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IMPAIRED TONIC RESPONSE TO EATING IN IBS
Patients with irritable bowel syndrome (IBS) often report exacerbation of symptoms after eating. Previous studies that have suggested an increased reactivity in IBS used very substantial (1000 kcal) meals and studied the response within the rectum. This study differs because it used a much smaller meal (200 kcal) and a barostat balloon was positioned at least 12 cm from the anal margin. While healthy volunteers all showed a rapid increase in tone as shown by an average 38% reduction in the barostat balloon volume, IBS patients with constipation showed little response and those patients with IBS with diarrhoea actually showed a reduction in tone, with the balloon volume rising an average of 35%. A cut off of <28% increase in tone accurately distinguished patients with IBS from those with organic disease in a separate group of patients. However, when larger meals were used (400/1000 kcal) this difference between IBS and healthy volunteers was lost, all then showing an increase in tone. This striking finding should encourage others to explore the mechanisms underlying these differences.
See p 1409
Mean rectal volume during fasting and after administration of a 200 kcal meal in constipation predominant IBS and diarrhoea predominant IBS patients, and healthy volunteers. The meal was administered after 30 min of fasting measurement. Data are expressed as mean (SEM).
ANTI-INFLAMMATORY ROLE OF MELANOCORTIN RECEPTOR 1 (MC1R) IN INTESTINAL MUCOSA
In addition to influencing pigmentation, alpha melanocyte stimulating hormone (αMSH) has anti-microbial and anti-inflammatory actions. There are five receptors, MC1R–MC5R. MC1R has the highest affinity for αMSH and is expressed in a range of cells, including immunocytes and enterocytes. Mice with a frameshift mutation in the MC1R gene (MC1Re/e) lack functional MC1R but appear normal apart from having a yellow coat. However, when these animals were given dextran sodium sulphate (DSS) they developed a much more severe colitis and lost weight more rapidly (see figure). Reconstituting the mutant mice with bone marrow from wild type mice failed to ameliorate DSS colitis, indicating that worsening inflammation is due to loss of MC1R on local mucosal cells rather than bone marrow derived immunocytes. This study raises the possibility of MSH agonists as a treatment for gut inflammation. Furthermore, there are several allelic variants in MCR genes associated with differences in pigmentation. The authors suggest that the distribution of these variants in patients with inflammatory bowel disease should also be examined.
See p 1415
Weight loss in the DSS colitis model. MC1Re/e mice were more severely affected than controls.
NARROW BAND IMAGING FOR ASSESSMENT OF DYSPLASIA IN ULCERATIVE COLITIS SURVEILLANCE
Narrow band imaging (NBI) illuminates the mucosa with narrowed bands of the optical spectrum, a technique that enhances the mucosal surface and the network of superficial capillaries, causing adenomas and carcinomas to appear a darker brown than normal mucosa. The current case report is of a 62-year-old man with long standing extensive ulcerative colitis who had multiple lesions noted with high-grade dysplasia but was unable to undergo surgery because of comorbity from Parkinson’s disease. The figure shows the enhanced contrast to be seen using NBI in a lesion which proved to harbour a mucinous adenocarcinoma. The authors simultaneously assessed the pit patterns but found the NBI to be more sensitive. As they point out, the most important features of the NBI system are its ease of use with the ability to switch between white light and NBI at the push of a button. Compared with chromoendoscopy, which relies on pit pattern alone, this new technique has the potential to be more specific in detecting dysplasia in these difficult lesions.
See p 1432
C shows sessile DALM viewed with white light, D same lesion viewed with NBI. The dysplastic tissue appears darker in contrast with the normal surrounding mucosa.
CASTING A LIGHT ON THE RISK OF COLORECTAL CANCER
Hereditary non-polyposis colorectal cancer (HNPCC or Lynch syndrome), which is the commonest form of hereditary colorectal cancer, is caused by mutations in the mismatch repair genes. Recent studies suggest abnormalities of the blood vessels in the oral cavity. This study used photographs of the oral mucosa, which were scanned by an imaging spectrophotometer, to perform reflectance analysis which clearly differs between HNPCC and controls (see figure). This difference is thought to reflect alterations in blood vessel geometry. This may in turn relate to abnormalities of the extracellular matrix, which may also increase the risk of developing colorectal cancer. Because family histories are often inadequate, this new marker might be clinically valuable to identify susceptibility to colorectal cancer and allow better focusing of the more expensive molecular diagnostic techniques.
See p 1436
Oral mucosal light reflectance versus wavelength. Differences between HNPCC and controls in the 590–700 nm wavelength range, p<0.0004.
INCREASED DNA METHYLATION IN THE NORMAL MUCOSA OF PATIENTS WITH HYPERPLASTIC POLYPOSIS
There are two types of hyperplastic polyposis, one characterised by multiple, small, mainly distal and essentially benign lesions and the other by larger, mainly proximal lesions with a predisposition to malignant transformation. This study examined three patients with the latter type of lesion who had multiple sessile serrated adenomas (see figure) and at least one colorectal cancer. Becuase methylation and inactivation of the promoter region of the DNA mismatch repair gene MLH1 is a key rate-limiting step in the development of colorectal cancer, they examined methylation of a range of genes in both polyps and cancers and the normal mucosal. There was extensive methylation in the tumours and polyps, but also in the normal mucosa of patients with the severe phenotype, something that was absent in patients with sporadic serrated polyps of the proximal colon. The authors speculate that the mutation of a gene that controls the regulation of DNA methylation could predispose to methylation of pro-apoptotic genes, the loss of its activity is thought to underlie the development of serrated adenomatas polyposis.
See p 1467
A sessile serrated adenoma showing dilated mucin filled crypts with exaggerated serration
COINFECTION WITH HIV REDUCES T CELL RESPONSE TO HEPATITIS C VIRUS
Because up to 80% of intravenous drug users and 98% of people with haemophilia are coinfected with both HIV and hepatitis C virus (HCV, the impact of HIV infection on the response to HCV is of great importance, especially now that highly active antiretroviral treatment (HAART) treated patients with HIV are surviving many years. This study examined the response to HCV antigens in HCV infected individuals both with and without HIV infection. As the figure shows, monoinfected individuals had a much stronger response with increased numbers of CD4+ T cells producing interferon-γ in response to either core or NS3-5 antigens. Coinfected individuals also had a much higher HCV viral load. The immune suppression did not appear specific to HCV because the CD4 response to HCV was only found in those who also had a response to HIV/P24 antigen. All these patients were studied without HAART and further studies are now required to identify means of restoring the HCV specific CD4+ positive T cell response in these individuals in order to control the HCV infection and its long term sequelae.
See p 1484
Percentage of individuals who had CD4+ T cell interferon-γ response to HCVantigens (core and NS3-5) as assessed by ELISpot.
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