Therapeutic targeting of naturally presented myeloperoxidase-derived HLA peptide ligands on myeloid leukemia cells by TCR-transgenic T cells.

T cells have been proven to be therapeutically effective in patients with relapsed leukemias, although target antigens on leukemic cells as well as T-cell receptors (TCRs), potentially recognizing those antigens, are mostly unknown. We have applied an immunopeptidomic approach and isolated human leukocyte antigen (HLA) ligands from primary leukemia cells. We identified a number of ligands derived from different genes that are restrictedly expressed in the hematopoietic system. We exemplarily selected myeloperoxidase (MPO) as a potential target and isolated a high-avidity TCR with specificity for a HLA-B*07:02-(HLA-B7)-restricted epitope of MPO in the single HLA-mismatched setting. T cells transgenic for this TCR demonstrated high peptide and antigen specificity as well as leukemia reactivity in vitro and in vivo. In contrast, no significant on- and off-target toxicity could be observed. In conclusion, we here demonstrate, exemplarily for MPO, that leukemia-derived HLA ligands can be selected for specific effector tool development to redirect T cells to be used for graft manipulation or adoptive T-cell therapies in diverse transplant settings. This approach can be extended to other HLA ligands and HLA molecules in order to provide better treatment options for this life-threatening disease.

Norepinephrine transporter heterozygous knockout mice exhibit altered transport and behavior.

The norepinephrine (NE) transporter (NET) regulates synaptic NE availability for noradrenergic signaling in the brain and sympathetic nervous system. Although genetic variation leading to a loss of NET expression has been implicated in psychiatric and cardiovascular disorders, complete NET deficiency has not been found in people, limiting the utility of NET knockout mice as a model for genetically driven NET dysfunction. Here, we investigate NET expression in NET heterozygous knockout male mice (NET(+/-) ), demonstrating that they display an approximately 50% reduction in NET protein levels. Surprisingly, these mice display no significant deficit in NET activity assessed in hippocampal and cortical synaptosomes. We found that this compensation in NET activity was due to enhanced activity of surface-resident transporters, as opposed to surface recruitment of NET protein or compensation through other transport mechanisms, including serotonin, dopamine or organic cation transporters. We hypothesize that loss of NET protein in the NET(+/-) mouse establishes an activated state of existing surface NET proteins. The NET(+/-) mice exhibit increased anxiety in the open field and light-dark box and display deficits in reversal learning in the Morris water maze. These data suggest that recovery of near basal activity in NET(+/-) mice appears to be insufficient to limit anxiety responses or support cognitive performance that might involve noradrenergic neurotransmission. The NET(+/-) mice represent a unique model to study the loss and resultant compensatory changes in NET that may be relevant to behavior and physiology in human NET deficiency disorders.

Fibrotest or Fibroscan for evaluation of liver fibrosis in haemophilia patients infected with hepatitis C.

Non-invasive modalities to estimate fibrosis stage are desirable in hepatitis C-infected haemophilia patients. Previous studies found a high rate of significant fibrosis both by Fibrotest (FT) and Fibroscan (FS) in these patients. To estimate liver fibrosis and to assess the concordance between FT and FS in hepatitis C-infected haemophilia patients. FT and FS were performed at different laboratories and were unaware of the results of the alternative test. Three successive liver stiffness measurements (LSM) were performed at different sites on the liver. Two-validated algorithms were used to improve evaluation of fibrosis by non-invasive methods. Fifty-seven hepatitis C-infected haemophilia patients were evaluated by FT and FS. Acquisition of LSMs was not feasible in two patients: obesity--one, surgical scars--one. Fibrosis stage > or=F2, > or =F3 or =F4 were estimated in about a half, about a third and in 15-20% of the evaluated patients by FS and FT respectively. The corresponding concordance rates and kappa score for fibrosis stage > or =F2, > or =F3 or =F4 between FT and FS were 62%, 69%, 85% and 0.24, 0.32, 0.44 respectively. Using the two aforementioned algorithms, additional 14 patients could be reliably estimated for fibrosis stage > or =F2. High proportion hepatitis C-infected haemophilia patients were estimated with significant or advanced stages of liver fibrosis using both tests. Nevertheless, the agreement between modalities was only fair and improved with more advanced stages of fibrosis. Practical algorithms for the accuracy of FT and FS may improve reliable evaluation of fibrosis in this population.

[Telemedicine in Germany: status, chances and limits]. / Stand, Möglichkeiten und Grenzen der Telemedizin in Deutschland.

In Germany there are many successful special applications of telemedicine. However, these projects are generally not extendable to the whole nation because of the highly complex German health care system, limited funding, heterogeneous IT standards in ambulatory and hospital care, insufficient official electronic health card use, the different data protection and privacy regulations of the federal and state governments, doubts of physicians and patients as well as unequal costs and benefits for the various persons involved in telemedicine. These problems can be overcome by better legal regulations for a seamless interaction of ambulatory and hospital care, improved IT standards and support of the interoperability of telemedical and other health care IT, adaption of the health care organization, work flow and reimbursement of telemedicine services, better information and education of all persons involved about the necessity and limits of telemedicine. There are no doubts about the benefits of telemedicine but to achieve these advantages for the whole healthcare system in Germany requires much work, time and good will.

[E-learning in the education and training of physicians. Methods, results, evaluation]. / E-Learning in der ärztlichen Aus- und Weiterbildung. Methoden, Ergebnisse, Evaluation.

E-learning has been established in the education and training of physicians in various types: linear sequential and hyper-textual forms of multimedia presentations and texts, tutorial systems and simulations. Case-based e-learning systems are of special importance in medicine because they allow for mediation of process and practical knowledge by presentation of authentic medical cases in a simulated environment. The integration into the medical education and advanced professional training is crucial for the long-term success of e-learning; in case-based systems this can be accomplished by blended learning approaches which combine elements of traditional teaching with e-learning. Learning management systems (LMS) support integration of traditional teaching and e-learning by serving as an organizational platform for content of teaching. Further, they provide means of communication for trainers and trainees, authoring tools, interactive components, course management and role-based sharing concept. The dissemination of e-learning can be fostered by attention to requirements and user analysis, early adoption to organizational structures, curricular integration and continuous cooperation with students. Summarized, didactic and organizational aspects determine the success of our own e-learning offers as well as they influence the general further development of e-learning more than technical features.

Selected impressions on the beginning of the electronic medical record and patient information.

OBJECTIVES: To present an overview of early European and American work on Electronic Medical Records and patient information. METHOD: The invited lectures of "pioneers of electronic patient information" given at the farewell symposium of Wolfgang Giere in Frankfurt, Germany, are summarized and discussed. RESULTS: The origin of medical record writing goes back to Hippocrates and over many centuries this important medical duty was regarded as an annoying, laborious and error-prone task. First steps towards a better medical record started in 1936 with punch cards. In the 1960s the minimum basic data set, a unique patient ID was introduced and even for outpatients first computerized medical record systems were developed applying some important standards and well accepted data structures. Nowadays multimedia are included in patient record systems, highly specialized subsystems e.g. for radiology or cardiology are available, and semantic and statistic mining techniques as well as medical classifications and standardized terminologies support evaluation. All these methods should primarily improve the quality of care, reduce errors, improve communication between multiple specialists, reduce wait times for patients and improve efficiency. CONCLUSIONS: Over decades it became obvious that the structure of a medical record notably for coded data but also for narrative text and pictures must be carefully modelled. Well maintained standardized health terminologies and medical classifications are important issues for a user-friendly electronic medical record, which bring benefits for clinicians and patients.

[Electronic distribution of patient records and images through PACS: implementation of data protection at the University Hospital in Freiburg]. / Elektronische Befund- und Bildverteilung aus einem PACS: Umsetzung der datenschutzrechtlichen Aspekte am Beispiel des Universitätsklinikums Freiburg.

In large installations of a Picture Archiving and Communication System (PACS), data protection becomes an issue. Above all, not every employee should have access to all data stored in the system. At the Freiburg University Hospital, we developed a concept of dynamic assignment of authorization, assuring that every physician is authorized to the data of all patients under his care. We describe the technical implementation of data protection developed for the integration of PACS and electronic patient records in Freiburg. The system was installed in January 2001 and the experience of its two years in operation is reported.

Health informatics world wide--a WWW service for the health informatics community.

Health Informatics World Wide, a Web index of research and educational institutions in the fields of Health Informatics and Medical Informatics has been available to WWW users since 1995. In this paper we report on the original conception of this service, its subsequent modifications and address its maintenance and related problems. Access statistics are presented which demonstrate its relevance as well as the geographical focus of Health Informatics research and development.

[Virtual conferences in medicine]. / Chatten statt Jetten? Virtuelle Konferenzen in der Medizin.

The Internet and high-speed communication facilities have tremendously simplified the exchange of multimedia data. E-mail and World Wide Web have become important tools for everyday information and communication. In recent years there have been numerous attempts to exploit web technology for virtual conferences. However, in the medical domain, only few virtual conferences could be established. We describe the architecture and typical features of virtual conferences, their organizational and technical requirements and discuss prerequisites for their successful implementation.

Automated coding of diagnoses--three methods compared.

In Germany, new legal requirements have raised the importance of the accurate encoding of admission and discharge diseases for in- and outpatients. In response to emerging needs for computer-supported tools we examined three methods for automated coding of German-language free-text diagnosis phrases. We compared a language-independent lexicon-free n-gram approach with one which uses a dictionary of medical morphemes and refines the query by a mapping to SNOMED codes. Both techniques produced a ranked output of possible diagnoses within a vector space framework for retrieval. The results did not reveal any significant difference: The correct diagnosis was found in approximately 40% for three-digit codes, and 30% for four-digit codes. The lexicon-based method was then modified by substituting the vector space ranking by a heuristic approach that capitalizes on the semantic structure of SNOMED, thus raising the number of correct diagnoses significantly (approximately 50% for three-digit codes, and 40% for four-digit codes). As a result, we claim that lexicon-based retrieval methods do not perform better than the lexicon-free ones, unless conceptual knowledge is added.

Semantic analysis of medical free texts.

The semantic interpretation of natural language utterances is usually based on a large number of transformation rules which map syntactic structures (parse trees) onto some kind of meaning representation. However, those interpretation rules exhibit an insufficient degree of abstraction so that the scalability and portability of such natural language processing systems is hard to maintain. In this paper, we introduce an approach that is able to cope with a wide variety of semantic interpretation patterns in medical free texts by applying a small inventory of abstract semantic interpretation schemata. These schemata address generalized graph configurations within syntactic dependency parse trees, which abstract away from specific syntactic constructions.

Realization of a CPR using HL7 queries from communication server to information server.

A communication server is often used in Germany to interface legacy systems. It handles the translation, duplication, and transmission of messages to all systems that might need this information. Based on the principles of "for every data there is only one master" and "information on demand" we have built an information server that reduces the messages required and simplifies the handling of messages, the update of data already sent compared to a communication server. It also allows to implement a security policy as required by the German data privacy legislature.

Towards a multilingual morpheme thesaurus for medical free-text retrieval.

We introduce a methodology for the segmentation of complex compounds into medically plausible morphemes. A tool for thesaurus compilation and management is presented, and design principles for a multilingual morpheme thesaurus are outlined. Our goal is to enhance the quality of medical free-text retrieval by replacing lexically based through morpheme-based search procedures.