Dendritic cell vaccination induces tumor epitope-specific Th1 immune response in medullary thyroid carcinoma.

The existence of inherited aggressive forms of medullary thyroid carcinoma (MTC) and their resistance to classical therapies make it a prime candidate for adoptive immunotherapy. Highly potent antigen-presenting cells, namely dendritic cells (DCs), may serve as an interesting tool for anticancer vaccination. Here we report on the IN VITRO findings of a vaccination trial in five MTC patients, who were treated with a new DC generation protocol consisting of granulocyte-macrophage colony-stimulating factor and interferon-alpha (IFN-DCs). These cells were pulsed with tumor-specific calcitonin and administered twice. In two patients who responded to therapy we found a large increase (in mean 2.9+/-1.9%) of antigen-specific IFN-gamma-secreting CD4+ cells as well as an increase of granzyme B positive CD8+ cells (mean 2.2+/-0.2%) in the peripheral blood. In parallel, a decrease of CD4+/CD25+/FoxP3+ regulatory T cells was seen. Importantly, IN VITRO stimulation of PBMC with 10 different 15mer calcitonin peptides resulted in the identification of two HLA class II epitope regions within the central part of full-length calcitonin. These data were in accordance with the results drawn from the computer-based algorithm epitope prediction software SYFPEITHI. Measurement of different pro- and anti-angiogenic factors did not allow for a distinct outcome of prediction of the treated patients. In summary, we have demonstrated that immunization with IFN-DCs leads to a tumor epitope-specific immune response in MTC patients and may, therefore, represent a promising tool for future vaccination trials.

Characterization of monocyte-derived IFNalpha-generated dendritic cells.

The antitumor effects of IFNalpha is mainly mediated by the activation of cytotoxic T lymphocytes (CTLs), the activation of natural killer (NK) cells, and the generation of highly potent antigen-presenting dendritic cells (IFN-DCs). Recently, we demonstrated that these cells partially express the NK cell marker CD56 and reveal a direct cytotoxic immunity towards tumor cells. The aim of the present study was to explore these cells in more detail with respect to their phenotypical and functional characteristics. Flowcytometric analyses revealed that a 5-day incubation time of CD14+ monocytes with IFNalpha results in a steady increase of CD56 surface expression of these cells from 25% (+/-2%) on day 1 up to 68% (+/-11%) on day 5. Interestingly, additional culturing of negatively selected CD56- IFN-DCs also resulted in a partial CD56 surface expression. By comparing both cell types in more detail we found a significant decrease of CD14 expression on CD56+ IFN-DCs (66+/-6%) compared to CD56- IFN-DCs (76+/-6%). On the basis of functional tests, CD56+ IFN-DCs revealed a slightly increased phagocytosis capacity compared to CD56- IFN-DCs as only 82% of CD56- IFN-DCs showed a positive intracytoplasmatic signal after 60 minutes coculturing with FITC-labeled albumin, whereas 91% of CD56+ IFN-DCs were positive. Moreover, CD56+ IFN-DCs revealed a stronger T cell stimulation capacity compared to CD56- IFN-DCs. These results together with our previously described data suggest that CD56+ IFN-DCs and CD56- IFN-DCs may represent one identical cell population with different maturation status rather than two separate cell entities. Because of their high stimulating capacity and their direct cytolytic effects these cells represent a new promising tool for cellular anticancer therapy.

[Detection of a previously unrecognized type 2 diabetes using a risk questionnaire. Efficiency for general population screening]. / Nachweis eines bisher unerkannten Diabetes mellitus Typ 2 mittels Risikofragebogen. Effizienz beim allgemeinen Populations-Screening.

BACKGROUND AND OBJECTIVE: The detection of unknown cases of diabetes mellitus is of great medical and public health interest. In the present study a stepwise screening procedure was used to examine the effectiveness of a diabetes-risk questionnaire at a population level. PATIENTS AND METHODS: 58,254 insured persons (34,179 men and 24,075 women (55 years and older) enrolled in the Health Insurance "Techniker Krankenkasse" of Thuringia and the Duesseldorf area were contacted per mail to participate. 21,218 returned the questionnaire. They were contacted again and encouraged to participate in a medical check-up for early detection of diabetes. RESULTS: Data of 4,314 individuals (20.3%) who participated in the medical check-up were analysed. Their fasting blood glucose was measured (FBG, n=3,888) and, if necessary, they underwent an additional oral glucose tolerance test (OGTT, n=2,048). In 192 cases (4.5%) the general practitioner (GP) diagnosed manifest diabetes mellitus. In an additional 393 patients (9.1%) an impaired glucose tolerance was found. Analysis of documented blood glucose measurements suggested a manifest diabetes mellitus in 3.5% (by OGTT) and 10.3% (by FBG), as well as an impaired glucose tolerance in 16.1% (by OGTT) and 36.6% (by FBG). CONCLUSIONS: These results demonstrate good effectiveness of the screening procedure among the participants of a medical check-up programme for early detection of diabetes mellitus and its precursors. However, the effectiveness of population-based diabetes screening with only a mailing of a risk questionnaire was unsatisfactory.

[Computer-assisted case-based education in surgery]. / Computergestützte fallbasierte Lehre in der Chirurgie.

INTRODUCTION: Computer technology is well established in the fields of medical diagnosis and monitoring. In recent years, there has also been an increase in the use of computers for the purpose of medical education. METHODS: With the aid of the "author's-system" CASUS, investigation of a case of acute abdominal pain was integrated into the practical medical training for students in the 4th. year of clinical studies. For patient history, clinical examination and laboratory tests, the method involves the use of 41 cards with pictorial and acoustic information (text, graphics, sound recordings and videos), including 23 questions to be answered by the students. At the end of the session, the acceptance, effectiveness and practicability of the computer-based training was evaluated by a questionnaire. RESULTS: In 356 students, a high rate of acceptance and satisfaction was achieved (positive judgement of various aspects: 55%-98%). Technical difficulties which occurred initially were overcome during the course of the evaluation. Some questions were answered more positively by female students. CONCLUSION: Most students share the view that computer-based training, though not able to take the place of bedside teaching, is a valuable addition to the armamentum of medical teaching.

[Model trial: use and evaluation of a problem-oriented learning program in internal medicine]. / Modellversuch: Einsatz und Evaluierung eines problemorientierten Lernprogrammes in der inneren Medizin.

BACKGROUND: Problem-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. METHOD: In 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. RESULTS: 96% 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. CONCLUSION: Case-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.

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.

[Clinical picture, diagnosis and therapy of acromegaly patients in Eastern and Western Germany]. / Klinik, Diagnostik, Therapie und Betreuung der Akromegaliepatienten im Ost-West-Vergleich.

Acromegaly, a chronic disease characterized by an excessive secretion of growth hormone (GH), is not commonly diagnosed timely enough. Therefore, investigations have been conducted through standardized questionnaires concerning the path to diagnosis, clinical data, therapy, and the patient care of 46 acromegalic patients. The acquired information has been compared in the former Eastern and Western German states. The mean duration of disease before diagnosis was estimated to be 6.1 +/- 5.3 years in the area surrounding Erlangen and 9.3 +/- 7.3 years in the Leipzig and Dresden areas. Despite current trends, a significant difference could not be established regarding the age in which the first symptoms are noted, time of diagnosis, and the delay between the two points in time General practitioners have diagnosed about 35 percent of the occurrences of acromegaly, 15 percent of the cases were accidentally found and about as many were discovered in hospitals. 11 percent of the occurrences were diagnosed by neurologists and another 11 percent by internists. The remaining cases were established by eye specialists. ENT departments, orthopedic specialists or gynaecologists. The most frequent symptoms are increased acral growth, coarse facial features and excessive sweating. For 91 percent of the acromegaly patients, surgery was voted as the therapy of choice. Acromegalic patients have learned the most about their disease through personal contact with doctors, especially endocrine specialists. Many patients are not informed enough about the possible complications of their disease. Through gathered data, it has been concluded that in Eastern and Western Germany the disease has not been identified soon enough. Interdisciplinary teamwork among doctors is a basis for early diagnosis, as well as better patient awareness and education.

[CASUS model trial. A computer-assisted author system for problem-oriented learning in medicine]. / Modellversuch CASUS. Ein computergestütztes Autorensystem für die problemorientierte Lehre in der Medizin.

The CASUS-project, a three year publicly funded effort to improve the quality of continuing medical education in Germany, has one major goal: The development and evaluation of an easy-to-handle author-system for problem-oriented learning in medicine. On the theoretical basis of the cognitive apprenticeship-approach, the concept of a teaching and learning database as a hypermedia system was built. The student should learn to manage authentical problems in the form of authentical clinical cases. The step-by-step learning process is expert-guided by the clinical authors of each case. The creation of various differential diagnoses by the learner is strongly supported in the process. The structure of the program can also be used for case-based examinations. In parallel to the technical development, a case-selection process for medical students students in internal medicine was initiated. About 120 relevant diseases were identified to be represented in the CASUS-case library. Prevalence, transferability of knowledge, treatability, urgence of treatment and preventive aspects were used as selection criteria. The system will be evaluated during the implementation of test cases and will then be available to be used by authors and students on a routine basis in 1997.

[Periodogram analysis for signal and noise evaluation in roentgen video signals]. / Die Periodogramm-Analyse zur Signal- und Rauschbewertung im Röntgenfernsehsignal.

Movements of the heart, the large vessels and the gastrointestinal tract can be evaluated for diagnostic purposes using fluoroscopic video systems. A new means of quantitatively evaluating the signal and noise components of the video signal is described. The signal and noise power components are determined from the periodogram after prior Fourier analysis. Variance is reduced by averaging and keeping the measuring conditions constant. For measurements of signal transfer properties, a radiological phantom capable of producing sinusoidal movements of the edge of the object was developed. An analysis of the performance of the theoretically derived evaluation parameters was carried out at a fluoroscopic unit under clinical conditions. Periodogram analysis makes possible objective image quality evaluation in clinical motion studies and in the technical quality assurance of fluoroscopic video systems. The use of a compact PC-based video measuring system renders application both practical and easy.

[Results of animal experiments with videodensitometry in the assessment of gastrointestinal motility]. / Tierexperimentelle Ergebnisse der Videodensitometrie zur Beurteilung der Magen-Darm-Motilität.

It is possible to register video-densitometrically the gastrointestinal motility visible in fluoroscopic image using a video-signal analyser. The influence of metoclopramide at the propulsive movement of the stomach wall of rats was checked in vivo. The propulsive gastric movement increased in case of small doses of metoclopramide, higher doses stopped the motility. The propulsive gastric movement is parallel to the evaluation of the stomach. Metoclopramide has only a mild influence on the contraction frequency. We found that videodensitometry is also a practical method for evaluation of local wall motility of an intestinal segment of a rabbit. The non-visible motion is recorded and evaluated by means of several physical parameters (frequency, moving velocity of waves). Videodensitometry does not supply information on the causes of motion; hence, a combination with other methods, i.e. the registration of the electromyogram (EMG), is useful. In this way the mechanical answer to EMG-changes is simple to quantify. The experiment with rabbits affords a proof regarding the practicability of the method for pharmaco-physiological investigations.

[Conventional roentgen functional diagnosis--videodensitometry. 4. Conventional roentgen videodensitometry exemplified with peri-cardiac vessels]. / Konventionelle Röntgen-Funktionsdiagnostik--Videodensitometrie. 4. Konventionelle Röntgenvideodensitometrie am Beispiel der herznahen Gefässe.

It is possible to record movement-parameters by means of roentgen videodensitometry of the great central vessels as well the pulmonary artery as the thoracic aorta visible in fluoroscopic image (provided by videorecorder). We could noninvasively measure pre-ejection periods (PEP) for the right heart (PEP f) as well for the left heart (PEP g) by synchronous electrocardiography for each cardiac action and for each examination process. It is important to form a quotient between PEP f and PEP g in the individual case. First findings in patients with cardiac septal defects (with and without right heart block and pulmonary hypertension) show characteristic quotients and figures of the curves. In cases with electrocardiographic left heart block the elongated PEP g can be stated in graduated form. Further investigations on the mechanic interaction between the right and left heart, especially in cases of disorders in the heart conduction system, might be of interest.

[Conventional roentgen functional diagnosis--videodensitometry. 3. Conventional roentgen videodensitometry exemplified by the heart]. / Konventionelle Röntgen-Funktionsdiagnostik--Videodensitometrie. 3. Konventionelle Röntgenvideodensitometrie am Beispiel des Herzens.

It is possible to record movement parameters video densitometrically and synchronously by means of a video signal analysator at various points of the organ surface visible via fluoroscopic images (provided by videorecorder). Movement parameters of the heart surface were signed just in the same cardiac action by synchronous electrocardiography. There are some difficulties in this method according to evaluation with reference to laevocardiography in consequence of functional variety of the heart and the different exercise conditions. Small aneurysms of the cardiac apex were only seen when they were separated and located at the cardiac margin. Extended cardiac aneurysms were video densitometrically recorded as a paradoxical movement at the cardiac surface. A paradoxical movement was never seen with negative findings in laevocardiography.

[Conventional roentgen functional diagnosis--videodensitometry. 2. Clinical imaging site for noninvasive diagnosis of organ motion]. / Konventionelle Röntgen-Funktionsdiagnostik--Videodensitometrie. 2. Klinischer Messplatz für die nichtinvasive Organbewegungsdiagnostik.

By means of the described system it is possible to measure and as well analog as digital process the organ movement, needing a X-ray television system for flouroscopy and a videotape for continuously recording. Using the densitometric principle measurements of time and a quantitative form analysis of the curves are performed. After border recognition and using the topometric principle, the local organ motion can be evaluated. The levels of signal and noise in the measured curves are computed by a fourier transformation. In the field of functional cardiology the video signal is recorded and processed synchronously with the electrocardiogram.

[Videodensitometry analysis of stomach wall motility--presentation of a new method]. / Videodensitometrische Analyse der Magenwandmotilität--Vorstellung einer neuen Methode.

The videodensitometry is a suitable method for recording the gastric wall motility. It provides biosignals amenable by computer. There are no special demands to any organic form or kind of contraction. The asymmetry of the stomach makes no difference, therefore. The hitherto usual manometry will not be superseded. Both methods complete themselves in an ingenious manner. The radiation exposure by videodensitometry can be diminished by modifying the system for image causation.