[The guideline clearing programme of the self-governmental bodies in the German health care system--a project to promote quality assurance in medicine]. / Das Leitlinien-Clearingprogramm der Selbstverwaltungskörperschaften im Gesundheitswesen--Ein Projekt zur Qualitätsförderung in der Medizin.

Within the German health system guidelines are increasing considered as a meaningful and necessary aid to decision making. In this context the effectiveness of guidelines essentially depends on their methodical quality. Because of the fact that most of the German-language guidelines introduced within the past years show obvious methodological defects, the Agency for Quality in Medicine developed within the last two years the following programme for quality-assurance and promotion of guidelines: 1. Definition of quality policies for clinical practice guidelines in Germany 2. Establishment of quality demands for guidelines 3. Methods and instruments for quality promotion of guideline programmes 4. Measures to promote and check the quality of guidelines ("German Guidelines Clearinghouse") The following article reports on background, aims, instruments, method development and acceptance of the programme.

[An online information system "LEITLINIEN-IN-FO"--a contribution to quality management in health care]. / Der Online-Informationsdienst "LEITLINIEN-IN-FO"--ein Beitrag zum Qualitätsmanagement im Gesundheitswesen.

An online-information service contianing clinical practice guidelines ("LEITLINIEN-INFO"--available via) based on similar programs from Scotland and Canada--was developed by the German Guidelines Clearinghouse (Agency for Quality in Medicine, Cologne). The service focuses on continuing medical education regarding guideline methodology and tools for critical appraisal of guidelines. It contains guideline appraisal reports developed in cooperation with the German Cochrane-Center. Special importance is given to a hyperlink collection of German and international guideline-data-bases. Backgrounds, aims, and structures of the information program are discussed.

Differential effects of recombinant human colony stimulating factor (rh G-CSF) on stem cells in marrow, spleen and peripheral blood in mice.

Previously it has been hypothesized that the granulopoietic and erythropoietic lineages may compete for differentiating stem cells. According to this hypothesis one would expect that a stimulation of granulopoiesis by G-CSF administration would lead to a reduction of the stem cell pool and be followed by a decline of erythropoietic progenitor numbers. In addition one would expect an enhanced response of granulopoiesis if G-CSF administration were combined with suppression of erythropoiesis by red cell transfusion. To evaluate whether this hypothesis holds true C57bl mice were injected subcutaneously for 6 d with 3.75 micrograms rh G-CSF/mouse/d (150 micrograms G-CSF/kg body weight/d). Marrow CFU-S numbers showed an increase to 160% on day 2, followed by a decrease to 50% of control on day 6. Splenic and peripheral blood CFU-S increased 20-fold and 10-fold, respectively. Marrow CFU-E declined to 40% of the control value. Splenic CFU-E increased 10-fold. The increase in marrow CFU-GM numbers ranged between 140% and 180%. CFU-GM obtained from the spleen and the peripheral blood increased 60-fold and 15-fold, respectively. Regarding the CFU-S and CFU-GM a similar pattern of response was found in an experiment where rh G-CSF administration was combined with an additional red cell transfusion. These data do not provide convincing evidence for an exhaustion of haemopoietic stem cells during treatment with G-CSF. They rather suggest that an important side effect of G-CSF treatment is a release of CFU-S and progenitors from the marrow to the peripheral blood and a reseeding in the spleen.

A mathematical model of erythropoiesis in mice and rats. Part 4: Differences between bone marrow and spleen.

In a preceding analysis we hypothesized that the most important parameter controlled by erythropoietic regulation in vivo is the degree of amplification (number of cell divisions) in the CFU-E and erythroblast cell stages. It was concluded that erythropoietic amplification in vivo is controlled according to a sigmoidal dose-response relationship with respect to the control parameter which is the haematocrit (or haemoglobin concentration). Here, this hypothesis is extended to include the differences in murine bone marrow and splenic erythropoiesis that are described and quantified by different dose-response relationships. Comparing several sets of experimental data with mathematical model simulations, this approach leads to the following conclusions: (i) in the unperturbed normal steady state at least one extra erythropoietic cell division takes place in the spleen compared with the bone marrow; (ii) a strong erythropoietic stimulus, such as severe bleeding or hypoxia, can induce five to six additional cell divisions in the spleen but only two to three additional divisions in the bone marrow; this results in a considerable increase in the spleen's contribution to erythropoiesis from about 10% in normal animals to over 40% during strong stimulation; (iii) under erythropoietic suppression, such as red cell transfusion, a similar number of cell divisions is skipped in both organs and the splenic contribution to erythropoiesis remains unchanged. In conclusion, the concept that bone marrow and spleen microenvironments differ in the dose-response relationship for erythropoietic regulation provides an explanation for the changing contribution of splenic murine erythropoiesis following a variety of experimental treatments.

Migration of stem cells and progenitors between marrow and spleen following thiamphenicol treatment of mice.

Recovery of hemopoiesis was studied after a 3-day treatment with the antibiotic thiamphenicol (TAP). A contrasting behavior of the spleen colony-forming units (CFU-S), granulocyte-macrophage colony-forming units (CFU-GM), erythroid burst-forming units (BFU-E), and erythroid colony-forming units (CFU-E) numbers in the bone marrow versus those in the spleen was found. Whereas the cell numbers reached nadirs in the marrow, they peaked 30 to 100-fold above control values in the spleen on day 4. Simultaneously the number of CFU-S, BFU-E, and CFU-GM, but not of CFU-E, increased drastically in the peripheral blood. The tritiated thymidine kill of the splenic CFU-S was too small to explain the endogenous splenic production of these cells. A quantitative analysis further revealed that an effective erythropoiesis was established in the spleen. As a consequence, the first part of a reticulocytosis was mainly due to the splenic contribution, whereas the second part predominantly originated from a delayed marrow erythropoiesis. In contrast, the CFU-GM of the spleen did not effectively differentiate into granuloid precursors. The bulk of the granuloid production occurred in the marrow. The best explanation for these results is a net migration of CFU-S, BFU-E, and CFU-GM from the marrow to the spleen during early recovery, and a back-migration of CFU-GM to the marrow later in the recovery phase. These observations indicate a link between migration of hemopoietic cells and their differentiation at the two hemopoietic sites.

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.

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.