Petra Wolf

Characterization of whole-genome autosomal differences of DNA methylation between men and women

AbstractBackgroundDisease risk and incidence between males and females reveal differences, and sex is an important component of any investigation of the determinants of phenotypes or disease etiology. Further striking differences between men and women are known, for instance, at the metabolic level. The extent to which men and women vary at the level of the epigenome, however, is not well documented. DNA methylation is the best known epigenetic mechanism to date.ResultsIn order to shed light on epigenetic differences, we compared autosomal DNA methylation levels between men and women in blood in a large prospective European cohort of 1799 subjects, and replicated our findings in three independent European cohorts. We identified and validated 1184 CpG sites to be differentially methylated between men and women and observed that these CpG sites were distributed across all autosomes. We showed that some of the differentially methylated loci also exhibit differential gene expression between men and women. Finally, we found that the differentially methylated loci are enriched among imprinted genes, and that their genomic location in the genome is concentrated in CpG island shores.ConclusionOur epigenome-wide association study indicates that differences between men and women are so substantial that they should be considered in design and analyses of future studies.

Lesions of the Biceps Pulley: Diagnostic Accuracy of MR Arthrography of the Shoulder and Evaluation of Previously Described and New Diagnostic Signs

PURPOSE To retrospectively determine the diagnostic accuracy of magnetic resonance (MR) arthrography of the shoulder in the evaluation of lesions of the biceps pulley and to evaluate previously described and new diagnostic signs. MATERIALS AND METHODS Institutional review board approval was obtained; the requirement for informed consent was waived. MR arthrograms of 80 consecutive patients (mean age, 34.2 years; 53 male, 27 female) with arthroscopically proved intact or torn pulley systems were assessed for the presence of a pulley lesion by three radiologists who were blinded to arthroscopic results. Criteria evaluated were displacement of the long head of the biceps tendon (LHBT) relative to the subscapularis tendon on oblique sagittal images (displacement sign), medial subluxation of the LHBT on transverse images, nonvisibility or discontinuity of the superior glenohumeral ligament (SGHL), presence of biceps tendinopathy, and rotator cuff tears adjacent to the rotator interval. RESULTS There were 28 pulley lesions noted at arthroscopy. For observers 1, 2, and 3, respectively: MR arthrography showed a sensitivity of 89%, 86%, and 82% and a specificity of 96%, 98%, and 87% in the detection of pulley lesions. Nonvisibility or discontinuity of the SGHL was sensitive (79%, 89%, and 79%) and specific (83%, 79%, and 75%). With the displacement sign, sensitivity was 86%, 82%, and 75% and specificity was 96%, 98%, 90%. Tendinopathy of the LHBT on oblique sagittal images showed a sensitivity of 93%, 82%, 64%; specificity was 81%, 96%, and 85%. Subluxation of the LHBT was insensitive (36%, 50%, and 64%) but specific (100%, 98%, and 96%). CONCLUSION MR arthrography is accurate in the detection of pulley lesions; the displacement sign, nonvisibility or discontinuity of the SGHL, and tendinopathy of the LHBT on oblique sagittal images are the most accurate criteria for the detection of pulley lesions.

Sensory Recovery Outcome after Digital Nerve Repair in Relation to Different Reconstructive Techniques: Meta-Analysis and Systematic Review

Good clinical outcome after digital nerve repair is highly relevant for proper hand function and has a significant socioeconomic impact. However, level of evidence for competing surgical techniques is low. The aim is to summarize and compare the outcomes of digital nerve repair with different methods (end-to-end and end-to-side coaptations, nerve grafts, artificial conduit-, vein-, muscle, and muscle-in-vein reconstructions, and replantations) to provide an aid for choosing an individual technique of nerve reconstruction and to create reference values of standard repair for nonrandomized clinical studies. 87 publications including 2,997 nerve repairs were suitable for a precise evaluation. For digital nerve repairs there was practically no particular technique superior to another. Only end-to-side coaptation had an inferior two-point discrimination in comparison to end-to-end coaptation or nerve grafting. Furthermore, this meta-analysis showed that youth was associated with an improved sensory recovery outcome in patients who underwent digital replantation. For end-to-end coaptations, recent publications had significantly better sensory recovery outcomes than older ones. Given minor differences in outcome, the main criteria in choosing an adequate surgical technique should be gap length and donor site morbidity caused by graft material harvesting. Our clinical experience was used to provide a decision tree for digital nerve repair.

Human thioredoxin 2 deficiency impairs mitochondrial redox homeostasis and causes early-onset neurodegeneration

Thioredoxin 2 (TXN2; also known as Trx2) is a small mitochondrial redox protein essential for the control of mitochondrial reactive oxygen species homeostasis, apoptosis regulation and cell viability. Exome sequencing in a 16-year-old adolescent suffering from an infantile-onset neurodegenerative disorder with severe cerebellar atrophy, epilepsy, dystonia, optic atrophy, and peripheral neuropathy, uncovered a homozygous stop mutation in TXN2. Analysis of patient-derived fibroblasts demonstrated absence of TXN2 protein, increased reactive oxygen species levels, impaired oxidative stress defence and oxidative phosphorylation dysfunction. Reconstitution of TXN2 expression restored all these parameters, indicating the causal role of TXN2 mutation in disease development. Supplementation with antioxidants effectively suppressed cellular reactive oxygen species production, improved cell viability and mitigated clinical symptoms during short-term follow-up. In conclusion, our report on a patient with TXN2 deficiency suggests an important role of reactive oxygen species homeostasis for human neuronal maintenance and energy metabolism.

PTK 7 Is a Transforming Gene and Prognostic Marker for Breast Cancer and Nodal Metastasis Involvement

Protein Tyrosin Kinase 7 (PTK7) is upregulated in several human cancers; however, its clinical implication in breast cancer (BC) and lymph node (LN) is still unclear. In order to investigate the function of PTK7 in mediating BC cell motility and invasivity, PTK7 expression in BC cell lines was determined. PTK7 signaling in highly invasive breast cancer cells was inhibited by a dominant-negative PTK7 mutant, an antibody against the extracellular domain of PTK7, and siRNA knockdown of PTK7. This resulted in decreased motility and invasivity of BC cells. We further examined PTK7 expression in BC and LN tissue of 128 BC patients by RT-PCR and its correlation with BC related genes like HER2, HER3, PAI1, MMP1, K19, and CD44. Expression profiling in BC cell lines and primary tumors showed association of PTK7 with ER/PR/HER2-negative (TNBC-triple negative BC) cancer. Oncomine data analysis confirmed this observation and classified PTK7 in a cluster with genes associated with agressive behavior of primary BC. Furthermore PTK7 expression was significantly different with respect to tumor size (ANOVA, p = 0.033) in BC and nodal involvement (ANOVA, p = 0.007) in LN. PTK7 expression in metastatic LN was related to shorter DFS (Cox Regression, p = 0.041). Our observations confirmed the transforming potential of PTK7, as well as its involvement in motility and invasivity of BC cells. PTK7 is highly expressed in TNBC cell lines. It represents a novel prognostic marker for BC patients and has potential therapeutic significance.

Which capabilities matter for successful business process change

Purpose – Business process change (BPC) initiatives are complex endeavors, which require many different sets of capabilities from the organization (e.g. IT, change management, project management capabilities). This study aims to examine which capabilities matter for successful BPC. Design/methodology/approach – The paper posits that a structured analysis of case studies will help in identifying the capabilities relevant for BPC. Against this background, the paper adopted a case survey methodology, which combines the richness of case studies with the benefit of analyzing large quantities of data. The paper identified and analyzed 130 case studies reporting the past BPC project experiences. Findings – The results show that project management, change management and IT capabilities have a positive impact on BPC project performance. IT capabilities also have a positive impact on the final process performance. Thus, IT capabilities matter for both BPC project and process performance. Research limitations/implic...

MRI Plaque Imaging Detects Carotid Plaques with a High Risk for Future Cerebrovascular Events in Asymptomatic Patients

Purpose The aim of this study was to investigate prospectively whether MRI plaque imaging can identify patients with asymptomatic carotid artery stenosis who have an increased risk for future cerebral events. MRI plaque imaging allows categorization of carotid stenosis into different lesion types (I–VIII). Within these lesion types, lesion types IV–V and VI are regarded as rupture-prone plaques, whereas the other lesion types represent stable ones. Methods Eighty-three consecutive patients (45 male (54.2%); age 54–88 years (mean 73.2 years)) presenting with an asymptomatic carotid stenosis of 50–99% according to ECST-criteria were recruited. Patients were imaged with a 1.5-T scanner. T1-, T2-, time-of-flight-, and proton-density weighted studies were performed. The carotid plaques were classified as lesion type I–VIII. Clinical endpoints were ischemic stroke, TIA or amaurosis fugax. Survival analysis and log rank test were used to ascertain statistical significance. Results Six out of 83 patients (7.2%) were excluded: 4 patients had insufficient MR image quality; 1 patient was lost-to-follow-up; 1 patient died shortly after the baseline MRI plaque imaging. The following results were obtained by analyzing the remaining 77 patients. The mean time of follow-up was 41.1 months. During follow-up, n = 9 (11.7%) ipsilateral ischemic cerebrovascular events occurred. Only patients presenting with the high-risk lesion types IV–V and VI developed an ipsilateral cerebrovascular event versus none of the patients presenting with the stable lesion types III, VII, and VIII (n = 9 (11.7%) vs. n = 0 (0%) during follow-up). Event-free survival was higher among patients with the MRI-defined stable lesion types (III, VII, and VIII) than in patients with the high-risk lesion types (IV–V and VI) (log rank test P<0.0001). Conclusions MRI plaque imaging has the potential to identify patients with asymptomatic carotid stenosis who are particularly at risk of developing future cerebral ischemia. MRI could improve selection criteria for invasive therapy in the future.

Osteoarthritis of the knee or hip significantly impairs driving ability (cross-sectional survey)

BackgroundAdvising patients about when they can drive after surgery is common practice after arthroplasty of the knee or hip. In the literature, the preoperative braking performance values of the patients are frequently taken as the “safe” landmark. We hypothesised that osteoarthritis (OA), the most frequent reason for arthroplasty, already compromises the ability to perform an emergency stop. We expected that both Reaction Time (RT) and Movement Time (MT) as components of the Total Brake Response Time (TBRT), would be prolonged in patients with OA of the knee or hip in comparison with healthy subjects. We also expected maximum pressure levels on the brake pedal to be reduced in such cases.MethodsA real car cabin was equipped with pressure sensors on the accelerator and brake pedals to measure RT, MT, TBRT and maximum Brake Force (BF) under realistic spatial constraints. Patients with OA of the knee (right n = 18, left n = 15) or hip (right n = 20, left n = 19) were compared with a healthy control group (n = 21).ResultsAll measured values for TBRT in the control group remained below 600 ms. OA of the right hip or knee significantly prolonged the braking performance (right hip: TBRT p = 0.025, right knee: TBRT p < 0.001), whereas OA of the left hip did not impair driving ability (TBRT p = 0.228). Intriguingly, OA of the left knee prolonged RT and MT to the same degree as OA on the contralateral side (RT p = 0.001, MT p < 0.001).ConclusionsThis study demonstrates that depending on the localisation of OA, driving capability can be impaired; OA can significantly increase the total braking distance. To ensure safe traffic participation the safety margin for TBRT should be strictly set, under our experimental conditions, at around 600 ms. Moreover, therapeutic approaches to OA, such as physiotherapy, and patients receiving surgery of the left knee should take into account that left knee OA can also impair driving ability.Trial registrationClinical trial registration number: Project number of the ethics committee of the University of Tübingen: 268/2009BO2; 267/2009BO2.

Factors Influencing Citizen Adoption of E-Government Services: A Cross-Cultural Comparison (Research in Progress)

E-government promises to transform the public sector by enhancing transparency, efficiency and accessibility of the public services. While most e-government endeavors continue to lag far behind their expected potentials, some nations adopt faster than others. Despite having one of the most advanced telecommunications infrastructures in the world, adoption of e-government in Germany has fallen far below expectations. Prior literature suggests that national culture shapes perception of the citizens thus facilitates or impedes adoption of new technologies. We argue that the high risk-averseness of the German nation hinders the current and future adoption of e-government services substantially. We present preliminary insights from our research in progress, which confirms this argumentation. Expected future results of our research include a cross-cultural analysis indicating the impact of national culture on e-government adoption by comparing Germany with United Kingdom and Sweden - two European nations with relatively low uncertainty avoidance and high e-government development indices.

A Review of Success Factors and Challenges of Public Sector BPR Implementations

Pressures to cut budgets and increase efficiency while maintaining performance prompted public managers to turn to the private sector for solutions. As a means of rightsizing government, cutting red tape, and reducing bureaucracy, the idea of BPR found its way into the realm of public organizations. The differing characteristics of private and public organizations introduce various challenges when transferring BPR methodologies between the sectors. With this research paper we consolidate the ample literature on BPR success from the private and public sector. We identify the relevant success factors and show that a surprising similarity exists between private and public BPR related success factors. In addition, we determine the specific characteristics and requirements of the public sector highlighting gaps in current literature. Finally, we structure the research gap in five propositions and provide directions for further research.