Toenail trace element status and risk of Barrett's oesophagus and oesophageal adenocarcinoma. Results from the FINBAR study

Trace elements have been cited as both inhibitory and causative agents of cancer but importantly exposure to them is potentially modifiable. Our study aimed to examine toenail trace element status and risk of Barrett's oesophagus (BO) and oesophageal adenocarcinoma (OAC). Toenail clippings from each hallux were obtained from 638 participants of the FINBAR (Factors Influencing the Barrett's Adenocarcinoma Relationship) study comprising 221 healthy controls, 98 reflux oesophagitis, 182 BO and 137 OAC cases. The concentrations of eight toenail trace elements were determined using instrumental neutron activation analysis. Using multivariable adjusted logistic regression analysis, odds ratios (OR) and 95% confidence intervals (CIs) were calculated within tertiles of trace element concentrations. A twofold increased risk of BO was observed, but not OAC, among individuals in the highest tertile of toenail zinc status OR 2.21 (95% CI, 1.11-4.40). A higher toenail selenium status was not associated with risk of OAC OR 0.94 (95% CI, 0.44-2.04) or BO OR 0.89 (95% CI, 0.37-2.12). A borderline significant increased risk of BO was detected with a higher toenail cobalt concentration, OR 1.97 (95% CI, 1.01-3.85). No association was found between toenail levels of chromium, cerium, mercury and OAC or BO risk. This is the first case-control study to investigate a variety of trace elements in relation to OAC and BO risk. Despite antioxidant and proapoptotic properties, no associations were found with selenium. Higher concentrations of toenail zinc and cobalt were associated with an increased BO risk, but not OAC. These findings need confirmation in prospective analysis.

Characterisation of the Timing and Prevalence of Receptor Tyrosine Kinase Expression Changes in Esophageal Carcinogenesis

Despite being common in epithelial malignancies, the timing of receptor tyrosine kinase (RTK) up-regulation is poorly understood and therefore hampers the identification of the receptor to target for effective treatment. We aimed to determine if RTK expression changes were early events in carcinogenesis. Esophageal adenocarcinoma and its pre-invasive lesion, Barrett's esophagus, were used for immunohistochemical analysis of the RTK panel, EGFR, ErbB2, ErbB3, Met and FGFR2, by utilising a cohort of patients with invasive disease (n = 367) and two cohorts with pre-invasive disease, one cross-sectional (n = 110) and one longitudinal in time (n = 91). The results demonstrated that 51% of esophageal adenocarcinomas over-expressed at least one of the RTK panel; with 21% of these over-expressing multiple receptors. Up-regulation of RTK expression was an early event corresponding with low grade dysplasia development (25% in areas without dysplasia vs. 63% in low grade dysplasia, p

Nonsteroidal anti-inflammatory drugs and the esophageal inflammation-metaplasia-adenocarcinoma sequence

Observational studies suggest that nonsteroidal anti-inflammatory drugs (NSAIDs) reduce the risk of esophageal adenocarcinoma, but it is not known at what stage they may act in the esophageal inflammation-metaplasia-adenocarcinoma sequence. In an all-Ireland case-control study, we investigated the relationship between the use of NSAIDs and risk of reflux esophagitis, Barrett's esophagus, and esophageal adenocarcinoma. Patients with esophageal adenocarcinoma, long-segment Barrett's esophagus and population controls were recruited from throughout Ireland. Esophagitis patients were recruited from Northern Ireland only. Data were collected on known and potential risk factors for esophageal adenocarcinoma and on the use of NSAIDs, including aspirin, at least 1 year before interview. Associations between use of NSAIDs and the stages of the esophageal inflammation-metaplasia-adenocarcinoma sequence were estimated by multiple logistic regression. In total, 230 reflux esophagitis, 224 Barrett's esophagus, and 227 esophageal adenocarcinoma and 260 population controls were recruited. Use of aspirin and NSAIDs was associated with a reduced risk of Barrett's esophagus [odds ratio [OR; 95% confidence interval (95% CI)], 0.53 (0.31-0.90) and 0.40 (0.19-0.81), respectively] and esophageal adenocarcinoma [OR (95% CI), 0.57 (0.36-0.93) and 0.58 (0.31-1.08), respectively]. Barrett's esophagus and esophageal adenocarcinoma patients were less likely than controls to have used NSAIDs. Selection or recall bias may explain these results and the results of previous observational studies indicating a protective effect of NSAIDs against esophageal adenocarcinoma. If NSAIDs have a true protective effect on the esophageal inflammation-metaplasia-adenocarcinoma sequence, they may act early in the sequence.

Consensus statements for management of Barrett's dysplasia and early-stage esophageal adenocarcinoma, based on a Delphi process

Esophageal adenocarcinoma (EA) is increasingly common among patients with Barrett's esophagus (BE). We aimed to provide consensus recommendations based on the medical literature that clinicians could use to manage patients with BE and low-grade dysplasia, high-grade dysplasia (HGD), or early-stage EA.

Have patients with esophagitis got an increased risk of adenocarcinoma?:Results from a population-based study

To examine an increased risk of esophageal adenocarcinoma is restricted to patients who develop Barrett's esophagus or whether esophagitis per se is a risk factor for adenocarcinoma.

Epigenetics in Vascular Disease - Therapeutic Potential of New Agents

Vascular diseases, including atherosclerosis, angioplasty-induced restenosis, vessel graft arteriosclerosis and hypertension-related stenosis, remain the most prevalent cause of death in the developed world. The aetiology of vascular diseases is multifactorial with both genetic and environmental factors. Recently, some of the most promising research identifies the epigenetic modification of the genome to play a major role in the disease development, linking the environmental insults with gene regulation. In this process, modification of DNA by methylation, and histone modification by acetylation, methylation, phosphorylation and/or SUMOylation are reported. Importantly, recent studies demonstrated that histone deacetylase (HDAC) enzymes are crucial in endothelial integrity, smooth muscle proliferation and in the formation of arteriosclerosis in animal models. The study of HDACs has shown remarkable specificity of HDAC family members in vascular cell growth/death that influences the disease process. Interestingly, the effects of HDACs on arteriosclerosis development in animal models have been observed after HDAC inhibition using specific inhibitors. This provides a new approach for the treatment of vascular disease using the agents that influence the epigenetic process in vascular cells. This review updates the rapid advances in epigenetics of vascular diseases focusing on the role of HDAC family in atherosclerosis. It will also discuss the underlying mechanisms of histone acetylation in vascular cells and highlight the therapeutic potential of such agents.

A comparison of Diamond Forrester and coronary calcium scores as gatekeepers for investigations of stable chest pain

To determine if calcium scores (CS) could act as a more effective gatekeeper than Diamond Forrester (DF) in the assessment of patients with suspected coronary artery disease (CAD). A sub-study of the Cardiac CT for the Assessment of Chest Pain and Plaque (CAPP) study, a randomised control trial evaluating the cost-effectiveness of cardiac CT in symptomatic patients with stable chest pain. Stable pain was defined as troponin negative pain without symptoms of unstable angina. 250 patients undergoing cardiac CT had both DF scores and CS calculated, with the accuracy of both evaluated against CT coronary angiogram. Criteria given in UK national guidelines were compared. Of the 250 patients, 4 withdrew. 140 (57 %) patients were male. The mean DF was 47.8 and mean CS 172.5. Of the 144 patients with non-anginal pain 19.4 % had significant disease (>50 % stenosis). In general the DF over estimated the presence of CAD whereas the CS reclassified patients to lower risk groups, with 91 in the high risk DF category compared to 26 in the CS. Both receiver operating curve and McNemar Bowker test analysis suggested the DF was less accurate in the prediction of CAD compared to CS [Formula: see text] Projected downstream investigations were also calculated, with the cost per number of significant stenoses identified cheaper with the CS criteria. Patients with suspected stable CAD are more accurately risk stratified by CS compared to the traditional DF. CS was more successful in the prediction of significant stenosis and appears to be more effective at targeting clinical resources to those patients that are in need of them.

British Society of Gastroenterology guidelines on the diagnosis and management of Barrett's oesophagus

These guidelines provide a practical and evidence-based resource for the management of patients with Barrett's oesophagus and related early neoplasia. The Appraisal of Guidelines for Research and Evaluation (AGREE II) instrument was followed to provide a methodological strategy for the guideline development. A systematic review of the literature was performed for English language articles published up until December 2012 in order to address controversial issues in Barrett's oesophagus including definition, screening and diagnosis, surveillance, pathological grading for dysplasia, management of dysplasia, and early cancer including training requirements. The rigour and quality of the studies was evaluated using the SIGN checklist system. Recommendations on each topic were scored by each author using a five-tier system (A+, strong agreement, to D+, strongly disagree). Statements that failed to reach substantial agreement among authors, defined as >80% agreement (A or A+), were revisited and modified until substantial agreement (>80%) was reached. In formulating these guidelines, we took into consideration benefits and risks for the population and national health system, as well as patient perspectives. For the first time, we have suggested stratification of patients according to their estimated cancer risk based on clinical and histopathological criteria. In order to improve communication between clinicians, we recommend the use of minimum datasets for reporting endoscopic and pathological findings. We advocate endoscopic therapy for high-grade dysplasia and early cancer, which should be performed in high-volume centres. We hope that these guidelines will standardise and improve management for patients with Barrett's oesophagus and related neoplasia.

Heller's myotomy and pneumatic dilatation in the treatment of achalasia: a population-based case–control study assessing long-term quality of life

Long-term health-related quality-of-life (HRQL) outcomes have not been widely reported in the
treatment of achalasia. The aims of this study were to examine long-term disease-specific and general HRQL in
achalasia patients using a population-based case–control method, and to assess HRQL between treatment interventions.
Manometrically diagnosed achalasia cases (n = 120) were identified and matched with controls (n = 115)
using a population-based approach. Participants completed general (SF-12) and disease-specific (Achalasia Severity
Questionnaire [ASQ]) HRQL questionnaires, as appropriate, in a structured interview. Mean composite scores
for SF-12 (Mental Component Summary score [MCS-12] and Physical Component Summary score [PCS-12]) and
ASQ were compared between cases and controls, or between intervention groups, using an independent t-test.
Adjusted mean differences in HRQL scores were evaluated using a linear regression model. Achalasia cases were
treated with a Heller’s myotomy (n = 43), pneumatic dilatation (n = 44), or both modalities (n = 33). The median
time from last treatment to HRQL assessment was 5.7 years (interquartile range 2.4–11.5). Comparing achalasia
patients with controls, PCS-12 was significantly worse (40.9 vs. 44.2, P = 0.01), but MCS-12 was similar. However,
both PCS-12 (39.9 vs. 44.2, P = 0.03) and MCS-12 (46.7 vs. 53.5, P = 0.004) were significantly impaired in those
requiring dual treatment compared with controls. Overall however, there was no difference in adjusted HRQL
between patients treated with Heller’s myotomy, pneumatic dilatation or both treatment modalities. In summary,
despite treatment achalasia patients have significantly worse long-term physical HRQL compared with population
controls. No HRQL differences were observed between the treatment modalities to suggest a benefit of one
treatment over another.

Serum- and HDL3-serum amyloid A and HDL3-LCAT activity are influenced by increased CVD-burden

BACKGROUND: High density lipoproteins (HDL) protect against cardiovascular disease (CVD). However, increased serum amyloid-A (SAA) related inflammation may negate this property. This study investigated if SAA was related to CVD-burden.

METHODS: Subjects referred to the rapid chest pain clinic (n = 240) had atherosclerotic burden assessed by cardiac computerised tomography angiography. Subjects were classified as: no-CVD (n = 106), non-obstructive-CVD, stenosis<50% (n = 58) or moderate/significant-CVD, stenosis ≥50% (n = 76). HDL was subfractionated into HDL2 and HDL3 by rapid-ultracentrifugation. SAA-concentration was measured by ELISA and lecithin cholesterol acyltransferase (LCAT) activity measured by a fluorimetric assay.

RESULTS: We illustrated that serum-SAA and HDL3-SAA-concentration were higher and HDL3-LCAT-activity lower in the moderate/significant-CVD-group, compared to the no-CVD and non-obstructive-CVD-groups (percent differences: serum-SAA, +33% & +30%: HDL3-SAA, +65% and +39%: HDL3-LCAT, -6% & -3%; p < 0.05 for all comparisons). We also identified a positive correlation between serum-SAA and HDL3-SAA (r = 0.698; p < 0.001) and a negative correlation between HDL3-SAA and HDL3-LCAT-activity (r = -0.295; p = 0.003), while CVD-burden positively correlated with serum-SAA (r = 0.150; p < 0.05) and HDL3-SAA (r = 0.252; p < 0.001) and negatively correlated with HDL3-LCAT-activity (r = -0.182; p = 0.006). Additionally, multivariate regression analysis adjusted for age, gender, CRP and serum-SAA illustrated that HDL3-SAA was significantly associated with modifying CVD-risk of moderate/significant CVD-risk (p < 0.05).

CONCLUSION: This study has demonstrated increased SAA-related inflammation in subjects with moderate/significant CVD-burden, which appeared to impact on the antiatherogenic potential of HDL. We suggest that SAA may be a useful biomarker to illustrate increased CVD-burden, although this requires further investigation.

Pleiotropic analysis of cancer risk loci on esophageal adenocarcinoma risk

Background: Several cancer-associated loci identified from genome-wide association studies (GWAS) have been associated with risks of multiple cancer sites, suggesting pleiotropic effects. We investigated whether GWAS-identified risk variants for other common cancers are associated with risk of esophageal adenocarcinoma (EA) or its precursor, Barrett's esophagus. 

Methods: We examined the associations between risks of EA and Barrett's esophagus and 387 SNPs that have been associated with risks of other cancers, by using genotype imputation data on 2,163 control participants and 3,885 (1,501 EA and 2,384 Barrett's esophagus) case patients from the Barrett's and Esophageal Adenocarcinoma Genetic Susceptibility Study, and investigated effect modification by smoking history, body mass index (BMI), and reflux/heartburn. 

Results: After correcting for multiple testing, none of the tested 387 SNPs were statistically significantly associated with risk of EA or Barrett's esophagus. No evidence of effect modification by smoking, BMI, or reflux/heartburn was observed. 

Conclusions: Genetic risk variants for common cancers identified from GWAS appear not to be associated with risks of EA or Barrett's esophagus. 

Impact: To our knowledge, this is the first investigation of pleiotropic genetic associations with risks of EA and Barrett's esophagus.

Characteristics, complications, and gaps in evidence-based interventions in rheumatic heart disease: the Global Rheumatic Heart Disease Registry (the REMEDY study)

AIMS: Rheumatic heart disease (RHD) accounts for over a million premature deaths annually; however, there is little contemporary information on presentation, complications, and treatment.

METHODS AND RESULTS: This prospective registry enrolled 3343 patients (median age 28 years, 66.2% female) presenting with RHD at 25 hospitals in 12 African countries, India, and Yemen between January 2010 and November 2012. The majority (63.9%) had moderate-to-severe multivalvular disease complicated by congestive heart failure (33.4%), pulmonary hypertension (28.8%), atrial fibrillation (AF) (21.8%), stroke (7.1%), infective endocarditis (4%), and major bleeding (2.7%). One-quarter of adults and 5.3% of children had decreased left ventricular (LV) systolic function; 23% of adults and 14.1% of children had dilated LVs. Fifty-five percent (n = 1761) of patients were on secondary antibiotic prophylaxis. Oral anti-coagulants were prescribed in 69.5% (n = 946) of patients with mechanical valves (n = 501), AF (n = 397), and high-risk mitral stenosis in sinus rhythm (n = 48). However, only 28.3% (n = 269) had a therapeutic international normalized ratio. Among 1825 women of childbearing age (12-51 years), only 3.6% (n = 65) were on contraception. The utilization of valvuloplasty and valve surgery was higher in upper-middle compared with lower-income countries.

CONCLUSION: Rheumatic heart disease patients were young, predominantly female, and had high prevalence of major cardiovascular complications. There is suboptimal utilization of secondary antibiotic prophylaxis, oral anti-coagulation, and contraception, and variations in the use of percutaneous and surgical interventions by country income level.

Desenvolvimento de um simulador de sinais de fluxo sanguíneo na válvula aórtica

Dissertação de mestrado, Engenharia de Sistemas e Computação, Unidade de Ciências Exactas e Humanas, Universidade do Algarve, 1997

Impact de l’axe de la parathormone sur la masse ventriculaire gauche suite à une chirurgie de remplacement de la valve aortique

L’hypertrophie du ventricule gauche est une complication fréquente chez les gens souffrant de sténose aortique. Lorsque ces patients subissent un remplacement de la valve aortique, l’ampleur de la régression de l’hypertrophie dépend de plusieurs facteurs hémodynamiques qui sont peu ou pas modifiables. Dans ce travail, l’implication de la parathormone dans l’hypertrophie du ventricule gauche chez ces patients a été évaluée. Il s’agit d’une étude transversale comptant 195 patients recrutés 8±3,5 ans après leur chirurgie. La fonction et la masse ventriculaire gauche ont été évaluées par échocardiographie Doppler. Des mesures du niveau plasmatique de parathormone, de vitamine D, de calcium et de phosphate ont été obtenues. Les résultats démontrent que le niveau de parathormone est associé de façon indépendante et significative avec la masse ventriculaire gauche et l’hypertrophie du ventricule gauche. De plus, le niveau de vitamine D et la fonction rénale étaient en corrélation inverse avec le niveau de parathormone.

Coronary Optical Coherence Tomography: A Practical Overview of Current Clinical Applications

Coronary optical coherence tomography has emerged as the most powerful in-vivo imaging modality to evaluate vessel structure in detail. It is a useful research tool that provides insights into the pathogenesis of coronary artery disease. This technology has an important clinical role that is still being developed. We review the evidence on the wide spectrum of potential clinical applications for coronary optical coherence tomography, which encompass the successive stages in coronary artery disease management: accurate lesion characterization and quantification of stenosis, guidance for the decision to perform percutaneous coronary intervention and subsequent planning, and evaluation of immediate and long-term results following intervention.