Impairment of monocyte “lectin-like” receptor activity in Type 1 (insulin-dependent) diabetic patients

Summary In order to investigate whether the ability of peripheral blood monocytes to bind bacteria is impaired in diabetes, we studied carbohydrate-binding (lectin-like) receptors and the receptor for the Fc portion of immunoglobulin on monocytes from 25 male Type 1 (insulin-dependent) diabetic patients and 10 age-matched healthy control subjects. Peripheral blood monocytes from the diabetic patients expressed lower levels of lectin-like receptors compared to the control subjects, whereas the expression of the receptor for the Fc portion of immunoglobulin was similar in both populations. There was no correlation between the degree of lectin-like binding activity and plasma glucose concentration or glycaemic control. Recognition of unopsonized bacteria by the lectin-like receptor is impaired in Type 1 diabetes; this may affect the efficient elimination of potential pathogens.     

Insulin and growth hormone responses to glucose loading in treated acromegalics

Summary The insulin and growth hormone responses to oral glucose load (100 g) in 23 acronaegalic patients, previously treated by external irradiation, are described. Based on current clinical findings, sixteen acromegalics were considered inactive and seven patients active. Two of the latter were treated diabetics. Thirteen healthy, non-obese subjects formed the control group. Five inactive acromegalics had blood glucose values exceeding the upper limits of normal after the glucose load. Both the inactive and active acromegalics had hyperinsulinemia in the fasting state and after glucose load. The observation of an exaggerated serum insulin response to glucose load in clinically inactive acromegalics suggested that chronically elevated levels of circulating growth hormone may have led to permanent changes in the responsiveness of the pancreatic islets to glucose stimulation. The mean fasting value of serum growth hormone was about the same in the controls and the inactive acromegalics; the latter did not show suppression in serum growth hormone levels after glucose load.Research Fellow, Medical Research Council of Canada     

Extrarenal nephroblastomas

Summary The cases of extrarenal nephroblastoma published in the world literature have been tabulated and reviewed, and are discussed from a historical point of view.The Journal of Cancer Research and Clinical Oncology publishes in loose succession Editorials and Guest editorials on current and/or controversial problems in experimental and clinical oncology. These contributions represent exclusively the personal opinion of the author     

Early and Late QRS Morphology and Width in Biventricular Pacing: Relationship to Lead Site and Electrical Remodeling

48 patients (40 Male), mean age 68 ± 8 years, in III–IV class, with intraventricular conduction delay, received a biventricular pacemaker. Heart failure aetiology was non-ischemic in 60%. Left ventricular lead positioning was inferior in 5 patients (10%), posterior in 12 (25%), lateral in 18 (37%) and anterior in 13 (27%). QRS duration and axis were evaluated in sinus rhythm, and during right ventricular pacing, left ventricular pacing and biventricular pacing, the last early after implant and late after 8.8 ± 4.3 months. QRS duration (ms) was 154 ± 29 in sinus rhythm, 175 ± 28 during right ventricular pacing, 196 ± 31 during left ventricular pacing, 122 ± 23 during biventricular pacing early and 120 ± 18 during biventricular pacing late. All the differences were statistically significant, but not between early and late biventricular pacing. Mean QRS axis (°) was –27 ± 32 in sinus rhythm, –75 ± 4 during right ventricular pacing, 112 ± 41 during left ventricular pacing, –82 ± 51 during biventricular pacing early and –80 ± 42 during biventricular pacing late. Only the difference between left ventricular pacing and all the other groups was statistically significant. QRS axis did not significantly differ according to left ventricular lead site during left and biventricular pacing. Late compared with early biventricular pacing axis showed variation >30° in 35% of patients, in spite of no significant changes in QRS duration and x-ray positioning. Conclusion: Biventricular pacing significantly reduced QRS width, which persisted long-term. Left and biventricular pacing axis was poorly related to left ventricular lead positioning. Biventricular pacing axis variability over time may suggest a role of electrical remodeling.     

Experimental toxicology of formaldehyde

Summary Formaldehyde is a reactive chemical which undergoes spontaneous reactions with various cellular constituents. Mutagenicity data may be interpreted on the background of this behavior. Mice are better able to reduce the irritating effect of formaldehyde than rats and to reduce their ventilation rate when formaldehyde acts on the respiratory tract. Subacute exposure of rats to concentrations higher than 2 ppm inhibits mucociliary clearance of the nasal epithelium and leads to progressive histological and ultrastructural lesions at this site. The occurrence of squamous cell carcinomas of the nasal epithelium of rats after 2 years inhalation of 14.3 ppm formaldehyde (CIIT study) is probably the result of chronic and recurrent local toxicity; this is supported by species differences in susceptibility to the tissue damaging and carcinogenic effect of formaldehyde (rat, mouse, hamster). Data on formaldehyde-DNA interaction further support the argument that a direct risk extrapolation from the formaldehyde effects in rats to those expected for man is not possible.Cancer Research and Clinical Oncology will publish in loose succession Editorials and Guest Editorials on topical and controversial problems in experimental and clinical oncology. These contributions will represent the personal opinion of the author. We would like to ask our readers to send their comments directly to the author.     

Gastric “pseudolymphoma” with restricted light chain expression in a patient with obscure gastrointestinal blood loss

Summary We present a case report of a gastric pseudolymphoma (GL) that exhibits restricted light chain expression and, therefore, illustrates the dilemma encountered when histologically benign lesions have phenotypic abnormalities suggesting malignancy. For many years this lesion has been considered usually benign; however, recent reports such as this one demonstrate immunologic signs of monoclonality in an otherwise histologically benign lesion. This finding challenges our assumptions as to the nature of this lesion and our definition of cancer. The lesion also displays Castleman-like features (angiofollicular hyperplasia) as well as common inflammatory germinal centers. In addition we briefly review the literature.     

Slow metabolic deterioration towards diabetes in islet cell antibody positive patients with autoimmune polyendocrine disease

Summary We studied metabolic progression to IDDM in a cohort of adults who are ICA-positive and have associated autoimmune endocrine disease or circulating organ-specific autoantibodies (the Polyendocrine Study). Of the 186 individuals recruited 27 developed overt diabetes after a median follow-up of 4.5 years (range 0.4–12). Of these, eight patients did not require insulin treatment until at least 6 months after clinical diagnosis, with an interval of 1.8 years (1.2–5.7). An IVGTT was performed in 38 subjects and 23 had sequential studies. Of the initial 38 subjects six developed diabetes and only three showed a loss of FPIR to glucose (below the first percentile of a normal control group) before clinical onset of the disease. An additional three subjects showed a loss of the FPIR, and all still have normal glucose tolerance after median follow-up of 28 months (22–95). A whole or mixed pattern of islet cell staining was found in five of the six patients who developed diabetes and antibodies against an islet 37 k-antigen were detectable in four patients, all of whom required insulin soon after diagnosis. A beta-cell selective ICA staining pattern was seen in 14 of 17 subjects who did not develop diabetes and the mixed pattern in only three. None of this group had detectable 37k-antibodies. We conclude that metabolic deterioration is slow in polyendocrine patients, and that the IVGTT has less prognostic significance in this group than in first degree relatives of patients with IDDM. In contrast, the presence of the whole or mixed ICA staining pattern or of 37k-antibodies can identify a high risk of progression to IDDM within this polyendocrine population and may indicate the rate of metabolic deterioration.Abbreviations IDDM Insulin-dependent diabetes mellitus - ICA islet cell antibodies - IVGTT intravenous glucose tolerance test - FPIR first phase insulin response - OGTT oral glucose tolerance test - GAD glutamic acid decarboxylase - JDF Juvenile Diabetes Foundation     

Functional and surface characteristics of lymphocytes from patients with warm-antibody type autoimmunhemolytic anemia (AIHA)

Summary As part of an overall assessment of immunological function, several aspects of cellular immunity and circulating lymphocyte subpopulations were evaluated in a group of 10 patients with idiopathic autoimmunhemolytic anemia (AIHA). The absolute numbers of circulating T and B cells were reduced in the patient group compared to normals. A shift from corticosteroid-sensitive to corticosteroid-resistent and activated cells in the cytogram of clustered Fe-(III)-hydroxide-glucane saccharose labeled T lymphocytes was apparent. In vitro studies of cellular reactivity, as evaluated by PHA, ConA, PWM, antigens and allogeneic cell induced proliferation showed a blend of general or selective depression and sometimes a normal or increased activity with no definite correlation with both the number of circulating T cells and the extent of the hemolytic activity by the disease. The possible significance of the findings is discussed.This work was supported by the Minister für Wissenschaft und Forschung des Landes NRW II B8-FA 6438     

Where is the origin of the activator calcium in cardiac ventricular contraction?

Summary Under normal experimental conditions, the force of rested-state contractions (i.e., contractions after a rest period of 15 min or longer) of mammalian ventricular myocardium is insignificant. In Mg²⁺-free solution, in low sodium solution or in the presence of a cardioactive steroid, a strong early restedstate contraction develops without delay after stimulation, indicating the accumulation during rest of intracellularly stored activator calcium. By contrast, catecholamines cause a late rested-state contraction with a characteristic latent period of about 100 ms between stimulation and onset of contraction.Inhibition of the slow inward current by nifedipine has no influence on the contraction velocity of the early rested-state contraction, indicating that Ca²⁺ of the slow inward current is not involved in the calcium release mechanism of prefilled stores during excitation-contraction coupling. Nifedipine suppresses the late rested-state contraction in the presence of noradrenaline. In view of the constancy of the latent period, it is proposed that the activator calcium for the late rested-state contraction enters the cell with the slow inward current, is sequestered at first by uptake sites of the sarcoplasmic reticulum and subsequently released from its release sites as long as the cell is depolarized.The model of the different origin of activator calcium is discussed, in its implication for high-frequency contractions.     

Growth Hormone (GH) Secretion in Primary Adrenal Insufficiency: Effects of Cortisol Withdrawal and Patterned Replacement on GH Pulsatility and Circadian Rhythmicity

We studied the effects of cortisol withdrawal and patterned replacement upon spontaneous GH secretion and circadian rhythmicity in 7 patients with Addison's disease. Hydrocortisone was administered in physiological daily total dosages, and all resulting plasma cortisol values were 2–15 g/dl. It was given in 3 pulsatile modes: simulating physiological rhythm, reverse diurnal rhythmicity and continuous pulsatility. All modes of cortisol administration increased mean 24h, GH pulse amplitude and interpulse GH levels. During saline infusions circadian GH rhythmicity was preserved, with GH being at its highest between 2400–0400 h. Administration of hydrocortisone in any mode did not modify circadian GH rhythmicity. We conclude: Cortisol replacement in physiological daily doses increases GH output in patients with Addison's disease by augmenting GH pulse amplitude and interpulse levels. This is likely due to the attenuation of hypothalamic somatostatin (SRIF) secretion by physiologic levels of cortisol. By inference, it implies that cortisol deficiency leads to diminution of GH output with low GH pulse amplitude, likely as a result of an augmented hypothalamic somatostatin secretion. However, circadian rhythmicity of GH secretion is glucocorticoid-independent.     

The problem of thresholds in chemical carcinogenesis some views on theoretical and practical aspects

Conclusions I have tried to show that the threshold problem for carcinogens is still unsolved and that this unsatisfactory situation creates many problems for the scientific evaluation of the carcinogenesis problem as well as for its regulative aspects. In view of the extremely low acceptance of cancer risks in the general population, which is justified as well as understandable, carcinogenesis research must present new ideas to come nearer to a solution of such problems. More sound data on dose-time-effect curves in the low incidence range of 10-0.1% tumor incidences could indicated whether the established linearity in the higher incidence range might eventually by interrupted. Increase of animal numbers could also increase reliability of carcinogenicity experiments and allow the detection of low-dose effect; the disadvantages of this approach (mega-mouse experiment) however, in regard to cost and space necessary are evident. Increases of the mean life span by optimization of animal husbandry still would be another way of approach. However, no real breakthrough is to be expected here.The most promising approach seems to be the use of other indicators for carcinogenicity instead of tumor formation. Binding studies of carcinogens to biopolymers (Neumann 1980), especially DNA, as well as the determination of preneoplastic, enzyme-deficient islands (Kunz et al. 1978) have been shown to give dose-response curves parallel to the corresponding curves from carcinogenicity studies (Kunz) and extendable over 6 orders of magnitude of doses, without deviation from linearity (Neumann). Additional parameters might be found, which, altogether, might prove to be an important step toward further knowledge in this important field of carcinogenesis research.Oh König, das kann ich dir nicht sagen, und was du frägst, das wirst du nie erfahren R. Wagner, Tristan und IsoldeJournal of Cancer Research and Clinical Oncology publishes in loose succession Editorials and Guest Editorials on actual and/or controversial problems in experimental and clinicial oncology. These contributions represent exclusively the personal opinion of the author. The Editors Die Zeitschrift Journal of Cancer Research and Clinical Oncology bringt in zwangloser Folge Editorials und Guest Editorials zu aktuellen und/oder kontroversen Problemen der experimentellen und klinischen Onkologie. Diese Beiträge geben ausschließlich die persönliche Meinung des Autors wieder.     

Differential survival of cell subpopulations in spheroids after treatment with bleomycin

Summary The cytotoxic effect of bleomycin (BLM) on Chinese hamster V79-cells grown as spheroids is compared to that on monolayer cultures in exponential vs. plateau phase of growth. Cells treated as intact spheroids with BLM (50 g/ml for 1 h) are more sensitive than monolayer cultures. Cell subpopulations derived from different zones of the spheroids survive BLM-treatment to different degrees: When treated as single cells in suspension, the formerly outer cells are less affected than the inner cells. Within intact spheroids, however, progressive cellular resistance with increasing distance from the outer rim is found.     

Interpretation of blood cultures yielding staphylococcus aureus

Summary Forty-eight patients with blood cultures positive for Staphylococcus aureus were classified according to clinical criteria in three groups: definite, possible, and doubtful septicemia. Using traditional blood culture sets with two bottles (thioglycollate and tryptic soy broths), we found that patients with definite septicemia always showed more than one positive bottle per day if more than one set was drawn, that the mean detection time was 1.7 days, and that 95% of the first positive bottles and 92% of all positive bottles grew within two days of incubation. Patients with doubtful septicemia were more often (88%) positive in one bottle only, the mean detection time for all bottles was 3.7 days, and only 35% of the first positive bottles and 33% of all positive bottles yielded growth within two days. Possible cases took a position between these two extremes but tended more towards the doubtful cases. The implications of these findings for the interpretation of blood cultures with S. aureus are discussed.

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Interpretation von Blutkulturen mit Staphylococcus aureus

Zusammenfassung 48 Patienten, aus deren Blutkulturen Staphylococcus aureus gezüchtet worden war, wurden nach klinischen Kriterien in drei Gruppen eingeteilt: unzweifelhafte, mögliche und zweifelhafte Septikämie. Bei Verwendung eines traditionellen Blutkultursystems mit zwei Flaschen pro Kultur (Thioglykolat- und Tryptic Soy-Bouillons) ergab sich, daß Patienten mit unzweifelhafter Septikämie stets mehr als eine positive Flasche pro Tag aufwiesen — sofern mehr als eine Kultur pro Tag entnommen worden war —, daß die mittlere Bebrütungsdauer bis zur Positivität 1,7 Tage betrug, und daß 95% der ersten positiven Flaschen und 92% aller positiven Flaschen innerhalb von zwei Tagen Wachstum von S. aureus zeigten. Patienten mit zweifelhafter Septikämie zeigten häufiger (in 88%) Wachstum in nur einer Flasche, die mittlere Bebrütungsdauer betrug 3,7 Tage, und nur 35% der ersten positiven Flaschen und 33% aller positiven Flaschen ergaben Wachstum innerhalb von zwei Tagen. Mögliche Septikämien nahmen eine Zwischenstellung ein, tendierten jedoch mehr nach der zweifelhaften Kategoric. Folgerungen für die Interpretation von Blutkulturen mit S. aureus werden diskutiert.

     

Ultrastructural features of the plasma cells in “non-secretory” myeloma

Summary A case of non-secretory multiple myeloma is described. The diagnosis was based on the clinical picture, typical radiological findings, and infiltration of the bone marrow by myeloma cells which showed specific immuno-fluorescence staining mainly with antisera for IgM and kappa light chains. An attempt is made to explain the absence of pathological proteins in the serum, based on the ultrastructural findings of the myeloma cells, which showed buddings of the cell membranes containing endoplasmic reticulum and cytoplasmic material. It is suggested that the cells of the non-secretory type of multiple myeloma possess a normal excretory mechanism, but the pathological proteins are prevented to be secreted in the serum being surrounded by portions of the cell membrane.Established Investigator of the Chief Scientist's Office, Ministry of Health, Israel     

Experimentelle Untersuchungen zur Frage der Seltenheit von Geschwulstmetastasen in der Skeletmuskulatur

Summary Authors injected a suspension of Brown-Pearce cancer cells into the left ventricle of 10 rabbits. The venous blood of the lower extremities of these first rabbits was injected into the ear vein of 20 intact second rabbits. In the surviving 7 first rabbits metastases in the skeletal muscles frequently developed. The majority of second rabbits developed tumors indicating a transmuscular passage of tumour cells emboli in the first rabbits. Transmuscular passage of tumour cell was found not only immediately after the injection of the tumour cells, but also three minutes later.These facts contradict the rather speculative theory according to which the skeletal muscle is an unsuitable soil for the development of secondary tumours.     

Can an algorithm predict appropriate utilization of emergency venous studies?

Venous duplex evaluation (VDE) has virtually supplanted venography in the diagnosis of deep vein thrombosis (DVT). To control low yield of VDE of ambulatory patients, performed at off-hours, we adopted an algorithm to improve the selection process and to increase efficiency. Off-hours studies are those performed after the normal daily working hours, weekends, or holidays. From January 1, 1996, through December 31, 1998, we performed 5393 lower extremities VDE, utilizing color duplex imaging with video taping. 2535 studies were done during the eighteen months prior to adoption of the algorithm on July 1, 1997 and 2858 studies were performed during the subsequent eighteen months. During the first 18 months, 314 requests for emergency studies came from the Emergency Department (ED). 132 were off-hours and 24 (18.2%) were positive for DVT compared to 427 after adoption of the algorithm, of which 79 were off-hours with 24 being positive for DVT (30.3%). Using an algorithm for dealing with requests for VDE originating in the ED on outpatients at off-hours resulted in an overall decrease in requests as well as a greater yield of positive studies without apparent compromise of the quality of care.Presented in part at the 41st Annual World Congress, International College of Angiology, Sapporo, Japan, July 1999.     

Zur Epidemiologie und Ätiologie des Oesophaguscarcinoms in China

Ohne Zusammenfassung

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The epidemiology and etiology of esophageal cancer in China

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Stipendiaten der Alexander von Humboldt-Stiftung aus der Volksrepublik China

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The Journal of Cancer Research and Clinical Oncology publishes in loose succession Editorials and Guest Editorials on actual and/or controversial problems in experimental and clinical oncology. These contributions represent exclusively the personal opinion of the author.Die Zeitschrift Journal of Cancer Research and Clinical Oncology bringt in zwangsloser Folge Editorials zu aktuellen und/oder kontroversen Problemen der experimentellen und klinischen Onkologie. Diese Beiträge geben ausschließlich die persönliche Meinung des Autors wieder.     

Prognostic relevance of histological findings on bone marrow biopsy in myelodysplastic syndromes

Summary Bone marrow biopsy (BMB) has aroused growing interest as a possible aid in the diagnostic and prognostic evaluation of myelodysplastic syndromes (MDS). Previous reports have pointed out that MDS patients with blastic aggregates or severe bone marrow (BM) fibrosis are characterized by a worse clinical outcome. BMBs of 106 MDS patients were retrospectively reviewed, and relationships among the different histological parameters as well as clinicopathological correlations were looked for. Three patterns of BM blastic infiltration (diffuse, cluster, and large) were recognized. Overt leukemic transformation and overall survival were selected as prognostic end points. BM infiltration was diffuse in 18, cluster in 48, and large in 40 cases. RAEB-t patients accounted for about half of the large cases, and none had a diffuse pattern (p<0.01). Nineteen patients showed extensive BM fibrosis; most of them were characterized by cluster blastic infiltration and megakaryocyte hyperplasia. Leukemic transformation occurred in 67% of large cases (p<0.001) and in none of the cluster cases with severe BM fibrosis (p<0.01); however, survival was equally poor in these two groups because of early leukemic transformation (large cases) and BM failure (cluster cases). The FAB classification did not significantly correlate with prognosis. Patients with cluster BM infiltration and severe fibrosis can be regarded as a true separate MDS subset characterized by unique clinicopathological and prognostic features. Because of the subacute clinical behavior of most cases, and the poor performance status of many elderly patients, there is still controversy as to the best therapeutic approach in MDS. Histological analysis allowed two groups of MDS patients to be identified, both characterized by poor life expectancy, who could benefit from early aggressive chemotherapy.     

Ca++ activation of ATPase activity,ATP-P1 exchange,and tension in briefly glycerinated heart muscle

Summary In the course of Mg-dependent ATP splitting by heart actomyosin, an energy rich actomyosin-ADP complex is formed, which promotes the incorporation of phosphate³²P into ATP in myofibrils. The rate of this ATP-phosphate exchange reaction depends on the extent of actin-myosin overlap which can be decreased by stretching glycerinated muscle fibres. In heart muscle, the calcium-ion dependence of this reaction is similar to that of the actomyosin ATPase, the tension, and immediate fibre stiffness (which is hookean and which is a measure for the number of myosin cross-bridges attached to and interacting with actin).These findings suggest that calcium increases the amount of contractile actomyosin-ADP complexes. The proportionality between tension and ATPase activity further suggests that the rate-limiting step of the cross-bridge cycle (which determines the molecular turnover number, the Wechselzahl of the ATPase) is only little affected by calcium ions. These ions act by recruiting more bridges rather than by accelerating their reactions.In addition, the depressing effect of inorganic phosphate on the contractile tension and its presumable role in energetic insufficiency will be discussed.

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Ca⁺⁺-Aktivinerug von ATPase-Aktivität, ATP-Phosphat-Austausch und Kontraktionskraft in glycerinextrahierten Herzmuskelfasern

Zusammenfassung Im Verlauf der Mg-aktivierten ATPase-Reaktion des Herzaktomyosins wird ein energiereicher Aktomyosin-ADP-Komplex gebildet, durch den die Inkorporation von³²P-Phosphat in ATP begünstigt wird. Die Rate dieser ATP-Phosphat-Austauschreaktion ist abhängig vom Gradder Aktin-Myosin-Überlappung Im Herzmuskel ist die Ca⁺⁺-Abhängigkeit dieser Reaktion ähnlich derjenigen der Aktomyosin-ATPase-Aktivität, der kontraktilen Spannung und der immediate fibre stiffness, die nachHuxley undSimmons (6) ein Maß für die Anzahl der zu jedem Moment angehefteten Querbrücken darstellt.Die Ergebnisse weisen darauf hin, daß Calciumionen die Konzentration des kontraktilen Aktomyosin-ADP-Komplexes erhöhen. Die Proportionalität zwischen Spannung und ATPase-Aktivität ist ferner ein Indiz dafür, daß der ratenlimitierende Schritt des Querbrückenzyklus (der die Wechselzahl der kontraktilen ATPase bestimmt), nur wenig durch Ca⁺⁺-Ionen beeinflußt wird. Calcium bewirkt eher eine Rekrutierung von Querbrücken als eine Beschleunigung ihrer Reaktion.Zusätzlich wird der hemmende Effekt von anorganischem Phosphat auf die kontraktile Spannung im Zusammenhang mit der Entstehung der energetischen Insuffizienz diskutiert.

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Paper, presented at the Erwin Riesch Symposium, Tübingen, September 26–29, 1976

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With 3 figures and 1 table

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Supported by the Deutsche Forschungsgemeinschaft SFB 90.     

Untersuchungen mit Phytoagglutininen bei Inzuchthühnern

Zusammenfassung Es wurde in einem Inzuchtstamm von rebhuhnfarbigen Italienern durch drei Generationen der Hi-Faktor mit sechs selbst hergestellten Phytoagglutininen untersucht. Das Vorhandensein des Hi-Antigens konnte bestätigt werden. Seine natürliche Nachweisbarkeit beschränkte sich auf weibliche Tiere. Das vorliegende Gen HI, das dominant vererbt wird, konnte bei beiden Geschlechtern und allen Altersstufen bei Vorhandensein des weiblichen Geschlechtshormons (Östrogen) nachgewiesen werden.

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Summary The Hi-factor was studied with six self-produced phytoagglutinins in an inbred strain of partridge coloured Italiens through three generations. The presence of Hi-antigen could be confirmed. It can only be demonstrated in female animals. The HI gen, which is inherited in a dominant manner, could be demonstrated in both sexes and at all ages in the presence of female sex hormone (estrogen).

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Die Arbeiten wurden mit Mitteln der Deutschen Forschungsgemeinschaft durchgeführt.