{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T05:56:05Z","timestamp":1779256565681,"version":"3.51.4"},"reference-count":36,"publisher":"BMJ","issue":"2","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Gut"],"published-print":{"date-parts":[[1996,8]]},"abstract":"<jats:p>BACKGROUND\/AIM: The aim of this study was to investigate epithelial cell turnover in childhood enteropathy to establish whether common disease related mechanisms operate. Levels of epithelial cell proliferation were measured in children with food intolerance (cows' milk protein intolerance and coeliac disease), and after infection with Giardia lamblia, Cryptosporidium, and enteropathogenic Escherichia coli. METHODS: Comparative measures of epithelial cell proliferation were performed by recording mitotic activity and MIB-1 immunoreactivity in proximal small intestinal biopsy specimens. RESULTS\/CONCLUSIONS: A hyperplastic crypt response was evident in all of the disease states examined and was particularly pronounced in coeliac disease and in infection with enteropathogenic E coli, where mitotic and MIB-1 labelling indices were significantly raised above control values. In contrast with coeliac disease, increased crypt cell production rates in enteropathogenic E coli infection were also due to an expansion of the crypt proliferation compartment, without a comparable increase in crypt cell numbers. Crypt hyperplasia is therefore a common tissue response to mucosal damage in food allergy and infection, although disease specific mechanisms are evident.<\/jats:p>","DOI":"10.1136\/gut.39.2.185","type":"journal-article","created":{"date-parts":[[2007,9,18]],"date-time":"2007-09-18T17:41:31Z","timestamp":1190137291000},"page":"185-193","source":"Crossref","is-referenced-by-count":38,"title":["Epithelial cell proliferation in childhood enteropathies."],"prefix":"10.1136","volume":"39","author":[{"given":"T C","family":"Savidge","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"A N","family":"Shmakov","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J A","family":"Walker-Smith","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"A D","family":"Phillips","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"239","published-online":{"date-parts":[[1996,8,1]]},"reference":[{"key":"ref_1","first-page":"5","article-title":"Time dimension in cell biology. A radioautographic survey of the dynamic features of cells, cell components, and extracellular matrix","volume":"160","author":"Leblond, C.P.","year":"1991","unstructured":"Leblond CP. Time dimension in cell biology. A radioautographic survey of the dynamic features of cells, cell components, and extracellular matrix. Protoplasma 1991; 160: 5-38.","journal-title":"Protoplasma"},{"key":"ref_2","article-title":"The biology of epithelial cell populations (Volumes I and II)","author":"Wright, N.A.; Alison, M.R.","year":"1984","unstructured":"Wright NA, Alison MR. The biology of epithelial cell populations (Volumes I and II). Oxford: Clarendon Press, 1984."},{"key":"ref_3","article-title":"Cell proliferation in the gastrointestinal tract","author":"Appleton, D.R.; Sunter, J.P.; Watson, A.J.","year":"1980","unstructured":"Appleton DR, Sunter JP, Watson AJ. Cell proliferation in the gastrointestinal tract. Bath: The Pitman Press, 1980."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1001","DOI":"10.1242\/dev.110.4.1001","article-title":"Stem cells: attributes, cycles, spirals, pitfalls and uncertainties. Lessons for and from the crypt","volume":"110","author":"Potten, C.S.; Loeffier, M.","year":"1990","unstructured":"Potten CS, Loeffier M. Stem cells: attributes, cycles, spirals, pitfalls and uncertainties. Lessons for and from the crypt. Development 1990; 110: 1001-20.","journal-title":"Development"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1242\/dev.103.4.785","article-title":"Development of the pattem of cell renewal in the crypt-villus unit of chimaeric mouse small intestine","volume":"103","author":"Schmidt, G.H.; Winton, D.J.; Ponder, B.A.J.","year":"1988","unstructured":"Schmidt GH, Winton DJ, Ponder BAJ. Development of the pattem of cell renewal in the crypt-villus unit of chimaeric mouse small intestine. Development 1988; 103: 785-90.","journal-title":"Development"},{"key":"ref_6","first-page":"537","article-title":"Origin, differentiation and renewal of the four main epithelial cell types in the mouse small intestine","volume":"141","author":"Cheng, H.; Leblond, C.P.","year":"1974","unstructured":"Cheng H, Leblond CP. Origin, differentiation and renewal of the four main epithelial cell types in the mouse small intestine. Am JAnat 1974; 141: 537-63.","journal-title":"Am JAnat"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"825","DOI":"10.1083\/jcb.117.4.825","article-title":"Expression of SV-40 T antigen in the small intestinal epithelium of transgenic mice results in proliferative changes in the crypt and reentry of villus-associated enterocytes into the cell cycle but has no apparent effect on cellular differentiation programs and does not cause neoplastic transformation","volume":"117","author":"Hauft, S.M.; Kin, S.H.; Schmidt, G.H.; Pease, S.; Rees, S.; Harris, S.","year":"1992","unstructured":"Hauft SM, Kin SH, Schmidt GH, Pease S, Rees S, Harris S, et al. Expression of SV-40 T antigen in the small intestinal epithelium of transgenic mice results in proliferative changes in the crypt and reentry of villus-associated enterocytes into the cell cycle but has no apparent effect on cellular differentiation programs and does not cause neoplastic transformation. J Cell Biol 1992; 117: 825-39.","journal-title":"J Cell Biol"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1146\/annurev.cb.08.110192.001105","article-title":"The differentiating intestinal epithelial cell: establishment and maintenance of functions through interactions between cellular structures","volume":"8","author":"Louvard, D.; Kedinger, M.; Hauri, H.P.","year":"1992","unstructured":"Louvard D, Kedinger M, Hauri HP. The differentiating intestinal epithelial cell: establishment and maintenance of functions through interactions between cellular structures. Annu Rev Cell Biol 1992; 8: 157-95.","journal-title":"Annu Rev Cell Biol"},{"key":"ref_9","first-page":"1239","article-title":"Intravenous epidermal growth factor\/urogastrone increases small intestinal cell proliferation in congenital microvillus atrophy","volume":"ii:","author":"Walker-Smith, J.A.; Phillips, A.D.; Walford, N.; Gregory, H.; Fitzgerald, J.D.; MacCullagh, K.","year":"1985","unstructured":"Walker-Smith JA, Phillips AD, Walford N, Gregory H, Fitzgerald JD, MacCullagh K, et al. Intravenous epidermal growth factor\/urogastrone increases small intestinal cell proliferation in congenital microvillus atrophy. Lancet 1985; ii: 1239-40.","journal-title":"Lancet"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1038\/343082a0","article-title":"Induction of a novel epidermal growth factor-secreting cell lineage by mucosal ulceration in human gastrointestinal stem cells","volume":"343","author":"Wright, N.A.; Pike, C.; Elia, G.","year":"1990","unstructured":"Wright NA, Pike C, Elia G. Induction of a novel epidermal growth factor-secreting cell lineage by mucosal ulceration in human gastrointestinal stem cells. Nature 1990; 343: 82-5.","journal-title":"Nature"},{"key":"ref_11","first-page":"564","article-title":"Epidermal growth factor-related peptides and their relevance to gastrointestinal pathophysiology","volume":"108","author":"Barnard, J.A.; Beauchamp, R.D.; Russel, W.E.; Dubois, R.N.; Coffey, R.J.","year":"1995","unstructured":"Barnard JA, Beauchamp RD, Russel WE, Dubois RN, Coffey RJ. Epidermal growth factor-related peptides and their relevance to gastrointestinal pathophysiology. Gaseroeneerologzy 1995; 108: 564-80.","journal-title":"Gaseroeneerologzy"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1007\/BF00048063","article-title":"The significance of spontaneous and induced apoptosis in the gastrointestinal tract of mice","volume":"11","author":"Potten, C.S.","year":"1992","unstructured":"Potten CS. The significance of spontaneous and induced apoptosis in the gastrointestinal tract of mice. Cancer Metastasis Rev 1992; 11: 179-95.","journal-title":"Cancer Metastasis Rev"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1097\/00005176-198406000-00008","article-title":"Quantitative analysis of small intestinal mucosa in cow's milk-sensitive enteropathy","volume":"3","author":"Maluenda, C.; Phillips, A.D.; Briddon, A.; Walker-Smith, J.A.","year":"1984","unstructured":"Maluenda C, Phillips AD, Briddon A, Walker-Smith JA. Quantitative analysis of small intestinal mucosa in cow's milk-sensitive enteropathy. 7 Pediatr Gastroenterol Nutr 1984; 3: 349-56.","journal-title":"7 Pediatr Gastroenterol Nutr"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1016\/0016-5085(78)90458-4","article-title":"Familial enteropathy: a syndrome of protracted diarrhea from birth, failure to thrive, and hypoplastic villus atrophy","volume":"75","author":"Davidson, G.P.; Cutz, E.; Hamilton, JR, Gall; D.G.","year":"1978","unstructured":"Davidson GP, Cutz E, Hamilton JR, Gall DG. Familial enteropathy: a syndrome of protracted diarrhea from birth, failure to thrive, and hypoplastic villus atrophy. Gastroenterology 1978; 75: 783-90.","journal-title":"Gastroenterology"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1056\/NEJM198903093201006","article-title":"Microvillus inclusion disease: an inherited defect of brush-border assembly and differentiation","volume":"320","author":"Cutz, E.; Rhoads, J.M.; Drumm, B.; Sherman, P.M.; Durie, P.R.; Fostner, G.G.","year":"1989","unstructured":"Cutz E, Rhoads JM, Drumm B, Sherman PM, Durie PR, Fostner GG. Microvillus inclusion disease: an inherited defect of brush-border assembly and differentiation. N Engl Jf Med 1989; 320: 646-51.","journal-title":"N Engl Jf Med"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1245","DOI":"10.1056\/NEJM197012032832302","article-title":"Epithelial-cell renewal in cultured duodenal biopsies in coeliac disease","volume":"283","author":"Trier, J.S.; Browning, T.D.","year":"1970","unstructured":"Trier JS, Browning TD. 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The cell cycle time in the flat (avillous) mucosa of the human small intestine. Gut 1973; 14: 603-6."},{"key":"ref_19","first-page":"1041","article-title":"Cell kinetics in the jejunal crypt epithelium in malabsorption syndrome with cow's milk protein intolerance and in coeliac disease of childhood","volume-title":"Gut","volume":"21","author":"Kosnai, I.; Kuitunen, P.; Savilahti, E.; Rapola, J.; Kohegyi, J.","year":"1980","unstructured":"Kosnai I, Kuitunen P, Savilahti E, Rapola J, Kohegyi J. Cell kinetics in the jejunal crypt epithelium in malabsorption syndrome with cow's milk protein intolerance and in coeliac disease of childhood. Gut 1980; 21: 1041-6."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1007\/BF02024340","article-title":"Evaluation of a casein and a whey hydrolysate for treatment of cow's milk sensitive enteropathy","volume":"149","author":"Walker-Smith, J.A.; Digeon, B.; Phillips, A.D.","year":"1989","unstructured":"Walker-Smith JA, Digeon B, Phillips AD. Evaluation of a casein and a whey hydrolysate for treatment of cow's milk sensitive enteropathy. EurJ Pediatr 1989; 149: 68-71.","journal-title":"EurJ Pediatr"},{"key":"ref_21","first-page":"461","article-title":"Diagnostic criteria in coeliac disease","volume":"59","author":"Meeuwisse, G.W.","year":"1970","unstructured":"Meeuwisse GW. Diagnostic criteria in coeliac disease. Acta PediatrScand 1970; 59: 461-3.","journal-title":"Acta PediatrScand"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1136\/adc.65.8.909","article-title":"Revised criteria for diagnosis of coeliac disease","volume":"65","author":"Walker-Smith, J.A.; Guandalini, S.; Schmitz, J.; Shmerling, D.H.; Visakorpi, J.K.","year":"1990","unstructured":"Walker-Smith JA, Guandalini S, Schmitz J, Shmerling DH, Visakorpi JK. Revised criteria for diagnosis of coeliac disease. Arch Dis Child 1990; 65: 909-11.","journal-title":"Arch Dis Child"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1057","DOI":"10.1136\/gut.33.8.1057","article-title":"Cryptosporidiosis, chronic diarrhoea and the proximal small intestinal mucosa","volume":"33","author":"Phillips, A.D.; Thomas, A.G.; Walker-Smith, J.A.","year":"1992","unstructured":"Phillips AD, Thomas AG, Walker-Smith JA. Cryptosporidiosis, chronic diarrhoea and the proximal small intestinal mucosa. Gut 1992; 33: 1057-61.","journal-title":"Gut"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1136\/gut.32.2.154","article-title":"Enteropathogenic E coli and life threatening chronic diarrhoea","volume":"32","author":"Hill, S.M.; Phillips, A.D.; Walker-Smith, J.A.","year":"1991","unstructured":"Hill SM, Phillips AD, Walker-Smith JA. Enteropathogenic E coli and life threatening chronic diarrhoea. Gut 1991; 32: 154-8.","journal-title":"Gut"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1002\/ijc.2910310104","article-title":"Production of a mouse monoclonal antibody reactive with a human nuclear antigen associated with cell proliferation","volume":"31","author":"Gerdes, J.; Schwab, H.; Lemke, H.; Stein, H.","year":"1983","unstructured":"Gerdes J, Schwab H, Lemke H, Stein H. Production of a mouse monoclonal antibody reactive with a human nuclear antigen associated with cell proliferation. Int Cancer 1983; 31: 13-20.","journal-title":"Int Cancer"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1083\/jcb.123.3.513","article-title":"The cell proliferationassociated antigen of antibody Ki- 67: a very large, ubiquitous nuclear protein with numerous repeated elements, representing a new kind of cell cycle-maintaining proteins","volume":"123","author":"Schluter, C.; Duchrow, M.; Wohlenberg, C.; Becker, M.H.G.; Key, G.; Flad, H.D.","year":"1993","unstructured":"Schluter C, Duchrow M, Wohlenberg C, Becker MHG, Key G, Flad HD, et al. The cell proliferationassociated antigen of antibody Ki-67: a very large, ubiquitous nuclear protein with numerous repeated elements, representing a new kind of cell cycle-maintaining proteins. Jf Cell Biol 1993; 123: 513-22.","journal-title":"Jf Cell Biol"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1471","DOI":"10.1177\/37.10.2476477","article-title":"Evolutionary conservation in various mammalian species of the human proliferation-associated epitope recognised by the Ki-67 monoclonal antibody","volume":"37","author":"Falini, B.; Flenghi, L.; Fagiolo, M.; Stein, H.; Schwarting, R.; Riccardi, C.","year":"1989","unstructured":"Falini B, Flenghi L, Fagiolo M, Stein H, Schwarting R, Riccardi C, et al. Evolutionary conservation in various mammalian species of the human proliferation-associated epitope recognised by the Ki-67 monoclonal antibody. J Histochem Cytochem 1989; 37: 1471-8.","journal-title":"J Histochem Cytochem"},{"key":"ref_28","first-page":"147","article-title":"A comparison of in vivo cell proliferation measurements in the intestine of mouse and man","volume":"1","author":"Kellet, M.; Potten, C.S.; Rew, D.A.","year":"1992","unstructured":"Kellet M, Potten CS, Rew DA. A comparison of in vivo cell proliferation measurements in the intestine of mouse and man. Epithelial Cell Biology 1992; 1: 147-55.","journal-title":"Epithelial Cell Biology"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1136\/gut.36.3.369","article-title":"Novel insights into human intestinal epithelial cell proliferation in health and disease using confocal microscopy","volume":"36","author":"Savidge, T.C.; Walker-Smith, J.A.; Phillips, A.D.","year":"1995","unstructured":"Savidge TC, Walker-Smith JA, Phillips AD. Novel insights into human intestinal epithelial cell proliferation in health and disease using confocal microscopy. Gut 1995; 36: 369-74.","journal-title":"Gut"},{"key":"ref_30","first-page":"645","article-title":"Role of small bowel biopsy in diagnosis","volume":"2","author":"Phillips, A.D.; Walker-Smith, J.A.","year":"1994","unstructured":"Phillips AD, Walker-Smith JA. Role of small bowel biopsy in diagnosis. Baillieres Clin Pediatr 1994; 2: 645-66.","journal-title":"Baillieres Clin Pediatr"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1016\/S0006-3495(88)83021-2","article-title":"Variation in crypt size and its influence on the analysis of epithelial cell proliferation in the intestinal crypt","volume":"54","author":"Totafurno, J.; Bjerkes, M.; Cheng, H.","year":"1988","unstructured":"Totafurno J, Bjerkes M, Cheng H. Variation in crypt size and its influence on the analysis of epithelial cell proliferation in the intestinal crypt. Biophys J 1988; 54: 845-58.","journal-title":"Biophys J"},{"key":"ref_32","first-page":"22","article-title":"Analysis of crypt cell proliferation in coeliac disease using MIB-1 antibody shows an increase in growth fraction","volume-title":"Gut","volume":"36","author":"Przemioslo, R.; Wright, N.A.; Elia, G.; Ciclitira, P.J.","year":"1995","unstructured":"Przemioslo R, Wright NA, Elia G, Ciclitira PJ. Analysis of crypt cell proliferation in coeliac disease using MIB-1 antibody shows an increase in growth fraction. Gut 1995; 36: 22-7."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1016\/0014-4827(67)90237-6","article-title":"A comparison of the relative efficiencies of various metaphase arrest agents","volume":"47","author":"Tannock, I.F.","year":"1967","unstructured":"Tannock IF. A comparison of the relative efficiencies of various metaphase arrest agents. Exp Cell Res 1967; 47: 345-56.","journal-title":"Exp Cell Res"},{"key":"ref_34","first-page":"321","article-title":"Conventional patterns of human intestinal proliferation in a severe-combined immunodeficient xenograft model","volume":"59","author":"Shmakov, A.N.; Morey, A.L.; Ferguson, D.J.P.; Fleming, K.A.; O'Brien, J.A.; Savidge, T.C.","year":"1995","unstructured":"Shmakov AN, Morey AL, Ferguson DJP, Fleming KA, O'Brien JA, Savidge TC. Conventional patterns of human intestinal proliferation in a severe-combined immunodeficient xenograft model. Differentiation 1995; 59: 321-30.","journal-title":"Differentiation"},{"key":"ref_35","first-page":"173","article-title":"A comparison of immunohistochemical markers of cell proliferation with experimentally determined growth fraction","volume":"165","author":"Scott, R.J.; Hall, P.A.; Haldane, J.S.; van Noorden, S.; Price, Y.; Lane, D.P.","year":"1991","unstructured":"Scott RJ, Hall PA, Haldane JS, van Noorden S, Price Y, Lane DP, et al. A comparison of immunohistochemical markers of cell proliferation with experimentally determined growth fraction. JPathol 1991; 165: 173-8."},{"key":"ref_36","first-page":"477","article-title":"Unsuccessful oral rehydration in an infant with enteropathogenic E coli diarrhoea","volume":"74","author":"Marin, L.; Aperia, A.; Zetterstom, R.; Gunoz, H.; Sokucu, S.; Saner, G.","year":"1985","unstructured":"Marin L, Aperia A, Zetterstom R, Gunoz H, Sokucu S, Saner G, et al. Unsuccessful oral rehydration in an infant with enteropathogenic E coli diarrhoea. Studies of fluid and electrolyte homeostasis. Acta Paediatr Scand 1985; 74: 477-9.","journal-title":"Studies of fluid and electrolyte homeostasis. 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