Breast cancer screening--prevalence of disease in women who only respond after an invitation reminder

An analysis of the Norwegian Breast Cancer Screening Programme, including 1,390,310 screening examinations, showed an attendance rate of 71.7% in response to one invitation letter (ordinary attendees) and a further 4.5% increase only after an additional reminder (reminded attendees). Our aim was to examine the prevalence of breast cancer in ordinary and reminded attendees, the frequency of positive mammograms, and the positive predictive value in the two groups. The prevalence of breast cancer in ordinary attendees was 5.6 per 1000 screens compared with 6.3 per 1000 screens in reminded attendees (p<0.001). The frequencies of positive mammograms were 3.5% and 4.0% (p<0.001), and the positive predictive values were 15.9% and 15.2% (p=0.387), respectively, in ordinary and reminded attendees. The risk of breast cancer is higher in women who respond only after a reminder letter, indicating that the value of sending a reminder should be assessed in the light of these results, as well as by the increase in the attendance rate.     

Design paper: the DEMO trial: a randomized, parallel-group, observer-blinded clinical trial of aerobic versus non-aerobic versus relaxation training for patients with light to moderate depression

BACKGROUND: In western countries, the yearly incidence of depression is estimated to be 3-5% and the lifetime prevalence is 17%. In patient populations with chronic diseases the point prevalence may be 20%. Depression is associated with increased risk for various conditions such as osteoporoses, cardiovascular diseases, and dementia. WHO stated in 2000 that depression was the fourth leading cause of disease burden in terms of disability. In 2000 the cost of depression in the US was estimated to 83 billion dollars. A predominance of trials suggests that physical exercise has a positive effect on depressive symptoms. However, a meta-analysis from 2001 stated: "The effectiveness of exercise in reducing symptoms of depression cannot be determined because of a lack of good quality research on clinical populations with adequate follow-up." OBJECTIVES: The major objective for this randomized trial is to compare the effect of non-aerobic, aerobic, and relaxation training on depressive symptoms using the blindly assessed Hamilton depression scale (HAM-D(17)) as primary outcome. The secondary outcome is the effect of the intervention on working status (i.e., lost days from work, employed/unemployed) and the tertiary outcomes consist of biological responses. DESIGN: The trial is designed as a randomized, parallel-group, observer-blinded clinical trial. Patients are recruited through general practitioners and psychiatrist and randomized to three different interventions: 1) non-aerobic, -- progressive resistance training, 2) aerobic training, -- cardio respiratory fitness, and 3) relaxation training with minimal impact on strength or cardio respiratory fitness. Training for all three groups takes place twice a week for 4 months. Evaluation of patients' symptoms takes place four and 12 months after inclusion. The trial is designed to include 45 patients in each group. Statistical analysis will be done as intention to treat (all randomized patients). Results from the DEMO trial will be reported according to the CONSORT guidelines in 2008-2009.     

Novel Plexor SNP genotyping technology: comparisons with TaqMan and homogenous MassEXTEND MALDI-TOF mass spectrometry

Analysis of SNPs for association, linkage, haplotype, and pharmacogenetic studies has led to a dramatic increase in the number and evolution of medium- to high-throughput genotyping technologies. This study introduces Plexor as a new method for medium-throughput (single SNP) genotyping. We compare this fluorescent-based chemistry for call rate, accuracy, affordability, throughput, and overall efficiency against two commonly used technologies. These include fluorescent-based TaqMan allelic discrimination for single SNP analysis (medium-throughput) and the homogenous MassEXTEND (hME) chemistry using matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry for multiple SNP analysis (high-throughput). Analysis of 11 SNPs, including all six possible nucleotide substitutions, showed Plexor to be highly comparable for both call rate (94.7%) and accuracy (99.2%) to the TaqMan (94.6% and 99.8%, respectively) and hME (91.9% and 98.1%, respectively) chemistries. We demonstrate that this novel method is an efficient, cost-effective alternative to TaqMan genotyping commonly used in diagnostic settings.     

The impact of recipient history of cardiovascular disease on kidney transplant outcome

Cardiovascular disease (CVD) leads to increased mortality rates among renal transplant recipients; however, its effect on allograft survival has not been well studied. The records from the United States Renal Data System and the United Network for Organ Sharing from January 1, 1995, through December 31, 2002, were examined in this retrospective study. The outcome variables were allograft survival time and recipient survival time. The primary variable of interest was CVD, defined as the presence of at least one of the following: cardiac arrest, myocardial infarction, dysrhythmia, congestive heart failure, ischemic heart disease, peripheral vascular disease, and unstable angina. The Cox models were adjusted for potential confounding factors. Of the 105,181 patients in the data set, 20,371 had a diagnosis of CVD. The presence of CVD had an adverse effect on allograft survival time (HR 1.12, p < 0.001) and recipient survival time (HR 1.41, p < 0.001). Among the subcategories, congestive heart failure (HR 1.14, p < 0.005) and dysrhythmia (HR 1.26, p < 0.05) had adverse effects on allograft survival time. In addition to increasing mortality rates, CVD at the time of end-stage renal disease onset is also a significant risk factor for renal allograft failure. Further research is needed to evaluate the role of specific forms of CVD in allograft and recipient outcome.     

Genes under positive selection in Escherichia coli

We used a comparative genomics approach to identify genes that are under positive selection in six strains of Escherichia coli and Shigella flexneri, including five strains that are human pathogens. We find that positive selection targets a wide range of different functions in the E. coli genome, including cell surface proteins such as beta barrel porins, presumably because of the involvement of these genes in evolutionary arms races with other bacteria, phages, and/or the host immune system. Structural mapping of positively selected sites on trans-membrane beta barrel porins reveals that the residues under positive selection occur almost exclusively in the extracellular region of the proteins that are enriched with sites known to be targets of phages, colicins, or the host immune system. More surprisingly, we also find a number of other categories of genes that show very strong evidence for positive selection, such as the enigmatic rhs elements and transposases. Based on structural evidence, we hypothesize that the selection acting on transposases is related to the genomic conflict between transposable elements and the host genome.     

Roles for the pro-neurotrophin receptor sortilin in neuronal development, aging and brain injury

Neurotrophins are essential for development and maintenance of the vertebrate nervous system. Paradoxically, although mature neurotrophins promote neuronal survival by binding to tropomyosin receptor kinases and p75 neurotrophin receptor (p75(NTR)), pro-neurotrophins induce apoptosis in cultured neurons by engaging sortilin and p75(NTR) in a death-signaling receptor complex. Substantial amounts of neurotrophins are secreted in pro-form in vivo, yet their physiological significance remains unclear. We generated a sortilin-deficient mouse to examine the contribution of the p75(NTR)/sortilin receptor complex to neuronal viability. In the developing retina, Sortilin 1 (Sort1)(-/-) mice showed reduced neuronal apoptosis that was indistinguishable from that observed in p75(NTR)-deficient (Ngfr(-/-)) mice. To our surprise, although sortilin deficiency did not affect developmentally regulated apoptosis of sympathetic neurons, it did prevent their age-dependent degeneration. Furthermore, in an injury protocol, lesioned corticospinal neurons in Sort1(-/-) mice were protected from death. Thus, the sortilin pathway has distinct roles in pro-neurotrophin-induced apoptotic signaling in pathological conditions, but also in specific stages of neuronal development and aging.     

Mental health policy development and implementation in four African countries

The purpose of the research programme introduced in this article is to provide new knowledge regarding comprehensive multisectoral approaches to breaking the negative cycle of poverty and mental ill-health. The programme undertakes an analysis of existing mental health policies in four African countries (Ghana, South Africa, Uganda, Zambia), and will carry out and evaluate interventions to assist in the development and implementation of mental health policies in those countries, over a five-year period. The four countries in which the programme is being conducted represent a variety of scenarios in mental health policy development and implementation.     

Inter-laboratory validation of PCR-based HPV detection in pathology specimens

The detection and typing of human papilloma virus (HPV) in pathology specimens is gaining increasingly in importance. In the context of the initiative for quality assurance in pathology (QuIP) of the German Society of Pathology and the Professional Association of German Pathologists, four panel laboratories with experience and expertise in polymerase chain reaction (PCR)-based HPV detection were selected to establish an inter-laboratory trial. In a first step, these laboratories performed an internal testing of their own methodologies, which comprised DNA sequencing, multiplex nested PCR and hybridization techniques. Material from 39 samples including paraffin sections and DNA preparations of tissues and plasmids were evaluated by each panel institute according to their own protocols. Despite the different methodologies, a high degree of inter-laboratory reliability was achieved. In this report, we summarise the results. Pretested specimens are available for the external trail and can be ordered from the steering institute via provitro GmbH Berlin (). Supplementary data are online available at (rubric "Forschung"), which includes a web-based photo gallery of HPV-associated lesions and their potential association with specific virus types. The initiative is intended to foster the quality assurance of molecular HPV analysis in pathology and its correlation with morphological changes.     

Genetic influences on mannan-binding lectin (MBL) and mannan-binding lectin associated serine protease-2 (MASP-2) activity

The lectin pathway of the complement system is activated when Mannan-binding lectin (MBL) in complex with MASP-2 binds microorganisms. Polymorphisms in both genes are responsible for low serum levels, which associate with increased risk of infection and autoimmune disease. The present study includes 1215 MBL measurements and 1214 MASP-2 activity measurements in healthy Danish adult twins. Total MASP-2 activity was estimated by C4 cleaving activity of samples diluted in an excess of MBL. Twin-twin correlations were higher in monozygotic (MZ) than in dizygotic (DZ) twins for both traits. Heritabilites of MBL levels and MASP-2 activity were estimated using structural equation modeling allowing assessment of the contribution of common genes affecting both traits. The estimated heritability was 0.77 [95% CI 0.64;0.91] for MBL levels and 0.75 [95% CI 0.59;0.81] for MASP-2 activity with the presence of additive genetic factors, shared environmental factors, and non-shared environmental factors. The genetic correlation, i.e., common genetic factors affecting MBL and MASP-2 activity was estimated to r(g) = 0.34 [0.25;0.42]. The data indicate a strong genetic influence for the serum levels of MBL and for MASP-2 activity with a significant genetic correlation between the two traits.