Charles H Knowles

University of London, Londinium, England, United Kingdom

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Publications (199)1538.72 Total impact

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    ABSTRACT: Background: Inflammatory bowel disease, comprising Crohn's disease and ulcerative colitis, is a life-long currently incurable illness. It causes bouts of acute intestinal inflammation, in an unpredictable relapsing-remitting course, with bloody diarrhoea and extreme urgency to access a toilet. Faecal incontinence is a devastating social and hygiene problem, impacting heavily on quality of life and ability to work and socialise. Faecal incontinence affects 2-10 % of adults in the general population. People with inflammatory bowel disease have a high risk of incontinence with up to 74 % affected. No previous study has explored conservative interventions for these patients. Methods: This randomised controlled trial will recruit 186 participants to answer the research question: does implementation of the UK nationally recommended guidance approach to stepwise management of faecal incontinence improve bowel control and quality of life in people with inflammatory bowel disease? We have worked with people with inflammatory bowel disease to translate this guidance into a condition-specific information booklet on managing incontinence. We will randomise participants to receive the booklet, or the booklet plus up to four 30-minute sessions with an inflammatory bowel disease specialist nurse. To be eligible, patients must be in disease remission and report incontinence. The primary outcome measure at 6 months after randomisation is the St Mark's incontinence score. Other outcomes include quality of life, MY-MOP (generic tool: participants set two goals for intervention, grading goals at baseline and then re-scoring after intervention) and EQ-5D-5 L to enable calculation of quality-adjusted life years. Analysis will be on an intention-to-treat basis. Qualitative interviews will explore participant and health professionals' views on the interventions. Discussion: Few high-quality studies of conservative interventions in inflammatory bowel disease, and none for faecal incontinence, have been conducted. We have collaborated with patients to design this study. Blinding to this behavioural intervention is not possible, but our self-report outcome measures with a degree of objectivity. There is genuine equipoise between the booklet only and booklet plus nurse arms, and the study will determine if additional support from a nurse is a crucial element in implementing advice. Trial registration: NCT02355834 (Date of registration: 12 December 2014). Protocol version: 4.0. 08.04.15.
    Trials 10/2015; 16(1):444. DOI:10.1186/s13063-015-0962-0 · 1.73 Impact Factor
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    ABSTRACT: Background: Normal defaecation involves activation of anorectal mechanoreceptors responsive to pressure and stretch. The aim of this study was to develop selective anal and rectal mucosal light-touch stimulation suitable for measurement of cortical evoked potentials (EPs) in order to explore the sensory arm of these pathways. New method: A novel device was manufactured to deliver selective rectal and/or anal light-touch stimulation using a shielded inter-dental brush mounted on a rotating stepper motor (1Hz, 1ms, 15(o)rotation). Resultant somatosensory EPs recorded with a 32-channel cortical multi-electrode array were compared to those elicited by electrical anorectal stimulation (2mm anal plug electrode [1Hz, 1ms, 10V]). Results: Eighteen anaesthetised female Wistar rats (body mass 180-250g) were studied. Electrical and mechanical stimulation provoked similar maximal response amplitudes (electrical anorectal 39.0μV[SEM 5.5], mechanical anal 42.2μV[8.1], mechanical rectal 45.8μV[9.0]). Response latency was longer following mechanical stimulation (electrical anorectal 8.8ms[0.5], mechanical anal 16.4ms[1.1], mechanical rectal 18.3ms[2.5]). The extent of activated sensory cortex was smaller for mechanical stimulation. Sensory inferior rectal nerve activity was greater during anal compared to rectal mechanical in a subgroup of 4 rats. Evoked potentials were reproducible over 40min in a subgroup of 9 rats. Comparison with existing methods: Cortical EPs are typically recorded in response to non-physiological electrical stimuli. The use of a mechanical stimulus may provide a more localised physiological method of assessment. Conclusions: To the authors' knowledge these are the first selective brush-elicited anal and rectal EPs recorded in animals and provide a physiological approach to testing of anorectal afferent pathways.
    Journal of Neuroscience Methods 09/2015; 256. DOI:10.1016/j.jneumeth.2015.09.006 · 2.05 Impact Factor
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    ABSTRACT: Background: Fecal incontinence is a socially disabling condition that affects ≤15% of adults. Neuromodulatory treatments for fecal incontinence are now well established. Less invasive, cheaper, and more ambulatory forms of neuromodulation are under exploration. Objective: The purpose of this study was to assess the acceptability and safety of a new ambulatory tibial nerve stimulation device and to determine clinical effect size for 2 differing regimens of therapy. Design: This was a randomized, investigator-blinded, parallel-arm, 6-week pilot trial. Settings: The study was conducted at 7 United Kingdom trial centers. Patients were initially reviewed in the trial center, with subsequent applications of the device performed in the patients home setting. Patients: A total of 43 eligible patients (38 women) who failed conservative management of fecal incontinence were included in the study. Intervention: The study intervention involved twice-weekly, 1- versus 4-hour transcutaneous tibial nerve stimulation for 6 weeks (total of 12 treatments). Main outcome measures: Standard fecal incontinence outcome tools (bowel diary, symptom severity score, and generic quality-of-life instruments) were used to collect data at baseline and at 2 weeks posttreatment cessation. Results: A total of 22 patients were randomly assigned to the 1-hour group and 21 to the 4-hour group. Improvements in fecal incontinence outcomes were observed for both groups, including median urge incontinence episodes per week at baseline and posttreatment (1-hour group 2.0 to 0.5 versus 4-hour group 4.0 to 1.0) and deferment time (1-hour group 2.0 to 2.0 minutes versus 4-hour group 0.5 to 5.0 minutes). Accompanying changes were observed in physical functioning domains of quality-of-life instruments. There were no adverse events, and the treatment was highly acceptable to patients. Limitations: Limitations included the pilot design and lack of control arm in the study. Future trials would need to address these limitations. Conclusions: This pilot study provides evidence that transcutaneous tibial nerve stimulation with a new ambulatory device is safe and acceptable for the management of fecal incontinence. Additional study is warranted to investigate clinical effectiveness.
    Diseases of the Colon & Rectum 09/2015; 58(10):974-982. DOI:10.1097/DCR.0000000000000444 · 3.75 Impact Factor
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    ABSTRACT: Faecal incontinence (FI) is a common condition which is often under-reported. It is distressing for those suffering from it, impacting heavily on their quality of life. When conservative strategies fail, treatment options are limited. Percutaneous tibial nerve stimulation (PTNS) is a minimally invasive outpatient treatment, shown in preliminary case series to have significant effectiveness; however, no randomised controlled trial has been conducted. Objectives To assess the effectiveness of PTNS compared with sham electrical stimulation in the treatment of patients with FI in whom initial conservative strategies have failed. Design Multicentre, parallel-arm, double-blind randomised (1 : 1) controlled trial. Setting Eighteen UK centres providing specialist nurse-led (or equivalent) treatment for pelvic floor disorders. Participants Participants aged > 18 years with FI who have failed conservative treatments and whose symptoms are sufficiently severe to merit further intervention. Interventions PTNS was delivered via the Urgent ® PC device (Uroplasty Limited, Manchester, UK), a hand-held pulse generator unit, with single-use leads and fine-needle electrodes. The needle was inserted near the tibial nerve on the right leg adhering to the manufacturer’s protocol (and specialist training). Treatment was for 30 minutes weekly for a duration of 12 treatments. Validated sham stimulation involved insertion of the Urgent PC needle subcutaneously at the same site with electrical stimulation delivered to the distal foot using transcutaneous electrical nerve stimulation. Main outcome measures Outcome measures were assessed at baseline and 2 weeks following treatment. Clinical outcomes were derived from bowel diaries and validated, investigator-administered questionnaires. The primary outcome classified patients as responders or non-responders, with a responder defined as someone having achieved ≥ 50% reduction in weekly faecal incontinence episodes (FIEs). Results In total, 227 patients were randomised from 373 screened: 115 received PTNS and 112 received sham stimulation. There were 12 trial withdrawals: seven from the PTNS arm and five from the sham arm. Missing data were multiply imputed. For the primary outcome, the proportion of patients achieving a ≥ 50% reduction in weekly FIEs was similar in both arms: 39 in the PTNS arm (38%) compared with 32 in the sham arm (31%) [odds ratio 1.28, 95% confidence interval (CI) 0.72 to 2.28; p = 0.396]. For the secondary outcomes, significantly greater decreases in weekly FIEs were observed in the PTNS arm than in the sham arm (beta –2.3, 95% CI –4.2 to –0.3; p = 0.02), comprising a reduction in urge FIEs ( p = 0.02) rather than passive FIEs ( p = 0.23). No significant differences were found in the St Mark’s Continence Score or any quality-of-life measures. No serious adverse events related to treatment were reported. Conclusions PTNS did not show significant clinical benefit over sham electrical stimulation in the treatment of FI based on number of patients who received at least a 50% reduction in weekly FIE. It would be difficult to recommend this therapy for the patient population studied. Further research will concentrate on particular subgroups of patients, for example those with pure urge FI. Trial registration Current Controlled Trials ISRCTN88559475. Funding This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol. 19, No. 77. See the NIHR Journals Library website for further project information.
    Health technology assessment (Winchester, England) 09/2015; 19(77):1-164. DOI:10.3310/hta19770 · 5.03 Impact Factor
  • Mohamed A Thaha · Amin A Abukar · Noel N Thin · Anthony Ramsanahie · Charles H Knowles ·
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    ABSTRACT: Background: Faecal incontinence (FI) and constipation are both socially-embarrassing and physically-disabling conditions that impair quality of life. For both, surgery may be required in a minority of people when more conservative measures fail. However, the invasiveness and irreversible nature of direct surgery on bowel and sphincter muscles, poor long-term outcomes and well-established compIications makes such procedures unappealing for these benign conditions. A less-invasive surgical option to treat faecal incontinence and constipation is direct, low-voltage stimulation of the sacral nerve roots, termed sacral nerve stimulation (SNS). SNS has become the first line surgical treatment for FI in people failing conservative therapies. Its value in the treatment of constipation is less clear. Objectives: To assess the effects of sacral nerve stimulation using implanted electrodes for the treatment of faecal incontinence and constipation in adults. Search methods: We searched the Cochrane Incontinence Group Specialised Register, which contains trials identified from the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, MEDLINE In-Process,, the World Health Organization (WHO) ICTRP and handsearched journals and conference proceedings (searched 5 February 2015), EMBASE (1 January 1947 to 2015 Week 5), and the reference lists of retrieved relevant articles. Selection criteria: All randomised or quasi-randomised trials assessing the effects of SNS for faecal incontinence or constipation in adults. Data collection and analysis: Two review authors independently screened the search results, assessed the methodological quality of the included trials, and undertook data extraction. Main results: Six crossover trials and two parallel group trials were included.Six trials assessed the effects of SNS for FI. In the parallel group trial conducted by Tjandra, 53 participants with severe FI in the SNS group experienced fewer episodes of faecal incontinence compared to the control group who received optimal medical therapy (mean difference (MD) -5.20, 95% confidence interval (CI) -9.15 to -1.25 at 3 months; MD -6.30, 95% CI -10.34 to -2.26 at 12 months). Adverse events were reported in a proportion of participants: pain at implant site (6%), seroma (2%) and excessive tingling in the vaginal region (9%).In the parallel group trial carried out by Thin, 15 participants with FI in the SNS group experienced fewer episodes of FI compared with the percutaneous tibial nerve stimulation (PTNS) group (MD -3.00, 95% CI -6.61 to 0.61 at 3 months; MD -3.20, 95% CI -7.14 to 0.74 at 12 months). Adverse events were reported in three participants: mild ipsilateral leg pain during temporary testing (n = 1); and stimulator-site pain following insertion of neurostimulator (n = 2).In the crossover trial by Leroi 7 of 34 recruited participants were excluded from the crossover due mainly to complications or immediate device failure. Twenty-four of the remaining 27 participants while still blinded chose the period of stimulation they had preferred. Outcomes were reported separately for 19 participants who preferred the 'on' and five who preferred the 'off' period. For the group of 19, the median (range) episodes of faecal incontinence per week fell from 1.7 (0 to 9) during the 'off' period to 0.7 (0 to 5) during the 'on' period; for the group of five, however, the median (range) rose from 1.7 (0 to 11) during the 'off' period compared with 3.7 (0 to 11) during the 'on' period. Four of 27 participants experienced an adverse event resulting in removal of the stimulator.In the crossover trial by Sørensen and colleagues, participants did not experience any FI episodes in either the one-week 'on' or 'off' periods.In the crossover trial by Vaizey, participants reported an average of six, and one, episodes of faecal incontinence per week during the 'off' and 'on' periods respectively in two participants with FI. Neither study reported adverse events.In the crossover trial by Kahlke, 14 participants with FI experienced significantly lower episodes of FI per week during the stimulator 'on' (1 (SD, 1.7)) compared with the 'off' period (8.4 (SD, 8.7)). Adverse events reported include: haematoma formation (n = 3); misplacement of tined lead (1); and pain at stimulator site (n = 1).Two trials assessed SNS for constipation. In the Kenefick trial, the two participants experienced an average of two bowel movements per week during the 'off' crossover period, compared with five during the 'on' period. Abdominal pain and bloating occurred 79% of the time during the 'off' period compared with 33% during the 'on' period. No adverse events occurred. In contrast, in the trial by Dinning with 59 participants, SNS did not improve frequency of bowel movements and 73 adverse events were reported, which included pain at site of the implanted pulse generator (32), wound infection (12), and urological (17) events. Authors' conclusions: The limited evidence from the included trials suggests that SNS can improve continence in a proportion of patients with faecal incontinence. However, SNS did not improve symptoms in patients with constipation. In addition, adverse events occurred in some patients where these were reported. Rigorous high quality randomised trials are needed to allow the effects of SNS for these conditions to be assessed with more certainty.
    Cochrane database of systematic reviews (Online) 08/2015; DOI:10.1002/14651858.CD004464.pub3 · 6.03 Impact Factor
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    ABSTRACT: 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. 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. 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). 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). National Institute for Health Research. Copyright © 2015 Elsevier Ltd. All rights reserved.
    The Lancet 08/2015; DOI:10.1016/S0140-6736(15)60314-2 · 45.22 Impact Factor

  • Gut 06/2015; 64(Suppl 1):A4.1-A4. DOI:10.1136/gutjnl-2015-309861.7 · 14.66 Impact Factor
  • V Kung · J Broad · M Machesney · M Thaha · C Knowles · G Sanger ·
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    ABSTRACT: Introduction Preoperative chemoradiotherapy may impair anorectal functions. Its effect on neuromuscular functions was investigated in human rectum ex-vivo. Method Following informed consent, 3 groups of patients undergoing surgery for anorectal cancer were studied: 13 patients treated by surgery alone (Group I); 13 with long course neoadjuvant chemoradiotherapy (capecitabine) (Group II); and 4 with prior platinum-based chemoradiotherapy (oxaliplatin/capecitabine n = 2, FOLFOX/capecitabine n = 1, carboplatin/paclitaxel n = 1) (Group III). Age and gender were similar between Group I and II. Group III [55 (range=51–60)] were younger than Group I [72 (range=50–87)]. Postoperatively, macroscopically-normal rectum (without taenia) was obtained 5–10cm away from tumour. Mucosa-free circular muscle strips were suspended in tissue baths for isometric recording and electrical field stimulation (EFS, 1–20Hz, 50V, 0.5ms, for 10s) applied.1Data are expressed as median (inter-quartile range) and analysed using ANOVA with multiple comparison post-tests. Results EFS usually caused contraction (or relaxation at low frequencies), often followed by an ‘after-contraction’ on termination. Amplitudes of contractions during and after EFS, and area under curve (AUC) of the full muscle movement increased with frequency (see table). Contractions were abolished by atropine 1 µM and tachykinin (NK1–3) receptor antagonists (n = 4) and greatly reduced by the neurotoxin tetrodotoxin 1 µM (n = 2). All parameters of the movements evoked by EFS at all frequencies [AUC, amplitude of responses during EFS and after EFS] were similar amongst the 3 groups. There were no significant differences in tension generated by carbachol 10 µM (maximally-effective concentration) between groups (see Table 1, P > 0.05 for all measurements). Conclusion In this pilot study, preoperative chemoradiotherapy with capecitabine or platinum-based agents does not appear to have short-term effects on human rectal neuromuscular function. Reported impairment of anorectal function may be due to its long term effects or via other mechanisms. Disclosure of interest V. Kung Grant/ Research Support from: AgeUK PhD studentship, Barts and the London Charity, J. Broad: None Declared, M. Machesney: None Declared, M. Thaha: None Declared, C. Knowles: None Declared, G. Sanger Grant/ Research Support from: Takeda. Reference
    Gut 06/2015; 64(Suppl 1):A527.1-A527. DOI:10.1136/gutjnl-2015-309861.1152 · 14.66 Impact Factor
  • E Dimidi · L Dibley · N Cotterill · CH Knowles · SM Scott · K Whelan · C Norton ·

    Gut 06/2015; 64(Suppl 1):A142.2-A143. DOI:10.1136/gutjnl-2015-309861.296 · 14.66 Impact Factor

  • Gastroenterology 04/2015; 148(4):S-304. DOI:10.1016/S0016-5085(15)31003-9 · 16.72 Impact Factor

  • Gastroenterology 04/2015; 148(4):S-305. DOI:10.1016/S0016-5085(15)31004-0 · 16.72 Impact Factor

  • Gastroenterology 04/2015; 148(4):S-924-S-925. DOI:10.1016/S0016-5085(15)33143-7 · 16.72 Impact Factor
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    ABSTRACT: AimSacral nerve stimulation (SNS) may be offered to patients with constipation who have failed to improve with conservative treatment. The response to SNS is variable with a significant loss of efficacy in some patients. An increased frequency of stimulation may improve the efficacy of SNS for faecal incontinence. This study aimed to see if alteration of the pulse width or frequency improved the outcome for those with constipation.Method Eleven patients with constipation currently being treated by SNS were recruited from three centres. They were randomised to five different protocols of stimulation each applied for five weeks. Group 1 used standard settings (pulse width 210 μsec, frequency 14 Hz) and in the other four (Groups 2-5), the pulse width and/or frequency were halved or doubled. Patients and investigators were blinded to the group allocation.ResultsThe Cleveland Clinic constipation score varied significantly between the five groups. Group 1 achieved the lowest score mean (±SD) 13.4 (±4.4) [p=0.03]. The number of digitations per defecation was the lowest in Group 4, 90 μsec and 14Hz (p<0.01). No other variable changed significantly. Standard settings were the most preferred by the recruited patients.Conclusion Alteration of pulse width or frequency of stimulation had no significant effect on the outcome of SNS for constipation.This article is protected by copyright. All rights reserved.
    Colorectal Disease 04/2015; 17(11). DOI:10.1111/codi.12982 · 2.35 Impact Factor
  • A. Fikree · R. Aktar · R. Grahame · A. J. Hakim · J. K. Morris · C. H. Knowles · Q. Aziz ·
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    ABSTRACT: Background The overlap of unexplained gastrointestinal (GI) and somatic symptoms is well established in patients with functional gastrointestinal disorders (FGID). Joint hypermobility syndrome (JHS) is a non-inflammatory connective tissue disorder associated with GI and somatic symptoms. We aimed to determine whether there is an association between diagnosis of JHS and FGID and the impact of this association on comorbidities and quality of life (QOL).Methods Prospective case–control study in secondary care GI clinics over 2 years. JHS was assessed by the first author prior to consultation in 641 consecutive new patients. Diagnosis of FGID (cases, n = 336) or organic disorders (controls, n = 305) was established blind to JHS status. JHS prevalence was compared in cases (FGID patients) and controls (organic disorders patients). Extra-intestinal comorbidity and QOL were compared in FGID patients with and without JHS.Key ResultsJHS prevalence was higher in FGID compared to organic GI disorders (39.0% vs 27.5%, ORadj: 1.51, CI: 1.07–2.12, p = 0.02), and particularly associated with functional gastroduodenal disorders (44.1%, ORadj: 2.08, CI: 1.25–3.46, p = 0.005), specifically postprandial distress syndrome (51%, ORadj: 1.99, CI: 1.06–3.76, p = 0.03). FGID patients with JHS had increased chronic pain (23.2% vs 11.9%, p = 0.01), fibromyalgia (10.5% vs 3.1%, p = 0.01), somatization scores (13 vs 10, p < 0.001), urinary autonomic scores (30.5 vs 20.7, p = 0.03), and worse pain-related QOL scores (45.0 vs 63.5, p = 0.004).Conclusions & InferencesJHS is significantly associated with FGID, and this subgroup of patients have increased comorbidity and decreased QOL. Further research is required to understand the pathophysiological basis of this association.
    Neurogastroenterology and Motility 04/2015; 27(4). DOI:10.1111/nmo.12535 · 3.59 Impact Factor

  • Gastroenterology 04/2015; 148(4):S-177. DOI:10.1016/S0016-5085(15)30591-6 · 16.72 Impact Factor
  • D C Bulmer · C A Botha · A Wheeldon · K Grey · C A Mein · K Lee · C H Knowles · W J Winchester · Q Aziz ·
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    ABSTRACT: The enzyme guanosine triphosphate-cyclohydrolase-1 (GCH-1) is a rate limiting step in the de novo synthesis of tetrahydrobiopterin (BH4) a co-factor in monoamine synthesis and nitric oxide production. GCH-1 is strongly implicated in chronic pain based on data generated using the selective GCH-1 inhibitor 2,4-diamino-6-hydroxypyrimidine (DAHP), and studies which have identified a pain protective GCH-1 haplotype associated with lower BH4 production and reduced pain. To investigate the role for GCH-1 in visceral pain we examined the effects of DAHP on pain behaviors elicited by colorectal injection of mustard oil in rats, and the pain protective GCH-1 haplotype in healthy volunteers characterized by esophageal pain sensitivity before and after acid injury, and assessed using depression and anxiety questionnaires. In rodents pretreatment with DAHP produced a substantial dose related inhibition of pain behaviors from 10 to 180 mg/kg i.p. (p < 0.01 to 0.001). In healthy volunteers, no association was seen between the pain protective GCH-1 haplotype and the development of hypersensitivity following injury. However, a substantial increase in baseline pain thresholds was seen between first and second visits (26.6 ± 6.2 mA) in subjects who sensitized to esophageal injury and possessed the pain protective GCH-1 haplotype compared with all other groups (p < 0.05). Furthermore the same subjects who sensitized to acid and possessed the haplotype, also had significantly lower depression scores (p < 0.05). The data generated indicate that GCH-1 plays a role in visceral pain processing that requires more detailed investigation. © 2015 John Wiley & Sons Ltd.
    Neurogastroenterology and Motility 03/2015; 27(5). DOI:10.1111/nmo.12538 · 3.59 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 · 14.66 Impact Factor
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    ABSTRACT: Background Sacral nerve stimulation (SNS) has proven short- to medium-term effectiveness for the treatment of faecal incontinence (FI); fewer long-term outcomes have been presented and usually in small series. Here, the long-term effectiveness of SNS was evaluated in a large European cohort of patients with a minimum of 5 years' follow-up.Methods Prospectively registered data from patients with FI who had received SNS for at least 5 years from ten European centres were collated by survey. Daily stool diaries, and Cleveland Clinic and St Mark's incontinence scores were evaluated at baseline, after implantation and at the last follow-up. SNS was considered successful when at least 50 per cent symptom improvement was maintained at last follow-up.ResultsA total of 407 patients underwent temporary stimulation, of whom 272 (66·8 per cent) had an impulse generator implanted; 228 (56·0 per cent) were available for long-term follow-up at a median of 84 (i.q.r. 70–113) months. Significant reductions in the number of FI episodes per week (from median 7 to 0·25) and summative symptom scores (median Cleveland Clinic score from 16 to 7, St Mark's score from 19 to 6) were recorded after implantation (all P < 0·001) and maintained in long-term follow-up. In per-protocol analysis, long-term success was maintained in 71·3 per cent of patients and full continence was achieved in 50·0 per cent; respective values based on intention-to-treat analysis were 47·7 and 33·4 per cent. Predictive analyses determined no significant association between pretreatment variables and successful outcomes. Risk of long-term failure correlated with minor symptom score improvement during the temporary test phase.ConclusionSNS remains an effective treatment for FI in the long term for approximately half of the patients starting therapy.
    British Journal of Surgery 02/2015; 102(4). DOI:10.1002/bjs.9740 · 5.54 Impact Factor
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    ABSTRACT: Background Sacral nerve stimulation (SNS) is a well established therapy for faecal incontinence (FI). Percutaneous tibial nerve stimulation (PTNS) is a newer, less invasive, treatment. The effectiveness and acceptability of these treatments have not been compared systematically.Methods An investigator-blinded randomized pilot trial of PTNS versus SNS with a parallel qualitative study was performed. Quantitative clinical outcomes and qualitative data from patient interviews were collected for both interventions.ResultsForty patients (39 women; mean age 59 years) met the eligibility criteria; 23 were randomized to receive SNS and 17 to PTNS. Fifteen patients progressed to permanent SNS implantation and 16 received a full course of PTNS. Within-group effect sizes were marginally greater for SNS than for PTNS on available-case analysis. Mean(s.d.) FI episodes per week at baseline, and 3 and 6 months of follow-up were: 11·4(12·0), 4·0(4·0) and 4·9(6·9) respectively for SNS compared with 10·6(11·2), 5·8(6·9) and 6·3(6·9) for PTNS. Mean(s.d.) Cleveland Clinic Incontinence Score values at baseline, and 3 and 6 months were: 16·2(3·0), 11·1(5·2) and 10·4(5·6) for SNS versus 15·1(2·7), 11·7(4·4) and 12·1(5·2) for PTNS. Improvement of at least 50 per cent in FI episodes per week at 6 months was seen in 11 of 18 patients in the SNS group compared with seven of 15 in the PTNS group. Effect estimates for SNS with chronic implanted stimulation were larger (10 of 15 patients at 6 months). Disease-specific and generic quality-of-life improvements complemented clinical outcome data. Qualitative analysis of interview data suggested that both treatments had high acceptability amongst patients.Conclusion In the short term, both SNS and PTNS provide some clinical benefit to patients with FI. Registration numbers: 2010-018728-15 and 10479 (
    British Journal of Surgery 01/2015; 102(4). DOI:10.1002/bjs.9695 · 5.54 Impact Factor

  • World Congress on Pain; 10/2014

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3k Citations
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  • 2008-2015
    • University of London
      Londinium, England, United Kingdom
  • 2006-2015
    • Barts Health NHS Trust
      Londinium, England, United Kingdom
  • 1997-2015
    • Queen Mary, University of London
      • The Blizard Institute of Cell and Molecular Science
      Londinium, England, United Kingdom
  • 2013
    • The University of Manchester
      Manchester, England, United Kingdom
  • 2008-2010
    • Homerton University Hospital NHS Foundation Trust
      Londinium, England, United Kingdom
  • 2009
    • The Peninsula College of Medicine and Dentistry
      Plymouth, England, United Kingdom
  • 2001-2004
    • Queen Mary Hospital
      Hong Kong, Hong Kong
  • 2000
    • Royal College of Surgeons of England
      Londinium, England, United Kingdom