Fostering Students' Understanding of Complex Biological Systems.

The main aim of this study is to teach students to take a systems perspective in understanding complex biological problems. Two lessons were designed and tested in two secondary classes (15- to 16-year-old students), using a lesson study approach. Three students from each class were observed more closely when visualizing and reasoning about two complex biological problems. The results, based on student worksheets, peer discussions, classroom observations, and interviews, indicated that students were able to visualize complex problems with the aid of a systems model based on eight system characteristics: boundary, components, interactions, input and output, feedback, hierarchy, dynamics, and emergence. Moreover, explicit scaffolds encouraged students to reason across different levels of biological organization. Based on the findings, four design guidelines were formulated: 1) Start with a central complex problem/question. 2) Let students visualize a complex biological problem using a systems model. 3) Assist students in reasoning step by step within and between the levels of biological organization. 4) Make students explicitly aware of the use of the system characteristics in various contexts. As systems thinking assists students in creating an overview of a system and reasoning about a complex problem systematically, it is also valuable outside the biology classroom.

The socioeconomic profile of a Barrett's oesophagus cohort assessed by the 2010 Index of Multiple Deprivation.

BACKGROUND: Several reports have described the relationship between socioeconomic status and oesophageal adenocarcinoma but only one with its precursor condition, Barrett's oesophagus. We therefore investigated such an association. PATIENTS: The majority (88%) of patients diagnosed with Barrett's at Rotherham District General Hospital between 28 April 1978 and 31 August 2012 consented to inclusion in the UK Barrett's Oesophagus Registry. Those residing within Rotherham form the basis of this study. METHODS: We assessed socioeconomic status using the Index of Multiple Deprivation 2010 scores which can be assigned to every English postcode. The scores for the whole of England were divided into five equal groups; those of the 6257 postcodes within Rotherham (including those of Barrett's patients) were compared against the national quintile relevant to their score. We examined the ratio of observed against expected numbers of Barrett's in each quintile before and since 2001, the median year of diagnosis. RESULTS: The study group comprised 1076 patients with Barrett's oesophagus. Before 2001 their distribution across the deprivation quintiles was similar to that expected. Since then it has changed significantly, with 37% more Barrett's patients than expected among the two least deprived quintiles, but 11% fewer than expected in the larger population comprising the two most deprived quintiles (P=0.0001). There was no significant difference in the distribution of sex (P=0.27), nor the mean age at diagnosis between the two time periods (P=0.92). CONCLUSION: Since 2001, there has been a major change in the distribution of Barrett's in relation to socioeconomic status, measured by the Index of Multiple Deprivation.

Comparative genomic analysis of esophageal cancers.

The following, from the 12th OESO World Conference: Cancers of the Esophagus, includes commentaries on comparative genomic analysis of esophageal cancers: genomic polymorphisms, the genetic and epigenetic drivers in esophageal cancers, and the collection of data in the UK Barrett's Oesophagus Registry.

Polymorphisms in the fetal progesterone receptor and a calcium-activated potassium channel isoform are associated with preterm birth in an Argentinian population.

OBJECTIVE: To investigate genetic etiologies of preterm birth (PTB) in Argentina through evaluation of single-nucleotide polymorphisms (SNPs) in candidate genes and population genetic admixture. STUDY DESIGN: Genotyping was performed in 389 families. Maternal, paternal and fetal effects were studied separately. Mitochondrial DNA (mtDNA) was sequenced in 50 males and 50 females. Y-chromosome anthropological markers were evaluated in 50 males. RESULT: Fetal association with PTB was found in the progesterone receptor (PGR, rs1942836; P=0.004). Maternal association with PTB was found in small conductance calcium activated potassium channel isoform 3 (KCNN3, rs883319; P=0.01). Gestational age associated with PTB in PGR rs1942836 at 32-36 weeks (P=0.0004). MtDNA sequencing determined 88 individuals had Amerindian consistent haplogroups. Two individuals had Amerindian Y-chromosome consistent haplotypes. CONCLUSION: This study replicates single locus fetal associations with PTB in PGR, maternal association in KCNN3, and demonstrates possible effects for divergent racial admixture on PTB.

The relationship between smoking and severe dysplastic disease in patients with Barrett's columnar-lined oesophagus.

The aim of this study was to examine the relationship between smoking and oesophageal high-grade dysplasia (HGD) or adenocarcinoma (AC) in a large cohort of patients with Barrett's columnar-lined oesophagus (CLO). A total of 1280 patients diagnosed with CLO and registered with the UK National Barrett's Oesophagus Registry were included. Data, including smoking habits, were collected from the patient's notes and development of HGD or AC noted. Analysis was performed with SPSS using logistic regression for calculation of odds ratios (ORs) for development of HGD/AC. Data on smoking habits were available in 956 (74.6%) patients. There was no significant difference between smokers and nonsmokers in mean age (P=0.877) or length of follow-up (P=0.359). There was a significant risk of HGD/AC in patients with any history of smoking compared with those who had never smoked (P<0.001, OR 2.81). Ex-smokers of 10 years or more remained at a significantly higher risk of HGD/AC compared with those who had never smoked (P=0.001, OR 3.37). Current smokers were not at a significantly higher risk of HGD/AC compared with ex-smokers (P=0.857) nor were those who smoked at least 20 a day compared with those who smoked fewer than 20 a day (P=0.632). In patients with CLO, smoking appears to be a significant risk factor for the development of severe dysplastic disease; however, we did not observe a dose-dependent effect of smoking on progression of disease.

Maternal imprinting and female predominance in familial Crohn's disease.

BACKGROUND AND AIM: Although the genetic risk factors for familial and sporadic inflammatory bowel disease (IBD) seem identical, the relative risk for contracting IBD in the familial setting is larger as that seen in the population at large, suggesting an important role of epi- and/or paragenetic factors in familial IBD. Epidemiological data indicate a female predominance in IBD, but how this relates to familial IBD has not been assessed. METHODS: Familial IBD patients (N=608) were compared with a cohort of 415 sporadic IBD patients with regards to the patterns of sex and disease type distribution. The imprinting pattern in 87 families in which both a parent and a child had IBD was tested using Galton binominal statistics. RESULTS: The percentage of females in familial IBD population was significantly higher (61%; female/male ratio 1.5) compared with sporadic IBD (54%; female/male ratio 1.2; p=0.011). The analysis of offspring sex distribution pattern revealed significantly higher female to female transmission compared with female to male transmission rate (36 vs. 18, respectively; p=0.02). A significantly higher number of mother to child transmissions (55 vs. 32 of father to child transmissions) was observed (p=0.018). The female imprinting was specifically related to Crohn's disease (31 vs. 14 mother vs. father to child transmissions, respectively; p=0.016). CONCLUSION: We propose that a female sex-specific epigenetic inheritance pattern for Crohn's disease is a major contributing factor in the family-specific risk in Crohn's disease. Sex-specific manifestation of familial Crohn's disease can partly explain the epidemiologically observed increased relative risk for females for contracting IBD.

Barrett's esophagus: surveillance and reversal.

The following on surveillance and reversal of Barrett's esophagus (BE) includes commentaries on criteria for surveillance even when squamous epithelium stains normally with a variety of biomarkers; the long-term follow-up of surgery versus endoscopic ablation of BE; the recommended surveillance intervals in patients without dysplasia; the sampling problems related to anatomic changes following fundoplication; the value of tissue spectroscopy and optical coherence tomography; the cost-effectiveness of biopsy protocols for surveillance; the quality of life of Barrett's patients; and risk stratification and surveillance strategies.

Barrett's esophagus registries.

The following on Barrett's esophagus registries contains commentaries on the data sets to be included, organizational issues, and the demographic, lifestyle, and diagnostic differences between the United States and Europe. The importance of collaborative studies is also discussed.

Barrett's, blood groups and progression to oesophageal cancer: is nitric oxide the link?

INTRODUCTION: Incidence of oesophageal adenocarcinoma (OAC) is increasing rapidly. OAC arises in columnar-lined oesophagus (CLO), a metaplastic change affecting some patients with gastro-oesophageal reflux disease (GORD). As yet there is no reliable method of identifying those at highest risk. Our earlier observation of an association between OAC and blood group O Rhesus negative, if confirmed, may help identify those at greatest risk. AIM AND METHODS: To assess the distribution of blood group and Rhesus D (RhD) factor in patients with GORD compared with the blood donating general population. GORD was categorized as nonerosive reflux (NER), erosive oesophagitis, CLO and OAC. The Rotherham Hospital database holds details of all GORD, CLO and OAC patients seen in the Gastroenterology Unit. Blood group information for patients with GORD was obtained from patients' records and the hospital's blood transfusion service. The blood group distribution in the general population was obtained from the National Blood Transfusion Service. The number of expected to observed patients in each blood group for each subtype was compared. RESULTS: Two thousand six hundred and ten NER, 2813 erosive oesophagitis, 568 CLO and 73 OAC patients had a recorded blood group. For RhD positive patients observed proportions in each blood group were similar to expected. The most striking difference was the marked excess of OAC in blood group O, Rhesus negative (P=0.002). CONCLUSION: CLO patients with blood group O, RhD negative carry a disproportionately higher risk of developing OAC. The mechanism is unknown but the finding has practical application in guiding risk stratification and intensity of surveillance.

Surveillance of Barrett's columnar-lined oesophagus in the UK: endoscopic intervals and frequency of detection of dysplasia.

OBJECTIVES: Endoscopic surveillance of patients with columnar-lined oesophagus (CLO) may identify those with early adenocarcinoma (AC). The benefits of surveillance are unproven and there is little evidence to support recommendations for precise endoscopic intervals. We sought to examine surveillance practice for CLO in the UK and the impact of endoscopic intervals on detection of dysplastic disease. METHODS: Eight hundred and seventeen patients with CLO, registered with the UK National Barrett's Oesophagus registry and undergoing surveillance were studied. Endoscopic intervals were calculated and frequency of detection of dysplastic disease analysed using chi2 test of association. Factors affecting surveillance intervals were analysed using multiple linear regression. RESULTS: 94.7% of patients with low-grade dysplasia (LGD), 95.0% with high-grade dysplasia (HGD) and 71.4% with AC were diagnosed on surveillance endoscopies. Mean endoscopic surveillance intervals varied between the centres from 1.07 to 1.63 years for nondysplastic CLO; 0.69-1.19 years for LGD, and 0.35-1.17 years for HGD; with overall mean surveillance intervals of 1.29, 1.01 and 0.44 years, respectively. When LGD was surveyed, significantly higher proportions of HGD/AC were detected at intervals of 3 months or less (P=0.013). Shorter endoscopic intervals were significantly associated with the presence of oesophageal strictures (P=0.002), ulcers (P=0.046), increasing patient age (P<0.001) and higher grade of dysplasia surveyed (P<0.001). CONCLUSION: A variation in surveillance practice for CLO was observed throughout the UK. A large proportion of dysplastic disease is detected on specific surveillance endoscopies. Shorter endoscopic intervals for surveillance of LGD are associated with an increased detection of HGD/AC.

Treatment modality and risk of development of dysplasia and adenocarcinoma in columnar-lined esophagus.

Columnar metaplasia is the precursor lesion for esophageal adenocarcinoma, resulting from prolonged gastroesophageal reflux. The influence of the efficacy of reflux control on the development of neoplastic change in columnar-lined esophagus is not established. This study compares the rate of development of dysplasia and adenocarcinoma in patients with columnar metaplasia of the esophagus between patients treated pharmacologically and those treated with antireflux surgery. This study is a retrospective review of a cohort of patients enrolled in a multicenter national registry involving 738 patients from seven UK centers. Forty-one were treated with antireflux surgery, 42 with H2 receptor antagonist, 532 with proton pump inhibitor, and 114 with a combination of these medications. Nine had none of these medications or surgery. Total follow-up was 3697 years. Mean age and follow-up for patients treated medically were 61.6 and 4.96 years and surgically were 50.5 and 6.19 years, respectively. No patient in the surgical group developed high-grade dysplasia (HGD) or adenocarcinoma. Twenty patients treated medically developed adenocarcinoma and 10 developed HGD. Hazards ratio comparing pharmacological to surgical therapy for development of all grades of dysplasia and adenocarcinoma 1.77 (P = 0.272). Log rank test comparing antireflux surgery to pharmacological therapy for development of HGD or adenocarcinoma P = 0.1287 and for adenocarcinoma P = 0.2125. Although there was a trend towards greater efficacy of antireflux surgery over pharmacological therapy in reducing the development of dysplasia and adenocarcinoma, this did not reach statistical significance.

Current United Kingdom practice in the diagnosis and management of columnar-lined oesophagus: results of the United Kingdom National Barrett's Oesophagus Registry endoscopist questionnaire.

The management of the columnar-lined oesophagus (CLO) has remained controversial for the last 10 years, with practices varying between individual physicians and centres throughout the United Kingdom. Various guidelines exist, although international consensus over issues such as the recognition of short-segment disease and surveillance policies for uncomplicated and dysplastic disease is lacking. Questionnaires examining the practice of diagnosis and surveillance of CLO were sent to 41 centres spread throughout the United Kingdom. Thirty (73%) centres replied. Twelve (40%) had a specific written policy for the management of CLO. Twenty-five (83%) centres made a diagnosis of CLO in the presence of any length of columnarization. Twenty-seven (90%) centres surveyed CLO with 81% of them undertaking a selective surveillance policy. Endoscopic surveillance intervals were fairly consistent for uncomplicated CLO and high-grade dysplasia, but were less consistent for low-grade dysplasia. Results confirmed that even amongst centres with a specialist interest in the management of CLO, marked variations exist in diagnosis and surveillance practice.

Barrett's Registries in Europe: report of an International Workshop.

A workshop on Barrett's Registries in Europe was held in Venice in February 2007 with the aim of establishing the feasibility of joint projects. It was concluded that there were enough areas of similarity and common objectives for EBRA to be set up for future collaboration.

Relevance of the detection of intestinal metaplasia in non-dysplastic columnar-lined oesophagus.

OBJECTIVE: In the USA, detection of intestinal metaplasia is a requirement for enrollment in surveillance programmes for dysplasia or adenocarcinoma in columnar-lined oesophagus. In the UK, it is believed that failure to detect intestinal metaplasia at index endoscopy does not imply its absence within the columnarized segment or that the tissue is not at risk of neoplastic transformation. The aim of this study was to investigate the factors predicting the probability of detection of intestinal metaplasia in the columnarized segment. MATERIAL AND METHODS: Demonstration of intestinal metaplasia was analysed in 3568 biopsies of non-dysplastic columnar-lined oesophagus from 1751 patients from 7 centres in the UK. Development of dysplasia and adenocarcinoma was analysed in 322 patients without intestinal metaplasia and compared with that in 612 patients with intestinal metaplasia. RESULTS: Intestinal metaplasia was more commonly detected in males than in females (odds ratio 1.244), longer segment length (10.3% increase per centimetre) and increasing number of biopsies taken (24% increase per unit increase). After 5 years of follow-up, 54.8% of patients without intestinal metaplasia at index endoscopy demonstrated intestinal metaplasia, and 90.8% after 10 years. There was no significant difference in the rate of development of dysplasia or adenocarcinoma between patients with or without intestinal metaplasia detection at index endoscopy. CONCLUSIONS: Detection of intestinal metaplasia is subject to significant sampling error. It increases with segment length and number of biopsies taken. In the majority of patients, if sufficient biopsies are taken over time, intestinal metaplasia will be demonstrated. The decision to offer surveillance should not be based upon the presence or absence of intestinal metaplasia at index endoscopy as the risk of dysplasia and adenocarcinoma is similar in both groups.

Short segment columnar-lined oesophagus: an underestimated cancer risk? A large cohort study of the relationship between Barrett's columnar-lined oesophagus segment length and adenocarcinoma risk.

OBJECTIVE: Longer columnar-lined oesophagus (CLO) segments have been associated with higher cancer risk, but few studies have demonstrated a significant difference in neoplastic risk stratified by CLO segment length. This study establishes adenocarcinoma risk in CLO by segment length. METHODS: This is a multicentre retrospective observational study. Medical records of 1000 patients registered from six centres were examined and data extracted on demographic factors, endoscopic features and histopathology of oesophageal biopsies. Adenocarcinoma incidence was evaluated for patients stratified by their diagnostic segment length. RESULTS: Seven hundred and eighty-one patients had biopsy-proven CLO and a segment length recorded. Four hundred and ninety patients had at least 1 year of follow-up, providing 2620 patient-years of follow-up for incidence analysis. The overall annual adenocarcinoma incidence was 0.62%/year (95% confidence interval: 0.36-1.01). The annual incidence in the segment length groups was 0.59% (0.19-1.37) in short segment (3 6 9 cm; P=0.004. CONCLUSION: This study demonstrates that the neoplastic risk of CLO varies according to segment length, and that overall, the risk of adenocarcinoma development is similar in short-segment and long-segment (>3 cm) CLO. The highest adenocarcinoma risk was found in the longest CLO segments and lowest risk in segments >3

Helicobacter pylori infection and severity of reflux-induced esophageal disease in a cohort of patients with columnar-lined esophagus.

The relationship between Helicobacter pylori infection and reflux-induced esophageal diseased is controversial. We examined esophageal disease severity in patients with columnar-lined esophagus and compared results between patients with and without Helicobacter pylori infection. Medical records of 1000 patients diagnosed with columnar-lined esophagus were examined. Endoscopic and histological findings of reflux-induced esophageal disease were compared between H. pylori-positive and H. pylori-negative patients. Four hundred twenty-nine patients (42.9%) showed evidence of H. pylori status, of whom 239 (55.7%) were positive and 190 (44.3%) negative. There were no significant differences in length of columnar-lined segment (P = 0.305), frequency of associated esophagitis (P = 0.583), or presence of gastroduodenal inflammation (P = 0.335, P = 0.131) between the two groups. Histological grade of esophageal disease severity was similar between them, with no statistically significant differences (P = 0.231). We conclude that in patients with established columnar-lined esophagus, there appears to be no difference in severity of reflux-induced esophageal disease between those with and those without H. pylori infection.

Age and sex distribution of the prevalence of Barrett's esophagus found in a primary referral endoscopy center.

BACKGROUND: Both the demographics underlying the sex ratio in the prevalence of Barrett's esophagus (BE) and the status of BE without intestinal metaplasia (IM) are unclear. AIMS: To establish the demographics of histologically proven BE, IM+ and IM-, over a 15-yr period from a primary referral, endoscopy unit. PATIENTS AND METHODS: For all BE patients aged 20-89 yr, identified between 1982 and 1996, IM+ or IM-, prevalences were calculated per 100 first endoscopies. RESULTS: A total of 492 cases of BE, 320 (248 IM+) in males, 175 (127 IM+) in females were identified in 21,899 first endoscopies (10,939 males, 10,960 females). Between ages 20 and 59 yr in males and 20-79 in females, IM+, IM- and all BE prevalences rose by +/-7.36% for each additional year of age (p= 0.92) with, however, a 20-yr age shift between the sexes, resulting in a male:female OR 4.15 95% CI 2.99-5.77. A declining rate of increase in over 59 males resulted in an overall male:female OR 2.14, 95% CI 1.77-2.58. Over the age of 79 yr, BE prevalences/100 first endoscopies fell from a maximum of 5.1 in males and 3.65 in females to 3.38 and 2.53, respectively. CONCLUSION: The 4:1 sex ratio and 20-yr age shift between males and females in the prevalence of BE, both IM+ and IM-, found in younger age groups, was the main cause of the overall BE 2:1 sex ratio. The very similar demographics of IM- and IM+ BE suggest they may be two consecutive stages in the same metaplastic process.