Effect of acute alcohol intoxication on granulocyte mobilization and kinetics

Granulocyte mobilization into skin abrasions in human volunteers was significantly inhibited by acute alcohol intoxication (45,-800 cells in 8 hr versus 353,000 in normal controls). Alcohol applied locally did not inhibit granulocyte delivery, and protection of the abrasion against heat loss did not reduce the inhibited delivery in intoxicated volunteers. Intoxication inhibited granulocyte adherence and local mobilization in parallel. Alcohol administration to rabbits shifted granulocytes from marginal to circulating pool in a manner similar to epinephrine. Mobilization of bone marrow granulocytes by glucocorticoid or endotoxin administration was not inhibited by intoxication, nor did it prevent the endotoxin-induced shift of granulocytes from circulating to marginal pool.     

The evaluation of neutropenia: the use of the granulocyte mobilization test

Summary. Ten individuals with idiopathic neutropenia and similar numbers of normal and abnormal controls were tested for mobilization of their marginal granulocyte pools and bone marrow reserve by using epinephrine and hydrocortisone intravenously. Individuals with ‘benign’ idiopathic neutropenia appeared to have a normal response while half the abnormal controls responded poorly. It is suggested that granulocyte mobilization tests are valuable in the assessment of individuals with neutropenia.     

Physiologic and pathologic consequences of granulocyte colony-stimulating factor deficiency

Published studies have extended our understanding of granulocyte colony-stimulating factor deficiency. In granulocyte colony-stimulating factor withdrawal in humans, apoptosis seems to account for the dramatic loss of neutrophils, but whether the apoptosis results from normal cellular aging processes or accelerated cell loss upon granulocyte colony-stimulating factor withdrawal is unclear. In granulocyte colony-stimulating factor(-/-) mice, the introduction of bcl-2, an antiapoptotic gene product, did not affect the number of neutrophils in the circulation. This finding suggests that apoptosis does not account for the lack of neutrophils in this setting and that the reduction in neutrophil numbers in these mice results from processes other than the loss of large numbers of granulocyte colony-stimulating factor-dependent cells after commitment to the neutrophil lineage. In an experimental model of the induction of antigranulocyte colony-stimulating factor antibodies, the animals appeared remarkably similar to granulocyte colony-stimulating factor(-/-) mice. This finding confirms that at least some neutrophils are produced by granulocyte colony-stimulating factor-independent mechanisms and suggests that the antigranulocyte colony-stimulating factor antibodies reported in clinical studies before and after granulocyte colony-stimulating factor administration do not lead to similar consequences. A gross loss of neutrophils as seen in these granulocyte colony-stimulating factor-immune mice has never been reported in patients, suggesting that such an occurrence is unlikely to have occurred.     

Mechanisms of mobilization of hematopoietic progenitors with granulocyte colony-stimulating factor

Hematopoietic progenitor cells can be mobilized from the bone marrow to the blood by a wide variety of stimuli, including hematopoietic growth factors, chemotherapy, and chemokines. Increasingly, mobilized peripheral blood hematopoietic progenitor cells instead of bone marrow hematopoietic progenitor cells have been used to reconstitute hematopoiesis after myeloablative therapy because of their reduced engraftment times and relative ease of collection. A striking feature of hematopoietic progenitor cell mobilization is the ability of hematopoietic growth factors with distinct cellular targets and biologic activities to mobilize a similar spectrum of pluripotent and lineage-committed hematopoietic progenitor cells into the blood. Recent studies have identified some of the key adhesive interactions that regulate hematopoietic progenitor cell trafficking in the bone marrow. In addition, pathways linking mobilizing agents to hematopoietic progenitor cell mobilization have begun to be elucidated. This review summarizes these advances, emphasizing the mechanisms regulating granulocyte colony-stimulating factor-induced mobilization.     

Use of a biosimilar granulocyte colony‐stimulating factor for peripheral blood stem cell mobilization: an analysis of mobilization and engraftment

Peripheral blood haematopoietic progenitor cell mobilization has become a standard procedure prior to autologous stem cell transplantation. Biosimilar granulocyte colony‐stimulating factors (GCSF) have recently been awarded European Union (EU) licences for stem cell mobilization but data for their use in this context remain limited. The biosimilar GCSF, Ratiograstim^® (Ratiopharm, Ulm, Germany) was granted an EU licence in September 2008 and incorporated into clinical practice in the Wessex Blood and Marrow Transplantation Programme in December 2008. Data were retrospectively collected for 154 consecutive patients undergoing peripheral blood stem cell harvest between January 2009 and December 2011 using the biosimilar GCSF. 131 consecutive patients from the preceding 3 years, who had received Neupogen^®, were used as a control. We analysed both parameters relevant to stem cell collection and engraftment data, where patients proceeded to transplantation. We found no statistically significant difference between the two groups when comparing CD34 predictors, total number of CD34⁺ stem cells collected, number of days required for collection, or for time to engraftment. This is, to our knowledge, the largest direct comparison of a biosimilar GCSF with originator GCSF for stem cell mobilization. The use of biosimilar GCSF can produce a significant cost saving, allowing investment in other areas of stem cell transplantation.     

Population oscillations and energy reserves in planktonic cladocera and their consequences to competition

Time lags in an individual's response to decreased food densities are responsible for oscillations in laboratory populations of Daphnia galeata mendotae. Visible energy reserves of triacylglycerols accumulate in the body of animals at low population densities when food is abundant and are later metabolized at high population densities when food is scarce to temporarily sustain activity and reproduction. After these energy reserves are metabolized many individuals, primarily juveniles, starve and die. The length of the time lags is a function of the amount of energy reserve accumulated in the individual. Because this sustained activity and reproduction further decreases food concentrations to very low levels, individuals of a second smaller-body-sized species, Bosmina longirostris, that do not have sufficient energy reserves quickly starve and die. Thus the accumulation of energy reserves in individuals underlies the time lags important in causing population oscillations and has consequences to interspecific competition.     

Mice lacking granulocyte colony-stimulating factor have chronic neutropenia, granulocyte and macrophage progenitor cell deficiency, and impaired neutrophil mobilization

Mice lacking granulocyte colony-stimulating factor (G-CSF) were generated by targeted disruption of the G-CSF gene in embryonal stem cells. G-CSF-deficient mice (genotype G-CSF-/-) are viable, fertile, and superficially healthy, but have a chronic neutropenia. Peripheral blood neutrophil levels were 20% to 30% of wild-type mice (genotype G- CSF+/+) and mice heterozygous for the null mutation had intermediate neutrophil levels, suggesting a gene-dosage effect. In the marrow of G- CSF-/- mice, granulopoietic precursor cells were reduced by 50% and there were reduced levels of granulocyte, macrophage, and blast progenitor cells. Despite G-CSF deficiency, mature neutrophils were still present in the blood and marrow, indicating that other factors can support neutrophil production in vivo. G-CSF-/- mice had reduced numbers of neutrophils available for rapid mobilization into the circulation by a single dose of G-CSF. G-CSF administration reversed the granulopoietic defect of G-CSF-/- mice. One day of G-CSF administration to G-CSF-/- mice elevated circulating neutrophil levels to normal, and after 4 days of G-CSF administration, G-CSF+/+ and G-CSF- /- marrows were morphologically indistinguishable. G-CSF-/- mice had a markedly impaired ability to control infection with Listeria monocytogenes, with diminished neutrophil and delayed monocyte increases in the blood and reduced infection-driven granulopoiesis. Collectively, these observations indicate that G-CSF is indispensible for maintaining the normal quantitative balance of neutrophil production during "steady-state" granulopoiesis in vivo and also implicate G-CSF in "emergency" granulopoiesis during infections.     

Causes and consequences of blood pressure alterations in obstructive sleep apnea

The obstructive sleep apnea (OSA) syndrome has been considered to be a cause of both transient blood pressure elevations during sleep and sustained hypertension during the awake state. The purpose of this review was to examine critically the existing literature regarding (1) the blood pressure alterations associated with OSA, (2) causal mechanisms relating specific blood pressure alterations to OSA, and (3) potential consequences of the systemic circulatory abnormalities associated with OSA. Particular attention was directed at studies that assessed the prevalence of OSA in patients with hypertension and that examined the effects on blood pressure of treatment of OSA. We conclude that patients with OSA have abnormal sleep blood pressure patterns, manifested most frequently by apnea-associated blood pressure elevations. Confounding factors such as obesity and antihypertensive drug therapy, and conflicting evidence regarding changes in daytime blood pressure after therapy for OSA, make it premature to conclude that OSA and daytime hypertension are directly associated. Circumstantial evidence suggests that the blood pressure alterations that occur during sleep could contribute to the high cardiovascular morbidity in patients with OSA. Further research into the relationship between OSA and hypertension should improve the future care of patients with these conditions and enhance our understanding of cardiopulmonary pathophysiology.     

Effect of granulocyte colony-stimulating factor mobilization on phenotypical and functional properties of immune cells

Some phenotypic and functional properties of lymphocytes from bone marrow or peripheral blood stem cell donors were compared in a randomized study.Lymphocyte subsets were analyzed by immunocytometry in blood harvested from bone marrow donors (n = 27) and from peripheral blood stem cell donors before and after granulocyte colony-stimulating factor mobilization (n = 23) and in bone marrow and peripheral blood stem cell grafts.Granulocyte colony-stimulating factor mobilization increased the blood T and B, but not NK, lymphocyte counts. All lymphocyte counts were approximately 10-fold higher in peripheral blood stem cell grafts than in bone marrow grafts. Analysis of CD25, CD95, HLA-DR, and CD45RA expression shows that T-cell activation level was lower after granulocyte colony-stimulating factor mobilization. Similarly, granulocyte colony-stimulating factor reduced by twofold to threefold the percentage of interferon-gamma, interleukin-2, and tumor necrosis factor-alpha-secreting cells within the NK, NK-T, and T-cell subsets and severely impaired the potential for interferon-gamma production at the single-cell level. mRNA levels of both type 1 (interferon-gamma, interleukin-2) and type 2 (interleukin-4, interleukin-13) cytokines were approximately 10-fold lower in peripheral blood stem cell grafts than in bone marrow grafts. This reduced potential of cytokine production was not associated with a preferential mobilization of so-called "suppressive" cells (CD3+CD4-CD8-, CD3+CD8+CD56+, or CD3+TCRVA24+CD161+), nor with a modulation of killer cell receptors CD161, NKB1, and CD94 expression by NK, NK-T, or T cells.Our data demonstrate in a randomized setting that quantitative as well as qualitative differences exist between a bone marrow and a peripheral blood stem cell graft, whose ability to produce type 1 and type 2 cytokines is impaired.     

Mars 520-d mission simulation reveals protracted crew hypokinesis and alterations of sleep duration and timing

The success of interplanetary human spaceflight will depend on many factors, including the behavioral activity levels, sleep, and circadian timing of crews exposed to prolonged microgravity and confinement. To address the effects of the latter, we used a high-fidelity ground simulation of a Mars mission to objectively track sleep–wake dynamics in a multinational crew of six during 520 d of confined isolation. Measurements included continuous recordings of wrist actigraphy and light exposure (4.396 million min) and weekly computer-based neurobehavioral assessments (n = 888) to identify changes in the crew''s activity levels, sleep quantity and quality, sleep–wake periodicity, vigilance performance, and workload throughout the record-long 17 mo of mission confinement. Actigraphy revealed that crew sedentariness increased across the mission as evident in decreased waking movement (i.e., hypokinesis) and increased sleep and rest times. Light exposure decreased during the mission. The majority of crewmembers also experienced one or more disturbances of sleep quality, vigilance deficits, or altered sleep–wake periodicity and timing, suggesting inadequate circadian entrainment. The results point to the need to identify markers of differential vulnerability to hypokinesis and sleep–wake changes during the prolonged isolation of exploration spaceflight and the need to ensure maintenance of circadian entrainment, sleep quantity and quality, and optimal activity levels during exploration missions. Therefore, successful adaptation to such missions will require crew to transit in spacecraft and live in surface habitats that instantiate aspects of Earth''s geophysical signals (appropriately timed light exposure, food intake, exercise) required for temporal organization and maintenance of human behavior.     

Peripheral blood progenitor cell mobilization in healthy donors receiving recombinant human granulocyte colony-stimulating factor

OBJECTIVE: We analyzed the incidence of primitive (LTC-IC) and committed (CFU-mix, BFU-E, CFU-GM) hematopoietic progenitors detected under steady-state conditions and upon progenitor cell mobilization in a cohort of healthy donors receiving recombinant human granulocyte colony-stimulating factor (rhG-CSF). MATERIALS AND METHODS: Healthy donors (n = 30) of HLA-mismatched or -matched stem cell transplants were mobilized with rhG-CSF (8 microg/Kg body weight subcutaneously twice daily until completion of leukapheresis). PBPC collections were started after 4 days of rhG-CSF therapy. RESULTS: Steady-state incidence of bone marrow LTC-IC, but not committed progenitors, significantly correlated with the numbers of mobilized CD34+ cells (r = 0.6, p = 0.004), CFU-GM (r = 0.79, p = 0.0005) and CFC (r = 0.76, p = 0.001) detected after 4 days of rhG-CSF therapy. Statistically significant correlations were also found between steady-state blood CFU-GM and peak numbers of CD341 cells (r = 0.68, p = 0.001), numbers of day 4 CD341 cells (r = 0.52, p = 0.005), CFU-GM (r = 0.63, p = 0.002), and CFC (r = 0.61, p = 0.003). CONCLUSION: Our data show that in normal volunteers baseline marrow LTC-IC and blood CFU-GM correlate with rhG-CSF-mobilized PBPC. The potential clinical relevance of these findings in the identification of poor mobilizers will be tested in a prospective study.     

Comparison between granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor in the mobilization of peripheral blood stem cells

Peripheral blood stem cells (PBSC) have become the preferred source of stem cells for autologous transplantation because of the technical advantage and the shorter time to engraftment. Mobilization of CD34+ into the peripheral blood can be achieved by the administration of granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), or both, either alone or in combination with chemotherapy. G-CSF and GM-CSF differ somewhat in the number and composition of PBSCs and effector cells mobilized to the peripheral blood. The purpose of this review is to give a recent update on the type and immunologic properties of CD34+ cells and CD34+ cell subsets mobilized by G-CSF or GM-CSF with emphasis on (1) relative efficacy of CD34+ cell mobilization; (2) relative toxicities of G-CSF and GM-CSF as mobilizing agents; (3) mobilization of dendritic cells and their subsets; (4) delineation of the role of adhesion molecules, CXC receptor 4, and stromal cell-derived factor-1 signaling pathway in the release of CD34+ cell to the peripheral blood after treatment with G-CSF or GM-CSF.