Marrow, development physiology

Hematopoietic (blood) cells transport oxygen and carbon dioxide, contribute to host immunity, and facilitate blood clotting [1], A complex, interrelated, and multistep process, called hematopoiesis, controls the production as well as the development of specific marrow cells from immature precursor cells to functional mature blood cells. This well-regulated process also allows for replacement of cells lost through daily physiologic activities. The proliferation of precursor cells, the maturation of these into mature cells, and the survival of hematopoietic cells require the presence of specific growth factors. 

Physiologically, body stores are maintained by extracting approximately 10% of the iron provided in a balanced diet and this corresponds to 1.5 mg each day for males and slightly more for females to compensate for pregnancy and menses. The trace element is derived from food by peptic digestion and after reduction the ferrous form crosses the enterocyte to be released at the serosal pole via the ferroportin-hepcidin mechanism to be transported, by plasma transferrin, to developing red cells in the marrow for haemoglobin synthesis. At the end of their life span effete erythrocytes are removed by the reticuloendothelial system in the spleen, bone marrow and the liver. 

Potential interfering substances in a biological matrix include endogenous matrix components, metabolites, decomposition products, and in the actual study, concomitant medication. Whenever possible, the same biological matrix as the matrix in the intended samples should be used for validation purposes. For tissues of limited availability, such as bone marrow, physiologically appropriate proxy matrices can be substituted. Method selectivity should be evaluated during method development and method validation and can continue during the analysis of actual study samples. 

A physiologically based pharmacokinetics (PBPK) model based on the ventilation rate, cardiac output, tissue blood flow rates, and volumes as well as measured tissue/air and blood/air partition coefficients has been developed (Medinsky et al. 1989a Travis et al. 1990). Experimentally determined data and model simulations indicated that during and after 6 hours of inhalation exposure to benzene, mice metabolized benzene more efficiently than rats (Medinsky et al. 1989a). After oral exposure, mice and rats appeared to metabolize benzene similarly up to oral doses of 50 mg/kg, above which rats metabolized more benzene than did mice on a per kg body weight basis (Medinsky et al. 1989b). This model may be able to predict the human response based on animal data. Benzene metabolism followed Michaelis-Menton kinetics in vivo primarily in the liver, and to a lesser extent in the bone marrow. Additional information on PBPK modeling is presented in Section 2.3.5. 

Description Of the Model. Travis et al. (1990) developed a model to describe the pharmacokinetics of benzene in mice, rats, and humans. The model contained five compartments, consisting of liver, fat, bone marrow, and muscle, and organs such as brain, heart, kidney, and viscera, connected by the arterial and venous blood pathways. Michaelis-Menten kinetics was assumed in all species, and occurred primarily in the liver, and to a lesser extent in the bone marrow. The species-specific physiological and chemical parameters were taken from the literature. The metabolic parameters were obtained by fitting the empirical data to the model. 

At the physiological level, various harmful processes have been identified such as hypoplasia of the bone marrow, thrombocytopenia, leucopenia particularly affecting polymorphonuclear leukocytes which promotes immunosupression, sharp decrease in the intestinal iron uptake and malfunctioning of liver and kidneys. These effects have been related to the deadly acute poisoning condition. Animals that ingest sublethal amounts of this fern may develop severe internal hemorrhages. Of... 

First successful kidney transplant (Joseph Edward Murray) American surgeon Murray performs the first successful kidney transplant, inserting one of Ronald Herrick s kidneys into his twin brother, Richard. Murray shares the 1990 Nobel Prize for Physiology or Medicine with E. Donnall Thomas, who developed bone marrow transplantation. 

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