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CONTEXTE : Le cancer colorectal (CCR) reste l’un des cancers les plus diagnostiqués au Canada et dans le monde. Malgré les efforts en matière de dépistage, la moitié des cancers colorectaux sont encore diagnostiqués à des stades avancés de la maladie, réduisant ainsi les chances de survie à ce cancer. La prévention du CCR reste encore primordiale et les efforts doivent être maintenus pour l’identification de ses facteurs de risque modifiables. Durant cette dernière décennie, on a assisté à un cumul d’évidence sur l’association entre l’enrichissement colorectal en une bactérie spécifique, Fusobacterium nucleatum (F. nucleatum), et le CCR. Ce qui a ressuscité le débat sur l’association même entre la maladie parodontale (MP) et le CCR, puisque F. nucleatum est non seulement une bactérie commensale de la bouche, mais surtout l’une des principaux agents pathogènes de la MP. Des études épidémiologiques antérieures avaient en effet déjà suggéré que le la MP serait associée au risque de CCR, mais leurs résultats sont restés non concluants à cause de leurs défaillances méthodologiques. La diffusion des bactéries parodontopathogènes, comme F. nucleatum, et de leurs produits de virulence de la bouche vers le côlon et la libération des médiateurs d’inflammation chronique dans la circulation générale sont les mécanismes incriminés dans l’association entre la MP et le CCR. OBJECTIFS: 1) Vérifier l’association entre la MP et le CCR; 2) Synthétiser la littérature sur l’association entre la détection de la bactérie F. nucleatum dans le côlon et le CCR et; 3) Vérifier la faisabilité d’investiguer l’expression concomitante de F. nucleatum, dans les deux milieux buccal et colorectal, en présence de lésions néoplasiques colorectales. Ces deux derniers objectifs sont un préambule à l’investigation du rôle des bactéries causales de la MP, précisément F. nucleatum, comme mécanisme d’association entre la MP et le CCR. MÉTHODES: Nous avons entrepris trois projets de recherche distincts qui répondent aux trois objectifs respectifs de recherche cités ci-dessus: 1) Une étude cas-témoins à base populationnelle (Projet COLDENT) a inclut 348 cas incidents de CCR et 310 témoins qui lui sont appariés dans des catégories d’âge et de sexe. Des données ont été collectées sur l’exposition à la MP et aux principaux facteurs de risque du CCR; 2) Une revue systématique avec méta-analyse d’études observationnelles ayant investigué la bactérie, F. nucleatum, dans des échantillons colorectaux, chez des cas de CCR et des témoins exempts de lésions cancéreuses ou précancéreuses colorectales; 6 et 3) Une étude pilote cas-témoins à base hospitalière, auprès de 22 cas de néoplasies colorectales et 21 témoins, examinés par coloscopie. Des échantillons de salive et des biopsies de muqueuse colorectale, ainsi que des données sur l’exposition à la MP et aux principaux facteurs de risque du CCR ont été collectées. RÉSULTATS: Les résultats de notre étude cas-témoins populationnelle suggèrent que le taux d’incidence de CCR était augmenté chez les personnes avec un historique positif de MP comparé aux personnes sans historique de MP, en ajustant pour la majorité des facteurs de confusion potentiels (Rapport des taux ajusté = 1,45 ; Intervalle de confiance (IC) à 95 % : 1,04-2,01). Les résultats de notre revue systématique incluant 24 études observationnelles ont montré que dans la majorité des études où la charge de F. nucleatum dans les échantillons colorectaux était quantifiée, celle-ci était significativement plus élevée chez les cas de CCR que chez les témoins. Les résultats de la méta-analyse de 12 études observationnelles qui ont rapporté le pourcentage des échantillons colorectaux où F. nucleatum était détecté montrent une association significativement positive entre la détection de la bactérie F. nucleatum dans le côlon et le CCR (Rapport de cotes combiné = 8,3; IC à 95 % = 5,2-13; Indice d’hétérogénéité I2 = 26,3 %; p pour hétérogénéité = 0,18). Enfin, les résultats préliminaires de l’étude de faisabilité appuient la faisabilité et l’utilité de mener une étude subséquente pour investiguer F. nucleatum dans la salive et le côlon en présence de néoplasies colorectales afin de vérifier son rôle dans l’association entre la MP et le CCR, mais des ajustements doivent être apportés à la méthodologie initiale. CONCLUSION: Nos résultats suggèrent que l’exposition à la MP peut augmenter le risque de CCR, bien qu’on ne puisse encore confirmer de lien causal. On espère que ce travail sensibilise les cliniciens, décideurs en santé et public à l’importance de prévenir et de contrôler les maladies buccodentaires, notamment la MP, pour la prévention même de maladies systémiques encore plus fatales, tels que le CCR., BACKGROUND: Colorectal cancer (CRC) remains one of the most diagnosed cancers in Canada and around the world. Despite screening efforts, half of colorectal cancers are still diagnosed at advanced stages of the disease, thus reducing the chances of survival from this cancer. Prevention of CRC still remains essential, and efforts must be maintained to identify its modifiable risk factors. Over the past decade, there has been an accumulation of evidence on the association between colorectal enrichment in a specific bacterium, Fusobacterium nucleatum (F. nucleatum), and CRC. This has sparked debate on the association between periodontal disease (PD) and CRC, since F. nucleatum is not only a commensal bacterium of the mouth, but above all one of the main pathogens of PD. Previous epidemiological studies had indeed already suggested that PD would be associated with the risk of CRC, but their results remained inconclusive because of their methodological flaws. Dissemination of periodontal pathogen bacteria such as F. nucleatum, and of their virulence products, from the mouth to the colon and the release of chronic inflammatory mediators into the bloodstream are suggested as the mechanisms involved in the association between PD and CRC. OBJECTIVES: 1) To verify the association between PD and CRC; 2) To synthesize the literature on the association between the detection of the bacterium F. nucleatum in the colon and CRC; and 3) To verify the feasibility of investigating the concomitant expression of F. nucleatum, in both oral and colorectal environments, in the presence of colorectal neoplasms. These last two objectives are a preamble to the investigation of the role of the causative bacteria of PD, specifically F. nucleatum, as a mechanism of association between PD and CRC. METHODS: We undertook three separate research projects that address the three respective research objectives listed above: 1) A population-based case-control study (COLDENT Project) included 348 incident cases of CRC and 310 age and sex frequency-matched controls. Data were collected on PD and on major risk factors for CRC; 2) A systematic review with meta-analysis of observational studies that have investigated the bacterium F. nucleatum in colorectal samples, in CRC cases and colorectal cancerous or precancerous-free controls; and 3) A pilot hospital-based case-control study, with 22 cases of colorectal neoplasms and 21 controls, examined by colonoscopy. Saliva samples and colorectal mucosal biopsies as well as data on exposure to PD and major risk factors for CRC were collected. 8 RESULTS: The results of our population-based case-control study suggest that the rate of CRC was increased in people with a positive history of PD compared to people without a history of PD, adjusting for the majority of potential confounders (adjusted rate ratio = 1.45; 95% Confidence interval (CI): 1.04-2.01). The results of our systematic review including 24 observational studies showed that in most studies where the load of F. nucleatum in colorectal samples was quantified, it was significantly higher in CRC cases than in controls. The results of the meta-analysis of 12 observational studies that reported the percentage of colorectal samples where F. nucleatum was detected show a significantly positive association between the detection of the bacterium F. nucleatum in the colon and CRC (pooled odds ratio = 8.3; 95% CI = 5.2-13; heterogeneity index I 2 = 26.3%; p for heterogeneity = 0.18). Finally, the preliminary results of the feasibility study support the feasibility and utility of conducting a subsequent study to investigate F. nucleatum in saliva and colon in the presence of colorectal neoplasms to verify its role in the association between PD and CCR, but adjustments need to be made to the original methodology. CONCLUSION: Our results suggest that exposure to PD may increase the risk of CRC, although a causal relationship cannot yet be confirmed. It is hoped that this work will sensitize clinicians, health policy makers and the public to the importance of preventing and controlling oral diseases, including PD, for the prevention of even more fatal systemic diseases, such as CRC.

We examine the expression of tight junction and adherence junction proteins in the colorectal mucosa of miniature dachshunds (MDs) with inflammatory colorectal polyps (ICRPs). Colorectal mucosa samples were endoscopically obtained from 8 MDs with ICRPs and 8 control dogs for immunoblotting. Paraffin-embedded tissues of surgically resected inflamed lesions from another 5 MDs with ICRPs and full-thickness colorectal specimens from 5 healthy beagles were obtained for immunohistochemistry. The expression patterns of claudin-1, -2, -3, -4, -5, -7 and -8, E-cadherin and β-catenin were analyzed in the non-inflamed mucosa and inflamed mucosa of ICRPs and colorectal mucosa of control dogs by immunoblotting. The localization of these proteins in the inflamed lesions was analyzed by immunohistochemistry. The expressions of each of claudin, E-cadherin and β-catenin were not significantly different between control dogs and non-inflamed colonic mucosa from MDs with ICRPs. In contrast, only E-cadherin and β-catenin were detected in the inflamed lesions of MDs with ICRPs. By immunohistochemistry, claudin-2, -3, -4, -5 and -7, E-cadherin and β-catenin were expressed in the colorectal epithelium within the inflamed mucosa, but not in granulation tissue. Distributions of claudin-2, -3, -4, -5, and -7, E-cadherin and β-catenin in the colonic epithelium were not different between MDs with ICRPs and control dogs. These results indicated that no significant alteration was detected in several tight junction or adherence junction proteins expression in the colorectal epithelium of ICRPs.

Procedures for in vitro culturing of human primary keratinocytes from normal colon mucosa specimens have not been fully feasible, thus far. The protocol described herein allows primary keratinocytes from small tissue fragments of colorectal mucosa biopsies to grow in vitro. The procedure develops in three steps: (a) the enzymatic digestion of the tissue biopsy; (b) the use of cloning rings to purify primary keratinocyte colonies, (c) a defined keratinocyte medium to grow these cells in long-term culture. Our cultural method enables normal primary keratinocytes to be obtained by simple and rapid techniques. In our culture condition, primary keratinocytes express specific epithelial markers. Colorectal mucosa keratinocyte colonies require approximately 2 weeks to grow. Compared with previous approaches, our protocol provides a valuable model of study for human primary keratinocytes from normal colorectal (NCR) mucosa both at the cellular and molecular levels. It is well known, that different mutations occurring during the multistep process of carcinogenesis in the NCR mucosa, are strictly associated to the onset/progression of the colorectal carcinoma. On this ground, normal keratinocytes grown with our protocol, may represent an innovative tool to investigate the mechanisms that lead to colorectal carcinoma and other diseases. Our innovative procedure may allow to perform comparative investigations between normal and pathological colorectal cells.

Tau protein is characterized by a complex pattern of phosphorylation and is localized in the cytoplasm and nucleus in both neuronal and non-neuronal cells. Human AT100 nuclear tau, endowed by phosphorylation in Thr212/Ser214, was recently shown to decline in cornus ammonis 1 (CA1) and dentate gyrus (DG) in Alzheimer's disease (AD), but a defined function for this nuclear tau remains unclear. Here we show that AT100 progressively increases in the nuclei of neuronal and non-neuronal cells during aging, and decreases in the more severe AD stages, as recently shown, and in cancer cells (colorectal adenocarcinoma and breast cancer). AT100, in addition to a co-localization with the DAPI-positive heterochromatin, was detected in the nucleolus of pyramidal cells from the CA1 region, shown to be at its highest level in the more senescent cells and in the first stage of AD (ADI), and disappearing in the more severe AD cases (ADIV). Taking into account the nuclear distribution of AT100 during cell aging and its relation to the chromatin changes observed in degenerated neurons, as well as in cancerous cells, which are both cellular pathologies associated with age, we can consider the Thr212/Ser214 phosphorylated nuclear tau as a molecular marker of cell aging.

Background: Chemo preventive and antitumor role of vitamin D is manifested through genetic and non genetic ways with a powerful antproliferatory and proapopoptic effect, which is proven by numerous epidemiologic studies. The genetic activity of vitamin D is determined through vitamin D receptors (VDR), a member of stero-thyreoidal family of nuclear receptors, which with vitamin D form a cell nucleus complex responsible for the chemo preventive and antitumor effect. VDR in tissue cells is present in the cytoplasm and the nucleus and manifests its genetic activity after transfer from the cytoplasm to the nucleus. The mechanisms for the transport and genetic control of the transport of VDR from cytoplasm to the nucleus in not yet completely understood. Subjects and methods: By using immunohystochemistry we are evaluating the correlation of cytoplasmic and nuclear expression of VDR during different stages of colorectal carcinoma: normal colorectal mucosa, hyperplasic polyp, low grade adenoma (LGD), high grade adenoma (HGD) and colorectal cancer. Results: Our results confirm that the nuclear VDR expression is strongest in normal colorectal mucosa and in hyper plastic polyps, is gradually weakened in low and high grade adenoma while it is extremely weak or absent in colorectal carcinoma. At the same time the expression of cytoplasm VDR is weakest in normal colorectal mucosa and hyper plastic polyps while it grows during the adenoma stage and is most expressed during colorectal carcinoma Conclusion: We conclude that vitamin D has a strong chemo preventive and antitumor effect in normal colorectal mucosa and hyper plastic polyps, while its antitumor and chemopreventive effect is progressively weakened and ultimately absent in colorectal carcinoma.

CD4+ T lymphocytes in the colorectal mucosa are key in HIV-1 transmission and dissemination. As such they are also the primary target for antiretroviral (ARV)-based rectal microbicides for pre-exposure prophylaxis. Drug transporters expressed in mucosal CD4+ T cells determine ARV distribution across the cell membrane and, most likely, efficacy of microbicides. We describe transporters for antiretroviral drugs in colorectal mucosal CD4+ T lymphocytes and compare gene expression with circulating α4β7+CD4+ T cells, which traffic to the intestine and have been shown to be preferentially infected by HIV-1. Purified total CD4+ T cells were obtained from colorectal tissue and blood samples by magnetic separation. CD4+ T cells expressing α4β7 integrin were isolated by fluorescence-activated cell sorting from peripheral blood mononuclear cells of healthy volunteers. Expressions of 15 efflux and uptake drug transporter genes were quantified using Taqman qPCR assays. Expression of efflux transporters MRP3, MRP5, and BCRP and uptake transporter CNT2 were significantly higher in colorectal CD4+ T cells compared to circulating CD4+ T cells (p = 0.01-0.03). Conversely, circulating α4β7+CD4+ T cells demonstrated significantly higher expression of OATPD compared to colorectal CD4+ T cells (p = 0.001). To the best of our knowledge this is the first report of drug transporter gene expression in colorectal CD4+ and peripheral α4β7+CD4+ T cells. The qualitative and quantitative differences in drug transporter gene expression profiles between α4β7+CD4+ T cells and total mucosal CD4+ T cells may have significant implications for the efficacy of rectally delivered ARV-microbicides. Most notably, we have identified efflux drug transporters that could be targeted by selective inhibitors or beneficial drug-drug interactions to enhance intracellular accumulation of antiretroviral drugs.

The recent progress in the biomaterials field and the need for novel 3D cell culture models has led us to develop a new model, the 3D mucosal outgrowth, with advanced characteristics: the simultaneous presence of two differentiated cytotypes (a polarized epithelium above a fibroblastic layer), a complex extracellular matrix (ECM) and the possibility for long-term exposures. This model can be used to grow different human mucosae in vitro, with two types of support scaffolds, a porous polyethylene terephthalate (PET) membrane, for which the model was initially developed, and a poly-L-lactide (PLLA) membrane that was later adapted to the model due to its biodegradability. A fragment of the tissue of interest is placed on the membrane and embedded within a synthetic extra cellular matrix; during the culture period, cells start to grow outwards from the central biopsy and form a new mucosa. Outgrowths grown on PET and PLLA were characterised morphologically by electron microscopy, and immunotyped by immunofluorescence and immunohistochemistry. When grown on PET, all tested mucosae (bronchial, oral and colorectal) showed good differentiation of the relevant cytotypes and proper organization of the ECM. For this reason, they were used for functional studies. Outgrowths developed on PLLA instead, showed a lower degree of cell differentiation and a tendency to form tubular growths that stained positively for endothelial markers. Further evaluations are needed to verify the possibility to use PLLA as a support scaffold for this model., Italian Journal of Anatomy and Embryology, Vol 119, No 1 (Supplement) 2014

OBJECTIVE Increased colonic epithelial cell proliferation has been found in various conditions associated with increased risk of colorectal cancer including acromegaly. In a placebo-controlled study we determined the effect of growth hormone (GH) replacement therapy in GH deficient adults on the colonic epithelial proliferation rate. PATIENTS AND DESIGN Sixteen GH deficient adults were randomised to low dose GH therapy (1 U (0.5 mg) subcutaneously per day, n = 5), high dose GH therapy (2 U daily, n = 5) or placebo (n = 6) during 6 months. Thereafter, all patients were treated with 2 U of GH daily during a 6-months open extension period. MEASUREMENTS Plasma Insulin-like growth hormone I (IGF-I) and IGF binding protein 3 (IGF BP3) concentrations were measured using commercial RIA kits. The colonic epithelial proliferation rate, expressed as overall crypt labelling index (LI) using 5-bromo-2'-deoxyuridine (BrdU) immunostaining, was determined at baseline, after 6 months treatment and at the end of the 6 months open extension period. RESULTS IGF-I rose from 8.9 +/- 6.7 to 34.6 +/- 20.0 nmol/l after 6 months in 8 GH treated patients (P 0.40 from baseline; P > 0.80 from change with placebo). In the extension study, overall crypt LI was also unchanged in those patients who received GH after placebo (n = 5, P > 0.40) and in those who continued GH replacement (n = 9, P > 0.60; P > 0.80 from change in initially placebo treated patients). Separate evaluation of the LI at the basal, mid and luminal portions of the colonic crypts also did not reveal any effect of GH treatment on BrdU labelling. CONCLUSIONS Six to 12 months of GH replacement therapy, aimed to increase plasma IGF-I into the (high) physiological range, does not adversely affect colonic epithelial cell proliferation as a biomarker for the risk of development of colorectal cancer.

Milk products may improve intestinal health by means of the cytoprotective effects of their high calcium phosphate (CaPi) content. We hypothesized that this cytoprotection may increase host defenses against bacterial infections as well as decrease colon cancer risk. This paper summarizes our studies of these proposed protective effects. In rats, lactic acid in yoghurt and CaPi in milk products inhibited the gastrointestinal survival and colonisation of salmonellae. CaPi also inhibited translocation of salmonellae to extraintestinal organs, probably because it stimulates protective bacteria, like lactobacilli, and strengthens the mucosal barrier in the small intestine. In the large intestine, cytotoxic surfactants, like secondary bile acids and fatty acids can damage colonic epithelial cells and thus induce a compensatory hyperproliferation of crypt cells, which increases colon cancer risk. In rats this carcinogenic sequence is inhibited by milk CaPi. Also in humans, milk CaPi precipitates colonic cytotoxic surfactants and thus inhibits colonic cytotoxicity. These results suggest that milk products may decrease colon cancer risk. (C) 1998 Elsevier Science Ltd. All rights reserved.

The relation between proliferation and apoptosis was studied in colorectal mucosal biopsies (N=41), tubular adenomas (TA) (N=104) and tubulovillous adenomas (TVA) (N=34) from 37 FAP patients. Proliferative activity was determined by cell cycle distribution analysis. In addition, transcriptional capacity was determined by chromatin in situ testing. For both, DNA flow cytometry was used. Cycling cells were identified by immunohistochemical staining with monoclonal antibody Ki67. The existence of subdiploid apoptotic cells was derived from DNA and/or DNA/protein patterns. In a follow‐up group, the mucosa is characterised by a balance between proliferation (S % + G2M % = 19) and apoptotic cells (% = 17). The percentage of Ki67 positive cells (16%) corresponds to the percentages mentioned above. In TA, the amount of apoptotic cells remains unaltered, in TVA it decreases to 8%. At the same time, the percentage of Ki67 positive cells increases significantly in both TA and TVA (39%, 42%). With patients who underwent surgery due to clinical signs without histological evidence for malignancy, apoptotic cells in TA continue to decrease significantly (9%), without any changes in cycling cells. Only in the carcinoma‐bearing bowel, cycling cells increase to 52%. Here, the percentage of apoptotic cells in TVA reaches the lowest level (5%). A connection between proliferation and apoptosis was observed in mucosa and TVA. The process of tumorigenesis is characterised by a stepwise increase in resistance to apoptosis followed by an increase in cycling cells.

To gain insight into the possible physiological mechanisms responsible for the increased incidence of colonic neoplasms in patients with acromegaly, a prospective cohort study was carried out in 30 patients with acromegaly. Seven patients had a newly diagnosed acromegaly and 23 were studied during follow-up. Serum growth hormone and insulin-like growth factor-1 (IGF-1) were determined on two separate occasions, During diagnostic endoscopy, mucosal biopsies were obtained for immunohistochemical determination of sigmoidal epithelial cell proliferation, expressed as labeling index (LI), Duodenal and fecal bile acid analyses were performed using gas-liquid chromatography. Results were compared with normal ranges of the laboratory.An increased overall LI was found in 54% of the patients, Increased LI of the luminal, middle, and basal crypt compartments was found in 11, 64, and 28%, respectively. Similarly, comparisons of the mean +/- SEM of the overall LI and the LI of the middle and basal compartments between acromegalic patients and a control group showed overall LI 10.0 +/- 0.8% versus 5.7 +/- 0.6% (P

Immunohistological study by a monoclonal antibody against DNA polymerase α was made for the investigation of labeling index (LI) and proliferative zone in normal mucosa and tumors (-like lesions) of the colon and rectum (normal mucosa ; n=9, hyperplastic polyps ; n=6, tubular adenomas ; n=30 and intramucosal carcinomas ; n=3). The normal mucosa and hyperplastic polyps showed a similar distribution of proliferating cells, forming a proliferative zone which restricted to the lower portion of the crypt (up to about 200μm from the glandular base). In adenomas, the distribution of proliferating cells differed by size ; small tubular adenomas, 5mm or less in size, had proliferative zone in the upper portion of neoplastic tubules (down to 200～400μm from the surface), oppositely to that of the non-neoplastic mucosa. While tubular adenomas more than 5mm showed even distribution of proliferative cells along the whole length of the tubules. In all three mucosal carcinomas, the distribution pattern was similar to that of the latter-group adenomas. The LIs was not significantly different between the proliferative zone of normal mucosa (60.8±6.6), and that of adenomas (small ; 64.6±1.6, larger ; 62.5±5.6). But in carcinomas, it was significantly higher (77.8±0.7). The formation of proliferative zone in small adenomas like non-neoplastic mucosa (but opposite location), suggests that they have a lower potential of proliferation. But the different distribution-patterns of proliferating cells in the larger adenomas indicates that the proliferating activity changes as adenomas grow.

Mucin-histochemical characteristics of normal human colorectal mucosa were investigated utilizing Culling et al.'s staining method which distinguishes the mode of C8-O-acylation of sialomucins. Normal mucosae of cecum, ascending, transverse and descending colon and rectum were obtained from autopsy and biopsy material. Japanese colorectal mucosa stained either entirely red or entirely blue, in contrast to previous reports dealing with Caucasians where all the normal mucosa reportedly stained red. The ratio of red to blue colon cases varied to some extent with age, i.e. it was found to be 1:1 in children aged 0 to 4, 2:1 in the 5-20 age group, and 4:1 in people older than 21 years, suggesting a tendency of shift from blue to red during early life in Japan. Each individual Japanese adult colorectal mucosa may thus be classified into either red or blue type mucin-histochemically.

OBJECTIVE Increased colonic epithelial cell proliferation has been found in various conditions associated with increased risk of colorectal cancer including acromegaly. In a placebo-controlled study we determined the effect of growth hormone (GH) replacement therapy in GH deficient adults on the colonic epithelial proliferation rate. PATIENTS AND DESIGN Sixteen GH deficient adults were randomised to low dose GH therapy (1 U (0.5 mg) subcutaneously per day, n = 5), high dose GH therapy (2 U daily, n = 5) or placebo (n = 6) during 6 months. Thereafter, all patients were treated with 2 U of GH daily during a 6-months open extension period. MEASUREMENTS Plasma Insulin-like growth hormone I (IGF-I) and IGF binding protein 3 (IGF BP3) concentrations were measured using commercial RIA kits. The colonic epithelial proliferation rate, expressed as overall crypt labelling index (LI) using 5-bromo-2'-deoxyuridine (BrdU) immunostaining, was determined at baseline, after 6 months treatment and at the end of the 6 months open extension period. RESULTS IGF-I rose from 8.9 +/- 6.7 to 34.6 +/- 20.0 nmol/l after 6 months in 8 GH treated patients (P 0.40 from baseline; P > 0.80 from change with placebo). In the extension study, overall crypt LI was also unchanged in those patients who received GH after placebo (n = 5, P > 0.40) and in those who continued GH replacement (n = 9, P > 0.60; P > 0.80 from change in initially placebo treated patients). Separate evaluation of the LI at the basal, mid and luminal portions of the colonic crypts also did not reveal any effect of GH treatment on BrdU labelling. CONCLUSIONS Six to 12 months of GH replacement therapy, aimed to increase plasma IGF-I into the (high) physiological range, does not adversely affect colonic epithelial cell proliferation as a biomarker for the risk of development of colorectal cancer.

6-Sulfo-sialyl Lewis X structure is attributable to recognition between lymphocytes and high endothelial venules. However, the biosynthetic pathway still remains unclear. We found that a beta-galactosyltransferase (betaGalT) in human colorectal mucosa preferentially acts on GlcNAc-6-O-sulfate (6S-GN). 6S-GN:beta4GalT was partially purified by UDP-hexanolamine-Sepharose and asialo-agalacto-ovomucin-Sepharose chromatographies. The optimum pH of this enzyme was found to be 6.5-7.5 and the Michaelis constants for 6S-GN and UDP-Gal were 0.43 mM and 16 microM, respectively. The enzymatic activity was dependent on divalent cations and the substrate specificity was not affected by alpha-lactalbumin. This is the first demonstration of the occurrence of 6S-GN:beta4GalT.

Milk products may improve intestinal health by means of the cytoprotective effects of their high calcium phosphate (CaPi) content. We hypothesized that this cytoprotection may increase host defenses against bacterial infections as well as decrease colon cancer risk. This paper summarizes our studies of these proposed protective effects. In rats, lactic acid in yoghurt and CaPi in milk products inhibited the gastrointestinal survival and colonisation of salmonellae. CaPi also inhibited translocation of salmonellae to extraintestinal organs, probably because it stimulates protective bacteria, like lactobacilli, and strengthens the mucosal barrier in the small intestine. In the large intestine, cytotoxic surfactants, like secondary bile acids and fatty acids can damage colonic epithelial cells and thus induce a compensatory hyperproliferation of crypt cells, which increases colon cancer risk. In rats this carcinogenic sequence is inhibited by milk CaPi. Also in humans, milk CaPi precipitates colonic cytotoxic surfactants and thus inhibits colonic cytotoxicity. These results suggest that milk products may decrease colon cancer risk. (C) 1998 Elsevier Science Ltd. All rights reserved.

To gain insight into the possible physiological mechanisms responsible for the increased incidence of colonic neoplasms in patients with acromegaly, a prospective cohort study was carried out in 30 patients with acromegaly. Seven patients had a newly diagnosed acromegaly and 23 were studied during follow-up. Serum growth hormone and insulin-like growth factor-1 (IGF-1) were determined on two separate occasions, During diagnostic endoscopy, mucosal biopsies were obtained for immunohistochemical determination of sigmoidal epithelial cell proliferation, expressed as labeling index (LI), Duodenal and fecal bile acid analyses were performed using gas-liquid chromatography. Results were compared with normal ranges of the laboratory. An increased overall LI was found in 54% of the patients, Increased LI of the luminal, middle, and basal crypt compartments was found in 11, 64, and 28%, respectively. Similarly, comparisons of the mean +/- SEM of the overall LI and the LI of the middle and basal compartments between acromegalic patients and a control group showed overall LI 10.0 +/- 0.8% versus 5.7 +/- 0.6% (P

In the present work we have investigated the cell proliferation pattern of flat serrated adenomas and flat tubular adenomas. For this purpose tissue sections from 23 consecutive flat serrated adenomas and 22 consecutive flat tubular adenomas of the colorcctal mucosa were challenged with MID1, a monoclonal antibody directed against a proliferation-related antigen. The results (including semi-quantitative studies) demonstrated that, whereas flat serrated adenomas had a high cell proliferation at the lower part of the crypts, flat tubular adenomas had a high cell proliferation in the upper part of the crypts. In serrated adenomas with invasive adenocarcinoma, high cell proliferation was demonstrated both at the lower portion of the crypts and in the subjacent submucosa. This suggests that the cells of the lower portion of the crypts in serrated adenomas are truely neoplastic, with the capacity to evolve into invasive growth. The difference in cell proliferation betweeen the two types of flat lesions reported here is a new argument in favor of the classification of flat serrated adenomas as a novel and independent type of neoplastic change of the colorectal mucosa.