A career start in the Third Reich : The pathologist and Rudolf Virchow Award recipient Walter Müller (1907-1983).

The pathologist Walter Müller is undoubtedly one of the most prominent post-war representatives of his profession. He became full professor and founding dean in Essen, and in 1983 the German Society for Pathology (DGP) awarded him the Rudolf Virchow Medal - the highest distinction of the society - for his merits to the field of pathology.But this glorious career was by no means predetermined. Rather, after the end of the Second World War there were signs of a career break that were still largely unknown. After fleeing Königsberg from the approaching Red Army, Müller had to fear for his professional existence and his scientific advancement, as he was threatened with a ban on his profession in connection with denazification. As a young assistant doctor, Müller had joined the Berlin SA soon after the National Socialists took power and had also applied for membership of the NSDAP in 1937.Using Müller as an example, this article deals with the political influences and effects of National Socialism on young scientists and their career development. It poses the question of typical political barriers and overarching patterns of adaptation.On the basis of the personal written estate, personal archive sources, and a reanalysis of the available secondary literature, existing self-portrayals and narratives of Walter Müller are critically reviewed and supplemented. Several examples show that Müller's career development was characterized by a willingness to adapt politically. After a brief career slump in the years 1946/47, he succeeded in consolidating his career thanks to a mild denazification process and subsequently became one of the leading experts in German-language pathology.

[A career start in the Third Reich : The pathologist and Rudolf Virchow Award recipient Walter Müller (1907-1983)]. / Ein Karrierestart im "Dritten Reich" : Der Pathologe und Rudolf-Virchow-Preisträger Walter Müller (1907­1983).

The pathologist Walter Müller is undoubtedly one of the most prominent post-war representatives of his profession. He became full professor and founding dean in Essen, and in 1983 the German Society for Pathology (DGP) awarded him the Rudolf Virchow Medal - the highest distinction of the society - for his merits to the field of pathology.But this glorious career was by no means predetermined. Rather, after the end of the Second World War there were signs of a career break that were still largely unknown. After fleeing Königsberg from the approaching Red Army, Müller had to fear for his professional existence and his scientific advancement, as he was threatened with a ban on his profession in connection with denazification. As a young assistant doctor, Müller had joined the Berlin SA soon after the National Socialists took power and had also applied for membership of the NSDAP in 1937.Using Müller as an example, this article deals with the political influences and effects of National Socialism on young scientists and their career development. It poses the question of typical political barriers and overarching patterns of adaptation.On the basis of the personal written estate, personal archive sources, and a reanalysis of the available secondary literature, existing self-portrayals and narratives of Walter Müller are critically reviewed and supplemented. Several examples show that Müller's career development was characterized by a willingness to adapt politically. After a brief career slump in the years 1946/47, he succeeded in consolidating his career thanks to a mild denazification process and subsequently became one of the leading experts in German-language pathology.

Major histocompatibility complex class I-presented antigenic peptides are degraded in cytosolic extracts primarily by thimet oligopeptidase.

Nearly all peptides generated by proteasomes during protein degradation are digested rapidly to amino acids, but a few proteasomal products escape this fate and are presented to the immune system on cell surface major histocompatibility complex class I molecules. To test whether these antigenic peptides may be inherently resistant to cytosolic peptidases, six different antigenic peptides were incubated with HeLa cell extracts. All six were degraded rapidly by a process involving o-phenanthroline-sensitive metallopeptidases. One antigenic peptide, FAPGNYPAL, was rapidly destroyed in the extracts by a bestatin-sensitive exopeptidase, apparently by the puromycin-sensitive aminopeptidase. The disappearance of the other five was reduced 30-90% by a specific inhibitor of the cytosolic endopeptidase, thimet oligopeptidase (TOP) (EC ), whose physiological function(s) have been unclear and controversial. All these peptides were sensitive to pure recombinant TOP. Furthermore, upon fractionation of the extracts, the major peptidase peak that degraded the ovalbumin-derived epitope, SIINFEKL, co-purified with TOP. In the extracts, TOP also catalyzed rapid degradation of N-extended variants of SIINFEKL and of other antigenic peptides, which in vivo can serve as precursors of these major histocompatibility complex-presented epitopes. This enzyme (unlike cell proteins that promote production of antigenic peptides) is not regulated by interferon-gamma. TOP seems to be primarily responsible for the rapid breakdown of antigenic peptides in cytosolic extracts, and our related studies (A. X. Y. Mo, K. Lemerise, W. Zeng, Y. Shen, C. R. Abraham, A. L. Goldberg, and K. L. Rock, submitted for publication) indicate that TOP by destroying such peptides limits antigen presentation in vivo.

Effects of antiinflammatory triterpenes isolated from Leptadenia hastata latex on keratinocyte proliferation.

Several triterpenes isolated from Leptadenia hastata latex were tested for their anti-inflammatory activity. Lupeol (1), its acetate (2) and palmitate (3) esters were found to be the main antiinflammatory constituents in the croton oil-induced ear oedema test. Furthermore, lupeol hemisuccinate (4), synthesized from lupeol, exhibited a higher activity than lupeol in the test. These results prove that the triterpenes play a pivotal role in the topical antiinflammatory effect of this latex. In addition, an in vitro model of human skin keratinocytes (epidermal explants) cultured at an air-liquid interface on a de-epidermized human dermis (DED) was used to investigate the effects of lupeol esters on skin repair in vitro. Compared with the control, compounds 2 and 3 improved keratinocyte proliferation at a concentration of 5 microM in the culture medium; however, they remained less active than compounds 1 and 4. In contrast to compound 1, all the lupeol esters (2-4), and particularly compound 4, induced a good differentiation of keratinocytes with a well-formed stratum corneum without parakeratosis. These results substantiate the topical use of Leptadenia hastata latex in traditional medicine and showed that both antiinflammatory activity and the effect on keratinocyte proliferation of compound 1 could be improved by its hemisuccinylation; on the contrary, esterification by acetylation or palmitoylation decreased these activities.

Apoptosis in established and healing psoriasis.

BACKGROUND: Previous studies have described apoptosis in the stratum granulosum and in the stratum corneum, but not in the germinative compartment in normal skin. In psoriasis, an increased epidermal apoptosis has been observed in the differentiated compartment, suggesting that apoptosis has a key role in the pathogenesis of psoriasis, as a counteracting factor to the overproduction of cells. Little is known on apoptosis in the germinative compartment. METHODS: Apoptosis was studied on biopsies of normal skin, established lesions of psoriasis and PUVA-treated psoriasis using the transferase-mediated uridine nick end labelling method, which detects fragmented DNA, and electron microscopy. Counting of apoptotic cells was restricted to the germinative compartment as defined by Mib1 staining to evaluate the impact of cell loss on cell production and tissue architecture. RESULTS: The apoptotic index was 0.12% in normal epidermis, 0.035% in established psoriasis and 0.31% in regressive psoriasis. CONCLUSION: These results have three implications: (1) they show the physiological presence of apoptosis in the germinative compartment in normal epidermis; (2) they suggest that induction of apoptosis is involved in the regression of psoriatic hyperplasia after PUVA therapy; (3) the decrease of physiological apoptosis in the psoriatic lesion suggests that this phenomenon could play a role in the induction of psoriatic hyperplasia.

Methotrexate induces apoptotic cell death in human keratinocytes.

The mechanism by which low doses of methotrexate act in psoriasis to restore a clinically normal skin is poorly understood. Apoptosis is a programmed cell death activated when cell removal is needed. The purpose of the present work was to examine using an organotypical model of keratinocyte culture, the possibility that low doses of methotrexate can induce apoptosis of keratinocytes. Epidermal explants were cultivated on dead deepidermized dermis under air-exposed conditions. After 10 days, methotrexate (10(-7) M) was added. After a further 5 days, one part of each culture was fixed and submitted to routine histology, DNA nick end labelling (TUNEL) to detect DNA fragmentation (a molecular marker of apoptotic cell death) and immunohistochemical detection of p53 (a protein involved in apoptosis induced by DNA-damaging agents). The other part of each culture was processed for electron microscopy. A significant proportion of keratinocytes (1%) were damaged and exhibited the morphological features of apoptotic cell death. Immunohistochemical overexpression of p53 was detected in the basal layer of the cultures treated with methotrexate. Low doses of methotrexate induce apoptosis. This mode of action could explain the reduction in epidermal hyperplasia during treatment of psoriasis with methotrexate.

Effects of low frequency pulsed electrical current on keratinocytes in vitro.

The effects of low frequency pulsed electrical current on epidermal repair in vitro were examined. Charge-balance current stimuli proposed for chronic wound treatment were tested on skin keratinocytes cultured at an air-liquid interface on dead human dermis. Results imply that the balance between proliferation and differentiation in electrically treated samples is significantly modified in favor of differentiation. More advanced differentiation, shown through epidermal histology, was obtained in cultures exposed to electrical current, whereas the culture growth, the result of keratinocyte migration and proliferation, was greater in control samples.

Renewal and differentiation of keratinocytes cultured on dead de-epidermalized dermis.

Human keratinocytes grown at an air-liquid interface on dead de-epidermalized dermis exhibit a pattern of organization similar to that seen in vivo. Cell renewal is limited to the basal layer. The cell cycle time determined after 7 days of culture, using a percentage labelled mitoses (PLM) technique, was about 15 h. This result is comparable with published data for cultivated keratinocytes but is shorter than the parameter proposed for epidermis in vivo. Appearance of labelled cells in the granular layer was observed 4 days after pulse labelling. Despite this high cell renewal, a normal cell differentiation with expression of various keratinization markers was maintained.

In vitro acantholysis induced by D-penicillamine, captopril, and piroxicam on dead de-epidermized dermis.

Drug-induced pemphigus has been recognized for 20 years, but the mechanisms leading to acantholysis are still unclear. It has recently been demonstrated that penicillamine, captopril, and thiopronin may produce acantholytic lesions, either by direct toxic or biochemical effect, in human skin explants. Our work confirms that penicillamine and captopril may induce acantholysis on the model of keratinocyte culture on dead, de-epidermized dermis. Moreover, it demonstrates that piroxicam, a new non-steroidal anti-inflammatory drug, of which one side effect is a pemphigus vulgaris-like eruption, is also able to produce in vitro acantholysis.

Kinetics of the calcium induced stratification of human keratinocytes in vitro.

In a low concentration of calcium (0.1 mM), keratinocytes form a monolayer with about 30% of cells synthesizing involucrin. After addition of calcium to the culture medium to a concentration of 1.2 mM, the monolayer stratifies within 24 h, with a preferential migration of involucrin positive keratinocytes. In the present study, we tried to determine if keratinocytes control the decision to migrate at a distinct cell cycle point. A percentage labelled mitosis (PLM) curve was constructed for keratinocytes grown in low calcium medium and values for the length of the cell cycle (47 h), S phase duration (11 h) and G2+M period (6 h), were obtained. Monolayer cultures at 80% confluence were switched to high calcium concentration at various times (from 0 to 48 h), after pulse labelling with [3H]-thymidine. Based on the PLM data, the behaviour of cells known to be in S, G1 and G2 at the time of the migration stimulus were followed. No significant difference in the percentage of labelled suprabasal cells was found for any point of the cell cycle. For cells submitting to stratification, in S phase involucrin staining showed that about 60% of the [3H]-thymidine labelled cells were also involucrin negative. These results indicate that upward migration of keratinocytes in cultured epithelium can be triggered at all points in the cell cycle with equal probability and is not restricted to those cells that already contained involucrin.

Reproduction of the characteristic morphologic changes of familial benign chronic pemphigus in cultures of lesional keratinocytes onto dead deepidermized dermis.

We report the in vitro reproduction of the classic histologic and ultrastructural features of familial benign chronic pemphigus (FBCP) by seeding suspensions of lesional keratinocytes onto healthy heterologous dead deepidermized dermis (DED). With the use of normal keratinocytes, control cultures showed a well-differentiated epidermis, with keratohyaline granules and lamellar bodies. To the best of our knowledge this is the first successful culture of FBCP with the use of dispersed lesional keratinocytes. The results suggest that in FBCP the epidermis is the site of the defect leading to acantholysis, without any dermal contribution.

Food intake and body composition in novice athletes during a training period to run a marathon.

The change in diet and body composition was studied in a group of 9 female and 18 male subjects, starting a training program for 18 months with the ultimate goal of running the marathon. Mean daily intakes from 7-day dietary records for macro- and micronutrients were calculated at the start, after 1 year of training, and just before running the marathon. Anthropometric measurements were taken on the same occasions. In males the body fat mass decreased 2.4 kg, while in females no change in body composition was observed over the 18-month training period. Energy intake increased significantly in males from 131 to 159 kJ/kg/day. In women no significant change was recorded (141 to 147 kJ/kg/day). However, in both sexes CHO intake was significantly higher after 18 months (males 63.7-81.7 kJ/kg, females 68.0-81.9 kJ/kg). Also En% CHO increased significantly in males from 48 to 52 EN% and in females from 47 to 55 En%. This extra energy intake of CHO in women was covered at the expense of dietary fat. These changes in food habits in both groups are favorable in relation to the nutritional guidelines for better cardiovascular health. Whether the sex difference found in economizing energy exchange as a response to an intensive training program is based on an increased food efficiency will require further investigation.