The Slavic NBN founder mutation: a role for reproductive fitness?

The vast majority of patients with Nijmegen Breakage Syndrome (NBS) are of Slavic origin and carry a deleterious deletion (c.657del5; rs587776650) in the NBN gene on chromosome 8q21. This mutation is essentially confined to Slavic populations and may thus be considered a Slavic founder mutation. Notably, not a single parenthood of a homozygous c.657del5 carrier has been reported to date, while heterozygous carriers do reproduce but have an increased cancer risk. These observations seem to conflict with the considerable carrier frequency of c.657del5 of 0.5% to 1% as observed in different Slavic populations because deleterious mutations would be eliminated quite rapidly by purifying selection. Therefore, we propose that heterozygous c.657del5 carriers have increased reproductive success, i.e., that the mutation confers heterozygote advantage. In fact, in our cohort study of the reproductive history of 24 NBS pedigrees from the Czech Republic, we observed that female carriers gave birth to more children on average than female non-carriers, while no such reproductive differences were observed for males. We also estimate that c.657del5 likely occurred less than 300 generations ago, thus supporting the view that the original mutation predated the historic split and subsequent spread of the 'Slavic people'. We surmise that the higher fertility of female c.657del5 carriers reflects a lower miscarriage rate in these women, thereby reflecting the role of the NBN gene product, nibrin, in the repair of DNA double strand breaks and their processing in immune gene rearrangements, telomere maintenance, and meiotic recombination, akin to the previously described role of the DNA repair genes BRCA1 and BRCA2

MED40/472: A WWW Multimedia Textbook of Internal Propedeutics

INTRODUCTION: Traditional ways of teaching techniques of physical examinations in the first clinical courses are rather demanding in terms of teacher involvement and a pool of patients suitable for demonstrations. For a long time, various audio-visual tools have been used to save teachers' and students' time and patients' patience. The modern technology of WWW publishing of multimedia allows good access to such teaching materials - and there already exist several collections of heart sounds, breath sounds etc. The aim of our project is to design and set up a comprehensive multimedia textbook of internal propedeutics that would present various physiological and pathological findings (auscultation, inspection, basic imaging) in the context of diagnostic patient investigation - the status praesens - as it is taught in the first clinical courses. METHODS: Unlike classical textbooks, hypertext presentation allows to ogranize the material into several structures - reflecting various approaches: systemic (digestive, cardiovascular etc.) approach, nosological, differential diagnoses, etc. To identify and implement the various useful approaches is the most difficult part of the task. The accompanying illustrative material is being prepared with the use of modern technologies - digital camera, scanner, video-camera and digitizer, digital audio recording, etc. RESULTS: In the first year of the project, the skeleton of the multimedia presentation is being constructed - corresponding to the various approaches to the subject. Concurrently, suitable illustrative material is being gathered from cases of the Internal Clinic. Various existing WWW presentations dealing with heart and breath sounds and other relevant investigations have been searched and listed. DISCUSSION: Experience and feedback from other projects of this type confirm that a rather elaborate logical and technical construction of multimedia textbooks is rewarded by a good acceptance by both students and teachers. Good access to Internet, sufficient for multimedia transfers, however, is a necessary prerequisite. Internal propedeutics is a very suitable field for internet-based multimedia textbooks: instant access to audio and video recordings is much welcome in development of clinical skills. The project is supported by a grant of the Czech Universities Development Fund

TME17/473: Web-Based Visualization and Processing of Anthropometric Data

INTRODUCTION: Body height and body weight are the most common anthropometric values that are observed in children by their parents. Basic anthropometric measurements are also a common and natural part of routine medical check-ups in infants, children and adolescents. Although commonly taken, this data is not always correctly interpreted: cases when anthropometric data might have served for an earlier diagnosis of e.g. an endocrine disorder still occur. To facilitate utilization of this data, a software module was developed that visualizes the data and also provides a basic interpretation of the curves obtained. This software module consists of the knowledge base which was written at the auxological department of 2nd Medical Faculty and its interpreter. This platform independent module is offered to software developers for integration into their GP systems. METHODS: To demonstrate the functions of the module offered to software developers and also to allow patient (and parent) growth self-assessment, the module that visualizes and interprets children's anthropometric data is ported into a WWW interface. Each pro-band is assigned a unique (and anonymous) ID, so that new data can be added in the course of time. Various anthropometric parameters can be followed - so that the system can serve not only parents to assess their children's growth, but also can help the practitioner to visualize and evaluate more intrinsic relations in children's development. RESULTS: The service is just being launched at the web site of the 2nd Medical Faculty of Charles University - so the most important result of the project is the function of the system itself, that allows for further refinements of the project. The WWW interface also allows extensive testing of the module and demonstration of the module's capabilities to the software developers, GPs and other potential users. DISCUSSION: During the future project development will be necessary to refine various components that surround the WWW portation of the core anthropometric module as the user interface, security issues, data storage etc.. We believe that the project will be found useful by parents and GPs, and we hope that it will also bring us interesting data for further analyses. We believe that this specialized software module developed by experts and integrated into the GP software systems will be a big step towards improvement of the computer assisted growth diagnosis