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M Loeffler

Publications and source records attributed to M Loeffler.

At least 109 records · Page 6Linked to original sources
PubMed1989

A mathematical model of erythropoiesis in mice and rats. Part 1: Structure of the model.

A mathematical model has been developed which describes the regulation of erythropoiesis in mice and rats. The main model assumptions are: (1) Regulation is mediated by erythropoietin (EPO). (2) The production of EPO depends exponentially on the tissue oxygen pressure (e.g. in the renal production sites). (3) There are sigmoidal dose-response curves relating the EPO concentration in the plasma to the mitotic activity of CFU-E and proliferative erythropoietic precursors. For maximum stimulation two to four additional mitoses may occur, while for an absent stimulus three to five mitoses may be omitted. (4) The normal precursor transit time of three to four days may be shortened by more than 50% during maximum stimulation. (5) The erythrocytes have a normal lifespan of 42-56 days, which may be reduced to 15-20 days under erythropoietic stimulation. Among these assumptions, the dose-response relationships between EPO and the mitotic activity of CFU-E and the proliferative erythropoietic precursors are the most important hypotheses of the model. This is the first of a series of three papers and gives a description of the mathematical formalism and the parameters used. In the subsequent papers computer simulations on erythropoietic stimulation and suppression are presented.

Animals↗
PubMed1989

A mathematical model of erythropoiesis in mice and rats. Part 2: Stimulated erythropoiesis.

A mathematical model of erythropoietic cell production and its regulation process has been proposed in a preceding paper. It is primarily based on the assumption that the number of cell divisions taking place in the CFU-E and erythropoietic precursor stages is regulated depending on the oxygen supply of the tissue. Quantitative dose-response relationships for in vivo erythropoiesis are suggested. Here, we demonstrate that this model adequately reproduces data obtained in situations of stimulated erythropoiesis in mice and rats. In detail, this implies a quantitative description of the following processes: (1) Changes in tissue oxygen tension (Pto2) following removal of red cells (bleeding, haemolytic anaemia) or increase in plasma volume (dilution anaemia) or decrease in atmospheric oxygen pressure (hypoxia). (2) Pto2 dependent erythropoietin (EPO) production. (3) Dose-response of EPO on erythropoietic amplification (up to two to four additional mitoses). (4) The changes of the marrow transit time. Model simulations are compared with experimental data for changes of erythropoiesis during hypoxia, EPO-injection, and different forms of anaemia. A satisfactory agreement suggests that the model adequately describes and correlates different direct and indirect ways to stimulate erythropoiesis. It quantifies the role and relative contribution of the haematocrit, haemoglobin concentration, atmospheric oxygen pressure, tissue oxygen pressure, and plasma volume as triggers in erythropoietic stimulation under various conditions. Furthermore, the model may allow to optimize the scheme of EPO-administration and to find the maximum increase of erythropoiesis for a given amount of erythropoietin.

Anemia↗
PubMed1989

A mathematical model of erythropoiesis in mice and rats. Part 3: Suppressed erythropoiesis.

A mathematical model of erythropoietic cell production and its regulation process has been proposed in a preceding paper. It is primarily based on the assumption that the number of cell divisions taking place in the CFU-E and erythropoietic precursor stages can be regulated depending on the oxygen supply to the tissue. Here we provide evidence that this model adequately describes situations of suppressed erythropoiesis. In detail this implies a quantitative description of the following processes: (1) changes in tissue oxygen tension (Pto2) due to increase in red cell numbers (red cell transfusion, posthypoxia), decrease in plasma volume (dehydration) or increase in atmospheric oxygen pressure (hyperoxia), (2) Pto2 dependent reduction of erythropoietin (EPO) production, (3) dose-response of reduced EPO-levels on erythropoietic amplification (omission of three to five mitoses). Model simulations are compared to experimental data obtained from red cell transfusion, posthypoxia, hyperoxia and dehydration. A satisfactory agreement suggests that the model adequately describes and correlates different ways to suppress erythropoiesis. It quantifies the role and relative contribution of the haematocrit, haemoglobin concentration, atmospheric oxygen pressure, tissue oxygen pressure and plasma volume as triggers in erythropoietic suppression under various conditions. In conjunction with the preceding two papers it could be shown that one unique set of model parameters is sufficient to describe erythropoiesis in steady state, stimulation and suppression. Limitations of the model are discussed and experiments for a more detailed investigation of the feedback mechanisms are proposed.

Animals↗
PubMed1989

Hemopoiesis during thiamphenicol treatment. I. Stimulation of stem cells during eradication of intermediate cell stages.

Continuous treatment of C57bl/6 mice for 4 days with the cytostatic antibiotic thiamphenicol revealed a dual response of hemopoietic cells. On one hand, morphologically recognizable erythroid precursors and late progenitors (erythroid colony-forming units; CFU-E) and, to a lesser extent, granuloid precursors were found substantially reduced. On the other hand, early granuloid (granulocyte-macrophage colony-forming units; CFU-GM) and erythroid (erythroid burst-forming units; BFU-E) progenitors increased on day 3 to 220%-240% and 120%-130% of the control value, respectively. This was accompanied by a decline of the initial spleen colony-forming units (CFU-S) (day 8) pool size to approximately 60%. These patterns were similar in the bone marrow and the spleen. In addition, the tritiated thymidine kill of femoral and splenic CFU-S rose significantly (p less than 0.05) from 16% +/- 3% to 38% +/- 2% and from 3% +/- 1% to 17% +/- 2%, respectively. A sudden decline of peripheral reticulocytes between days 2 and 3 from 2.8% +/- 0.3% to 0.6% +/- 0.2% was observed, whereas the hematocrit gradually decreased from day 1 to day 4 from 45.2% +/- 0.1% to 39.3% +/- 0.3%. The white blood cells were not affected. From these results we conclude that stem cells were stimulated as a consequence of the suppression of the intermediate cell stages. As analyzed in the accompanying paper, this confirms a prediction stated by a quantitative theoretical concept of in vivo stem cell regulation.

Animals↗
PubMed1989

Hemopoiesis during thiamphenicol treatment. II. A theoretical analysis shows consistency of new data with a previously hypothesized model of stem cell regulation.

In a recent theoretical model of stem cell regulation, specific quantitative assumptions were made about an in vivo feedback process from erythroid and granuloid precursor cell stages to the spleen colony-forming units (CFU-S), erythroid burst-forming units (BFU-E), and granulocyte-macrophage colony-forming units (CFU-GM). Utilizing specific effects of the antibiotic thiamphenicol (TAP), new experiments have been performed to challenge this model. Here these data are treated in an analysis that implies three steps. First, model assumptions about TAP toxicity are justified. The toxic TAP effects on erythroid and granuloid precursors are quantified as a continuous reduction of the normal amplification coefficient for CFU-E (down to 1/250), proerythroblasts, basophilic erythroblasts, and proliferating granuloid precursors (down to 1/4). Second, the original model predictions for the behavior of CFU-S, CFU-GM, and BFU-E are compared with the corresponding data. Third, discrepancies are discussed and it is demonstrated that adjustment of one single parameter resolves most of them. Thus one can quantitatively explain the experimental results for CFU-S, BFU-E, and CFU-GM by an activation of the regulatory process postulated: the decline in erythroid (and granuloid) cell numbers enhances the cycling of CFU-S while their self-renewal probability is reduced; consequently CFU-S numbers decline; as more cells differentiate towards BFU-E and CFU-GM per unit time the cell numbers of these cell stages increase. Thus the new data on stem cell behavior during TAP treatment support the hypothesis of a feedback from erythroid and granuloid precursors to the stem cells.

Animals↗
PubMed1988

Prognostic risk factors in advanced Hodgkin's lymphoma. Report of the German Hodgkin Study Group.

In a national multicentre trial in the FRG patients with Hodgkin's lymphoma in stages CS/PS III B/IV were entered into the HD 3 protocol and received induction chemotherapy with 3 x (COPP + ABVD). Patients in complete remission (CR) received consolidation therapy by either radiotherapy (20 Gy IF) or chemotherapy (COPP + ABVD). Patients not in CR received salvage therapy (40 Gy in case of persisting nodal disease, else 4 x CEVD chemotherapy). Between July 1983 and May 1987 230 untreated patients aged 15 to 60 qualified for this HD 3 protocol. This analysis is based on the first 137 patients evaluable for response. Of these, 86 (63%) achieved CR after induction chemotherapy. Including salvage therapy a total of 104 patients (76%) achieved CR. Univariate and multivariate prognostic risk factor analyses were performed using freedom from treatment failure (FFTF) as endpoint. Sex, age, splenectomy, bone marrow, liver and bone involvement had no prognostic impact nor had stage according to the Ann Arbor classification. In contrast, a pretreatment erythrocyte sedimentation rate (ESR) above 80 mm/h and a serum alkaline phosphatase (AP) above 230 IU/ml appeared as significant risk factors (p less than 0.01, relative risk 2.3). The two parameters were not independent. Comparing a group A (ESR less than or equal to 80 and AP less than or equal to 230) versus a pooled group B (ESR greater than 80 and/or AP greater than 230) increased the difference (p less than 0.001, relative risk of 2.8) which was also significant for survival (p less than 0.04).

Adolescent↗
PubMed1988

Scoring mitotic activity in longitudinal sections of crypts of the small intestine.

Various counts have been made of the number of mitotic figures in whole crypts and sections of crypts of the small intestine of the mouse. Samples were analysed from animals killed at different times of the day and at different times after administration of vincristine. Measurements have been made of the size of mitotic and interphase nuclei and of the radial position of mitotic figures. The correction factor, f, which is required to take into account the enhancement of mitotic counts in sections as a consequence of their centripetal position has been investigated. The results indicate the following: (1) transverse sections of the crypt differ from longitudinal sections if they involve cutting the intestine before fixation which may result in a relaxation of the crypt and its widening by 25%; (2) columnar cell nuclei have a shape that resembles a sphere flattened so that the average diameter is 20% greater in crypt transverse sections; (3) mitotic nuclei tend to be about half-way between the crypt edge and the central axis of the crypt; (4) between about four and seven times more mitotic figures have their mitotic axis parallel to the long axis of the crypt; (5) about one-third of all mitotic figures in a crypt are seen in a longitudinal section of the crypt. If this is related to the number of cells in the crypt as a whole and in a section, a correction factor fD for the mitotic index of 0.59 is obtained; (6) the correction factor fT derived from the shape and position of the mitotic figures measured in 3 microns longitudinal sections is 0.53; (7) relating cell cycle and mitotic accumulation data using a computer-based model of the crypt also permits a correction factor fmod to be estimated. This gives a value of 0.66. When sectioned material is used to calculate a mitotic index the most appropriate correction factor is fD; for mouse small intestine it is 0.59.

Animals↗
PubMed1988

Intestinal crypt proliferation. II. Computer modelling of mitotic index data provides further evidence for lateral and vertical cell migration in the absence of mitotic activity.

The position-dependent mitotic index before, and 1, 2 and 3 h after vincristine was scored. The accumulation of cells in mitosis leads to an increase in the mitotic index from 0.06 to 0.34 at crypt positions 8-12. Surprisingly, the leading edge of the position-related mitotic index distribution moves to higher crypt positions although cell division was stopped. In addition, the vertical clustering of mitotic figures in sections was recorded. The data were examined using a previously described computer crypt model. We conclude: the average mitotic phase duration is about 0.7 h (40 min) and varies little with cell position; the geometrical correction factor for overscoring mitoses in crypt sections is about 0.6-0.7 and adjacent cell columns can merge. Lateral cell displacement after mitosis, as predicted in a previous model analysis, would be a mechanism to counteract other forces that tend to reduce the crypt circumference. In the normal steady state merging and expansion processes would just balance each other. This would not follow if one mechanism was blocked. Thus we propose a new concept in which the crypt geometry would be dynamically determined by cell proliferative activity in connection with lateral positioning of new cells on one hand and contracting forces on the other hand.

Animals↗
PubMed1988

A concept of hemopoietic regulation and its biomathematical realization.

Although the amount of experimental data on the behavior of the hemopoietic system after various perturbations is considerable, a conclusive understanding of hemopoietic regulation is still absent. In the last years, we have examined murine erythropoiesis, thrombopoiesis, granulopoiesis, and stem cell hemopoiesis by means of mathematical modeling in order to identify some of the underlying principles. Our results can be summarized in four hypotheses. 1) The regulation of hemopoiesis is governed by three interrelated control loops: autoregulation of stem cells, feedback from progenitors and precursors to the stem cells, and feedback from mature cells to progenitor and precursor cells. 2) The feedback from mature cells to the progenitor and precursor cells predominantly varies the number of cell divisions taking place during hemopoietic maturation. 3) Two distinct properties of the stem cells are regulated: their cyclic activity and their self-renewal. Both are under the control of stem cell autoregulation and the feedback from progenitors and precursors. 4) A large variance in the maturation time from the stem cells to the mature cells stabilizes the hemopoietic control. The mathematical formulation of these assumptions allows us to understand a broad range of experimental observations including recovery from stem cell damage, hypoproliferative and hyperproliferative situations, and interactions between different cell lines.

Animals↗
PubMed1987

A comprehensive model of the crypts of the small intestine of the mouse provides insight into the mechanisms of cell migration and the proliferation hierarchy.

A comprehensive model has been formulated for the proliferative behaviour of the crypts of the small intestine based on individual cell to cell relationships rather than on the average effects of all cells. The model accommodates a wide range of cell kinetic data and provides an insight into the mechanisms involved in cell movement within the columnar sheet of cells and into the relationship between the stem cells and their progeny. The model permits the number of stem cells and transit generations to be estimated. The number of stem cells is predicted to be not less than 4 and not more than 16 per crypt with cell cycle times of between 12 and 32 h respectively. Certain conclusions can be drawn concerning the mechanisms involved in the initial cell displacements after cell division. The model also allows an estimation of parameters which cannot be measured directly such as the degree of cell generation disorder and the amount of dispersion of cells within a cell lineage.

Animals↗
PubMed1987

Lomustine, etoposide, vindesine, and dexamethasone (CEVD) in Hodgkin's lymphoma refractory to cyclophosphamide, vincristine, procarbazine, and prednisone (COPP) and doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD): a multicenter trial of the German Hodgkin Study Group.

Thirty-two patients with advanced Hodgkin's lymphoma resistant to cyclophosphamide, vincristine, procarbazine, and prednisone (COPP) and doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) were treated with a salvage chemotherapy regimen consisting of lomustine, etoposide, vindesine, and dexamethasone (CEVD). Twenty-seven patients were treated because of primary resistance to COPP/ABVD, and five patients were treated in early relapse (less than 12 months) after COPP/ABVD-induced complete remission. Fourteen patients (44%) achieved complete remission, and four patients achieved partial remission, with an overall response rate of 56%. Two partial responders achieved complete remission after additional radiotherapy. Four of five patients in early relapse after COPP/ABVD achieved complete remission. Consolidation radiotherapy was given for only one complete responder. Median duration of complete remission is greater than 10 months, and median survival is greater than 26 months. The treatment was well-tolerated. The main side effects were leukopenia, thrombocytopenia, mild nausea/vomiting, and cushingoid side effects. CEVD is a very active and well-tolerated salvage chemotherapy regimen in patients with Hodgkin's disease resistant to or relapsing after COPP and ABVD.

Adolescent↗
PubMed1987

Epidermal cell proliferation. I. Changes with time in the proportion of isolated, paired and clustered labelled cells in sheets of murine epidermis.

A new technical approach to analysing labelled cells in sheets of epidermis is presented. The changes in the proportion of isolated single labelled cells, paired or clusters of 3, 4, or more than 4, labelled cells in sheets of epidermis from the back of the mouse have been analysed at various times up to 500 h after 3HTdR administration at either 03.00 h or 15.00 h. The technique is not dependent on the relative number of labelled cells (i.e. the labelling index) but on the spatial distribution of labelled cells. The data cannot be adequately explained on the basis of a simple homogeneous stem cell population in the basal layer but can be better understood on the basis of an hierarchical stem cell-dividing transit proliferative model. The data are consistent with an average cell cycle time of about 100 h but there are suggestions of considerable cell kinetic heterogeneity. The data also suggest that the amount of lateral cell movement within the basal layer is small. The results may suggest that some stem cells either loose label in a manner similar to that suggested by Cairns (1975) i.e. through a process of selective segregation of their DNA strands, or that they have an extremely short S phase duration as postulated earlier (Potten et al. 1982). The present data have been extensively mathematically modelled in an accompanying paper. The model which best fits all the data is an hierarchical scheme with three cell divisions in the transit population but some branches of the lineage may be prematurely terminated by the early production of post-mitotic cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Epidermal cell proliferation. II. A comprehensive mathematical model of cell proliferation and migration in the basal layer predicts some unusual properties of epidermal stem cells.

The clustering of 3HTdR labelled cells in the epidermal basal layer and their changes with time have been modelled mathematically and cannot be adequately fitted by an earlier model of the cell kinetic organisation of the skin. A more refined model analysis was performed based on Monte Carlo computer simulations of cell layers which take cell division, cell aging and lateral as well as vertical cell migration into account. A large variety of hypothetical scenarios was tested to see if each could provide a fit to the clustering data. The analysis provides further support for the concept of a cell kinetic heterogeneity with a stem-transit-postmitotic differentiation scheme. In the best overall model scheme three transit divisions are predicted but unlike in the earlier model it is now postulated that postmitotic cells can be produced at all stages in the lineage rather than only at the end of the amplification scheme. Most important, the model predicts that stem cells and most of the transit cells differ in the way they process 3HTdR label. Grain dilution is an important mechanism to explain the fate of some labelled cells in the tissue, but on its own it can only consistently explain the data if the stem cells have a very low labelling index (LI less than or equal to 1%) which implies a very short biologically unreasonable S-phase. If a higher LI (longer S-phase) is assumed for the stem-cells other mechanisms must be predicted to explain the lack of large clusters and the increase in time of the singles. The selective segregation of chromosomes at mitosis is one such mechanism. However, on its own a large number of cells would have to behave in this way (i.e. both stem and T1 cells). If combined with other assumptions such as some grain dilution this selective segregation may be restricted only to stem cells. In addition the model allows cell production and migration rates to be estimated and the analysis can be related to the EPU-concept. Indeed the model itself would tend to automatically generate an EPU like structure. The model quantitatively reproduces LI, PLM, CL and clustering data.

Autoradiography↗
PubMed1986

Analysis of the changes in the proportion of clustered labelled cells in epidermis.

A new cell kinetic approach is presented from which the duration of the S and G2 + M phases can be estimated. The technique involves an analysis of the spatial distribution of labelled cells in sections or sheets of epithelium (i.e. an analysis of clustered labelled cells). The technique is largely independent of the absolute number of labelled cells and hence is not influenced by factors which affect the absolute number of labelled cells. The technique is described and experimental data from dorsal murine skin are presented. The technique has also been simulated mathematically so that the phase durations and their variances could be estimated. The advantages of the technique are: it is technically simple; it provides at least two independent estimates of the phase durations; unlabelled cells need not be counted (compare with LI or PLM analysis); it is independent of variations in the absolute yield of labelled cells, and it is applicable if the LI is low and the S phase is short (where the PLM technique tends to fail).

Animals↗
PubMed1986

Intestinal cell proliferation. I. A comprehensive model of steady-state proliferation in the crypt.

Cell replacement in the crypt of the murine small intestine has been studied and modelled mathematically under steady-state conditions. A great deal of information is available for this system, e.g. cell cycle times, S phase durations, the rate of daily cell production, the Paneth cell distribution etc. The purpose of the present work was to consider simultaneously as much of these data as possible and to formulate a model based upon the behaviour of individual cells which adequately accounted for them. A simple mathematical representation of the crypt has been developed. This consists of sixteen stem cells per crypt (TC = 16 hr, TS = 9 hr), and four subsequent transit cell divisions (TC = 11 to 12 hr, TS = 8 hr) before maturation. Experimental data considered to test the modelling were LI and data on the number of vertical runs of similarly labelled cells. All data were obtained from the ileum after 25 microCi [3H]TdR given at 09:00 hours. A number of alternative assumptions have been considered and either accepted or rejected. Two alternative model concepts of cell displacement explain the data equally well. One is dependent upon strong local cell generation age determinance while the other could accommodate any weak local cell displacement process in conjunction with an environmental cut-off determinant at the middle of the crypt. Both models provide new interpretations of the data, e.g. certain rates of lateral cell exchange between neighbouring columns (250 to 350 per crypt per day out of a total of 420 cell divisions per day) can be concluded from run data, while LI data provide information about the mechanisms involved in maintaining a position-related age order in the crypt.

Animals↗
PubMed1985

Growth dependent cell proliferation kinetics of a human malignant melanoma grown in nude mice.

A human malignant melanoma was grown in nude mice. The tumour showed an exponential growth for several weeks which gradually slowed down, until following week 8 the tumour growth ceased. The reasons for this growth pattern were examined by labelling techniques (PLM, LI). The tumour cell production as quantified by the growth fraction, showed only a moderate reduction which, taken alone, could not explain the growth cessation. The important mechanism seems to be an increased loss of tumour cells during the intermitotic interval. While the loss of cells/h remains constant the total intermitotic cell loss is increased because the cell cycle times are prolonged by 50% from the exponential phase (45 h in week 3) to the plateau phase (66 h in week 8).

Adult↗