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  1. 1. CiCRA Fellowship Report (2001-2004)Dr Ronald BremnerUniversity of Southampton School of Medicine and Southampton General HospitalSupervisors: Prof TT MacDonald, Dr RM BeattieDuring my CiCRA fellowship I have undertaken both laboratory and clinical research.I am currently completing my MD thesis for submission to the University ofSouthampton. I have been involved in the clinical care of children with inflammatorybowel disease (IBD), including experience of the use of Enteral Nutrition as therapy,management of acute severe ulcerative colitis, Infliximab infusions and peri-operativemanagement. I attended the paediatric gastroenterology outpatient clinic andendoscopy list weekly. I have also been involved in the monthly multidisciplinaryhistopathology meetings. I have co-authored reviews of the management of paediatricIBD and gut responses to gut microbes. I have been involved in the development oflocal guidelines for investigating suspected IBD and the use of Infliximab in children.During my fellowship I had the opportunity to travel to Italy to the University ofRome at Tor Vergata to undertake a collaborative project with Prof GiovanniMonteleone for a month in 2002. I presented this work at the European Society ofPaediatric Gastroenterology annual conference in Prague (2003) and it formed thebasis of a publication in the prestigious Journal of Biological Chemistry (2004). Ihave presented my own research at several national and international conferences. Ihave spoken at CiCRA meetings at St Bartholemew’s Hospital, for the 25thanniversary (2003) and at the annual meeting (2002). 1
  2. 2. The fellowship has allowed me develop my interest and experience in clinical andresearch paediatric gastroenterology. For this report, I have summarised the researchthat I have undertaken and included a list of presentations and publications I have co-authored.Laboratory researchProject Title: “The role of Smad7 in inflammatory bowel disease.”Smad7 is a protein found inside cells that regulates responses to Transforming GrowthFactor (TGF)-β, an anti-inflammatory cytokine and growth factor involved in woundhealing. The presence of Smad7 in the cell prevents it responding to TGF-b, despite itbeing present in the tissue and abel to bind to the receptors on the cell surface. It is notknown how Smad7 expression is controlled in the human gut. My researchestablished a new technique to measure Smad7 gene expression (mRNA) andexamined the role of pro-inflammatory cytokines in Smad7 protein expression.Smad7 in gut biopsies:I have examined the Smad7 expression in gut mucosal biopsies from children withCrohn’s disease and ulcerative colitis, taken at colonoscopy at diagnosis or follow-up.I investigated the amount of Smad7 protein and mRNA. This data showed that theSmad7 protein expression in the gut mucosal is higher in children with active gutinflammation. However, the mRNA levels are not different. This suggests that Smad7levels are not controlled by changing gene expression, but after the protein isproduced. Recent data from other groups suggest that this is controlled by altering the 2
  3. 3. Smad7 protein is stabilised by acetylation and targeted for degradation by binding toubiqitin.Smad7 in lamina propria mononuclear cells (LPMC):I have isolated gut immune cells from operative resection specimens from normaltissue (adults undergoing treatment for bowel cancer), and from patients with severeIBD. These cells were cultured ex-vivo and I then investigated the expression ofSmad7. I have found that Smad7 expression is stable in LPMC ex-vivo, and higher inLPMC from patients with IBD. Stimulating LPMC form normal gut tissue with pro-inflammatory cytokines showed that Smad7 expression is increased after stimulationwith Tumour Necrosis Factor-α, but not by interferon-γ. TGF-β had no effect onSmad7 expression in LPMC form normal tissue.Clinical researchDuring my fellowship, I have been involved in prospective observational clinicalstudies involving children with IBD evaluating faecal calprotectin and ultrasoundscanning. These are both non-invasive methods to assess bowel inflammation. I haveco-authored two case reports illustrating rare and important aspects of paediatricCrohn’s disease, an association with celiac disease and post-cardiac transplant. I havebeen involved in data analysis of two other research projects undertaken by theclinical team, evaluating dietary energy requirements and energy expenditure inchildren with Crohn’s disease. This provided me with experience of planning andundertaking all the stages of clinical research, including ethics approval, datacollection, analysis and submission to medical journals for publication. 3
  4. 4. Calprotectin:Calprotectin is a protein present in neutrophils, cells involved in inflammation. Faecalcalprotectin is raised in inflammatory bowel disease. A new commercially availabletesting kit with high sensitivity was evaluated in children with chronic intestinalsymptoms seen by the paediatric gastroenterology team, to test its potential as a partof the investigation of suspected IBD. One hundred children provided samples fortesting. The results showed that raised calprotectin is not specific for IBD, but a lowlevel means that IBD extremely unlikely. Calprotectin levels were higher children inchildren with raised blood levels of C-reactive protein (a marker of inflammation). InIBD, calprotectin levels were related to disease activity in children with ulcerativecolitis, but not in Crohn’s disease. These findings have been accepted for publication.Ultrasound scanning:Ultrasound scanning (USS) is a non-invasive investigation that can image the bowelwall without radiation and is well tolerated by children. I undertook a retrospectiveaudit of the results of USS and Barium follow-through results of a group of 24children who underwent USS and Barium studies during the same period of Crohn’sdisease relapse. These data suggested that USS has good specificity for inflammationin the terminal ileum. For children in whom USS showed abnormality, Barium studiesprovided no further useful information. Thus, an abnormal USS can obviate Bariumstudies.I then undertook a prospective evaluation of USS in 44 children with IBD undergoingcolonoscopy and Barium studies. This study examined the accuracy of USS imagingof the colon and ileum, and blood flow into the gut by Doppler analysis. The data 4
  5. 5. showed that USS cannot detect mildly inflamed bowel segment, but that it is reliablein detecting moderate or severe disease in the colon (specificity 93%) and in theterminal ileum (specificity 92%). Doppler analysis showed that blood flow did notcorrelate with disease activity. These findings are currently being prepared forsubmission for publication.These studies suggest that USS has a role in the routine evaluation of IBD, and couldreduce the requirement for more invasive investigation with Barium studies orcolonoscopy.Concluding Remarks and Future Directions:CiCRA’s support has allowed me to develop my experience in clinical work andresearch, which has produced 12 publications, with potential for more. Researchsupported by CiCRA has been presented at three national meetings and threeinternational meetings, including the World Conference in 2004. Implementation ofclinical protocols and participating in clinical research has directly affected the care ofchildren with IBD in the Wessex region. Since starting my fellowship, the paediatricgastroenterology service in Southampton has expanded with the appointment of asecond consultant and a specialist nurse. I have since returned to my clinical trainingin paediatrics, and aim to sub-specialise with a national training post in paediatricgastroenterology, and develop a particular interest in IBD disease evaluation andtreatment. 5
  6. 6. Research Presentations:Nov 2002“Ultrasound obviates the need for Barium radiology in Crohn’s disease”Oral presentation to the Society of Paediatric Radiologists, Sheffield, UKApril 2002“The role of Smad7 in inflammatory bowel disease”Poster presentation at the AGM of the Association of Physicians, Winchester, UKApril 2003“Ultrasound scanning can reduce the need for barium radiology in Crohn’s disease”Oral presentaion to the Joint Meeting of the British and Italian Societies of PaediatricGastroenterology (BSPGHAN and SIGEP), Lucca, Italy.June 2003“A failure in Smad signalling contributes to the sustained NF-κB activation in chronicinflammatory bowel disease”Oral presentation to The European Society of Peadiatric Gastroenterology,Hepatology and Nutrition (ESPGHAN), Prague, Czeck RepublicJanuary 2004“Smad7 and TGF-beta signalling in inflammatory bowel disease”Poster presentation for SET for Britain, Houses of Parliament, LondonJuly 2004“Ultrasound scanning in chronic inflammatory colitis”Poster presentation at the World Congress of Paediatric Gastroenterology(WCPHAN), Paris, FranceResearch Citations:In press (October 2005):1. Bremner AR, Roked SY, Robinson RC, Phillips IJ, Beattie RMFaecal calprotectin in children with chronic gastrointestinal symptomsActa Paediatrica2. Hart JW, Bremner AR, Wootton SA, Beattie RMMeasured versus predicted energy expenditure in children with inactive Crohn’sdiseaseClinical NutritionPublished:1: Gavin J, Anderson CE, Bremner AR, Beattie RM.Energy intakes of children with Crohns disease treated with enteral nutritionas primary therapy.J Hum Nutr Diet. 2005 Oct;18(5):337-42. 6
  7. 7. PMID: 16150129 [PubMed - in process]2: Bremner AR, Pridgeon J, Fairhurst J, Beattie RM.Ultrasound scanning may reduce the need for barium radiology in the assessmentof small-bowel Crohns disease.Acta Paediatr. 2004 Apr;93(4):479-81.PMID: 15188974 [PubMed - indexed for MEDLINE]3: Pickard KM, Bremner AR, Gordon JN, MacDonald TT.Microbial-gut interactions in health and disease. Immune responses.Best Pract Res Clin Gastroenterol. 2004 Apr;18(2):271-85. Review.PMID: 15123069 [PubMed - indexed for MEDLINE]4: Harms B, Bremner AR, Mulligan J, Fairhurst J, Griffiths DM, Salmon T,Beattie RM.Crohns disease post-cardiac transplantation presenting with severe growthfailure and delayed onset of puberty.Pediatr Allergy Immunol. 2004 Apr;15(2):186-9.PMID: 15059198 [PubMed - indexed for MEDLINE]5: Monteleone G, Mann J, Monteleone I, Vavassori P, Bremner R, Fantini M, DelVecchio Blanco G, Tersigni R, Alessandroni L, Mann D, Pallone F, MacDonald TT.A failure of transforming growth factor-beta1 negative regulation maintainssustained NF-kappaB activation in gut inflammation.J Biol Chem. 2004 Feb 6;279(6):3925-32. Epub 2003 Nov 4.PMID: 14600158 [PubMed - indexed for MEDLINE]6: Bremner AR, Griffiths DM, Beattie RM.Current therapy of ulcerative colitis in children.Expert Opin Pharmacother. 2004 Jan;5(1):37-53. Review.PMID: 14680434 [PubMed - indexed for MEDLINE]7: Chakraborty A, Bremner AR, Moore I, Beattie RM.Coeliac disease and Crohns disease: an association not to be forgotten.Hosp Med. 2003 Nov;64(11):684-5.PMID: 14671883 [PubMed - indexed for MEDLINE]8: Bremner AR, Beattie RM.Therapy of Crohns disease in childhood.Expert Opin Pharmacother. 2002 Jul;3(7):809-25. Review.PMID: 12083982 [PubMed - indexed for MEDLINE]9: Bremner AR, Anderson CE, Beattie RM.Paediatric Crohns disease: Supporting long term health through nutrition.Complete Nutrition 2002: 2(1) 9-11. Review.10. Bremner AR, Anderson CE, Beattie RM.Paediatric Crohns disease: Supporting long term health through nutrition.Complete Nutrition Primary Care Review 2002: 1(2) ; 9-11. Review. 7