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Differential effect of CTLA4Ig on murine graft-versus-host disease (GVHD) development: CTLA4Ig prevents both acute and chronic GVHD development but reverses only chronic GVHD.

The role of costimulation was examined in an in vivo model of alloantigen-driven Th1 or Th2 cytokine responses, the parent-into-F1 model of acute or chronic graft-vs-host disease (GVHD), respectively. The soluble fusion protein, murine CTLA4Ig, which blocks engagement of CD28 by its natural ligand B7-1 and B7-2, was administered either early, at the time of GVHD induction, or delayed, after the establishment of Th1 or Th2 effector responses (day 7). Early administration of CTLA4Ig prevented the development of both acute and chronic GVHD by preventing the activation of donor T cells, i.e., by blocking characteristic Th1 or Th2 cytokine production and blocking memory marker up-regulation on donor T cells. Delayed CTLA4Ig administration was unable to alter acute GVHD but did reverse chronic GVHD as evidenced by normalization of serum autoantibody levels, normal host B cell numbers and MHC class II expression, reduced donor T cell expression of CD40 ligand, and reduced numbers of donor CD4+ memory T cells. The percentage of donor memory cells was not altered by delayed CTLA4Ig. We conclude that in this model, alloantigen-driven Th1 or Th2 responses are equally susceptible to costimulatory blockade at the onset of disease; however, once effector mechanisms become established, only Th2-driven responses have a requirement for further costimulation for the continued expansion of CD4+ T cells. These data suggest that humoral, lupus-like autoimmunity requires continuous T cell help for B cells, and agents that interrupt this process may be beneficial.

Abatacept↗

[Quality development in family practice--development and use of health indicators].

In 1995 the Norwegian general practitioners' associations embarked upon a three-year project to assess a new model for improving the quality of primary health care. Indicators are proposed for assessing quality and setting standards in local practice. Software has been developed to simplify collection of data and production of reports from computerized medical records. Peer groups of 5-10 practitioners discuss results, agree on local standards and plan improvements. General practitioners who participate in a cycle of quality improvement will be awarded credits for recertification as specialists in general practice. The initial topics are: care of diabetics, use of laboratory tests, management of sore throat, and management of migraine. This national project will be evaluated both in terms of improvement in the quality of care, and of the views of the participating practitioners.

Family Practice↗

The development of human megakaryocytes: III. Development of mature megakaryocytes from highly purified committed progenitors in synthetic culture media and inhibition of thrombopoietin-induced polyploidization by interleukin-3.

Megakaryocyte (MK) progenitors, CD34+CD41+ cells, were isolated from human bone marrow with a purity greater than 98% and a viability of 95%, using affinity techniques with magnetic beads followed by fluorescence-activated cell sorting. These cells were incubated in synthetic media containing the cytokines thrombopoietin (TPO), interleukin-3 (IL-3), stem cell factor (SCF), and IL-6, obviating the confounding effects of serum growth factors or cytokine secretions of non-MK cells on MK maturation. MK number, MK colony-forming units (CFU-MK), and MK ploidy and phenotype were examined during 7 days in culture. TPO in serum-free cultures without any other exogenously added cytokine supported MK growth and maturation. SCF synergized with TPO to augment MK production and maturation and could partially replace it under some conditions. Both TPO and IL-3 alone increased MK number (12- and 5-fold, respectively) and CFU-MK (approximately 15-fold each). SCF alone had no effect on MK proliferation in the absence of TPO, but increased both MK number and CFU-MK by 1.5- to 2.0-fold in the presence of TPO. When combined with IL-3, SCF increased both MK number and CFU-MK by 15- to 20-fold in the absence of TPO. In the presence of TPO, the combination of IL-3 and SCF produced only modest increases (1.5- to 2.0-fold) in both MK number and CFU-MK. The proportion of polyploid MK increased greater than fivefold in the presence of TPO. SCF had little effect on MK ploidy in the presence of TPO, but enhanced ploidy twofold to threefold in the absence of TPO. IL-3 alone never increased the level of polyploidization. Rather, it consistently inhibited TPO- and SCF-induced polyploidization of MK. This inhibition was observed in cultures with or without SCF or IL-6. Although IL-3 also supported the proliferation of CD41+ cells and CFU-MK production, the cells that developed under the influence of IL-3 were phenotypically unusual (CD41dim, CD42dim) and of relatively low ploidy. Mature MK were not produced. When added with TPO, IL-3 suppressed polyploidization. Therefore, TPO stimulates MK growth and maturation, whereas IL-3 stimulates growth without maturation and may serve to conserve the immature MK compartment.

Cell Differentiation↗

The effect of ethanol upon early development in mice and rats. XXIII. The effect of indomethacin on beer-induced disturbances of preimplantation development in rats.

The effect of Indomethacin on beer-induced modifications of preimplantation development was investigated in rats (control on day 5 of pregnancy), using the following criteria: the mean number of embryos/animal, topographical distribution of embryos, the developmental stage attained, the appearance of pathological forms, the mean cell number/embryo. It resulted that previous administration of Indomethacin antagonized the main deleterious effect of repeated acute administration of beer in the preimplantation period, supporting the hypothesis of prostaglandins (PG) being involved in the pathogenetic action of this alcoholic beverage.

Animals↗

Practice guideline for examination of the placenta: developed by the Placental Pathology Practice Guideline Development Task Force of the College of American Pathologists.

The Placental Pathology Practice Guideline Development Task Force, a multidisciplinary group, has prepared this guideline to assist those involved with placental examination. It provides recommendations related to indications and methods for placental examination as well as sample worksheets. An algorithm for the handling of placentas summarizes the recommendations of the guideline. A summary of specific findings of placental examination together with their pathogenesis and clinical associations is also provided. Recommendations related to reporting with sample reporting formats are included. The guideline is intended as an educational tool, and its use should be guided by the individual circumstances and care setting of specific cases.

Humans↗

[Development of treatment guidelines and procedure guidelines within the scope of developing case fees and a modular quality management system (MQM)].

Since 1991 Diagnostic Related Groups (DRGs) are systematically developed for standardized operation procedures. They are included in a Quality Management System of the DIN EN ISO 9001 ff. norm and are part of the process system. In additional the internal and external evaluation of quality completes a Modular Quality Management System (MQM). These procedures meet the requirements for a Total Quality Management (TQM).

Algorithms↗

Apoptosis during the development of radiogenic thymic lymphomas: effects of treatments inhibiting lymphoma development.

INTRODUCTION: Whole body fractionated irradiation induces thymic lymphomas in C57BL/Ka mice after a latent period during which preleukemic cells progressively transform into leukemic cells within an abnormal thymic microenvironment. A bone marrow graft or repeated cytokine injections prevent lymphoma development. We think that these treatments restore altered mechanisms controlling apoptosis. MATERIALS AND METHODS: Apoptosis was analyzed by flow cytometry in thymocytes from different groups of mice (control, preleukemic, prevented mice). RESULTS: The apoptotic rates did not change in freshly isolated thymocytes from different experimental groups. However, after culture, the level of apoptosis increased in preleukemic thymuses; and returned to normal value in cultured thymocytes from irradiated mice after lymphoma preventing treatments. Furthermore, thymic microenvironmental factors can control thymocyte apoptosis. CONCLUSION: We propose that after leukemogenic irradiation, there is an increase of cells with an activated suicide program, but that alterations of thymic environmental factors rescue them from apoptosis, allowing their further neoplastic transformation.

Animals↗