Endothelial colony-forming cells and pro-angiogenic cells: clarifying definitions and their potential role in mitigating acute kidney injury.

Acute kidney injury (AKI) represents a significant clinical concern that is associated with high mortality rates and also represents a significant risk factor for the development of chronic kidney disease (CKD). This article will consider alterations in renal endothelial function in the setting of AKI that may underlie impairment in renal perfusion and how inefficient vascular repair may manifest post-AKI and contribute to the potential transition to CKD. We provide updated terminology for cells previously classified as 'endothelial progenitor' that may mediate vascular repair such as pro-angiogenic cells and endothelial colony-forming cells. We consider how endothelial repair may be mediated by these different cell types following vascular injury, particularly in models of AKI. We further summarize the potential ability of these different cells to mitigate the severity of AKI, improve perfusion and maintain vascular structure in pre-clinical studies.

Using dislocations to probe surface reconstruction in thick freely suspended liquid crystalline films.

Surface interactions can cause freely suspended thin liquid crystalline films to form phases different from the bulk material, but it is not known what happens at the surface of thick films. Edge dislocations can be used as a marker for the boundary between the bulk center and the reconstructed surface. We use noncontact mode atomic force microscopy to determine the depth of edge dislocations below the surface of freely suspended thick films of 4-n-heptyloxybenzylidene-4-n-heptylaniline (7O.7) in the crystalline B phase. Here, 3.0±0.1 nm high steps are found with a width that varies with temperature between 56 and 59°C. Using a strain model for the profile of liquid crystalline layers above an edge dislocation to estimate the depth of the dislocation, we find that the number of reconstructed surface layers increases from 4 to 50 layers as the temperature decreases from 59 to 56°C. This trend tracks the behavior of the phase boundary in the thickness dependent phase diagram of freely suspended films of 7O.7, suggesting that the surface may be reconstructed into a smectic F region.

Helicobacter species in the human colon.

OBJECTIVE: To determine the prevalence, frequency and colonization patterns of Helicobacter species throughout the colon. METHOD: Patients having initial colonoscopy for nonspecific gastrointestinal disturbance had colonic biopsies taken from up to four sites during colonoscopy and examined for evidence of the Helicobacteraceae family using a group-specific PCR. Serum was also collected and examined for IgG reactivity to Helicobacter pylori. RESULTS: 100 patients had colonoscopy of whom 35 were found to have DNA evidence of Helicobacter species throughout the colon, with 22 having H. pylori. Fifteen patients had a demonstrable serum IgG response to H. pylori that was not always associated with molecular evidence of H. pylori DNA in colon biopsies and vice versa. No specific association with colon disease was found in patients with H. pylori infection. CONCLUSION: We found evidence of Helicobacter infection in a significant number of patients presenting for colonoscopy but no specific association between the presence of these bacteria and colon disease. Our finding of disparity between molecular and serological techniques to detect Helicobacter species suggests that future studies should not rely on serology alone to detect these bacteria in the human colon.

Thiopurine S-methyltransferase (TPMT) genotype does not predict adverse drug reactions to thiopurine drugs in patients with inflammatory bowel disease.

BACKGROUND: Azathioprine and mercaptopurine (MP) are well established treatments for inflammatory bowel disease but they have severe adverse effects that prevent their use in some patients. The likelihood and type of adverse effect may relate to thiopurine methyltransferase (TPMT) enzyme activity and genotype. AIM: To compare the TPMT genotype frequencies in patients with inflammatory bowel disease who have had severe adverse effects to those who tolerate azathioprine or MP (controls). METHODS: Patients with inflammatory bowel disease who had been treated with azathioprine or MP in Christchurch between 1996 and 2002 were identified. Patients with adverse effects, and controls, were invited to provide a peripheral blood sample for analysis of TPMT genotype. The genotype frequencies were then compared between the two groups. RESULTS: Fifty-six patients were identified with adverse effects requiring cessation of therapy, of which 50 were genotyped. Reactions included allergic-type (25%), hepatitis (33%), nausea/vomiting (14%), bone marrow suppression (10%), pancreatitis (6%) and other (12%). Five of 50 patients with reactions had TPMT genotype *1/*3, one had *3/*3, and the rest had the wildtype genotype *1/*1. The patient with genotype *3/*3 had severe pancytopenia requiring hospitalization. Three of 50 controls had the *1/*3 genotype and the rest were *1/*1. CONCLUSIONS: The TPMT allele frequency in our population with inflammatory bowel disease is similar to that reported elsewhere. There was a slight trend for more frequent TPMT mutations in the patients with adverse reactions, but this was not statistically significant. Most patients with reactions did not have gene mutations.

High prevalence of coeliac disease in a population-based study from Western Australia: a case for screening?

OBJECTIVES: To determine the prevalence of coeliac disease in an Australian rural community. DESIGN: Retrospective analysis of stored serum samples from 3,011 random subjects from the Busselton Health Study. IgA antiendomysial antibodies (AEA) were detected by indirect immunofluorescence, and subjects testing positive were contacted and offered small-bowel biopsy. MAIN OUTCOME MEASURES: Prevalence of AEA positivity and biopsy-proven coeliac disease in the community with reference to the proportion of symptomatic to asymptomatic patients. RESULTS: 10 of 3,011 subjects were AEA positive. One subject had died, one subject could not be traced and one refused small-bowel biopsy. All subjects with detectable AEA who consented to biopsy had pathological changes consistent with coeliac disease. The prevalence of newly diagnosed biopsyproven coeliac disease is 7 in 3,011 (1 in 430). Two further subjects had a diagnosis of coeliac disease before this study. When all AEA-positive patients and those previously diagnosed are included, the prevalence is 12/3,011 (1 in 251). There was a significant clustering of cases in the 30-50-years age range, with 10/12 (83%; 95% CI, 52%-98%) aged between 30 and 50 years, compared with 1,092/3,011 (36%; 95% CI, 35%-38%) of the total population (P<0.03). Of the eight AEA-positive subjects who could be contacted, four had symptoms consistent with coeliac disease and four were asymptomatic. Three subjects were iron-deficient, four subjects had first-degree relatives with coeliac disease and one subject had type 1 diabetes mellitus. CONCLUSIONS: The prevalence of coeliac disease is high in a rural Australian community. Most patients are undiagnosed, and asymptomatic.

Fecal occult blood and flexible sigmoidoscopy screening for colorectal cancer: modeling the impact on colonoscopy requirements and cancer detection rates.

AIM: The aim of this study was to estimate the colonoscopy requirements and the likely impact of fecal occult blood and flexible sigmoidoscopy screening on the detection of colorectal cancer by using previously published data. METHODS: Fecal occult blood and flexible sigmoidoscopy screening programs were applied to the 2.04 million subjects aged 50-65 years, at a participation rate of 40%. The following strategies were evaluated: Fecal occult blood testing with colonoscopy follow up of all positive tests; flexible sigmoidoscopy with colonoscopy follow up of all adenomatous polyps; and flexible sigmoidoscopy with colonoscopy follow up of all adenomatous polyps > 10 mm in size. RESULTS: The fecal occult blood program detected 5.6% of all colorectal cancer cases at a rate of 2,914 colonoscopies/percentage of detection of colorectal cancer. The flexible sigmoidoscopy program detected 14% of all colorectal cancer cases at a rate of 8,160 colonoscopies/percentage of detection of colorectal cancer. The flexible sigmoidoscopy program with follow up of adenomatous polyps > 10 mm in size detected 13% of all colorectal cancer cases at a rate of 1,230 colonoscopies/percentage of detection of colorectal cancer. CONCLUSIONS: Flexible sigmoidoscopy screening followed by colonoscopic follow up of adenomatous polyps > 10 mm in size is the most efficient screening strategy in terms of colonoscopies generated and cases of colorectal cancer detected.

Adult coeliac disease: prevalence and clinical significance.

BACKGROUND AND AIMS: Although coeliac disease is a common condition, the role of population screening is not clear. The aim of this study was to determine the prevalence and clinical significance of coeliac disease in the adult population of Christchurch, New Zealand. METHODS: A total of 1064 adults randomly selected from the 1996 Christchurch electoral rolls were enlisted. The subjects were screened for coeliac disease using the anti-endomysial antibody test (EMA), and all those with positive tests were reviewed and underwent a small bowel biopsy. RESULTS: Twelve of the 1064 persons tested (1.1%) were EMA positive and all had small bowel biopsy histology consistent with coeliac disease. Two of the 12 subjects were previously known to be EMA positive although neither had a small bowel biopsy. One additional subject with known and treated coeliac disease was also enrolled but was EMA negative. Thus, the overall prevalence of coeliac disease was 13 of 1064 subjects (1.2%, or 1:82), 10 of whom were newly diagnosed (0.9%, or 1:106) and three were previously known or suspected to have coeliac disease (0.3%, or 1:355). The prevalence in both sexes was similar. Nine of the 12 EMA-positive coeliac disease subjects identified by the use of screening reported symptoms, of which tiredness and lethargy were the most common. The subjects were of normal stature, although females tended to be lean. None of the subjects were anaemic, but four were iron deficient and four folate deficient. Five of the 12 had sustained bone fractures. Bone mineral density was reduced in males but not in females. CONCLUSIONS: The prevalence of coeliac disease in the adult population of Christchurch, New Zealand, is 1.2%. Unrecognized coeliac disease which was detected by population screening was three-fold more common than proven or suspected coeliac disease. Population screening may identify subjects who could benefit from treatment.

The prevalence of viral hepatitis (HAV, HBV and HCV) in the Christchurch community.

AIM: To determine the prevalence of hepatitis A (HAV), hepatitis B (HBV) and hepatitis C (HCV) in adults randomly selected from the Christchurch community. METHODS: A list of names was randomly generated from the Christchurch electoral roll and subjects were sequentially contacted and invited to participate. A blood sample was taken and tested for hepatitis A (IgG anti-HAV antibody), hepatitis B (HBsAg and anti-HBc) and HCV (anti-HCV antibody) using Abbott Elisa kits. Subjects positive for HBsAg were also tested for HBeAg/HBV DNA. Those positive for anti-HBc were tested for anti-HBs. HCV antibody positive samples were tested for HCV RNA using PCR. RESULTS: 1064 subjects (30.3% of those invited) participated in the study. The prevalence of HAV antibodies was 27.9%, and increased with age. The overall prevalence of HBV markers was 42/1064 (4.2%), and of these 0.3% were HBsAg positive and 3.9% were considered immune. No gender or ethnic differences in these proportions were observed. The seroprevalence of HVC antibody was 3/1064 (0.3%), two of whom were also PCR positive for HCV RNA. CONCLUSION: In the Christchurch community there was a high prevalence of antibodies to HAV, which increased with age. The prevalence of HBsAg and antibody to HCV were both low at 0.3%.

Flexible sigmoidoscopy screening for colorectal cancer in average-risk people: update of a community-based project.

OBJECTIVES: To analyse results of a screening program for colorectal cancer using flexible sigmoidoscopy. DESIGN: Survey of results of screening program and follow-up colonoscopies and identification of missed cases from State cancer registry data. PARTICIPANTS: Asymptomatic, average-risk people aged 55-64 years who were either mailed invitations after random selection from the electoral roll or volunteered after hearing about the program. SETTING: Fremantle Hospital, Western Australia (a public teaching hospital), July 1995 to November 1999 (first 4.5 years of the screening program). MAIN OUTCOME MEASURES: Participation rates; lesions detected; stage of colorectal cancers diagnosed at the hospital before and after the screening program began (1989-1995 versus 1996-1999); and diagnoses of colorectal cancer in previously screened individuals (from State cancer registry data). RESULTS: 6446 people were mailed invitations, and 1483 were screened (23% participation rate). Another 1122 people volunteered, giving 2605 people screened overall. Flexible sigmoidoscopy showed adenomatous polyps in 352 people (14%), and colonoscopy was recommended in 399 (15%) on the basis of clinically suspicious lesions. Colonoscopy was performed in 302 (76% participation rate). Screening and follow-up colonoscopy detected 14 colorectal cancers (10 invasive, with eight of these Dukes stage A). One participant was diagnosed with colorectal cancer 12 months after sigmoidoscopy gave normal results. Incidence of colorectal cancer was 119 per 100000 per year, and prevalence was 0.5%. Before the screening program, 12% of cancers diagnosed at our hospital were Dukes stage A, compared with 28% after (P<0.001). CONCLUSIONS: Flexible sigmoidoscopy screening is an acceptable strategy in asymptomatic, average-risk people which detects colorectal cancer and adenomatous polyps. Screening has been associated with a trend to earlier presentation of cancer in our institution.

Seroprevalence of Helicobacter pylori in the adult population of Christchurch: risk factors and relationship to dyspeptic symptoms and iron studies.

AIM: To determine the prevalence of Helicobacter pylori infection in subjects randomly selected from the Christchurch population and to determine the risk factors and symptoms related to the infection. METHODS: A list of names was randomly generated from the 1996 electoral roll and subjects were sequentially contacted and invited to participate. A questionnaire on dyspeptic symptoms was completed and the subject's serum was analysed for H. pylori antibodies using the Roche method. Equivocal samples were retested by the Meridian method. RESULTS: One thousand and sixty-four subjects participated in the study. In four subjects results for H. pylori were indeterminate and these subjects were excluded from analysis. Of the remaining 1060 subjects, 254 (24.0%) were seropositive for H. pylori. The seropositivity in males (n=444) was 25.9% and in females (n=616) 22.6%. On multivariate analysis age, ethnicity, low income and smoking > 20 cigarettes per day were all independent predictors of H. pylori seropositivity. H. pylori positive subjects had shorter stature compared to those who were seronegative. The symptom scores for dyspepsia were similar in both the seropositive and seronegative subjects. In males the serum iron levels were lower in seropositive subjects but there were no significant differences in serum ferritin in either males or females between seropositive and seronegative subjects. CONCLUSION: H. pylori is a common infection in the Christchurch community with the prevalence increasing significantly with age. H. pylori positive subjects had shorter stature and in males lower serum iron levels were observed. Infection was not associated with an increased risk of dyspeptic symptoms.

Distal colonic neoplasms predict proximal neoplasia in average-risk, asymptomatic subjects.

Flexible sigmoidoscopy has been recommended as a screening method to reduce the incidence of colorectal cancer in asymptomatic, average-risk subjects through the early detection and removal of polyps. However, the association between distal and proximal colonic neoplasia and, hence, the requirement for colonoscopic follow up of screen-detected distal neoplasms is unclear. Our aims were: (i) to evaluate the risk of having proximal neoplasms in those with distal colonic neoplasms; and (ii) to determine whether the risk was dependent on the number, size, histology or morphology of the distal lesions. We prospectively evaluated asymptomatic subjects in a flexible sigmoidoscopy based screening programme. Those with rectosigmoid neoplasia underwent colonoscopy. The number, size, histology and morphology of the polyps were recorded. Advanced lesions were defined as adenomas > 1 cm or with a villous component or severe dysplasia, carcinoma in situ or cancer. Adenomatous polyps were found in 17% (135) of screening flexible sigmoidoscopies. At colonoscopy, up to 30% of subjects with distal colonic neoplasms had synchronous proximal lesions at colonoscopy and up to 20% had advanced proximal lesions. The risk of proximal colonic neoplasia was increased in those with distal sessile colonic neoplasms but appeared independent of distal lesion size, number or morphology. In conclusion, distal colonic neoplasia predicts proximal neoplasia in up to 30% of subjects and these were advanced lesions in up to 20%. We recommend that all subjects with biopsy proven distal colonic neoplasia undergo colonoscopy.

The significance of haemochromatosis gene mutations in the general population: implications for screening.

BACKGROUND: Haemochromatosis is associated with mutations in the HFE gene but the significance of these mutations in the general population is unknown. AIMS: To determine the frequency of HFE gene mutations in the general population, their effect on serum iron indexes, and their role in screening for haemochromatosis. METHODS: Deoxyribonucleic acid (DNA) from 1064 randomly selected subjects was analysed for the C282Y and H63D mutations in the HFE gene. Serum iron, transferrin saturation, and ferritin were measured and individuals with increased iron indexes were investigated to confirm or exclude a clinical diagnosis of haemochromatosis. RESULTS: Mutations were identified in 409 individuals (38.4%) with heterozygote (carrier) frequencies of 13.2% and 24.3% for the C282Y and H63D mutations respectively. Heterozygosity for either mutation significantly increased serum iron and transferrin saturation but despite a similar trend for ferritin, this was only significant for C282Y homozygotes. Five individuals (0.47%) were homozygous for the C282Y mutation, three of whom had haemochromatosis confirmed by liver biopsy (0.28%). The other two C282Y homozygotes would not have been detected by phenotypic screening alone. CONCLUSIONS: HFE mutations are present in 38.4% of the population, affect serum iron indexes, and are important determinants of iron status. The population frequency of genetically defined haemochromatosis (C282Y homozygosity) is approximately one in 200 and is higher than the prevalence of clinically apparent haemochromatosis.

Gallbladder polyps: prospective study.

The aim of this study was to describe the natural history of gallbladder polyps. Thirty-eight subjects who had been previously identified as having gallbladder polyps in an epidemiologic study of gallstone prevalence in 627 diabetic subjects and matched controls were followed longitudinally. Follow-up sonograms were obtained on 33 and 22 of the 38 subjects at 2 and 5 years, respectively. Prevalence for gallbladder polyps in this population was 6.7%, with a marked male predominance (odds ratio 2.3). No statistical difference in prevalence was found between diabetic subjects and nondiabetic controls. Ninety percent of the polyps were less than 10 mm in diameter, with no polyp being larger than 12 mm. During the follow-up period no changes suggestive of malignant transformation were observed. In conclusion, we found that gallbladder polyps were relatively common and that few significant changes occurred over a 5 year period. In asymptomatic subjects in whom gallbladder polyps less than 10 mm in diameter are found incidentally, the likelihood of malignant transformation is low.

Treatment of chronic hepatitis C with interferon alpha.

AIM: To evaluate the response to interferon alpha in patients with chronic hepatitis C in Christchurch. METHOD: Fifteen patients with chronic HCV were given interferon alpha 3 million units subcutaneously three times a week for up to 24 weeks. A complete and partial biochemical response was defined by relative changes in the serum alanine aminotransferase (ALT) during the treatment period. Detection of HCV RNA by the polymerase chain reaction was used to determine the virological response to treatment. RESULT: A complete or partial response was seen in nine of the 15 patients (60%). Histological improvement was demonstrated in all patients for whom paired liver biopsies were taken. Following treatment two of the five complete responders have shown a sustained biochemical response but only one has remained PCR negative, ie, a sustained virological responder. The other three, complete responders and all four partial responders relapsed. CONCLUSION: The response to treatment and relapse was comparable with other studies. It remains to be shown whether investigation of the viral titre and/or viral type will help to explain the high relapse rate in these patients with chronic HCV.