K R Gardiner

Flexible sigmoidoscopy and the changing distribution of colorectal cancer: implications for screening.

BACKGROUND AND AIMS There has been a significant proximal shift in the distribution of colorectal cancer (CRC) in Northern Ireland over recent decades. The aim of this study was to investigate the potential implications of this proximal shift in CRC distribution on the efficacy of flexible sigmoidoscopy (FS) as a screening tool. PATIENTS AND METHODS The site distribution of 5153 CRCs was available from the Northern Ireland Colorectal Cancer Register for the period 1990–1997. Similar data on 1241 CRCs between 1976 and 1978 were available from a previous study. Data on the site reached by FS were obtained from a prospectively collected endoscopy database at one of Northern Irelands main teaching hospitals for the period 1993–1998. RESULTS There was a significant proximal shift in CRC distribution between the two periods (23.5% proximal to the splenic flexure between 1976 and 1978v 36.7% between 1990 and 1997; p<0.001). The descending colon was visualised during 74.4% of FS examinations. By combining the observed extent of FS examination with CRC site distribution, it was calculated that FS could have visualised 68.8% of CRCs between 1976 and 1978 but only 56.0% between 1990 and 1997. Extrapolating these data to a Northern Ireland screening programme involving FS and faecal occult blood testing suggests that significantly more CRCs could have been detected between 1976 and 1978 than between 1990 and 1997 (51.7% v 48.2%, respectively; p=0.03). CONCLUSIONS This study confirms the previously documented left to right shift in CRC distribution in Northern Ireland and demonstrates that if this shift continues, FS will become less successful as a screening tool than is currently predicted.

Probiotic Therapy Fails to Improve Gut Permeability in a Hapten Model of Colitis

BACKGROUND Studies in clinical and experimental inflammatory bowel disease (IBD) have shown disturbances in intestinal bacterial flora with an increase in potentially pathogenic and a decrease in protective organisms. It was hypothesized that Lactobacillus plantarum species 299 (LP299), a probiotic, would ameliorate colitis and improve intestinal permeability in experimental colitis. This study investigated the effect of LP299 in the trinitrobenzenesulfonic acid/ethanol (TNBS/E) rat model of colitis. METHODS Twelve week old male Wistar rats were randomized to receive rectal instillates of either TNBS/E (n = 48) or saline (n = 16). For the next 7 days the animals were gavaged with 2.5 ml of oat fibre suspension containing 10(9) colony forming units (CFU) of LP299 (LP299/OF), oat fibre suspension alone (OF) or no treatment. At the end of the experiment rats received radiolabelled polyethylene glycol and urine was collected for 24 h to assess permeability. Animals were then anaesthetized and colons were harvested for colon macroscopic scoring (CMS). RESULTS TNBS/E per rectum resulted in a greater CMS (P < 0.001) and gut permeability (P = 0.006) than saline. Administration of LP299/OF or oat fibre alone did not result in a reduction in CMS or gut permeability when compared to colitic controls. CONCLUSIONS LP299/OF, when administered after TNBS instillation, does not reduce the severity of colitis or improve gut permeability in this hapten model of colitis.Background: Studies in clinical and experimental inflammatory bowel disease (IBD) have shown disturbances in intestinal bacterial flora with an increase in potentially pathogenic and a decrease in protective organisms. It was hypothesized that Lactobacillus plantarum species 299 (LP299), a probiotic, would ameliorate colitis and improve intestinal permeability in experimental colitis. This study investigated the effect of LP299 in the trinitrobenzenesulfonic acid/ethanol (TNBS/E) rat model of colitis. Methods: Twelve week old male Wistar rats were randomized to receive rectal instillates of either TNBS/E (n = 48) or saline (n = 16). For the next 7 days the animals were gavaged with 2.5 ml of oat fibre suspension containing 109 colony forming units (CFU) of LP299 (LP299/OF), oat fibre suspension alone (OF) or no treatment. At the end of the experiment rats received radiolabelled polyethylene glycol and urine was collected for 24 h to assess permeability. Animals were then anaesthetized and colons were harvested for colon macroscopic scoring (CMS). Results: TNBS/E per rectum resulted in a greater CMS (P < 0.001) and gut permeability (P = 0.006) than saline. Administration of LP299/OF or oat fibre alone did not result in a reduction in CMS or gut permeability when compared to colitic controls. Conclusions: LP299/OF, when administered after TNBS instillation, does not reduce the severity of colitis or improve gut permeability in this hapten model of colitis.

Ischemic preconditioning ameliorates ischemia- and reperfusion-induced intestinal epithelial hyperpermeability in rats.

We hypothesized that ischemic preconditioning (IPC) would ameliorate ischemia (I) and reperfusion (R)-induced intestinal mucosal hyperpermeability and that this effect would be diminished by lowering local adenosine concentrations using adenosine deaminase (ADA). The small intestine of anesthetized rats (group 1; n = 6) was divided into six 10-cm segments (A1-F1) each perfused by a different set of mesenteric branches. Segments D1-F1 were subjected to 3 cycles of IPC (2 min I/5 min R). Segments A1, B1, and C1 were excised at baseline, after 60 min of I (160), and after 60 min of I followed by 60 min of R (160/R60), respectively. Segment D1 was excised immediately after the last cycle of IPC, E1 was excised at 160 after IPC, and F1 was excised at 160/R60 after IPC. In group 2 (n = 6), the intestine was divided into five 10-cm vascularly isolated segments (A2-E2). Segment A2 was resected at baseline. The lumen of the remaining segments was filled with ADA (32 U/50 cm). Segment B2 was removed at the end of the experiment having been exposed to ADA for 150 min (ADA150). Segments C2, D2, and E2 were subjected to IPC. Segment C2 was excised immediately thereafter. Segments D2 and E2 were excised at 160 and 160/R60, respectively. Intestinal permeability to fluorescein isothiocyanate-labeled dextran (molecular weight 4000 D) was assessed ex vivo by using an everted gut sac method. IPC ameliorated intestinal hyperpermeability induced by 160 (43.0+/-7.6 vs. 70.4+/-8.3 nLmin/cm2; P = 0.024) and 160/R60 (20.2+/-3.7 vs. 69.5+/-10.8 nL/min/cm2; P= 0.003). IPC prevented ischemia-induced reduction in villus height. Treatment with ADA partially reversed the protective effect of IPC on the changes in permeability and villus height induced by I/R. We conclude that IPC partially protects against mucosal barrier dysfunction in rats subjected to mesenteric I/R. Adenosine is a mediator of IPC in the gut mucosa, but other factors also may be important.

Mucosal barrier function and the commensal flora

We read with interest the article by Garcia-Lafuente et al ( Gut 2001; 48 :503–7). Their results demonstrate that strains of endemic gut bacteria can affect gut mucosal barrier function, as measured by intestinal permeability, and that the effect may be potentially beneficial or harmful depending on the specific bacterial strains administered. These findings help to explain and corroborate the interesting findings that have been emerging from clinical and experimental studies investigating the use of probiotics in inflammatory bowel disease (IBD). It is known that development of colonic inflammation in genetic models of IBD is dependent on the presence of intestinal bacteria. In human studies, an imbalance …

Plasma concentrations of glucagon-like peptide-2 in adult patients with treated and untreated coeliac disease

Background Coeliac disease is a common chronic inflammatory enteropathy characterized by villous atrophy and crypt hyperplasia in the small intestine. The mechanism of the intestinal damage in coeliac disease remains unclear. Glucagon-like peptide (GLP)-2 is an enterotrophic peptide that causes crypt hyperplasia and intestinal cell proliferation. We postulate that GLP-2 may be involved in the mucosal changes found in coeliac disease. Objectives To study plasma concentrations of GLP-2 in untreated patients with coeliac disease and determine the response to a gluten-free diet (GFD). Methods A 440 kcal gluten-free test meal was given to seven controls and 12 coeliac patients at three time intervals: (1) before commencing a GFD; (2) 3 months after a GFD; and (3) 9 months after a GFD. Serial blood sampling was performed over a 2-h period. Each sample was analysed using radioimmunoassay for GLP-2, GLP-1, N-terminal glucagon (N-glucagon) and C-terminal glucagon (C-glucagon). Results Untreated coeliac patients had significantly higher basal and peak GLP-2 and N-glucagon plasma concentrations compared with controls. After 3 months on a GFD, there was a significant decrease in basal GLP-2 plasma concentrations. There was no significant difference between GLP-1 or C-glucagon in untreated coeliac patients compared with controls. Conclusion This is the first reported study of GLP-2 in coeliac disease. After a GFD there is recovery of the intestine and a reduction in the GLP-2 trophic response. Our findings support the theory that GLP-2 may be part of the mucosal healing and maintenance mechanisms in coeliac disease.

Changing patterns of colorectal cancer.

TO THE EDITOR: We read with great interest the report in a recent issue of this journal by Rabeneck et al. (1). This large study confirms that the proportion of colorectal cancer (CRC) located in the right colon has indeed increased over the last 20 yr in the United States, as has been previously noted in other geographical regions in the same period. The authors demonstrate that this increase has taken place without a corresponding rise in the incidence of right-sided CRC. They also show that the proportion of right-sided CRC diagnosed has increased as the age of the population increases. Our published data comparing CRC diagnosed in 1976– 1978 and in 1995–1997 in Northern Ireland show the same pattern of an increasing proportion of right-sided CRC over two decades (23.6% in 1976–1978 vs 35.1% in 1995–1997) (2, 3). Further data from the 1995–1997 period confirm that the proportion of right-sided CRC in Northern Ireland increases with age (34% for 41–50 yr of age vs 46% for >80 yr of age). However, our data also demonstrate that the agestandardized incidence of right-sided CRC has increased in both sexes over this period in Northern Ireland (rates per 100,000: males: 4.7 in 1976–1978 vs 9.5 in 1995–1997; females: 4.7 in 1976–1978 vs 8.7 in 1995–1997), although the incidence of CRC at other sites has not changed. Census data also show that the proportion of the Northern Ireland population over 80 yr of age has almost doubled in the period 1977–1996 (from 1.6% to 2.7%). These data suggest that the increased incidence of rightsided CRC in Northern Ireland may be related to aging of the population. These results also suggest that different mechanisms are responsible for similar changes observed in CRC distribution in different geographical regions. Local data collection and the maintenance of local cancer registries remain important to determine these underlying patterns in CRC distribution.

Distribution of glucagon-like peptide-2 in normal colonic tissue

Glucagon-like peptide-2 (GLP-2) is a regulatory peptide with trophic effects on the intestine achieved through intestinal epithelial proliferation, crypt cell hyperplasia and inhibition of apoptosis (1). GLP-2 is released from the enteroglucagon cells (L-cells) and is derived from the breakdown of proglucagon that undergoes tissue-specific processing. Several authors have suggested that the terminal ileum and proximal colon are important regions in the colon for the production of GLP-2 (2, 3). The density of L cells in human colonic mucosa increases distally in the intestine and is maximal in the rectum (4). It is surprising that GLP-2 production should be maximal in the proximal colon and therefore the aim was to establish the distribution of GLP-2 cells in the human colon.

The changing scope of colorectal cancer

The nature and significance of the relationship between vitamin K status and bone health has been debated for some years. Vitamin K is required for the gamma carboxylation of glutamic acid residues in three bone proteins, namely osteocalcin, matrix Gla protein, and protein S. Although the roles of these proteins have not been clearly defined, there is evidence that osteocalcin, which is produced by cells of the osteocyte/osteoblast lineage and has three vitamin K dependent gamma carboxyglutamic acid (Gla) residues, may be involved in the mineralisation of bone matrix; in addition, it may function as a negative regulator of bone formation, deletion of the osteocalcin gene in mice resulting in increased bone mass. Approximately 30% of synthesised osteocalcin is released into the circulation and serum levels of the protein are widely used as an indicator of bone formation. Vitamin K deficiency is associated with a reduction in circulating osteocalcin concentrations and a decrease in the gamma carboxylated fraction, the latter being associated with reduced binding of the protein to bone mineral. Despite this theoretical basis for adverse eVects of vitamin K deficiency in the skeleton, however, direct evidence is lacking. Thus although low vitamin K levels and undercarboxylation of osteocalcin have been described in patients with osteoporosis, 6 these findings may reflect poor nutritional status rather than a specific eVect of vitamin K deficiency on bone. Similarly, there is currently no direct evidence that therapy with warfarin, which inhibits the secretion by osteoblasts of osteocalcin, increases the risk of osteoporosis, and although increased fracture risk has been reported in patients receiving oral anticoagulants, this finding has not been universal. Malabsorption of fat soluble vitamins is a recognised complication of Crohn’s disease and, in particular, an increased prevalence of vitamin D deficiency has been reported in many studies. In rare cases this results in osteomalacia but more importantly it contributes to the increased prevalence of osteoporosis associated with Crohn’s disease as a consequence of secondary hyperparathyroidism and the resulting increase in bone turnover. In contrast, vitamin K status has been less well studied although in one study a high prevalence of deficiency of the vitamin was found in patients with ileal Crohn’s disease. The study by Schoon et al in this issue of Gut, performed in a cohort of patients with small intestinal Crohn’s disease, provides some evidence, albeit indirect, that there may be an inverse association between vitamin K status and bone mineral density of the spine (see page 473). Thus undercarboxylation of osteocalcin was higher and binding of circulating osteocalcin to hydroxyapatite lower in patients with Crohn’s disease compared with controls, indicating reduced vitamin K status. Furthermore, serum levels of undercarboxylated osteocalcin were inversely related to bone mineral density in the spine, although this relationship was not observed for proximal femur or total body bone mineral density. Interestingly, although there was a significant correlation between serum levels of the major circulating metabolite of vitamin D, 25hydroxyvitamin D, and serum vitamin K, no correlation was observed between vitamin D status and bone mineral density at any of the sites assessed. The results of this study would thus be consistent with a role for vitamin K deficiency in the pathogenesis of osteoporosis associated with Crohn’s disease. Nevertheless, further studies are required in view of the relatively small sample size in this study (n=32) and lack of a statistically significant correlation between serum vitamin K levels and bone mineral density. In addition, the reduction in bone mineral density was relatively modest in this cohort, with mean z scores higher than −0.5 at all sites, and in this respect it would be of interest to investigate the relationship between vitamin K status and bone mass across a wider spectrum of bone disease. Failure to demonstrate a correlation between the serum “free” (undercarboxylated) osteocalcin and bone mineral density in the femoral neck and total body may reflect inadequate statistical power or alternatively might indicate diVerential eVects on cancellous and cortical bone. The pathogenesis of osteoporosis in patients with Crohn’s disease is multifactorial, glucocorticoid therapy, hypogonadism, vitamin D deficiency, and malnutrition all being potential contributory factors. In the study of Schoon et al, patients were in remission at the time of assessment and were treated with no more than 5 mg of oral prednisolone daily. Nevertheless, bone mineral density values assessed at one point in time reflect multiple past and present influences and thus the eVects of glucocorticoids and disease activity could not be excluded completely, as the authors claimed. The question of whether vitamin K supplementation prevents or reduces bone loss in patients with Crohn’s disease (or in other populations) has not been established and this will be an important area for future research if an association between vitamin K status and bone mineral density is confirmed in subsequent studies.

Phagocyte priming as a prognostic indicator in the intensive care unit.

BACKGROUND The purpose of this study was to study the temporal changes in circulating phagocyte respiratory burst activity and its relationship to mortality in intensive care unit (ICU) patients. METHODS Thirty-seven consecutive patients over a 3-week period were studied on their first, third, and seventh day of admission to the regional ICU in Northern Ireland. Blood samples were assayed for respiratory burst activity using luminol-enhanced whole blood chemiluminescence. RESULTS Compared with survivors, nonsurvivors exhibited significantly higher Acute Physiology and Chronic Health Evaluation II scores, a base deficit, and reduced phagocyte activity (median [interquartile range]) (24.00% [18.00%, 56.00%] vs. 38.00% [30.00%, 63.50%], p = 0.047, Mann-Whitney U test) on day 3 of admission to the ICU. CONCLUSION Temporal changes in phagocyte activation dependent on the underlying insult were seen in ICU patients. Furthermore, the degree of phagocyte activation was able to distinguish between survivors and nonsurvivors on day 3 of admission to the ICU. Nonsurvivors exhibited reduced phagocyte activation, suggesting patients at risk of mortality exhibit systemic anergy.