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PubMed1993

Mobilization of hematopoietic stem and progenitor cell subpopulations from the marrow to the blood of mice following cyclophosphamide and/or granulocyte colony-stimulating factor.

Committed progenitor cells and primitive stem cells mediate early and sustained engraftment, respectively, after lethal irradiation and stem cell transplantation. Peripheral blood stem cells (PBSC) from unstimulated mice are deficient in both cell types. To study techniques to mobilize both progenitor cells and primitive stem cells from the marrow to the blood, we collected peripheral blood from C57BL/6 mice 6 to 7 days after a single dose of cyclophosphamide (CY; 200 mg/kg intraperitoneally), after recombinant human granulocyte colony-stimulating factor (rhG-CSF) (250 micrograms/kg/d twice per day subcutaneously for 4 days), or after CY followed by G-CSF. Significant increases in white blood cell counts (1.6- to 2.7-fold) and circulating day 8 colony-forming unit spleen (CFU-S) (11- to 36-fold) were seen with all three mobilization methods compared with unstimulated control mice. Transplantation of mobilized blood stem cells into lethally irradiated hosts decreased the time to erythroid engraftment. Blood stem cells were analyzed for primitive stem cell content by Rs, an assay for CFU-S self-renewal, and competitive repopulation index (CRI), an assay of long-term repopulating ability. The primitive stem cell content of unstimulated blood was clearly deficient, but was significantly increased following mobilization, approaching normal bone marrow levels. These results were confirmed by an in vitro limiting dilution long-term culture assay that measures the frequency of progenitor cells and primitive stem cells. Mobilization following CY + G-CSF was accompanied by a marked loss of both progenitor cells and primitive stem cells in the marrow. In contrast, following G-CSF alone the progenitor cell and primitive stem cell content of the marrow was unchanged. Stem cell mobilization following CY + G-CSF was not affected by previous exposure of donors to cytosine arabinoside or cyclophosphamide, but was significantly reduced by previous exposure to busulfan. These data show that stem cell content in the blood may reach near-normal marrow levels after mobilization, the mobilization from the marrow to the blood is temporary and reversible, the specific technique used may mobilize different subpopulations of stem cells, and the type of prior chemotherapy may influence the ability to mobilize stem cells into the blood.

Animals↗

PubMed1996

Granulocyte colony-stimulating factor recruitment of CD34+ progenitors to peripheral blood: impaired mobilization in chronic granulomatous disease and adenosine deaminase--deficient severe combined immunodeficiency disease patients.

Peripheral blood (PB) CD34+ cells mobilized by granulocyte colony-stimulating factor (G-CSF) administration are potentially useful for transplantation and as a target of gene transfer for therapy of hematopoietic disorders. Efficient harvest and planning for clinical use of PB CD34+ cells ideally requires foreknowledge of the expected mobilization kinetics and yield. We developed a sensitive flow cytometric assay for accurately enumerating CD34+ cells throughout the range seen at baseline to peak mobilization. We used this assay to assess the kinetics of G-CSF-mediated mobilization of CD34+ cells to PB in normal volunteers and in patients with chronic granulomatous disease (CGD) or adenosine deaminase (ADA)-deficient severe combined immunodeficiency disease (SCID). Two dose levels of G-CSF were examined (5 and 10 micrograms/kg/d for 7 days). Both doses were well tolerated. For normal subjects and patients an increase in PB CD34+ cells was first detected only preceding the third dose of G-CSF (day 3), peaked transiently on day 5 or 6, and then decreased thereafter despite additional doses of G-CSF. With 32 normal volunteers mean peak CD34+ cell counts were 57 and 76 cells/mm2 of blood (5 and 10 micrograms doses, respectively), whereas for 18 CGD patients the mean peaks were 31 and 40 cells/mm2 of blood. For 2 ADA-deficient SCID patients studied at a G-CSF dose of 5 micrograms/kg/d, the average peak was 16 cells/mm2 of blood. For both of these patient groups mobilization of CD34+ cells to PB was impaired compared with similarly treated normal subjects (P < .05). By contrast to the kinetics of the CD34+ cell mobilization, the absolute neutrophil count (ANC) increased markedly by 6 hours after the first dose of G-CSF and then increased steadily through day 8. At days 5 and 6 (peak mobilization of CD34+ cells) the mean ANC of CGD and ADA patients was only slightly lower ( < or = 15%) than that seen with normal subjects, whereas the difference in CD34+ cell mobilization was > 48%. Thus, ANC is not a reliable surrogate to predict peak PB CD34+ cell counts and direct enumeration of PB CD34+ counts should be undertaken in decisions regarding timing and duration of apheresis to harvest a specific number of these cells. Finally, unexpected, but significant differences in the PB CD34+ cell mobilization between normal subjects and patients with inherited disorders can occur and underscores the importance of establishing the expected mobilization of PB CD34+ cells in the planning of treatment approaches using these cells.

Adenosine Deaminase↗

PubMed1996

[Biomechanics of the pubic symphysis. Which forces lead to mobility of the symphysis in physiological conditions?].

For estimation of the loads of fixation devices, physiological movements and acting forces at the symphysis pubis are examined. Experimentally, Walheim determined the movements of the pubic symphysis under physiological conditions (one-leg stance, walking): there is no effective mobility in the horizontal direction. During the one-leg stance he observed symphyseal mobility of up to 2.6 mm (Phi 1.2 mm) in the vertical direction and 1.3 mm (Phi 0.6 mm) in the sagittal direction. During walking he found symphyseal mobility of up to 2.2 mm (Phi 0.9 mm) in the vertical direction and 1.3 mm (Phi 0.6 mm) in the sagittal direction. Until now the forces leading to symphyseal mobility have not been estimated either experimentally or mathematically. In our experimental study we examined ten fresh cadaver anterior pelvic rings by means of a multidirectional force-mobility measurement. Maximal physiological movements, as determined by Walheim, were increasingly induced in ten equal steps, and the forces required were measured for every single step. Out of the resulting force-mobility curves for the ten cadaver specimens the mean force required (with standard deviation) was calculated for each of the ten measure points, separately for the vertical (y-) direction and sagittal (z-) direction. The values were graphically transferred, and a regression curve was created. This curve allows the acting force to be estimated for every movement of the pubic symphysis: During the one-leg stance the mean force to induce mean mobility is 169 N in vertical direction and 148 N in sagittal direction; for maximal mobility a force of 398 N in the vertical direction and 148 N in the sagittal direction is necessary. During walking, the force required to induce mean movement of the symphysis pubis is 120 N in the vertical direction and 68 N in the sagittal direction; for maximal mobility 333 N is required in the vertical direction and 136 N in the sagittal direction. For mobilization of patients with a symphyseal rupture (type Tile B 1) with partial weight-bearing, neutralization of the mean acting forces during the one-leg stance (169 N in the vertical direction, 68 N in the sagittal direction) must be achieved by an adequate fixation device. In cases where full weight bearing is desirable, such as in patients with limited compliance, stability can only be reached by neutralization of the maximal acting forces during walking (333 N in the vertical direction, 136 N in the sagittal direction).

Adult↗

PubMed1996

Pluripotent and lineage-committed CD34+ subsets in leukapheresis products mobilized by G-CSF, GM-CSF vs. a combination of both.

To define an optimal regimen for mobilizing blood-derived progenitor cells from healthy donors for allogeneic transplantation, we have studied the early and lineage-committed CD34+ subsets in the leukapheresis products after mobilization with G-CSF (10 micrograms/kg/d), GM-CSF (10 micrograms/kg/d), and the combination of G-CSF and GM-CSF (G/GM, 5 micrograms/kg/d of each). We used three color and five dimensional flow cytometry with a panel of monoclonal antibodies against CD3, CD7, CD10, CD11b, CD15, CD33, CD34, CD38, CD45, CD61, and CD71. As reference, we also analyzed CD34+ subsets in samples from umbilical cord blood (UCB) and from adult bone marrow (BM). The level of total CD34+ cells was 0.04 +/- 0.03% (mean +/- SD) in peripheral blood at baseline, and reached a maximum on day 5 or day 6 of administration of growth factors. The percentages of CD34+ cells in the leukapheresis products were 1.06 +/- 0.37% (mean +/- SD) with G-CSF mobilization, 0.35 +/- 0.24% with GM-CSF, and 0.92 +/- 0.61% with the combination of both. Among the CD34+ subsets, the percentage of cells that were CD34+/CD38- was highest in UCB (7.18 +/- 5.58%) and lowest in G-CSF mobilized peripheral blood (0.80 +/- 0.22%), whereas GM-CSF or G/GM mobilized products gave rise to intermediate levels (4.43 +/- 3.40%, 3.61 +/- 2.42%, respectively). The differences between G/GM and G-CSF, between UCB and G-CSF, or between UCB and BM are significant. The absolute numbers of CD34+/CD38- and CD34+/CD38-/HLA-DR+ subsets are also significantly higher in the G/GM mobilized products than in G-CSF products. The cloning efficiency of G/GM mobilized CD34+ cells was 2 times higher than that of G-CSF mobilized CD34+ cells, albeit the difference was statistically marginal. The profile of CD34+ subsets mobilized by the combination of G/GM approaches that found in UCB. Our data illustrate that different growth factors and regimens can preferentially mobilize different CD34+ subsets from normal donors, and that the combination of G-CSF and GM-CSF might be an optimal regimen.

Antigens, CD34↗

PubMed1996

Mobility in the cervico-thoracic motion segment: an indicative factor of musculo-skeletal neck-shoulder pain.

The aim of the study was first to evaluate whether mobility in the cervico-thoracic motion segment is an indicative factor of musculo-skeletal neck-shoulder pain and secondly to compare differences in individual factors between cases and controls for female and male subjects. One-hundred-and-forty-two male electricians and 139 female laundry workers participated in a cross-sectional study. An examination of the Cervico-Thoracic Ratio and a classification of mobility at level C7-T1 was done. All subjects answered a questionnaire about musculo-skeletal complaints. The analysis of relationship between relative flexion mobility in motion segments C7-T5 and neck-shoulder pain showed significant relationships between mobility in specific motion segments and neck-shoulder pain. The overall fit of the multiple regression analysis explained 10% of the variation in neck index (N1) for subjects classified as hypomobile at level C7-T1 and 18% for subjects classified as having an inverse C7-T1 function. Both female and male subjects classified as hypomobile at level C7-T1 showed elevated odds ratios of 2.7 and 2.2, respectively, to have had more than 7 days of neck pain during the previous 12 months, compared to subjects classified as having ordinary mobility at level C7-T1. The factor age showed that young subjects with hypoar hypermobility at level C7-T1 showed elevated odds ratios for neck pain compared to subjects with ordinary mobility in the same age group. In old subjects hypermobility at level C7-T1 was protective compared to subjects with ordinary mobility in the same age group. The factor number of working years showed significant difference between cases and controls among female subjects in the ordinary and hypermobile classes. The factor height showed no significant differences between female or male cases and controls; it did show significant correlation to C7-T1 mobility among female subjects, but not among male subjects. The factors exercise and smoking showed significant differences between cases and controls among female subjects in the ordinary mobility class. The conclusion was that relative flexion mobility is a factor related to the development of neck-shoulder pain rather than the cause of pain.

Adolescent↗

PubMed2006

Association of long-distance corridor walk performance with mortality, cardiovascular disease, mobility limitation, and disability.

CONTEXT: Aerobic fitness, an important predictor of cardiovascular disease and mortality, is difficult to assess by maximal exercise testing in older adults. Extended walking tests have been examined as outcome predictors in medically ill populations but not in community-dwelling older adults. OBJECTIVE: To determine whether an extended walking test predicts poor outcomes in older adults. DESIGN, SETTING, AND PARTICIPANTS: Observational cohort study enrolling 3075 community-dwelling adults aged 70 to 79 years living in Pittsburgh, Pa, or Memphis, Tenn. Of those participating in the Health, Aging, and Body Composition Study, 1584 (52%) were women and 1281 (42%) were black. Participants enrolled from March 1997 to April 1998. Ability to complete the long-distance corridor walk and total performance time was assessed at the baseline examination. MAIN OUTCOME MEASURES: Total mortality, incident cardiovascular disease, incident mobility limitation, and mobility disability were ascertained after a mean (SD) of 4.9 (0.9) years. RESULTS: Among patients eligible to exercise, 351 died, 308 had episodes of incident cardiovascular disease, 1116 had occurrences of mobility limitation, and 509 had occurrences of mobility disability. Inability to complete walking 400 m tended to be associated with a higher risk of mortality and incident cardiovascular disease and, after accounting for potential confounders, was associated with incident mobility limitation (212.6 vs 79.1 events/1000 person-years; adjusted hazard ratio [HR], 1.86; 95% confidence interval [CI], 1.58-2.18; P<.001) and mobility disability (85.2 vs 28.8 events/1000 person-years; adjusted HR, 1.95; 95% CI, 1.56-2.44; P<.001). Of those who completed 400 m, each additional minute of performance time was associated with an adjusted HR of 1.29 (95% CI, 1.12-1.48) for mortality, 1.20 (95% CI, 1.01-1.42) for incident cardiovascular disease, 1.52 (95% CI, 1.41-1.63) for mobility limitation, and 1.52 (95% CI, 1.37-1.70) for disability after adjustment for demographics, health behaviors, clinical and subclinical disease, and cardiovascular disease risk factors. Findings were consistent in both men and women and blacks and whites. Among participants who completed the test and after adjusting for potential confounders, those in the poorest quartile of functional capacity (walk time >362 seconds) had a higher risk of death than those in the best quartile (walk time <290 seconds; adjusted HR, 3.23; 95% CI, 2.11-4.94; P<.001). CONCLUSIONS: Older adults in the community who reported no difficulty walking had a wide range of performance on this extended walking test. Ability to do the test and performance were important prognostic factors for total mortality, cardiovascular disease, mobility limitation, and mobility disability in persons in their eighth decade.

Aged↗

PubMed1993

Gender differences in occupational mobility and structure of employment in the British Civil Service.

In all industrialized societies health status in adults has been found to vary with social position. Attempts to explain this are usually grouped under headings of artefact, material, lifestyle and selective mobility of the healthiest. Such attempts have to date been unsuccessful in fully accounting for this relationship, and whilst they have merit have left unconsidered the effects of the process whereby social stratification occurs. The present study is a prelude to subsequent studies that will endeavour to distinguish between three separate influences on health--the effects of current social position, the long term effects stemming from one's initial class position, and the effects of the processes governing mobility. The purpose of our present investigation is to describe patterns of occupational mobility, that will enable us to identify possible predictors of subsequent mobility and therefore to indicate to what extent mobility might be a process governed by social rules. The work presented in this paper comprises part of the Whitehall II study of occupational, social and lifestyle influences upon health in a Civil Service population. Using multiple regression techniques almost half the variation in mobility is modelled in terms of educational level, fathers' social class, gender, marital status, age on entry into the Civil Service, length of time in Civil Service employment and grade of entry into the Civil Service. Using estimates derived from this model it is suggested that a number of sub-groups within the Civil Service suffer adverse mobility (mobility appears particularly restricted for women and for those entering the Civil Service above 30 years of age). The results obtained suggest that the issue of obstructed opportunity at the workplace could become a focus for fruitful investigation, linking issues of personal autonomy, expectations and control to health. A number of methodological problems in this kind of work are considered together with discussion of how the model can be used to increase our understanding of mobility.

Adult↗

PubMed2004

Genetic analysis of progenitor cell mobilization by granulocyte colony-stimulating factor: verification and mechanisms for loci on murine chromosomes 2 and 11.

OBJECTIVE: It is notable that there is significant inter-individual variability in humans and inter-strain variability in mice in the ability to mobilize hematopoietic stem and progenitor cells, suggesting that there is genetic regulation of mobilization. In the murine system, loci on chromosomes 2 and 11 have been linked to an inter-strain variation in granulocyte colonystimulating factor (G-CSF)-induced stem cell mobilization proficiency. The aim of this study was to verify this linkage and to gain insight into the function of these loci. METHODS: Animals congenic for the loci on chromosomes 2 and 11 were generated by a speed-congenic approach and the function of the loci were further analyzed in doubly congenic animals and with a competitive transplantation/mobilization protocol. RESULTS: The analysis of congenic animals verified that both loci are linked to mobilization proficiency. Analysis of mobilization in doubly congenic animals suggested that both loci act in the same regulatory pathway. Mobilization experiments conducted with mice that had previously been competitively repopulated with congenic and parental-strain BM revealed that the locus on chromosome 11 operates via a progenitor cell-intrinsic mechanism. CONCLUSION: We confirmed linkage of loci on chromosomes 2 and 11 to G-CSF-induced mobilization and thus validated their role as regulators of hematopoietic progenitor cell mobilization in mice. These findings will be useful for further studies directed at identifying genes that regulate mobilization proficiency.

Animals↗

PubMed2004

PBSC mobilization.

Intentional recruitment of hematopoietic stem cells from bone marrow to peripheral blood is a clinical process termed peripheral blood stem cell (PSBC) mobilization. Mobilized PSBC has replaced bone marrow as the preferred source of stem cells for patients undergoing high-dose chemotherapy because of rapid and durable engraftment and reconstitution of functional bone marrow. Although the mechanism involved in the process of PBSC mobilization by cytokines is largely unknown, granulocyte colony-stimulating factor (G-CSF) alone or chemotherapy combined with GCSF is used as a mobilizing agent in current clinical practice. To date, G-CSF is the best cytokine for PBSC mobilization. However, there are some controversies in its efficacy (poor mobilizer) and safety (in allogeneic donors). Recent research progress has revealed some part of the mechanistic scenarios of PBSC mobilization and found promising candidates for the agents for PBSC mobilization. Until the research at molecular and cellular levels elucidates the precise mechanisms, collecting and comparing clinical observations is the best way to find more optimal condition for PBSC mobilization.

Cytokines↗

PubMed1991

Equivalence of mobile and fixed lithotriptors for upper tract stones.

Although mobile renal lithotripsy appears to be a cost-efficient method for a urologist to treat patients at the local hospital the quality issue has been raised with occasional use of a mobile lithotriptor. We reviewed 4,278 kidneys in 3,900 patients treated by 129 urologists using a mobile Dornier HM3 and a mobile Medstone lithotriptor at 21 mobile sites in 6 upper midwest states during 3 1/2 years. These results were compared with those in 524 kidneys in 480 patients treated by our fixed Medstone lithotriptor. After the procedure auxiliary treatments were needed in 3% of the patients treated with the mobile units and 2% of those treated with the fixed unit. The rate in 2 large published series was approximately 9%. The retreatment rates were 5% with the mobile lithotriptors and 6% with the fixed (reported average 16%), and the over-all stone-free rates at 3 months were 69% and 68% (versus 66%). Of note, the mobile units were as effective as the fixed unit against difficult stones. A mobile lithotriptor with a constant support staff that is used 1 or 2 times per month by many trained urologist will perform as well as fixed lithotriptor used regularly by a small unvarying staff of trained urologists.

Evaluation Studies as Topic↗

PubMed2005

Global mobility for psychologists: the role of psychology organizations in the United States, Canada, Europe, and other regions.

Global mobility for psychologists is rapidly improving because of an emerging consensus on recognition standards, the demand for cross-border mobility both internal and external to the profession, and the efforts of membership, credentialing, and regional organizations to promote mobility. In the United States, multiple credentialing organizations promote mobility, primarily through individual endorsement of credentials. The Canadian regulatory boards signed a mutual recognition agreement implementing fast-track mechanisms for licensed psychologists seeking mobility and a competency-based assessment for initial registration. Europe plans to reduce barriers to mobility through mutual recognition of qualifications via a EuroPsy diploma that provides a benchmark for professional psychology education and training. Other regions have not made as much progress with regard to promoting mobility, as many do not yet even regulate the practice of psychology. The authors examine who seeks mobility, which geographic regions promote mobility, and by which mechanisms.

Canada↗

PubMed2004

Ancestim (recombinant human stem cell factor, SCF) in association with filgrastim does not enhance chemotherapy and/or growth factor-induced peripheral blood progenitor cell (PBPC) mobilization in patients with a prior insufficient PBPC collection.

Up to a third of autologous transplantation candidates fail to mobilize hematopoietic progenitors into the peripheral blood with chemotherapy and/or growth factor treatment, thus requiring innovative mobilization strategies. In total, 20 cancer patients unable to provide adequate PBPC products after a previous mobilization attempt were treated with ancestim (20 microg/kg/day s.c.) and filgrastim (10 microg/kg/day s.c.). In 16 patients, the pre-study mobilization was with filgrastim alone. Eight patients underwent single large volume leukapheresis (LVL) and 12 multiple standard volume leukaphereses (SVL) in both mobilizations. Pairwise comparison of peripheral blood CD34(+) cell concentrations on the day of first leukapheresis failed to document synergism - median CD34(+)/microl of 3.2 (<0.1 to 15.4) and 4.5 (1-28.56) for the pre-study and on-study mobilizations (P = 0.79, sign test), and 4.2 (<0.1-15.4) and 5 (1-28.56), respectively, for the 16 patients previously mobilized with filgrastim alone (P = 1, sign test). The number of CD34(+) cells/kg collected per unit of blood volume (BV) processed was similar in both mobilizations - median 0.1 x 10(6)/kg/BV and 0.09 x 10(6)/kg/BV, respectively (P = 1, sign test). In this phase II study, the combination of ancestim and filgrastim did not allow adequate PBPC mobilization and collection in patients with a previous suboptimal PBPC collection.

Adult↗

PubMed2006

Peripheral blood stem cell mobilization by granulocyte colony-stimulating factor alone and engraftment kinetics following autologous transplantation in children and adolescents with solid tumor.

In 56 pediatric and adolescent patients (median age 7 years, range 1-21) with various solid tumors, peripheral blood stem cells (PBSC) were mobilized with granulocyte colony-stimulating factor (G-CSF) alone, and the yields of PBSC and engraftment kinetics following autologous peripheral blood stem cell transplantation (PBSCT) were evaluated retrospectively. Granulocyte colony-stimulating factor (10 microg/kg) was injected subcutaneously for mobilization when patients showed no influence of previous chemotherapy, and administration was continued for 5 days. The peaks of CD34+ cells and colony-forming units-granulocyte/macrophage in the blood were observed on days 4 through 6 of G-CSF administration in all patients. Peripheral blood stem cell harvest was commenced on day 5 of G-CSF treatment. Compared to the results in patients mobilized by chemotherapy plus G-CSF (N=18), the progenitor cell yields were lower in patients mobilized with G-CSF alone. However, there were no significant differences in WBC and ANC engraftment compared to the chemotherapy plus G-CSF mobilization group. Platelet recovery following autologous PBSCT was delayed in patients mobilized with G-CSF alone. The median time taken for ANC and platelet counts to reach 0.5 x 10(9) and 20 x 10(9)/l was 12 days (range: 9-28) and 15 days (8-55), respectively, in all patients who received PBSC mobilized by G-CSF alone. In summary, mobilization with G-CSF alone can mobilize sufficient CD34+ cells for successful autografting and sustained hematological reconstitution in pediatric and adolescent patients with solid tumors, and even in heavily pre-treated patients.

Adolescent↗

PubMed1999

Prolonged release and c-kit expression of haemopoietic precursor cells mobilized by stem cell factor and granulocyte colony stimulating factor.

Mobilization of haemopoietic precursor cells into the circulation by the combination of cytokines, stem cell factor (SCF) and G-CSF in previously untreated patients with carcinoma of the breast resulted in increased yield of collected peripheral blood precursor cells (PBPC). This mobilization of PBPC by SCF with G-CSF lasted several days after ceasing the cytokines in comparison to the rapid fall of PBPC after ceasing G-CSF. Possible mechanisms for this increased and prolonged mobilization were investigated. Immunological phenotyping with CD38, Thy-1 and MDR-1 of the CD34-positive mobilized PBPC detected no difference in maturity compared to PBPC mobilized by G-CSF alone. However, the down-regulation of c-kit, which is associated with the mechanism of mobilization, was much greater in the PBPC mobilized by SCF and G-CSF. The potential clinical implication of increased and prolonged mobilization is increased yield, allowing transplantation of heavily pre-treated patients, transplantation with PBPC from a single apheresis, or PBSC support for multiple courses of high-dose therapy from one mobilization procedure.

Antigens, CD34↗

PubMed2002

Matrix metalloproteinase-9 (gelatinase B) is elevated during mobilization of peripheral blood progenitor cells by G-CSF.

BACKGROUND: Matrix metalloproteinase-9 (MMP-9 or gelatinase B) has recently been implicated in the IL-8-induced mobilization of HPCs in rhesus monkeys and mice. It is not known whether administration of G-CSF causes expression of MMP-9 during HPC mobilization. STUDY DESIGN AND METHODS: Blood samples from 15 allogeneic progenitor cell donors were collected before and during G-CSF-induced HPC mobilization. The expression of the gelatinases MMP-2 and MMP-9 in the plasma of the donors was analyzed by ELISA and zymographic analysis. Gelatinolytic activity was measured with a fluorometric assay that was specific for gelatinases. Expression of IL-6, IL-8, and soluble vascular cell adhesion molecule (VCAM) was measured by ELISA. RESULTS: Highly elevated latent gelatinolytic activity was found on Days 4 and 5 of G-CSF treatment in comparison to pretreatment activity. ELISA and zymographic analyses revealed pro-MMP-9 as the major source of the latent gelatinolytic plasma activity during mobilization. Pro-MMP-2 was not elevated compared with pretreatment levels. As IL-8 has been implicated in the expression of MMP-9, IL-8 concentrations were measured in plasma samples from donors and patients immediately before the start of HPC apheresis, but no significantly elevated IL-8 concentrations were noted. In contrast, pro-MMP-9 and latent gelatinolytic activity was highly correlated with IL-6, which was strongly elevated during mobilization therapy. Finally, soluble VCAM was equally significantly elevated on the days of apheresis. CONCLUSIONS: G-CSF mobilization treatment induces MMP-9, IL-6, and soluble VCAM. Expression of MMP-9 might be involved in the mobilization of human HPCs and might be a final common pathway of different mobilization therapies. Our data do not support a role of IL-8 in G-CSF-induced mobilization. In contrast, IL-6 might be involved in the G-CSF-induced expression of MMP-9.

Cells, Cultured↗

PubMed2000

Mobilization of hematopoietic stem cells.

Hematopoietic stem cell transplantation has been extensively exploited as a therapeutic and research modality and has revolutionized current patient care. At present, more and more medical centers use peripheral blood progenitor cells for transplantation by mobilizing hematopoietic stem cells from bone marrow to peripheral blood because of potential advantages of peripheral blood stem cell transplantation over bone-marrow transplantation. Different effective mobilization regimens have been developed recently with chemotherapeutic agents, hematopoietic growth factors or their combination. This article reviews current developments related to hematopoietic stem cell mobilization including the biology of hematopoietic stem cells, strategies for mobilization, management for mobilization failure, mechanisms of mobilization, and side effects during mobilization. Finally, the Initiation-Amplification-Emigration-Adaptation Model is proposed to help aid understanding of the mechanisms of hematopoietic stem cell mobilization and to stimulate development of novel and optimal mobilization strategies for patient care.

Hematopoietic Stem Cell Mobilization↗

PubMed2006

Serpina1 is a potent inhibitor of IL-8-induced hematopoietic stem cell mobilization.

Here, we report that cytokine-induced (granulocyte colony-stimulating factor and IL-8) hematopoietic stem cell (HSC) and hematopoietic progenitor cell (HPC) mobilization is completely inhibited after low-dose (0.5 Gy) total-body irradiation (TBI). Because neutrophil granular proteases are regulatory mediators in cytokine-induced HSC/HPC mobilization, we considered a possible role for protease inhibitors in the induction of HSC/HPC mobilization. Bone marrow (BM) extracellular extracts that were obtained from murine femurs after 0.5 Gy of TBI contained an inhibitor of elastase. Also, after low-dose TBI, both Serpina1 mRNA and protein concentrations were increased in BM extracts, compared with extracts that were obtained from controls. The inhibitory activity in BM extracts of irradiated mice was reversed by addition of an Ab directed against Serpina1. To further study a possible in vivo role of Serpina1 in HSC/HPC mobilization, we administered Serpina1 before IL-8 injection. This administration resulted in an almost complete inhibition of HSC/HPC mobilization, whereas heat-inactivated Serpina1 had no effect. These results indicate that low-dose TBI inhibits cytokine-induced HSC/HPC mobilization and induces Serpina1 in the BM. Because exogenous administration of Serpina1 inhibits mobilization, we propose that radiation-induced Serpina1 is responsible for the inhibition of HSC/HPC mobilization. Also, we hypothesize that cytokine-induced HSC/HPC mobilization is determined by a critical balance between serine proteases and serine protease inhibitors.

Animals↗

PubMed2003

Poor mobilization of peripheral blood stem cells is a risk factor for worse outcome in lymphoma patients undergoing autologous stem cell transplantation.

The effect of poor blood stem cells mobilization on the outcome of autologous stem cell transplantation (ASCT) has not been well studied. Our aim is to evaluate poor mobilization as a prognostic factor in lymphoma patients undergoing ASCT. We analyzed 90 consecutive patients with Hodgkin's (HD) and non-Hodgkin's lymphoma (NHL) who underwent ASCT. Poor mobilization was defined as the inability to obtain > or = 1 x 10(6) CD34+ cells/kg ideal body weight with two large volume aphereses. Patients were divided into 2 groups: group 1 = poor mobilizers, and group 2 = good mobilizers. The poor mobilizers received lower median transplant CD34+ cell dose (2 x 10(6) vs. 4.5 x 10(6)/kg for good mobilizers, P = 0.001), were more heavily pretreated (P = 0.01), and required higher number of aphereses for PBSC collection (P = 0.0006). The median progression-free survival (PFS) in groups 1 and 2 was 10 and 41 months (P = 0.04), while the median overall survival (OS) was 38 months and not reached (P = 0.02), respectively. Univariate analysis showed that > or = 3 pre-transplant treatments, CD34+ cell dose < or = 2 x 10(6), elevated LDH before transplant, and poor mobilization were significant prognostic factors for poor PFS, while only the first three were significant for worse OS. Multivariate analysis using these same four factors revealed that number of pre-transplant treatments (HR = 6.03, P = 0.001), CD34+ cell dose (HR = 0.1, P = 0.0007) were the only independent predictive factors for worse overall outcome. In conclusion, our data show that poor mobilization could indicate poor outcome in lymphoma patients undergoing ASCT, however, it is more likely to be a reflection of the heavy pre-transplant therapy and lower CD34+ cell dose re-infused in this group of patients.

Adolescent↗