Periodic oscillation of blood leukocytes, platelets, and reticulocytes in a patient with chronic myelocytic leukemia.

A patient with chronic myelocytic leukemia had a cyclic oscillation of blood neutrophils, eosinophils, monocytes, platelets, normoblasts, and reticulocytes but not of lymphocytes. The cycle interval was 53--69 days. Except for reticulocytes all other cells cycled with neutrophils. Plasma colony-stimulating factor (CSF) oscillated out of phase with neutrophils, suggesting that granulocytopoiesis is regulated through CSF by a feed-back mechanism. Plasma erythropoiesis-stimulating factor (ESF) also oscillated. ESF crests preceded or coincided with reticulocyte crests, indicating that the ESF elevation may have been responsible for the reticulocyte peaks. The relationship between neutrophils and reticulocytes and their oscillations with plasma CSF and ESF suggests that there is a common stem cell which differentiates along one cell line or the other depending upon the balance of regulatory stimuli. The fraction of blood neutrophilic precursors (myeloblasts, promyelocytes, and myelocytes) in DNA synthesis fluctuated with neutrophil level. The calculated generation time was shorter at the crests than at the troughs of the neutrophil cycles. This finding suggested that the rate of proliferation of the neutrophils changed periodically. This observation, along with a periodic increase in differentiation of the stem cell toward the neutrophilic cells, is the probable explanation of oscillation of the neutrophil count in the blood.

Culture of autologous bone marrow in diffusion chambers: effect of host irradiation.

Autologous bone marrow (BM) cells were cultured in diffusion chambers (DC) implanted into whole-body irradiated, non-irradiated, or sham-irradiated goats. Proliferation was apparent in DC implanted in both irradiated and nonirradiated goats. However, cells in DC cultured in irradiated hosts increased in number beginning earlier, proceeded at a faster rate, and reached higher numbers than in DC in nonirradiated hosts. Growth enhancement could not have occurred as a result of radiation-induced immunosuppression in autologous hosts. The nonirradiated "target cells" in the DC therefore constituted an indicator system for stimulatory or inhibitory substances in the host. The simultaneous increase in the number of granulocytes in peripheral blood and in DC of irradiated hosts was paralleled by an initial rise in serum colony-stimulating factor (CSF). A second, prolonged period of severe granulocytopenia following irradiation of the host correlated with high levels of serum CSF. Increased numbers of megakaryocytes were seen in DC as thrombocytopenia developed in the irradiated host. DC erythropoiesis disappeared rapidly in nonirradiated goats; however, in DC of irradiated goats, the number of erythrocytic precursors increased exponentially during ablation of host erythroid marrow. Anemia did not develop in the host during the culture period. Proliferation of mononuclear cells in DC was markedly stimulated by irradiation of the host. Proliferation of macrophages appeared independent of host treatment. These observations provide strong evidence for diffusion of specific and/or nonspecific humoral hematopoietic stimulators from the host into the DC. This stimulation appears to be elicited and/or intensified by irradiation of the host.

Thermal noise in cells. A cause of spontaneous loss of cell function.

Background noise due to random thermal perturbations of molecules has a disruptive effect on all information handling systems, including cells and organisms. This thermal noise appears to be largely responsible for the spontaneous loss of proliferative cells in cell cultures. The rates at which proliferative cells are lost as a result of heat injury, in cultured hamster cells, have been measured at high temperatures and extrapolated down to 37 C. This gives an expected 0.2% loss per hour due to thermal injury at physiologic temperature. That such a loss does in fact occur can be shown by comparing cell generation time with population doubling time, when these cells are growing at physiologic temperatures. Apparently, internal thermal noise presents a primary hazard to the reliable functioning of the cell quite apart from the insults it receives from its external environment.

Thermal injury due to normal body temperature.

BY MEASURING THE RATES OF THERMAL INJURY OF HAMSTER CELLS IN CULTURE AT VARIOUS TEMPERATURES WE HAVE FOUND THE FOLLOWING: (1) The number of cells surviving heat injury declines exponentially with time with a characteristic rate constant for each temperature. (2) The temperature dependence of the rate constant follows an Arrhenius law from 46 through 41 C. (3) Extrapolation of the Arrhenius curve to 37 C indicates that over 0.2% of cells are irreversibly lost from the proliferating population each hour as a result of heat injury due to physiologic temperature. (4) The effective activation energy for the thermal destruction of the proliferative capacity of a cell is only 8 eV, which is equivalent to the rupture of less than 50 hydrogen bonds. (5) It is possible to calculate from the Arrhenius law the theoretic upper temperature limit for growth of a cell population. For the cells used in this study, the theoretic limit is 40.6 C.