A novel pathogenic MLH1 missense mutation, c.112A > C, p.Asn38His, in six families with Lynch syndrome

<p>Abstract</p> <p>Background</p> <p>An unclassified variant (UV) in exon 1 of the <it>MLH1 </it>gene, c.112A > C, p.Asn38His, was found in six families who meet diagnostic criteria for Lynch syndrome. The pathogenicity of this variant was unknown. We aim to elucidate the pathogenicity of this <it>MLH1 </it>variant in order to counsel these families adequately and to enable predictive testing in healthy at-risk relatives.</p> <p>Methods</p> <p>We studied clinical data, microsatellite instability and immunohistochemical staining of MMR proteins, and performed genealogy, haplotype analysis and DNA testing of control samples.</p> <p>Results</p> <p>The UV showed co-segregation with the disease in all families. All investigated tumors showed a microsatellite instable pattern. Immunohistochemical data were variable among tested tumors. Three families had a common ancestor and all families originated from the same geographical area in The Netherlands. Haplotype analysis showed a common haplotype in all six families.</p> <p>Conclusions</p> <p>We conclude that the <it>MLH1 </it>variant is a pathogenic mutation and genealogy and haplotype analysis results strongly suggest that it is a Dutch founder mutation. Our findings imply that predictive testing can be offered to healthy family members. The immunohistochemical data of MMR protein expression show that interpreting these results in case of a missense mutation should be done with caution.</p

Integrating Entrepreneurship into the Design Classroom: Case Studies from the Developing World

© 2017, Springer Science+Business Media, LLC. Developing countries are more and more committed to building a knowledge-based economy as a means to diversify from their current resource-based economy. The current focus of many governments is on technology with real insights on creative economy and arts. In this context, universities are seen as a key partner of the government. This article presents the results of two innovative case studies of professors working in the College of Art and Design collaborating with a professor in the College of Business to integrate the concepts of entrepreneurship into their interior design courses. This was done through designing space for entrepreneurial projects and by the students acting as entrepreneurs themselves with an external client. This dual model of training combines (1) learning processes about the habits and the needs of entrepreneurs and (2) learning by acting as an entrepreneur. Such methods demonstrate the role of universities to provide a proper theoretical background for students and to foster entrepreneurial behaviors through arts entrepreneurship education. Furthermore, the central role of professors to introduce innovative teaching methods to combine entrepreneurship and the creative economy into non-business courses is an important finding in these case studies

Boundaryless work, psychological detachment and sleep: Does working 'anytime - anywhere' equal employees are 'always on'?

Item does not contain fulltextEmployees have gained increased flexibility in organizing their work in time and space, that is boundaryless work. Managing the boundaries between work and personal life would seem to be crucial if one is to psychologically detach from work during leisure in order to unwind and get sufficient sleep. Drawing from a sample of Swedish professional workers (N = 3,846), a theoretical model was proposed testing the inter-relationships between boundaryless work in time and space, weekly work hours, psychological detachment, sleeping problems and sleep duration using a structural equation modelling (SEM) analysis. Findings showed that working boundlessly in time, that is spread out during the working day and week, was directly associated with both long weekly work hours and lack of psychological detachment. In contrast, working boundlessly in space, that is at several different places, was inversely associated with weekly work hours and had no association with psychological detachment. Psychological detachment, in turn, was directly associated with sleeping problems and inversely associated with sleep duration. Sleeping problems were inversely associated with sleep duration. Employees with long weekly work hours had a low degree of sleeping problems. There was also no association between long weekly work hours and sleep duration. These findings contradict earlier research, however, we interpret these findings as that if one works a great deal but is able to mentally detach from work-related feelings and thoughts during free time, then sleep will not be hampered because perseverative cognitions associated with prolonged biological activation will have been interrupted. As such, psychological detachment can be regarded as the mechanism that mediates the relationships between working 'anytime' and long weekly work hours, and sleep. It was concluded working boundlessly in time increases the likelihood for long weekly work hours and lack of psychological detachment. Hence, employees working 'anytime - all the time' run the risk of 'always being on' resulting in disturbed sleep

After the Introduction into the National Newborn Screening Program:Who Is Receiving Genetic Counseling for Hemoglobinopathies in The Netherlands?

OBJECTIVE: Universal newborn screening for hemoglobinopathies started in The Netherlands in 2007. Herewith severe conditions, such as sickle cell disease, β-thalassemia major and hemoglobin H disease are putatively identified. Additionally, at least 1,800 carriers of hemoglobin variants associated with severe conditions in homozygote or compound heterozygote forms are identified yearly. Thus far, approximately 60 patients and 800 healthy sickle cell (HbS) carriers are reported each year among 180,000 newborns. Results are sent to the general practitioner with the recommendation to inform and diagnose both parents of the healthy carriers to exclude genetic risk, while patients and their parents are referred directly to a pediatrician. This study was performed to determine how often parents of identified carriers and affected newborns are seen in genetic centers for counseling. METHODS: In this retrospective study, we collected anonymized data from 7 of the 8 Dutch clinical genetic centers from January 1, 2007, until December 31, 2010. RESULTS: After an initial general increase in total counseling intakes, a decline was noticed in the third year, while the requests for prenatal diagnoses remained relatively stable. In 2007 and 2013, genetic counselors were asked for self-reported knowledge. They found hemoglobinopathy counseling complex, but by 2013, they indicated they had acquired sufficient knowledge on most hemoglobinopathy aspects. CONCLUSION: We could not observe a significant increase in genetic counseling for hemoglobinopathy after its introduction into newborn screening. Although 120 HbS carriers and 60 patients are expected to be born from couples at risk annually, only 33 at risk couples out of 540 families of diagnosed newborns received optimal care and information at a genetics center in 4 years