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Sökning: WFRF:(Scholefield J.)

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  • Simpson, J., et al. (författare)
  • Post inflammatory damage to the enteric nervous system in diverticular disease and its relationship to symptoms
  • 2009
  • Ingår i: Neurogastroenterology and Motility. - : Wiley-Blackwell. - 1350-1925. ; 21:8, s. 847-847
  • Tidskriftsartikel (refereegranskat)abstract
    • Some patients with colonic diverticula suffer recurrent abdominal pain and exhibit visceral hypersensitivity, though the mechanism is unclear. Prior diverticulitis increases the risk of being symptomatic while experimental colitis in animals increases expression of neuropeptides within the enteric nervous system (ENS) which may mediate visceral hypersensitivity. Our aim was to determine the expression of neuropeptides within the ENS in diverticulitis (study 1) and in patients with symptomatic disease (study 2). Study 1 - Nerves in colonic resection specimens with either acute diverticulitis (AD, n = 16) or chronic diverticulitis (CD, n = 16) were assessed for neuropeptide expression recording % area staining with protein gene product (PGP9.5), substance P (SP), neuropeptide K (NPK), pituitary adenylate cyclase activating polypeptide (PACAP), vasoactive intestinal polypeptide (VIP) and galanin. Study 2 - Seventeen symptomatic and 15 asymptomatic patients with colonic diverticula underwent flexible sigmoidoscopy and multiple peridiverticular mucosal biopsies. Study 1- Neural tissue, as assessed by PGP staining was increased to a similar degree in circular muscle in both AD and CD. The CD specimens showed significant increases in the immunoreactivity of SP, NPK and galanin in both mucosal and circular muscle layer compared with controls. Study 2 - Mucosal histology was normal and PGP9.5 staining was similar between groups however patients with symptomatic diverticular disease demonstrated significantly higher levels of SP, NPK, VIP, PACAP and galanin within the mucosal plexus. Patients with symptomatic diverticular disease exhibit increased neuropeptides in mucosal biopsies which may reflect resolved prior inflammation, as it parallels the changes seen in acute and chronic diverticulitis.
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  • Simpson, J, et al. (författare)
  • Prolonged elevation of galanin and tachykinin expression in mucosal and myenteric enteric nerves in trinitrobenzene sulphonic acid colitis
  • 2008
  • Ingår i: Neurogastroenterology and Motility. - : Wiley-Blackwell. - 1350-1925. ; 20:4, s. 392-406
  • Tidskriftsartikel (refereegranskat)abstract
    • Diverticulitis causes recurrent abdominal pain associated with increased mucosal expression of mucosal galanin and substance P (SP). We studied changes in mucosal and myenteric plexus neuropeptides in adult rats using a model of colonic inflammation, trinitrobenzenesulphonic acid colitis. We assessed the effects on the pan-neuronal markers protein gene product 9.5 (PGP9.5) and neurofilament protein, as well as specific neuropeptides at 1, 2, 3, 4, 6, 8, 10 and 14 weeks. Following the acute injury there was macroscopic resolution of inflammation but minor microscopic abnormalities persisted. Percent area stained of mucosal PGP9.5 fell initially but average levels on days 21 and 28 levels were significantly elevated (P < 0.001), returning to normal by day 42. Percent area staining of PGP9.5 in the muscle rose immediately and remained significantly elevated at 70 days (P < 0.001). SP, neuropeptide K and galanin followed a similar overall pattern. SP to PGP9.5 ratio was significantly increased in the muscle both acutely (days 1-28) and in the long term (days 70 and 98), whereas the galanin to PGP9.5 ratio was significantly increased in the mucosa throughout the study. Low-grade chronic inflammation after an acute initial insult causes a persistent increase in the expression of galanin in the mucosa and SP in muscle layer.
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  • Siproudhis, L., et al. (författare)
  • Libertas : a phase II placebo-controlled study of NRL001 in patients with faecal incontinence showed an unexpected and sustained placebo response
  • 2016
  • Ingår i: International Journal of Colorectal Disease. - 0179-1958 .- 1432-1262. ; 31:6, s. 1205-1216
  • Tidskriftsartikel (refereegranskat)abstract
    • Faecal incontinence (FI) is distressing, significantly reduces quality of life (QoL) and has few pharmacological treatments. The alpha(1)-adrenoceptor agonist NRL001 (1R,2S-methoxamine hydrochloride) improves anal sphincter tone. NRL001 efficacy was evaluated by changes in Wexner scores at week 4 vs. baseline in NRL001-treated patients compared with placebo. Impact of NRL001 on QoL and safety were also assessed. Four hundred sixty-six patients received NRL001 (5, 7.5 or 10 mg) or placebo as suppository, once daily over 8 weeks. Wexner score, Vaizey score and QoL were analysed at baseline, week 4 and week 8. FI episodes and adverse events were recorded in diaries. At week 4, mean reductions in Wexner scores were -3.0, -2.6, -2.6 and -2.4 for NRL001 5, 7.5, 10 mg and placebo, respectively. All reduced further by week 8. As placebo responses also improved, there was no significant treatment effect at week 4 (p = 0.6867) or week 8 (p = 0.5005). FI episode frequency improved for all patients, but not significantly compared with placebo (week 4: p = 0.2619, week 8: p = 0.5278). All patients' QoL improved, but not significantly for all parameters (p > 0.05) except depression/self-perception at week 4 (p = 0.0102) and week 8 (p = 0.0069), compared with placebo. Most adverse events were mild and judged probably or possibly related to NRL001. All groups demonstrated improvement in efficacy and QoL compared with baseline. NRL001 was well-tolerated without serious safety concerns. Despite the improvement in all groups, there was no statistically significant treatment effect, underlining the importance of relating results to a placebo arm.
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