H19-DMR allele-specific methylation analysis reveals epigenetic heterogeneity of CTCF binding site 6 but not of site 5 in head-and-neck carcinomas: A pilot case-control analysis

Aberrant methylation of seven potential binding sites of the CTCF factor in the differentially methylated region upstream of the H19 gene (H19-DMR) has been suggested as critical for the regulation of IGF2 and H19 imprinted genes. In this study, we analyzed the allele-specific methylation pattern of CTCF binding sites 5 and 6 using methylationsensitive restriction enzyme PCR followed by RFLP analysis in matched tumoral and lymphocyte DNA from head-and-neck squamous cell carcinoma (HNSCC) patients, as well as in lymphocyte DNA from control individuals who were cancer-free. The monoallelic methylation pattern was maintained in CTCF binding site 5 in 22 heterozygous out of 91 samples analyzed. Nevertheless, a biallelic methylation pattern was detected in CTCF binding site 6 in a subgroup of HNSCC patients as a somatic acquired feature of tumor cells. An atypical biallelic methylation was also observed in both tumor and lymphocyte DNA from two patients, and at a high frequency in the control group (29 out of 64 informative controls). Additionally, we found that the C/T transition detected by HhaI RFLP suppressed one dinucleotide CpG in critical CTCF binding site 6, of a mutation showing polymorphic frequencies. Although a heterogeneous methylation pattern was observed after DNA sequencing modified by sodium bisulfite, the biallelic methylation pattern was confirmed in 9 out of 10 HNSCCs. These findings are likely to be relevant in the epigenetic regulation of the DMR, especially in pathological conditions in which the imprinting of IGF2 and H19 genes is disrupted.

When one depends on the other: reporting of interaction in case-control and cohort studies

BACKGROUND: Interaction refers to the situation in which the effect of 1 exposure on an outcome differs across strata of another exposure. We did a survey of epidemiologic studies published in leading journals to examine how interaction is assessed and reported. METHODS: We selected 150 case-control and 75 cohort studies published between May 2001 and May 2007 in leading general medicine, epidemiology, and clinical specialist journals. Two reviewers independently extracted data on study characteristics. RESULTS: Of the 225 studies, 138 (61%) addressed interaction. Among these, 25 (18%) presented no data or only a P value or a statement of statistical significance; 40 (29%) presented stratum-specific effect estimates but no meaningful comparison of these estimates; and 58 (42%) presented stratum-specific estimates and appropriate tests for interaction. Fifteen articles (11%) presented the individual effects of both exposures and also their joint effect or a product term, providing sufficient information to interpret interaction on an additive and multiplicative scale. Reporting was poorest in articles published in clinical specialist articles and most adequate in articles published in general medicine journals, with epidemiology journals in an intermediate position. CONCLUSIONS: A majority of articles reporting cohort and case-control studies address possible interactions between exposures. However, in about half of these, the information provided was unsatisfactory, and only 1 in 10 studies reported data that allowed readers to interpret interaction effects on an additive and multiplicative scale.

Case-control analysis on metformin and cancer of the esophagus

PURPOSE Metformin use has been associated with decreased cancer risks, though data on esophageal cancer are scarce. We explored the relation between use of metformin or other anti-diabetic drugs and the risk of esophageal cancer. METHODS We conducted a case-control analysis in the UK-based general practice research database (GPRD, now clinical practice research datalink, CPRD). Cases were individuals with an incident diagnosis of esophageal cancer between 1994 and 2010 at age 40-89 years. Ten controls per case were matched on age, sex, calendar time, general practice, and number of years of active history in the GPRD prior to the index date. Various potential confounders including diabetes mellitus, gastro-esophageal reflux, and use of proton-pump inhibitors were evaluated in univariate models, and the final results were adjusted for BMI and smoking. Results are presented as odds ratios (ORs) with 95 % confidence intervals (CI). RESULTS Long-term use (≥30 prescriptions) of metformin was not associated with a materially altered risk of esophageal cancer (adj. OR 1.23, 95 % CI 0.92-1.65), nor was long-term use of sulfonylureas (adj. OR 0.93, 95 % CI 0.70-1.23), insulin (adj. OR 0.87, 95 % CI 0.60-1.25), or of thiazolidinediones (adj. OR 0.71, 95 % CI 0.37-1.36). CONCLUSION In our population-based study, use of metformin was not associated with an altered risk of esophageal cancer.

Seizures in patients with Alzheimer's disease or vascular dementia: a population-based nested case-control analysis

PURPOSE Patients with Alzheimer's disease (AD) have an increased risk of developing seizures or epilepsy. Little is known about the role of risk factors and about the risk of developing seizures/epilepsy in patients with vascular dementia (VD). The aim of this study was to assess incidence rates (IRs) of seizures/epilepsy in patients with AD, VD, or without dementia, and to identify potential risk factors of seizures or epilepsy. METHODS We conducted a follow-up study with a nested case-control analysis using the United Kingdom-based General Practice Research Database (GPRD). We identified patients aged ≥65 years with an incident diagnosis of AD or VD between 1998 and 2008 and a matched comparison group of dementia-free patients. Conditional logistic regression was used to estimate the odds ratio (OR) with a 95% confidence interval (CI) of developing seizures/epilepsy in patients with AD or VD, stratified by age at onset and duration of dementia as well as by use of antidementia drugs. KEY FINDINGS Among 7,086 cases with AD, 4,438 with VD, and 11,524 matched dementia-free patients, we identified 180 cases with an incident diagnosis of seizures/epilepsy. The IRs of epilepsy/seizures for patients with AD or VD were 5.6/1,000 person-years (py) (95% CI 4.6-6.9) and 7.5/1,000 py (95% CI 5.7-9.7), respectively, and 0.8/1,000 py (95% CI 0.6-1.1) in the dementia-free group. In the nested case-control analysis, patients with longer standing (≥3 years) AD had a slightly higher risk of developing seizures or epilepsy than those with a shorter disease duration, whereas in patients with VD the contrary was observed. SIGNIFICANCE Seizures or epilepsy were substantially more common in patients with AD and VD than in dementia-free patients. The role of disease duration as a risk factor for seizures/epilepsy seems to differ between AD and VD.

Metformin and the risk of head and neck cancer: a case-control analysis

AIMS Metformin use has been associated with a decreased risk of some cancers, although data on head and neck cancer (HNC) are scarce. We explored the relation between the use of antidiabetic drugs and the risk of HNC. METHODS We conducted a case-control analysis in the UK-based Clinical Practice Research Datalink (CPRD) of people with incident HNC between 1995 and 2013 below the age of 90 years. Six controls per case were matched on age, sex, calendar time, general practice and number of years of active history in the CPRD prior to the index date. Other potential confounders including body mass index (BMI), smoking, alcohol consumption and comorbidities were also evaluated. The final analyses were adjusted for BMI, smoking and diabetes mellitus (or diabetes duration in a sensitivity analysis). Results are presented as odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS Use of metformin was neither associated with a statistically significant altered risk of HNC overall (1-29 prescriptions: adjusted OR 0.87, 95% CI 0.61-1.24 and ≥ 30 prescriptions adjusted OR 0.80, 95% CI 0.53-1.22), nor was long-term use of sulphonylureas (adjusted OR 0.87, 95% CI 0.59-1.30), or any insulin use (adjusted OR 0.92, 95% CI 0.63-1.35). However, we found a (statistically non-significant) decreased risk of laryngeal cancer associated with long-term metformin use (adjusted OR 0.41, 95% CI 0.17-1.03). CONCLUSIONS In this population-based study, the use of antidiabetic drugs was not associated with a materially altered risk of HNC. Our data suggest a protective effect of long-term metformin use for laryngeal cancer.

Incidence of and risk factors for severe hypoglycaemia in treated type 2 diabetes mellitus patients in the UK - a nested case-control analysis

AIMS To assess incidence rates (IRs) of and identify risk factors for incident severe hypoglycaemia in patients with type 2 diabetes newly treated with antidiabetic drugs. METHODS Using the UK-based General Practice Research Database, we performed a retrospective cohort study between 1994 and 2011 and a nested case-control analysis. Ten controls from the population at risk were matched to each case with a recorded severe hypoglycaemia during follow-up on general practice, years of history in the database and calendar time. Using multivariate conditional logistic regression analyses, we adjusted for potential confounders. RESULTS Of 130,761 patients with newly treated type 2 diabetes (mean age 61.7 ± 13.0 years), 690 (0.5%) had an incident episode of severe hypoglycaemia recorded [estimated IR 11.97 (95% confidence interval, CI, 11.11-12.90) per 10,000 person-years (PYs)]. The IR was markedly higher in insulin users [49.64 (95% CI, 44.08-55.89) per 10,000 PYs] than in patients not using insulin [8.03 (95% CI, 7.30-8.84) per 10,000 PYs]. Based on results of the nested case-control analysis increasing age [≥ 75 vs. 20-59 years; adjusted odds ratio (OR), 2.27; 95% CI, 1.65-3.12], cognitive impairment/dementia (adjusted OR, 2.00; 95% CI, 1.37-2.91), renal failure (adjusted OR, 1.34; 95% CI, 1.04-1.71), current use of sulphonylureas (adjusted OR, 4.45; 95% CI, 3.53-5.60) and current insulin use (adjusted OR, 11.83; 95% CI, 9.00-15.54) were all associated with an increased risk of severe hypoglycaemia. CONCLUSIONS Severe hypoglycaemia was recorded in 12 cases per 10,000 PYs. Risk factors for severe hypoglycaemia included increasing age, renal failure, cognitive impairment/dementia, and current use of insulin or sulphonylureas.

A case-comparison interview study of brain tumors and employment in occupations with presumed electric and magnetic field exposures

Results from epidemiologic studies suggest that persons working in occupations with presumed electric and magnetic field (EMF) exposures are at increased risk of brain cancer. This study utilized data from a completed, population-based, interview case-control study of central nervous system (CNS) tumors and employment in the petrochemical industry to test the hypothesis that employment in EMF-related occupations increases CNS tumor risk. A total of 375 male residents of the Texas-Louisiana Gulf Coast Area, age 20 to 79, with primary neuroglial CNS tumors diagnosed during the period 1980-84 were identified. A population-based comparison group of 450 age, race and geographically matched males was selected. Occupational histories and potential risk factor data were collected via personal interviews with study subjects or their next-of-kin.^ Adjusted odds ratios were less than 1.0 for persons ever employed in an electrical occupation (OR = 0.65; 95% CI = 0.40-1.09) or whose usual occupation was electrical (OR = 0.76; 95% CI = 0.33-1.73). Relative risk estimates did not increase significantly as time since first employment or duration of employment increased. Examination of CNS tumor risk by high (OR = 0.80), medium (OR = 0.88) and low (OR = 0.45) exposure categories for persons whose usual occupation was electrical did not indicate a dose-response pattern. In addition, the mean age of exposed cases was not significantly younger than that for unexposed cases. Analysis of risk by probability of exposure to EMFs showed non-significant elevations in the adjusted odds ratio for definite exposed workers defined by their usual occupation (OR = 1.78; 95% CI = 0.70-4.51) and ever/never employed status (OR = 1.54; 95% CI = 0.17-4.91).^ These findings suggest that employment in occupations with presumed EMF exposures does not increase CNS tumor risk as was suggested by previous investigations. The results of this study also do not support the EMF-tumor promotion hypothesis. ^

The estrogen receptor 1 G594A polymorphism is associated with migraine susceptibility in two independent case/control groups

Migraine is a painful and debilitating disorder with a significant genetic component. Steroid hormones, in particular estrogen, have long been considered to play a role in migraine, as variations in hormone levels are associated with migraine onset in many sufferers of the disorder. Steroid hormones mediate their activity via hormone receptors, which have a wide tissue distribution. Estrogen receptors have been localized to the brain in regions considered to be involved in migraine pathogenesis. Hence it is possible that genetic variation in the estrogen receptor gene may play a role in migraine susceptibility. This study thus examined the estrogen receptor 1 (ESRalpha) gene for a potential role in migraine pathogenesis and susceptibility. A population-based cohort of 224 migraine sufferers and 224 matched controls were genotyped for the G594A polymorphism located in exon 8 of the ESR1 gene. Statistical analysis indicated a significant difference between migraineurs and non-migraineurs in both the allele frequencies (P=0.003) and genotype distributions (P=0.008) in this sample. An independent follow-up study was then undertaken using this marker in an additional population-based cohort of 260 migraine sufferers and 260 matched controls. This resulted in a significant association between the two groups with regard to allele frequencies (P=8x10(-6)) and genotype distributions (P=4x10(-5)). Our findings support the hypothesis that genetic variation in hormone receptors, in particular the ESR1 gene, may play a role in migraine.

Risk Prediction for Epithelial Ovarian Cancer in 11 United States-Based Case-Control Studies: Incorporation of Epidemiologic Risk Factors and 17 Confirmed Genetic Loci.

Previously developed models for predicting absolute risk of invasive epithelial ovarian cancer have included a limited number of risk factors and have had low discriminatory power (area under the receiver operating characteristic curve (AUC) < 0.60). Because of this, we developed and internally validated a relative risk prediction model that incorporates 17 established epidemiologic risk factors and 17 genome-wide significant single nucleotide polymorphisms (SNPs) using data from 11 case-control studies in the United States (5,793 cases; 9,512 controls) from the Ovarian Cancer Association Consortium (data accrued from 1992 to 2010). We developed a hierarchical logistic regression model for predicting case-control status that included imputation of missing data. We randomly divided the data into an 80% training sample and used the remaining 20% for model evaluation. The AUC for the full model was 0.664. A reduced model without SNPs performed similarly (AUC = 0.649). Both models performed better than a baseline model that included age and study site only (AUC = 0.563). The best predictive power was obtained in the full model among women younger than 50 years of age (AUC = 0.714); however, the addition of SNPs increased the AUC the most for women older than 50 years of age (AUC = 0.638 vs. 0.616). Adapting this improved model to estimate absolute risk and evaluating it in prospective data sets is warranted.

Contribution Of Antepartum And Intrapartum Hemorrhage To The Burden Of Maternal Near Miss And Death In A National Surveillance Study

Objective To evaluate the occurrence of severe obstetric complications associated with antepartum and intrapartum hemorrhage among women from the Brazilian Network for Surveillance of Severe Maternal Morbidity.Design Multicenter cross-sectional study.Setting Twenty-seven obstetric referral units in Brazil between July 2009 and June 2010.Population A total of 9555 women categorized as having obstetric complications.Methods The occurrence of potentially life-threatening conditions, maternal near miss and maternal deaths associated with antepartum and intrapartum hemorrhage was evaluated. Sociodemographic and obstetric characteristics and the use of criteria for management of severe bleeding were also assessed in these women.Main outcome measures The prevalence ratios with their respective 95% confidence intervals adjusted for the cluster effect of the design, and multiple logistic regression analysis were performed to identify factors independently associated with the occurrence of severe maternal outcome.Results Antepartum and intrapartum hemorrhage occurred in only 8% (767) of women experiencing any type of obstetric complication. However, it was responsible for 18.2% (140) of maternal near miss and 10% (14) of maternal death cases. On multivariate analysis, maternal age and previous cesarean section were shown to be independently associated with an increased risk of severe maternal outcome (near miss or death).Conclusion Severe maternal outcome due to antepartum and intrapartum hemorrhage was highly prevalent among Brazilian women. Certain risk factors, maternal age and previous cesarean delivery in particular, were associated with the occurrence of bleeding.

Magnetic fields and acute lymphoblastic leukemia in children: a systematic review of case-control studies

Leukemia incidence in children has increased worldwide in recent decades, particularly due to the rise in acute lymphoblastic leukemia. Studies have associated exposure to non-ionizing radiation generated by low frequency magnetic fields with childhood leukemia. The current article reviews the case-control studies published on this subject. Of 152 articles tracked in different databases, ten studies from North America, Asia, and Europe met the defined selection criteria, with patients diagnosed from 1960 to 2004. Methodological limitations were observed in these articles, including difficulties with the procedures for assessing exposure. An association may exist between exposure to low frequency magnetic fields and acute lymphoblastic leukemia in children, but this association is weak, preventing the observation of consistency in the findings. Future studies from a wider range of geographic regions should focus on the analysis of acute lymphoblastic leukemia, which is the subtype with the greatest impact on the increasing overall incidence of childhood leukemia.

Efficiency and feasibility of product disassembly: A case-based study

The productivity associated with commonly available disassembly methods today seldomly makes disassembly the preferred end-of-life solution for massive take back product streams. Systematic reuse of parts or components, or recycling of pure material fractions are often not achievable in an economically sustainable way. In this paper a case-based review of current disassembly practices is used to analyse the factors influencing disassembly feasibility. Data mining techniques were used to identify major factors influencing the profitability of disassembly operations. Case characteristics such as involvement of the product manufacturer in the end-of-life treatment and continuous ownership are some of the important dimensions. Economic models demonstrate that the efficiency of disassembly operations should be increased an order of magnitude to assure the competitiveness of ecologically preferred, disassembly oriented end-of-life scenarios for large waste of electric and electronic equipment (WEEE) streams. Technological means available to increase the productivity of the disassembly operations are summarized. Automated disassembly techniques can contribute to the robustness of the process, but do not allow to overcome the efficiency gap if not combined with appropriate product design measures. Innovative, reversible joints, collectively activated by external trigger signals, form a promising approach to low cost, mass disassembly in this context. A short overview of the state-of-the-art in the development of such self-disassembling joints is included. (c) 2008 CIRP.

Serious criminal offending and mental disorder - Case linkage study

Background A relationship exists between mental disorder and offending behaviours but the nature and extent of the association remains in doubt. Method Those convicted in the higher courts of Victoria between 1993 and 1995 had their pyschiatric history explored by case linkage to a register listing virtually all contacts with the public psychiatric services. Results Prior psychiatric contact was found in 25% or offenders, but the personality disorder and substance misuse accounted for much of this relationship. Schizophrenia and affective disorders were also over-represented, particularly those with coexisting substance misuse. Conclusions The increased offending in schizophrenia and affective illness is modest and may often be mediated by coexisting substance misuse. The risk of a serious crime being committed by someone with a major mental illness is small and does not justify subjecting them, as a group, to either increased institutional containment or greater coercion.

Continuity of care and readmission in two service systems: a comparative Victorian and Groningen case-register study

Objective: We compared service consumption, continuity of care and risk of readmission in a record linkage follow-up study of cohorts of patients with schizophrenia and related disorders in Victoria (Australia) and in Groningen (The Netherlands). These areas are interesting to compare because mental health care is in a different stage of deiustitutionalization. More beds are available in Groningen and more community resources are available in Victoria. Method: The cohorts were followed for 4 years, since discharge from inpatient services using record linkage data available in the psychiatric case-registers in both areas. Survival analysis was used to study continuity of care and risk of readmission. Results: Available indicators showed a higher level of continuity of care in Victoria. While the relative risk of readmission was the same in both areas and not affected by aftercare contact after discharge, the number of days spent in hospital was much higher in the Groningen register area. Conclusion: These findings provide further support for earlier reports that the risk of readmission is predominantly affected by attributes of mental illness. However, the duration of admissions, is strongly affected by service system variables, including the provision of continuity of care.

Impact of undergraduate and postgraduate rural training, and medical school entry criteria on rural practice among Australian general practitioners: national study of 2414 doctors

Objective To determine the association between rural undergraduate training, rural postgraduate training and medical school entry criteria favouring rural students, on likelihood of working in rural Australian general practice. Methods National case - control study of 2414 rural and urban general practitioners (GPs) sampled from the Health Insurance Commission database. Participants completed a questionnaire providing information on demographics, current practice location and rural undergraduate and postgraduate experience. Results Rural GPs were more likely to report having had any rural undergraduate training [ odds ratio ( OR) 1.61, 95% confidence interval (CI) 1.32 - 1.95] than were urban GPs. Rural GPs were much more likely to report having had rural postgraduate training ( OR 3.14, 95% CI 2.57 - 3.83). As the duration of rural postgraduate training increased so did the likelihood of working as a rural GP: those reporting that more than half their postgraduate training was rural were most likely to be rural GPs ( OR 10.52, 95% CI 5.39 - 20.51). South Australians whose final high school year was rural were more likely to be rural GPs ( OR 3.18, 95% CI 0.99 - 10.22). Conclusions Undergraduate rural training, postgraduate training and medical school entry criteria favouring rural students, all are associated with an increased likelihood of being a rural GP. Longer rural postgraduate training is more strongly associated with rural practice. These findings argue for continuation of rural undergraduate training opportunities and rural entry schemes, and an expansion in postgraduate training opportunities for GPs.