Charles H Knowles

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

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Publications (108)851.8 Total impact

  • Gastroenterology 04/2015; 148(4):S-177. DOI:10.1016/S0016-5085(15)30591-6 · 13.93 Impact Factor
  • Gastroenterology 04/2015; 148(4):S-304. DOI:10.1016/S0016-5085(15)31003-9 · 13.93 Impact Factor
  • Gastroenterology 04/2015; 148(4):S-305. DOI:10.1016/S0016-5085(15)31004-0 · 13.93 Impact Factor
  • Gastroenterology 04/2015; 148(4):S-924-S-925. DOI:10.1016/S0016-5085(15)33143-7 · 13.93 Impact Factor
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    ABSTRACT: The diagnostic accuracy of anorectal manometry (AM), which is necessary to diagnose functional defecatory disorders (FDD), is unknown. Using blinded analysis and standardised reporting of diagnostic accuracy, we evaluated whether AM could discriminate between asymptomatic controls and patients with functional constipation (FC). Derived line plots of anorectal pressure profiles during simulated defecation were independently analysed in random order by three expert observers blinded to health status in 85 women with FC and 85 age-matched asymptomatic healthy volunteers (HV). Using accepted criteria, these pressure profiles were characterised as normal (ie, increased rectal pressure coordinated with anal relaxation) or types I-IV dyssynergia. Interobserver agreement and diagnostic accuracy were determined. Blinded consensus-based assessment disclosed a normal pattern in 16/170 (9%) of all participants and only 11/85 (13%) HV. The combined frequency of dyssynergic patterns (I-IV) was very similar in FC (80/85 (94%)) and HV (74/85 (87%)). Type I dyssynergia ('paradoxical' contraction) was less prevalent in FC (17/85 (20%) than in HV (31/85 (36.5%), p=0.03). After statistical correction, only type IV dyssynergia was moderately useful for discriminating between FC (39/85 (46%)) and HV (17/85 (20%)) (p=0.001, positive predictive value=70.0%, positive likelihood ratio=2.3). Interobserver agreement was substantial or moderate for identifying a normal pattern, dyssynergia types I and IV, and FDD, and fair for types II and III. While the interpretation of AM patterns is reproducible, nearly 90% of HV have a pattern that is currently regarded as 'abnormal' by AM. Hence, AM is of limited utility for distinguishing between FC and HV. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to
    Gut 03/2015; DOI:10.1136/gutjnl-2014-308835 · 13.32 Impact Factor
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    Annals of surgery 09/2014; 261(1). DOI:10.1097/SLA.0000000000000887 · 7.19 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; 155(10). DOI:10.1016/j.pain.2014.06.015 · 5.84 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. DOI:10.1136/gutjnl-2014-307263.420 · 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; 64(4). DOI:10.1136/gutjnl-2013-306698 · 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; 64(3). DOI:10.1136/gutjnl-2014-307049 · 13.32 Impact Factor
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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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    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: 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; 44(11). DOI:10.1007/s00595-014-0898-0 · 1.21 Impact Factor
  • Gastroenterology 05/2014; 146(5):S-722. DOI:10.1016/S0016-5085(14)62619-6 · 13.93 Impact Factor
  • Gastroenterology 05/2014; 146(5):S-714. DOI:10.1016/S0016-5085(14)62593-2 · 13.93 Impact Factor
  • Gastroenterology 05/2014; 146(5):S-264. DOI:10.1016/S0016-5085(14)60932-X · 13.93 Impact Factor
  • Rebecca Burgell, Charles H. Knowles, S. Mark Scot
    Gastroenterology 05/2014; 146(5):S-355. DOI:10.1016/S0016-5085(14)61283-X · 13.93 Impact Factor
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    International Journal of Colorectal Disease 04/2014; 29(7). DOI:10.1007/s00384-014-1874-2 · 2.42 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; 16(7). DOI:10.1111/codi.12595 · 2.02 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; 12(10). DOI:10.1016/j.cgh.2014.01.014 · 6.53 Impact Factor

Publication Stats

1k Citations
851.80 Total Impact Points


  • 1997–2015
    • Queen Mary, University of London
      • • Barts and The London School of Medicine and Dentistry
      • • The Blizard Institute of Cell and Molecular Science
      Londinium, England, United Kingdom
  • 2006–2014
    • Barts Health NHS Trust
      Londinium, England, United Kingdom
  • 2008–2013
    • University of London
      Londinium, England, United Kingdom
  • 2009
    • The Peninsula College of Medicine and Dentistry
      Plymouth, England, United Kingdom
  • 2004
    • Queen Mary Hospital
      Hong Kong, Hong Kong
  • 2002
    • University of Milan
      Milano, Lombardy, Italy
  • 2000
    • Royal College of Surgeons of England
      Londinium, England, United Kingdom