ABSTRACT
Only 50% of patients who would benefit from warfarin therapy for atrial fibrillation (AF) receive treatment because of clinical concerns regarding chronic anti-coagulation. Percutaneous strategies to treat AF, including pulmonary vein isolation with a curative intent or atrioventricular nodal ablation and implantation of a permanent pacemaker for palliative rate control, have not eliminated the need to manage thromboembolic risk. With the development of a percutaneous left atrial appendage (LAA) occlusion device (the WATCHMAN percutaneous left atrial appendage occluder - Atritech Inc., Plymouth, MN, USA) for thromboembolic protection in non-valvular AF a significant therapeutic option for select patients may be available. We present the first case performed in Australia (24 November 2009) and explore this new methodology.
Subject(s)
Atrial Appendage/surgery , Atrial Fibrillation/complications , Septal Occluder Device , Thromboembolism/prevention & control , Aged , Anticoagulants/adverse effects , Anticoagulants/therapeutic use , Aspirin/therapeutic use , Atrial Appendage/diagnostic imaging , Cardiac Catheterization , Female , Humans , Hypertension/complications , Ischemic Attack, Transient/complications , Patient Preference/psychology , Risk , Risk Assessment , Septal Occluder Device/psychology , Tomography, X-Ray Computed , Ultrasonography , Warfarin/adverse effects , Warfarin/therapeutic useABSTRACT
A mathematical model for the kinetics of haemopoietic cells, including CD34+cells, is proposed. This minimal model reflects the known kinetics of haemopoietic progenitor cells, including peripheral blood CD34+ cells, white blood cells and platelets, in the presence of granulocyte colony-stimulating factor. Reproducing known perturbations within this system, subjected to granulocyte colony-stimulating factor treatment and apheresis of peripheral blood progenitor cells (CD34+ cells) in healthy individuals allows validation of the model. Predictions are made with this model for reducing the length of time with neutropenia after high-dose chemotherapy. Results based on this model indicate that myelosuppressive treatment together with infusion of CD34+ peripheral blood progenitor cells favours a faster recovery of the haemopoietic system than with granulocyte colony-stimulating factor alone. Additionally, it predicts that infusion of white blood cells and platelets can relieve the symptoms of neutropenia and thrombocytopenia, respectively, without drastically hindering the haemopoietic recovery period after high dose chemotherapy.
Subject(s)
Hematopoiesis , Hematopoietic Stem Cells/physiology , Models, Theoretical , Antigens, CD34/metabolism , Blood Platelets/physiology , Granulocyte-Macrophage Colony-Stimulating Factor/physiology , Hematopoietic Stem Cell Transplantation , Humans , Kinetics , Leukocytes/physiology , Neutropenia/physiopathology , Neutropenia/therapyABSTRACT
PURPOSE: To establish a mathematical model describing changes in cell density in squamous epithelia induced by single-dose irradiation. Detailed data from previous studies in mouse tongue epithelium have been used for this study. MATERIALS AND METHODS: The major mechanisms of the epithelial regeneration response, i.e. loss of division asymmetry and accelerated proliferation of stem cells, in combination with residual, abortive proliferation of sterilized cells, have been included in a tissue compartment model. These phenomena have been incorporated via three parameters; T(delay), the duration of the cell cycle block; T(min), the minimum stem cell cycle time due to acceleration; and T(stop), the duration of abortive proliferation. The compartments introduced in the model are normal stem cells, S1; sterilized stem cells, S2; and post-mitotic, functional cells, F. The flux rats between the tissue compartments were defined by autoregulation of the stem cell population, and by overall cell numbers. The model was applied to fit experimental data on changes in oral mucosal cell density after single-dose exposure with 13 and 20 Gy. The best-fit sets of parameters were identified by L2 norm error analysis based on the total cell count. RESULTS: For 13 Gy, the best fit was achieved with T(min) = 1.0 days, T(delay) = 1.2 days and T(stop) = 7.5 days. For 20 Gy, the parameters were, T(min) =0.7 days, T(delay)= 1.0 days and T(stop) =9.5 days. In both data sets, T(min) was the most influential parameter. The resulting fluctuations in stem cell numbers were in good accordance with changes in radiation tolerance after 13 Gy. CONCLUSIONS: The model can be used to define dose-dependent parameters describing the morphological response of squamous epithelia to single-dose irradiation. Based on these parameters, post-irradiation fluctuations in radiosensitivity can be predicted. For developing more complex and reliable mathematical models, which could incorporate transit divisions or fractionated radiotherapy, further experimental data at various dose levels are required.
Subject(s)
Cell Division/radiation effects , Animals , Cell Count , Dose-Response Relationship, Radiation , Epidermis/radiation effects , Epithelium/radiation effects , Mathematics , Mice , Models, Biological , Radiation Tolerance , Stem Cells/radiation effectsABSTRACT
A modified version of a previously developed mathematical model [Obeyesekere et al., Cell Prolif. (1997)] of the G1-phase of the cell cycle is presented. This model describes the regulation of the G1-phase that includes the interactions of the nuclear proteins, RB, cyclin E, cyclin D, cdk2, cdk4 and E2F. The effects of the growth factors on cyclin D synthesis under saturated or unsaturated growth factor conditions are investigated based on this model. The solutions to this model (a system of nonlinear ordinary differential equations) are discussed with respect to existing experiments. Predictions based on mathematical analysis of this model are presented. In particular, results are presented on the existence of two stable solutions, i.e., bistability within the G1-phase. It is shown that this bistability exists under unsaturated growth factor concentration levels. This phenomenon is very noticeable if the efficiency of the signal transduction, initiated by the growth factors leading to cyclin D synthesis, is low. The biological significance of this result as well as possible experimental designs to test these predictions are presented.
Subject(s)
Cell Cycle/physiology , Intercellular Signaling Peptides and Proteins/physiology , Models, Biological , Computer Simulation , Cyclin D , Cyclins/biosynthesis , KineticsABSTRACT
A mathematical model integrating the roles of cyclin D, cdk4, cyclin E, cdk2, E2F and RB in control of the G1 phase of the cell cycle is described. Experimental results described with murine embryo fibroblasts (MEFs), either Rb+/+ or Rb-/-, and with the RB-deficient osteosarcoma cell line, Saos-2, served as the basis for the formulation of this mathematical model. A model employing the known interactions of these six proteins does not reproduce the experimental observations described in the MEFs. The appropriate modelling of G1 requires the inclusion of a sensing mechanism which adjusts the activity of cyclin E/cdk2 in response to both RB concentration and growth factors. Incorporation of this sensing mechanism into the model allows it to reproduce most of the experimental results observed in Saos-2 cells, Rb-/- MEFS, and Rb+/+ MEFs. The model also makes specific predictions which have not been tested experimentally.
Subject(s)
CDC2-CDC28 Kinases , Carrier Proteins , Cell Cycle Proteins , Computer Simulation , DNA-Binding Proteins , G1 Phase/physiology , Models, Theoretical , Proto-Oncogene Proteins , Retinoblastoma Protein/deficiency , Animals , Cyclin D , Cyclin E/metabolism , Cyclin-Dependent Kinase 2 , Cyclin-Dependent Kinase 4 , Cyclin-Dependent Kinases/metabolism , Cyclins/metabolism , E2F Transcription Factors , Embryo, Mammalian/cytology , Fibroblasts/cytology , Mice , Mice, Mutant Strains , Osteosarcoma , Protein Serine-Threonine Kinases/metabolism , Retinoblastoma Protein/genetics , Retinoblastoma-Binding Protein 1 , Transcription Factor DP1 , Transcription Factors/metabolism , Tumor Cells, CulturedABSTRACT
A mathematical model of cyclin E, cdk2 and retinoblastoma protein control of the G1 phase of the human cell cycle is proposed. The model includes retinoblastoma (Rb) protein phosphorylation by a cyclin E/cdk2 complex and its subsequent dephosphorylation at the end of the cell cycle. The numerical solutions to this model demonstrates the cyclic behavior of the cyclin E/cdk2 complex, with and without Rb function, cell cycle. This model suggests an inhibition of cyclin E/cdk2 complex formation (or its activation) by hypophosphorylated retinoblastoma protein. The experimental results of cell cycle arrest upon injection of transforming growth factor-beta, alpha-interferon or D-erythro-sphingosine during G1 phase are reproduced. Cell cycle behavior predicted by this model for increasing the concentration of hypophosphorylated retinoblastoma protein during the G1 phase is discussed. Additional results are obtained by numerical simulation.
Subject(s)
CDC2-CDC28 Kinases , Carrier Proteins , Cell Cycle Proteins , Cyclin-Dependent Kinases/metabolism , Cyclins/metabolism , DNA-Binding Proteins , G1 Phase , Protein Serine-Threonine Kinases/metabolism , Retinoblastoma Protein/metabolism , Cyclin-Dependent Kinase 2 , E2F Transcription Factors , Humans , Interferon-alpha/pharmacology , Mathematics , Models, Biological , Retinoblastoma-Binding Protein 1 , Transcription Factor DP1 , Transcription Factors/metabolism , Transforming Growth Factor beta/pharmacologyABSTRACT
A mathematical model for the cell cycle is proposed that incorporates the known biochemical reactions involving both cyclin A and cyclin B, the interactions of these cyclins with cdc2 and cdk2, and the controlling effects of cdc25 and weel. The model also postulates the existence of an as yet unknown phosphatase involved in the formation of maturation promoting factor. The model produces solutions that agree qualitatively with a wide variety of experimentally observed cell-cycle behaviour. Conditions under which the model could explain the initial rapid divisions of embryonic cells and the transition to the slower somatic cell cycle are also discussed.
Subject(s)
Cell Cycle/physiology , Cyclin A/metabolism , Cyclin B/metabolism , Models, Biological , Animals , Cells/metabolismABSTRACT
Several mathematical models have been proposed for regulation of the cell cycle in early embryos by cyclin and maturation-promoting factor (MPF). In this paper the previously proposed models for cyclin and MPF activity are analyzed, and the validity of those models based on the mathematical behavior of their solutions and on physical considerations are discussed. In addition, three further models are proposed that exhibit the periodic behavior necessary for modeling the mitotic clock but that do not have certain of the limitations of the other models.
