Thomas Baehring

IFN-alpha skews monocytes into CD56+-expressing dendritic cells with potent functional activities in vitro and in vivo.

The antitumor effect of IFN-α is mediated by the activation of CTLs, NK cells, and the generation of highly potent Ag-presenting dendritic cells (IFN-DCs). In this study, we show that IFN-DCs generated in vitro from monocytes express CD56 on their surface, a marker which has been thought to be specific for NK cells. FACS analyses of CD56+ and CD56− IFN-DCs showed a nearly identical pattern for most of the classical DC markers. Importantly, however, only CD56+ IFN-DCs exhibited cytolytic activity up to 24% that could almost completely be blocked (−81%) after coincubation with anti-TRAIL. Intracytoplasmatic cytokine staining revealed that the majority of IFN-DCs independently of their CD56 expression were IFN-γ positive as well. In contrast, CD56+ IFN-DCs showed stronger capacity in stimulating allogenic T cells compared with CD56− IFN-DC. Based on these results, five patients with metastasized medullary thyroid carcinoma were treated for the first time with monocyte-derived tumor Ag-pulsed IFN-DCs. After a long term follow-up (in mean 37 mo) all patients are alive. Immunohistochemical analyses of delayed-type hypersensitivity skin reaction showed a strong infiltration with CD8+ cells. In two patients no substantial change in tumor morphology was detected. Importantly, by analyzing PBMCs, these patients also showed an increase of Ag-specific IFN-γ-secreting T cells. In summary, we here describe for the first time that cytotoxic activity of IFN-DCs is mainly mediated by an IFN-DC subset showing partial phenotypic and functional characteristics of NK cells. These cells represent another mechanism of the antitumor effect induced by IFN-α.

Using the World Wide Web—a new approach to risk identification of diabetes mellitus

Diabetes mellitus is a major health problem with a rising tendency world-wide. A new strategy for risk evaluation and data collection of undiagnosed non-insulin-dependent diabetes mellitus (NIDDM) using the World Wide Web (WWW) is presented. An easy-to-handle questionnaire on typical risk factors was converted into an interactive WWW document. The Internet provides the suitable platform for the net-based distribution of the questionnaire form as well as the computer-assisted entering and interpretation of the data (http:(/)/www.uni-leipzig.de/-diabetes). The analysis program, installed on our WWW server, interprets the information and sends the assessment on-line back to the inquiring user PC. The data are also collected anonymously in a database for epidemiological studies. In the test period, 744 world-wide accesses were registered: 433 men, mean age 39.8 +/- 14.4 years (range 10-83) and 311 women, mean age 36.7 +/- 12.7 years (range 11-77). An increased risk for undiagnosed diabetes was identified to 43.6%. The risk profile of male and female users showed no significant gender-related differences. Using the WWW technology can support early detection and adequate treatment of undiagnosed diabetes. This innovative strategy to screen for a high risk profile is an useful, cost-effective and up-to-date tool for broad community health education and epidemiological studies world-wide.

The value of training in communication skills for continuing medical education.

OBJECTIVE Question arises as to what extent communication skills are considered in continuing medical education (CME). METHODS Analysis for CME-courses in communication skills in the area of the Chamber of Physicians North Rhine (ÄkNo), Germany. Supply Arm(A): CME events (n = 19,320) certified in 2007 were evaluated. Demand Arm(B): course participation of 850 family physicians in the period 2002-2007 was analyzed (n = 37,724). Tests were calculated to the level 0.05 using Mann-Whitney U-test. RESULTS (A) 388 (2.0%) events were concerned with the topic communications. 59.3% involved active cooperation of the participants. 0.5% events devoted more than 50% of their duration to the topic communication. Proportions in the subjects of internal medicine, general medicine and pediatrics amounted to 0.2%. (B) 803 (2.1%) events with a focus on communication were identified. Women took part in significantly more events than men (p<0.002) and selected more interactive courses. CONCLUSION Content on communication training was small. Increasing experience does not automatically improve communication skills but an extent of deliberate praxis seems to be necessary and must be sought and developed. PRACTICE IMPLICATIONS Communication skills are still insufficiently provided in CME-courses and should be more directed to focus as treatment strategies and scientifically investigated for outcome improvements.

Dendritic Cell Vaccination with Xenogenic Polypeptide Hormone Induces Tumor Rejection in Neuroendocrine Cancer

Purpose: No relevant breakthrough has yet been achieved in the identification of tumor antigens in many neuroendocrine cancer types that exist, such as malignant gastrinoma, insulinoma, or medullary thyroid carcinoma. The aim of this study was to proof the concept of dendritic cell immunization with a tumor cell-specific polypeptide hormone as a target molecule in a transgenic mouse model for medullary thyroid carcinoma (Ret/Cal mice). Experimental Design: Ret/Cal mice were repeatedly immunized for up to 6 months with amino acid–modified (xenogenic) calcitonin-pulsed dendritic cells. Xenogenic calcitonin was chosen for immunization due to its higher immunogenicity as compared with murine calcitonin. Results: Lymph nodes from control protein-immunized mice did not show any macroscopic abnormalities, whereas tumor peptide-treated mice revealed in general profoundly enlarged lymph nodes. In tetramer analysis of paratumorous lymph nodes, 1.9% to 3.1% of all infiltrating CD8+ T cells were specific for one of three tumor epitopes tested. Analysis of the activated IFN-γ-secreting component in splenic cells revealed an average of 2.8% tumor epitope-specific CD8+ cells. Immunohistochemistry revealed strong CD8+ tumor infiltration in calcitonin-vaccinated mice. In addition, these cells also showed strong in vitro lysis capacity at up to 63.3%. Most importantly, calcitonin-immunized mice revealed largely diminished tumor outgrowth (−74.3%) compared with control mice (P < 0.0001). Likewise, serum calcitonin levels in calcitonin-vaccinated Ret/Cal mice were lower than in the control group. Conclusion: These results have a major effect, as they are the first to establish a role for xenogenic polypeptide hormones as target molecules for immunotherapy in endocrine malignancies.

Comparison between Long-Menu and Open-Ended Questions in computerized medical assessments. A randomized controlled trial

BackgroundLong-menu questions (LMQs) are viewed as an alternative method for answering open-ended questions (OEQs) in computerized assessment. So far this question type and its influence on examination scores have not been studied sufficiently. However, the increasing use of computerized assessments will also lead to an increasing use of this question type.Using a summative online key feature (KF) examination we evaluated whether LMQs can be compared with OEQs in regard to the level of difficulty, performance and response times. We also evaluated the content for its suitability for LMQs.MethodsWe randomized 146 fourth year medical students into two groups. For the purpose of this study we created 7 peer-reviewed KF-cases with a total of 25 questions. All questions had the same content in both groups, but nine questions had a different answer type. Group A answered 9 questions with an LM type, group B with an OE type. In addition to the LM answer, group A could give an OE answer if the appropriate answer was not included in the list.ResultsThe average number of correct answers for LMQs and OEQs showed no significant difference (p = 0.93). Among all 630 LM answers only one correct term (0.32%) was not included in the list of answers. The response time for LMQs did not significantly differ from that of OEQs (p = 0.65).ConclusionLMQs and OEQs do not differ significantly. Compared to standard multiple-choice questions (MCQs), the response time for LMQs and OEQs is longer. This is probably due to the fact that they require active problem solving skills and more practice. LMQs correspond more suitable to Short answer questions (SAQ) then to OEQ and should only be used when the answers can be clearly phrased, using only a few, precise synonyms.LMQs can decrease cueing effects and significantly simplify the scoring in computerized assessment.

Amino Acid-Modified Calcitonin Immunization Induces Tumor Epitope-Specific Immunity in a Transgenic Mouse Model for Medullary Thyroid Carcinoma

Up to now, no relevant tumor antigen has been identified in medullary thyroid carcinoma (MTC). The aim of the present study was to prove the concept of an immunization with an amino acid-modified calcitonin (CT) for the treatment of MTC in a transgenic mouse model. Amino acid-modified (human) CT has been chosen for vaccination because of its higher binding affinity to the murine H2-Kb-MHC molecule. Mice were immunized over 6 months with monthly injections of amino acid-modified CT-pulsed dendritic cells. For enumeration of tumor epitope-specific CD8+ cytotoxic T cells, tetramer analyses were performed. CT peptide-treated mice revealed a mean 0.73 +/- 0.45 and 0.91 +/- 0.59% positive cells, depending on the two tetramers tested, whereas no increase was seen in control protein-immunized mice (0.08-0.12% tetramer-positive cells). Importantly, the subset of CT-specific CD8+ T cells also showed a high expression of interferon-gamma. In line with these results, CT-immunized mice also showed an intratumor infiltration with CD8+ T lymphocytes. Importantly, we also found a diminished tumor outgrowth of -57% and a decrease of the serum CT levels (2.0 +/- 0.1 pg/ml) compared with control protein-immunized Ret/Cal mice (3.0 +/- 0.4 pg/ml). In summary, we show that amino acid-modified CT is recognized from the immune system leading to a specific antitumor immune response and a diminished tumor outgrowth in transgenic MTC mice. The results are of potential importance because they might be applicable to patients with metastatic spread of a MTC.

Modellversuch: Einsatz und Evaluierung eines problemorientierten Lernprogrammes in der inneren Medizin

Zusammenfassung□ HintergrundProblemorientiertes Lernen ist ein neuer Ansatz im Medizinstudium. Wesentlich ist hierbei die aktive Bearbeitung authentischer Lernfälle. Die Nutzung moderner Software eignet sich für die interaktive und multimediale Aufarbeitung von Fallbeobachtungen und den Einsatz im Studentenunterricht. Die curriculare Integration dieser Lernform ist bisher gering.□ MethodeIn einer modellhaften Anwendung wurde das Computerlernprogramm CASUS zum Fall Makroprolaktinom im Seminargruppenunterricht der inneren Medizin eingesetzt, an dem 287 Studierende teilnahmen.□ ErgebnisBei einer Rücklaufquote von 78% der eingesetzten Fragebögen war für 96% der Studierenden die Bedienung des Programms leicht erlernbar. Als kritisch erwies sich die zielgruppengerechte inhaltliche Gestaltung der Lernfälle. Die Bewertung des Programms war unabhängig von der individuellen Computervorerfahrung. 82% der Studierenden würden das Lernsystem gern weiter nutzen.□ SchlußfolgerungProblemorientiertes computergestütztes Lernen anhand authentischer Fälle führt zu einer Motivationssteigerung und möglicherweise zu einer nachhaltigen Verbesserung der Ausbildung. Zur Beurteilung des erzielbaren Lernerfolgs und der „Aufwand-Nutzen”-Relation im Vergleich zu herkömmlichen Lemmethoden müssen weitere kontrollierte Studien durchgeführt werden.Abstract□ BackgroundProblem-based training is a new approach in medical education. It is in particular essential that students work actively with authentic medical cases. Modern software is appropriate for developing interactive case-based training systems and the use in teaching environments. This method is still rarely integrated within medical curricula.□ MethodIn an educational trial with 287 students the conceptual background, feasibility and evaluation are discussed. The learning program CASUS was used to present the case of a macroprolactinoma for interactive training. A questionnaire with a return rate of 78% was used for evaluation.□ Results96% of the students had no problems in learning how to handle and use the program. A major problem was to focus the contents of the program exactly to the students’ needs. The students’ judgement was independent of the individual computer skills. 82% of the students would like to use the program in the future.□ ConclusionCase-based and computer-assisted learning increases motivation and probably improves the quality in medical education. Controlled trials have to be implemented in future to show the effectiveness and the long-term output of these learning systems.