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METHYLATION OF SOCS-3 AND SOCS-1 IN THE CARCINOGENESIS OF BARRETT’S ADENOCARCINOMA
The suppressors of cytokine signalling (SOCS) have tumour suppressor activity (SOCS-1) and have been implicated in cancers of the liver and pancreas (SOCS-3). Tischoff et al studied the role of SOCS-1 and SOCS-3 in Barrett’s adenocarcinoma and its precursor lesions. Tumour DNA from Barrett’s adenocarcinomas, Barrett’s intraepithelial neoplasias (low and high grade), Barrett’s mucosa without neoplasia, normal squamous and gastric epithelium, and four cell lines were studied using methylation specific PCR following microdissection. Normal oesophageal squamous and gastric mucosa showed no SOCS-3 or SOCS-1 methylation. There was an increasing level of methylation of SOCS-3 in Barrett’s mucosa without intraepithelial neoplasia (13%), low grade (22%) and high grade intraepithelial neoplasias (69%), and Barrett’s adenocarcinomas (74%) (see table). Similar but smaller changes were seen for SOCS-1. Methylation of the SOCS-3 promoter correlated with downregulation of SOCS-3 transcripts and protein expression in these tumours and various cell lines. The authors conclude that promoter methylation and subsequent transcript downregulation of SOCS-3 transcripts and, to a much lesser extent SOCS-1, are involved in the multistep carcinogenesis of Barrett’s adenocarcinoma.
See p 1047
HLA RELATED GENETIC RISK FOR COELIAC DISEASE
Several studies have shown a higher prevalence of coeliac disease (CD) in sibs of affected patients but the meaning of these estimates is unclear. Bourgey et al evaluated the risk in the Italian population that a sib of a symptomatic patient will develop any of the three recognised forms of CD (latent, silent and symptomatic). They also estimated the risk for any future child. They studied a cohort of 188 families composed of probands with CD, at least one sib and both parents. The overall risk that a sib of a patient with CD will develop the disease was estimated at 10% in this sample (range 0.1%–29% when HLA-DQ information of the proband, parents and sib was considered, see fig). The authors conclude that an antenatal estimate of the order of risk of CD is now possible and a combination of serological tests with a robust estimate of the genetic risk is likely to significantly reduce the burden of clinical disease in at-risk families.
See p 1054
INHIBITORY EFFECT OF DEXAMETHASONE ON VISCERAL HYPERSENSITIVITY INDUCED BY INTRALUMINAL PAR-2 AGONIST
Protease activated receptor-2 (PAR-2) is found on visceral afferent nerves that, when activated by luminal proteases, can induce visceral hypersensitivity. Interest in this topic increased when it was demonstrated that colonic biopsies from patients with irritable bowel syndrome (IBS) show increased numbers of mast cells and release products that sensitise visceral afferents. The figure shows that the PAR-2 agonist SILGRL, when delivered intrarectally, increased abdominal contractions, suggesting hyperalgesia. This effect was abolished by dexamethasone at a dose that markedly reduced mast cell numbers. A similar benefit was seen with a mast cell stabiliser, implying that the luminal PAR-2 agonist acted via mucosal mast cells. Previous studies from the same group reported increased faecal protease levels in IBS, although the origin of these proteases, bacterial vs mast cell, is unclear. This raises the possibility that a mast cell stabiliser or inhibitor would benefit pain in IBS.
See p 1072
SCREENING FOR COLORECTAL CANCER WITHOUT BOWEL PREPARATION: FEASIBILITY AND LIMITATIONS
Although screening for colorectal cancer (CRC) has the potential to save lives, time consuming and unpleasant bowel preparations contribute to poor uptake in many screening programmes. This study compared colonoscopy with a non-invasive magnetic resonance colonography (MRC) technique involving 2 days of bowel preparation without purgation. This required ingesting 250 ml of 5% gastrograffin, 1% barium sulphate and 0.2% locust bean gum with each meal. On the day of the study, a 2 l enema of warm tap water was given with 40 mg scopolamine to suppress bowel contractions. Colonoscopy preparation was with standard, large volume, oral, polyethylene glycol saline solution. Eighteen of 320 colonoscopies and five MRC were unsuccessful because of technical problems. The figure shows that MRC detected few lesions <5 mm and only 62% of lesions >5 mm. However, most missed lesions were hyperplastic polyps and only 17% of adenoma >5 mm were missed. On a patient-basis, sensitivity for adenomas >5 mm was 80% and specificity for all lesions >5 mm was 98%. Eighteen of 31 missed lesions >5 mm were in segments with poor image quality due to inadequate faecal tagging or motion artefact. Further developments to improve faecal tagging and image quality should make this even more attractive for screening.
See p 1079
EXPERIMENTAL ACUTE PANCREATITIS IN PAP/HIP KNOCK-OUT MICE
The pancreatitis-associated protein PAP/HIP is expressed during acute pancreatitis in response to several cytokines but the physiological role remains unclear. There is evidence that this stress protein can be mitogenic, anti-apoptotic and anti-inflammatory, and it is speculated that it could coordinate defence–repair activities upon cell injury. To test this, Gironella et al used a model of caerulein-induced pancreatitis to compare the outcome in PAP/HIP-/-and wild-type mice. As expected, they found that pancreatic necrosis was less severe in PAP/HIP-/- mice than in wild-type mice, while pancreas from the knock-out mice was more sensitive to apoptosis. Surprisingly, pancreatic inflammation was more extensive in PAP/HIP-/- mice, as judged from histological parameters, increased myeloperoxidase activity and increased pro-inflammatory cytokine expression (see fig). This result could be explained by the known anti-inflammatory function previously reported in vitro for PAP/HIP. Interestingly, administration of recombinant PAP/HIP to PAP/HIP-/-mice led to reversion of the apoptotic and inflammatory phenotypes. The authors have, therefore, confirmed a physiological role for PAP/HIP in the pancreatic response to acute pancreatitis injury.
See p 1091
MORTALITY IN HEPATITIS C VIRUS INFECTION
As the epidemic of hepatitis C virus (HCV) develops in the UK the implications for medical services are unclear, thus the results of the Trent Hepatitis C Cohort Study are of great interest. Data are available for 2285 patients infected with HCV with a mean follow-up of 6.7 years (>10 years in 19%). The standardised mortality ratio was 3.0 for both men and women. As the figure shows, liver-related deaths were commonest in those >40 years old, with appreciable numbers of hepatocellular carcinomas in the >50 year olds. Drug-related causes (overdose and sepsis) were the commonest cause of death in the 20−39-year-old age group. Multivariate analysis indicated male sex, older age and liver fibrosis adversely affected mortality, while treatment with ribavirin and pegylated interferon reduced mortality, although interpretation of this is difficult as this combination treatment has only relatively recently been available. One major finding was that only 23% of death certificates mentioned HCV, suggesting that national statistics will substantially underestimate the true impact of HCV on mortality.
See p 1098
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