenty-one healthy volunteers (22-38 years) underwent antroduodenojejunal manometry recordings for 4h after a bolus injection of either saline or the NO synthase inhibitor NG-monomethyl-L-arginine (L-NMMA, 10 mg/kg IV) with or without atropine (1mg) or ondansetron (8mg). Effects on the MMC pattern and the subsequent MMC were determined. Exhaled and rectal NO was monitored throughout the experiments. Peptide hormones ghrelin, motilin and somatostatin with known effects of the MMC were measured. Supplementary in vitro studies were done on human small bowel muscle strips with bethanechol (10-5M) in the presence of L-NMMA (10-4M) and tetrodotoxin (TTX, 10-6M). Results: L-NMMA elicited pre-mature duodeno-jejunal phase III in all subjects but one, irrespective of atropine or ondansetron. L-NMMA also shortened the MMC cycle length and shifted motility towards phase II with strong suppression of phase I of the subsequent MMC. This effect was not seen after pretreatment with atropine or ondansetron. Instead, atropine extended phase II activity of the MMC, whereas ondansetron had no effect. After administration of L-NMMA no increase of gut hormones was found. L-NMMA reduced exhaled NO levels in all subjects, whereas only 12 of 17 had reduced rectal NO. Systemic blood pressure was consistently elevated for two hours after L-NMMA. In vitro, L-NMMA enhanced bethanechol-induced contractions that were insensitive to TTX. Conclusions: NO exerts an inhibitory action on the MMC by suppressing the phase III activity independently of muscarinic and 5-HT3 receptor blockade. Furthermore, the motility intensity over the different phases of the MMC seems to be under influence of NO. Phase I of the MMC seems strongly dependent on NO, being counter-regulated by cholinergic and serotonergic mechanisms, whereas phase II is dependent on atropine-sensitive mechanisms for transition into the next phase III of MMC. The sensitization of motility by inhibition of NO is due to a direct effect on the smooth muscle cells, as neither gut peptide hormone release, nor neuronal mechanisms are related to the increased motor activity.
    Digestive Disease Week, USA; 05/2014
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    International Journal of Colorectal Disease 04/2014; 29(7). · 2.24 Impact Factor
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    ABSTRACT: Background High-resolution anorectal manometry (HRAM) is a relatively new method for collection and interpretation of data relevant to sphincteric function, and for the first time allows a global appreciation of the anorectum as a functional unit. Historically, traditional anal manometry has been plagued by lack of standardization and healthy volunteer data of variable quality. The aims of this study were: (i) to obtain normative data sets for traditional measures of anorectal function using HRAM in healthy subjects and; (ii) to qualitatively describe novel physiological phenomena, which may be of future relevance when this method is applied to patients.Methods115 healthy subjects (96 female) underwent HRAM using a 10 channel, 12F solid-state catheter. Measurements were performed during rest, squeeze, cough, and simulated defecation (push). Data were displayed as color contour plots and analysed using a commercially available manometric system (Solar GI HRM v9.1, Medical Measurement Systems). Associations between age, gender and parity were subsequently explored.Key ResultsHRAM color contour plots provided clear delineation of the high-pressure zone within the anal canal and showed recruitment during maneuvers that altered intra-anal pressures. Automated analysis produced quantitative data, which have been presented on the basis of gender and parity due to the effect of these covariates on some sphincter functions. In line with traditional manometry, some age and gender differences were seen. Males had a greater functional anal canal length and anal pressures during the cough maneuver. Parity in females was associated with reduced squeeze increments.Conclusions & InferencesThe study provides a large healthy volunteer dataset and parameters of traditional measures of anorectal function. A number of novel phenomena are appreciated, the significance of which will require further analysis and comparisons with patient populations.
    Neurogastroenterology and Motility 03/2014; · 2.94 Impact Factor
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    ABSTRACT: Interpretation of evacuation proctography (EP) images is reliant on robust normative data. Previous studies of EP in asymptomatic subjects have been methodologically limited. The aim of this study was to provide parameters of normality for both genders using EP. EP was prospectively performed on 46 healthy volunteers (28 females). Proctograms were independently analysed by two reviewers. All established and some new variables of defaecatory structure and function were assessed objectively: anorectal dimensions, anorectal angle changes, evacuation time, percentage contrast evacuated and incidence of rectal wall morphological 'abnormalities'. Normal ranges were calculated for all main variables. Mean end evacuation time was 88 sec (CI 63-113) in males and 128 sec (98-158) in females; percentage contrast evacuated was 71% (63-80) in males and 65% (58-72) in females. 26 / 28 female subjects (93%) had a rectocoele with a mean depth of 2.5 cm (upper limit 3.9 cm). Recto-rectal intussusception was a finding in 9 subjects (approximately 20% of both genders); however, recto-anal intussusception was not observed. Only rectal diameter differed significantly between genders. Qualitatively, three patterns of evacuation were present. This study defines normal ranges for anorectal dimensions and parameters of emptying as well as the incidence and characteristics of rectal wall 'abnormalities' observed or derived from EP. These ranges can be applied clinically for subsequent disease comparison. This article is protected by copyright. All rights reserved.
    Colorectal Disease 02/2014; · 2.02 Impact Factor
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    ABSTRACT: Two forms of tibial nerve stimulation are used to treat faecal incontinence (FI): percutaneous (PTNS) and transcutaneous (TTNS) tibial nerve stimulation. This article critically appraises the literature on both procedures. A systematic review was performed adhering to the PRISMA framework. A comprehensive literature search was conducted, with systematic methodological quality assessment and data extraction. Summary measures for individual outcome variables are reported. Twelve articles met eligibility criteria; six related to PTNS, five to TTNS, and one to both procedures. These included ten case series and two randomized clinical trials (RCTs). Case series were evaluated using the National Institute for Health and Care Excellence quality assessment for case series, scoring 3-6 of 8. RCTs were evaluated using the Jadad score, scoring 4 of a possible 5 marks, and the Cochrane Collaboration bias assessment tool. From one RCT and case series reports, the success rate of PTNS, based on the proportion of patients who achieved a reduction in weekly FI episodes of at least 50 per cent, was 63-82 per cent, and that of TTNS was 0-45 per cent. In an RCT of TTNS versus sham, no patient had a reduction in weekly FI episodes of 50 per cent or more, whereas in an RCT of PTNS versus TTNS versus sham, 82 per cent of patients undergoing PTNS, 45 per cent of those having TTNS, and 13 per cent of patients in the sham group had treatment success. PTNS and TTNS result in significant improvements in some outcome measures; however, TTNS was not superior to sham stimulation in a large, adequately powered, RCT. As no adequate RCT of PTNS versus sham has been conducted, conclusions cannot be drawn regarding this treatment.
    British Journal of Surgery 01/2014; · 4.84 Impact Factor
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    ABSTRACT: The Joint Hypermobility Syndrome (JHS) is a common connective tissue disorder characterised by joint hyperflexibility, dysautonomia and chronic pain. Gastrointestinal (GI) symptoms are reported in JHS patients attending rheumatology clinics but the prevalence and symptom pattern of previously undiagnosed JHS in GI clinics is unknown. Using validated questionnaires, a prospective cross-sectional study in secondary care GI clinics estimated the prevalence of JHS in new consecutively referred patients, compared GI symptoms in patients with and without JHS, and using multiple regression determined whether the burden of GI symptoms in JHS patients was dependent on chronic pain, autonomic, psychological and medication related factors. A positive control group consisted of JHS patients referred from rheumatology clinics with GI symptoms (JHS-Rh). From 552 patients recruited, 180 (33%) had JHS (JHS-G) and 372 did not (Non-JHS-G). 44 JHS-Rh patients were included. JHS-G patients were more likely to be younger, female with poorer quality of life (p=0.02) than non-JHS-G patients. Following age and sex matching, heartburn (OR1.66, CI 1.1-2.5 p=0.01), waterbrash (OR: 2.02, CI: 1.3-3.1, p=0.001) and postprandial fullness (OR 1.74, CI 1.2-2.6 p=0.006) were commoner in JHS-G vs. Non-JHS-G. Many upper and lower GI symptoms increased with increasing severity of JHS phenotype. Upper GI symptoms were dependent on autonomic and chronic pain factors. JHS is common in GI clinics, with increased burden of upper GI and extraintestinal symptoms and poorer quality of life. Recognition of JHS will facilitate multidisciplinary management of GI and extra-GI manifestations.
    Clinical gastroenterology and hepatology: the official clinical practice journal of the American Gastroenterological Association 01/2014; · 5.64 Impact Factor
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    ABSTRACT: Rectal intussusception and external rectal prolapse are uncommon proctographic findings in men reflecting the lack of studies investigating such patients. The aim of this study was to identify the demographic, clinical, and physiological characteristics of this population with a view to appreciate the mechanism of development of this condition. All men, presenting with symptoms of constipation or fecal incontinence, who were diagnosed proctographically with recto-rectal intussusception (RRI)/recto-anal intussusception (RAI) or external rectal prolapse (ERP) between 1994 and 2007 at a tertiary academic colorectal unit were studied. Demographics, relevant comorbidities, distribution and symptom duration, and anorectal physiology results were analyzed retrospectively for each proctographic group and intergroup comparisons performed. Two hundred five men (median age 50 y; range, 13-86) including 155 (75.6%) without any relevant comorbidities were studied. A significant proportion of patients in all proctographic groups reported rectal evacuatory difficulty ([RRI, 46.4%], [RAI, 39.4%], [ERP, 44.8%]; P = 0.38,analysis of variance). Patients also reported a combination of fecal incontinence symptoms (e.g., urge, passive, postdefecatory leakage) that did not differ across the proctographic groups. Anorectal physiological parameters were within normal range and were not found to be statistically different between the proctographic groups with the exception of anal resting pressure, which was lowest in ERP patients (62 cm H2O; range, 14-155) compared with patients with RRI (89 cm H2O; range, 16-250; P = 0.003) and RAI (92 cm H2O; range, 38-175; P = 0.006). Men with rectal intussusception and prolapse present with a combination of symptoms, predominantly defective rectal evacuation. Anorectal physiological assessment has failed to shed light into the mechanism of development of this condition and thus, the need for large observational studies incorporating integrated defecographic and manometric assessments of the evacuation process.
    Journal of Surgical Research 12/2013; · 2.12 Impact Factor
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    ABSTRACT: Despite chronic pain being a feature of functional chest pain (FCP) its experience is variable. The factors responsible for this variability remain unresolved. We aimed to address these knowledge gaps, hypothesizing that the psychophysiological profiles of FCP patients will be distinct from healthy subjects. 20 Rome III defined FCP patients (nine males, mean age 38.7 years, range 28-59 years) and 20 healthy age-, sex-, and ethnicity-matched controls (nine males, mean 38.2 years, range 24-49) had anxiety, depression, and personality traits measured. Subjects had sympathetic and parasympathetic nervous system parameters measured at baseline and continuously thereafter. Subjects received standardized somatic (nail bed pressure) and visceral (esophageal balloon distension) stimuli to pain tolerance. Venous blood was sampled for cortisol at baseline, post somatic pain and post visceral pain. Patients had higher neuroticism, state and trait anxiety, and depression scores but lower extroversion scores vs controls (all p < 0.005). Patients tolerated less somatic (p < 0.0001) and visceral stimulus (p = 0.009) and had a higher cortisol at baseline, and following pain (all p < 0.001). At baseline, patients had a higher sympathetic tone (p = 0.04), whereas in response to pain they increased their parasympathetic tone (p ≤ 0.008). The amalgamating the data, we identified two psychophysiologically distinct 'pain clusters'. Patients were overrepresented in the cluster characterized by high neuroticism, trait anxiety, baseline cortisol, pain hypersensitivity, and parasympathetic response to pain (all p < 0.03). In future, such delineations in FCP populations may facilitate individualization of treatment based on psychophysiological profiling.
    Neurogastroenterology and Motility 10/2013; · 2.94 Impact Factor
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    ABSTRACT: Over the past 18 years neuromodulation therapies have gained support as treatments for faecal incontinence (FI); sacral nerve stimulation (SNS) is the most established of these. A systematic review was performed of current evidence regarding the clinical effectiveness of neuromodulation treatments for FI. The review adhered to the PRISMA framework. A comprehensive search of the literature included PubMed, MEDLINE, Embase and Evidence-Based Medicine Reviews. Methodological quality assessment and data extraction were completed in a systematic fashion. For SNS, 321 citations were identified initially, of which 61 studies were eligible for inclusion. Of studies on other neuromodulation techniques, 11 were eligible for review: seven on percutaneous tibial nerve stimulation (PTNS) and four on transcutaneous tibial nerve stimulation (TTNS). On intention-to-treat, the median (range) success rates for SNS were 63 (33-66), 58 (52-81) and 54 (50-58) per cent in the short, medium and long terms respectively. The success rate for PTNS was 59 per cent at the longest reported follow-up of 12 months. SNS, PTNS and TTNS techniques also resulted in improvements in Cleveland Clinic Incontinence Score and quality-of-life measures. Despite significant use of neuromodulation in treatment of FI, there is still no consensus on outcome reporting in terms of measures used, aetiologies assessed, length of follow-up or assessment standards. Emerging data for SNS suggest maintenance of its initial therapeutic effect into the long term. The clinical effectiveness of PTNS is comparable to that of SNS at 12 months, although there is no evidence to support its continued effectiveness after this period. PTNS may be a useful treatment before SNS. The clinical effectiveness of TTNS is still uncertain owing to the paucity of available evidence. A consensus to standardize the use of outcome measures is recommended in order that further reports can be compared meaningfully.
    British Journal of Surgery 10/2013; 100(11):1430-47. · 4.84 Impact Factor
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    ABSTRACT: Cholinesterase inhibitors such as neostigmine are used for acute colonic pseudo-obstruction, but cardio-bronchial side-effects limit use. To minimise side-effects, lower doses could be combined with a 5-HT4 receptor agonist, which also facilitates intestinal cholinergic activity. However, safety concerns, especially in the elderly, require drugs with good selectivity of action. These include the acetylcholinesterase inhibitor donepezil (used for Alzheimer's disease, with reduced cardio-bronchial liability) and prucalopride, the first selective, clinically-available 5-HT4 receptor agonist. This study examined their individual and potential synergistic activities in human colon. Neuronally-mediated muscle contractions and relaxations of human colon were evoked by electrical field stimulation (EFS) and defined phenotypically as cholinergic, nitrergic or tachykinergic using pharmacological tools; the effects of drugs were determined as changes in 'area under the curve'. Prucalopride increased cholinergically-mediated contractions (EC50 855 nM; 33% maximum increase), consistent with its ability to stimulate intestinal motility; donepezil (477%) and neostigmine (2326%) had greater efficacy. Concentrations of donepezil (30-100 nM) found in venous plasma after therapeutic doses had minimal ability to enhance cholinergic activity. However, donepezil (30 nM) together with prucalopride (3, 10 μM) markedly increased EFS-evoked contractions compared to prucalopride alone (P=0.04). For example, the increases observed with donepezil and prucalopride 10 μM together or alone were, respectively, 105 ± 35%, 4 ± 6% and 35 ± 21% (n=3-7, each concentration). Potential synergy between prucalopride and donepezil activity calls for exploration of this combination as a safer, more effective treatment of colonic pseudo-obstruction.
    British Journal of Pharmacology 09/2013; · 5.07 Impact Factor

Publication Stats

2k Citations
920.96 Total Impact Points

Institutions

  • 2003–2014
    • Queen Mary, University of London
      • • Centre for Digestive Diseases
      • • The Blizard Institute of Cell and Molecular Science
      Londinium, England, United Kingdom
  • 2008–2013
    • University of London
      • The London School of Medicine and Dentistry
      Londinium, England, United Kingdom
  • 2010
    • Homerton University Hospital NHS Foundation Trust
      Londinium, England, United Kingdom
  • 2006
    • Barts Health NHS Trust
      Londinium, England, United Kingdom