Boosting Wnt activity during colorectal cancer progression through selective hypermethylation of Wnt signaling antagonists.

BACKGROUND: There is emerging evidence that Wnt pathway activity may increase during the progression from colorectal adenoma to carcinoma and that this increase is potentially an important step towards the invasive stage. Here, we investigated whether epigenetic silencing of Wnt antagonists is the biological driver for this increased Wnt activity in human tissues and how these methylation changes correlate with MSI (Microsatelite Instability) and CIMP (CpG Island Methylator Phenotype) statuses as well as known mutations in genes driving colorectal neoplasia. METHODS: We conducted a systematic analysis by pyrosequencing, to determine the promoter methylation of CpG islands associated with 17 Wnt signaling component genes. Methylation levels were correlated with MSI and CIMP statuses and known mutations within the APC, BRAF and KRAS genes in 264 matched samples representing the progression from normal to pre-invasive adenoma to colorectal carcinoma. RESULTS: We discovered widespread hypermethylation of the Wnt antagonists SFRP1, SFRP2, SFRP5, DKK2, WIF1 and SOX17 in the transition from normal to adenoma with only the Wnt antagonists SFRP1, SFRP2, DKK2 and WIF1 showing further significant increase in methylation from adenoma to carcinoma. We show this to be accompanied by loss of expression of these Wnt antagonists, and by an increase in nuclear Wnt pathway activity. Mixed effects models revealed that mutations in APC, BRAF and KRAS occur at the transition from normal to adenoma stages whilst the hypermethylation of the Wnt antagonists continued to accumulate during the transitions from adenoma to carcinoma stages. CONCLUSION: Our study provides strong evidence for a correlation between progressive hypermethylation and silencing of several Wnt antagonists with stepping-up in Wnt pathway activity beyond the APC loss associated tumour-initiating Wnt signalling levels.

Safety of the colonoscope magnetic imaging device (ScopeGuide) in patients with implantable cardiac devices.

BACKGROUND AND STUDY AIMS: Use of the colonoscope magnetic imaging device (ScopeGuide, Olympus Medical Systems, Tokyo, Japan) is currently contraindicated by the manufacturer for patients with implantable cardiac devices, a group of patients that is increasing annually along with the number of colonoscopies performed in the era of colorectal cancer screening. This is the first study to examine the safety of ScopeGuide in patients with permanent pacemakers, implantable cardioverter defibrillators, and cardiac resynchronization therapy. PATIENTS AND METHODS: Nonimplanted cardiac devices were exposed to the electromagnetic field of ScopeGuide ex vivo and assessed for evidence of interference or change in device settings. Following this, consecutive patients attending device check clinics were prospectively recruited and exposed to the ScopeGuide electromagnetic field. After an initial device check, patients underwent continuous external cardiac monitoring and device interrogation while a colonoscope was placed on the abdomen over clothing and connected to ScopeGuide to simulate colonoscopy. Patients were monitored for 2 minutes to assess for any interference. ScopeGuide was then disconnected and devices were checked for any change in settings. RESULTS: A total of 230 patients were invited to participate and 100 were recruited to the study. There was no evidence of interference on device leads or change in programming following exposure to the electromagnetic field generated by ScopeGuide. CONCLUSION: ScopeGuide does not appear to cause interference or change in settings and is therefore likely to be safe for use in patients with implantable cardiac devices.

Sir James Young Simpson and religion: myths and controversies.

This paper analyses two key aspects of the life and work of Sir James Young Simpson: his evangelical Christianity and his reaction to criticism following his use of anaesthesia in obstetrics. Simpson's personal religious struggle is placed in the context of the devastating events surrounding the Disruption of the established Church of Scotland in 1843. Whatever his involvement in the events of that year, the development of his faith demonstrates his simple evangelical conviction in the atonement of Christ, very much in keeping with that of many believers in Victorian Britain. There has arisen the notion (still current as is clear from publications in medical journals within recent years) that there was a savage religious response, especially in Presbyterian Scotland, to his use of chloroform - in reality the attack on Simpson's enthusiastic promotion of chloroform was brief, sporadic and of little moment. Simpson's carefully constructed counter to criticism of anaesthesia, drawing on considerable theological and linguistic expertise, reveals a complexity at odds with the simplicity of his faith. The contrast is so great and the reaction so elaborate that it is proposed that Simpson deliberately exaggerated the affair, believing the publicity could only be valuable.

Helicobacter pylori: antibiotic resistance and eradication rates in Suffolk, UK, 1991-2001.

Helicobacter pylori infection causes a number of gastrointestinal diseases and its current treatment is based on multidrug regimes including acid suppression and antimicrobials. The success of these regimes is determined by a number of factors including antibiotic resistance, which varies widely but is an increasing problem. Local data are important in establishing the most cost-effective eradication regime. Data have been collected prospectively on antibiotic resistance at Ipswich Hospital (Suffolk, UK) in all consecutive isolates of H. pylori from 1991 to 2001. The success of regimes consisting of a proton pump inhibitor, amoxycillin and metronidazole (PPI/A/M) has also been evaluated in patients found positive on serological testing in primary care using urea breath testing. Overall, metronidazole resistance was found in 31.7 % of isolates and clarithromycin resistance in 5.3 %. A significant increase in metronidazole resistance from 29.1 to 37.0 % (P = 0.022) and a decrease in clarithromycin resistance from 10.3 to 3.8 % (P = 0.014) was seen over the study period. Metronidazole resistance was significantly more common in women (P < 0.001) and young patients (P < 0.001). Eradication with PPI/A/M was successful in 89.9 % of patients and did not change significantly over the study period. Eradication rates were lower in young patients (P < 0.001). Whilst metronidazole resistance is increasing in Suffolk, this does not seem to have a significant effect on eradication rates. Metronidazole-based regimes are still effective first-line treatments in most patients.

Three-year prospective validation of a pre-endoscopic risk stratification in patients with acute upper-gastrointestinal haemorrhage.

OBJECTIVE: To assess the accuracy of a risk stratification that is used at initial assessment to identify groups with increased risk of mortality and requirement for urgent treatment intervention. DESIGN: Prospective assessment of risk stratification in consecutive patients with acute upper-gastrointestinal haemorrhage. METHODS: Over a 3-year period, 1349 consecutive patients with acute upper-gastrointestinal haemorrhage presenting to a single teaching hospital were prospectively risk stratified before endoscopy and followed up for outcome. MAIN OUTCOME MEASURES: Two-week, all-cause mortality, re-bleeding, and need for urgent treatment intervention. RESULTS: Stratification within the high-risk group predicted a significant increased risk of 2-week, all-cause mortality (P < 0.001) when compared with intermediate- and low-risk patients (11.8%, 3% and 0%, respectively), re-bleeding (P < 0.001) (44.1%, 2.3% and 0%, respectively), and need for urgent treatment intervention (P < 0.001) (71%, 40.6% and 2.6%, respectively). CONCLUSIONS: Over a 3-year period, medical staff at this institution have routinely used this risk stratification, which identifies groups of patients at high and low risk of mortality, re-bleeding and need for urgent treatment intervention following acute upper-gastrointestinal haemorrhage. Use of this risk stratification should allow targeting of more intensive treatment where it might be of most benefit. Those patients at lowest risk from outpatient management are also identified.