Perturbations in the erythroid marrow progenitor cell pools may play a role in the augmentation of HbF by 5-azacytidine

In vivo observations on the kinetics of F cells and of fetal hemoglobin (HbF) synthesis and in vitro studies of erythroid progenitors, their number, and the gamma-gene expression in their progeny were carried out in baboons (Papio cynocephalus) treated with 5-azacytidine. Maximum effect on the increase of HbF production in vivo was observed only when an expanded erythroid marrow population was present. In these animals, as well as in normal animals, treatment resulted in a significant reduction of the late erythroid progenitor cell pools (erythroid clusters and erythroid colony-forming units, CFU-E) in the marrow. This reduction was more pronounced among those progenitors grown in the absence of added erythropoietin, and it was followed by a rebound a few days after treatment cessation, reflecting the accumulation of regenerating progenitors. An early increase in the in vitro synthesis of HbF in erythroid clusters and CFU-E colonies was observed. This increase was further documented at the cellular level, with immunofluorescent labeling of colonies with monoclonal anti-gamma- globin chain antibodies. In contrast to the findings in late progenitors, the number of erythroid burst-forming unit (BFU-E) colonies and the synthesis of HbF in these colonies was not influenced significantly by 5-azacytidine treatment. It is proposed that the toxic effects of 5-azacytidine on late progenitors, leading to faster mobilization of earlier progenitors to the next more mature compartment, play a role in the in vivo augmentation of HbF synthesis by this drug. This perturbation in the progenitor cell population kinetics and the presumed hypomethylation of the surviving differentiating cells may act synergistically to produce a maximum HbF response after 5-azacytidine treatment.     

Effects of human FLT3 ligand on myeloid leukemia cell growth: heterogeneity in response and synergy with other hematopoietic growth factors

A novel hematopoietic growth factor for primitive hematopoietic progenitor cells, the ligand for the flt3/flk2 receptor, (FL), has been recently purified and its gene has been cloned. In the present study, we investigated the effects of FL on the proliferation and differentiation of normal and leukemic myeloid progenitor cells. We demonstrate that FL is a potent stimulator of the in vitro growth of granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin- 3 (IL-3), or G-CSF-dependent granulocyte-macrophage committed precursors from Lin- CD34+ bone marrow cells of normal donors. By contrast, FL does not affect the growth of erythroid-committed progenitors even in the presence of erythropoietin. The effect of FL on the proliferation and on the in vitro growth of clonogenic leukemic precursor cells was studied in 54 acute myeloid leukemia (AML) cases. Fresh leukemia blasts from 36 of 45 patients with AML significantly responded to FL without any relation to the French-American-British (FAB) subtype. FL stimulated the proliferation of leukemic blasts in a dose-dependent fashion. Synergistic activities were seen when FL was combined with G-CSF, GM-CSF, IL-3, or stem cell factor (SCF). FL as a single factor induced or increased significantly colony formation by clonogenic precursor cells from 21 of 24 patients with AML. In the presence of suboptimal and optimal concentrations of G-CSF, GM-CSF, IL3, SCF, or a combination of all factors, FL strongly enhanced the number of leukemic colonies (up to 18-fold). We also evaluated the induction of tyrosine phosphorylated protein on FL stimulation in fresh AML cells. We demonstrate that, on FL stimulation, a band of phosphorylated protein(s) of about 90 kD can be detected in FL- responsive, but not in FL-unresponsive cases. This study suggests that FL may be an important factor for the growth of myeloid leukemia cells, either as a direct stimulus or as a synergistic factor with other cytokines.     

Effect of a deep breath on gas mixing and diffusion in the lung

We examined the effect of a previous deep breath on both inert gas mixing and the single breath diffusing capacity (DLCOSB) during submaximal single breath maneuvers in normal subjects. Single breath washouts were performed either immediately after a deep breath or after breathing tidally for 10 min. Maneuvers consisted of inhaling test gas from functional residual capacity to 50% inspiratory capacity and, after either 0 or 6 s of breath holding, exhaling slowly back to residual volume. We measured the Fowler dead space, the Phase III slope of the alveolar plateau of the He washout (delta He/L), the amplitude of the cardiogenic oscillations (Oc), closing capacity, mixing efficiency (Emix) and DLCOSB using the three equation method. For maneuvers immediately after a deep breath we found that delta He/L was steeper and the Oc were larger for washouts with 6 s but not 0 s of breath holding, while Emix was significantly lower and DLCOSB significantly higher for both the 0 s and the 6 s breath holding maneuvers. We conclude that a deep breath increases DLCOSB but simultaneously also increases convective-dependent inhomogeneity in the lung.     

Wisconsin’s Lifecourse Initiative for Healthy Families: Application of the Maternal and Child Health Life Course Perspective Through a Regional Funding Initiative

National experts are calling for more integrated approaches such as the life course perspective to reduce health disparities and achieve greater health equity. The translation and application of the life course perspective is therefore of great interest to public health planners, policy makers and funders to promote community-wide improvements in maternal and child health. However, few organizations have applied the life course perspective in designing strategic funding initiatives. For over three decades, Wisconsin has observed persistent racial disparities in birth outcomes. This complex public health issue led to the development of the Lifecourse Initiative for Health Families, a regional multi-million dollar funding initiative created and supported by the Wisconsin Partnership Program of the University of Wisconsin School of Medicine and Public Health (Created by the UW SMPH from an endowment following the conversion of Blue Cross Blue Shield United of Wisconsin, the Partnership Program makes investments in research, education, and public health and prevention initiatives that improve health and reduce health disparities in the state.). Over a 2-year period, the program funded four collaboratives to adopt a life course perspective and develop strategic plans for improving African American birth outcomes. The Twelve-point plan to close the black–white gap in birth outcomes provided the framework for the planning process. Despite the conceptual challenges, the life course perspective was embraced by the collaboratives, challenged community assumptions on the root causes of poor birth outcomes and provided a unifying funding construct for organizing and planning complementary individual-level interventions with social and physical environmental change strategies. These integrated and complimentary approaches provide a long-term opportunity to address the persistent racial birth outcome disparity in Wisconsin.     

Comparison of urinary thallium levels in non-occupationally exposed people and workers

Purpose

To determine a reference background urinary thallium level; to compare urinary thallium data from workers to this background level; to investigate factors affecting these levels and whether creatinine correction is appropriate.

Methods

Urine samples from non-occupationally exposed people (n = 273, from 113 individuals) and workers (n = 896, from 447 individuals) were analysed for thallium by ICP-MS. A reference background level was calculated, defined as the 95th percentile value of a non-occupationally exposed population. Worker data were divided into two subsets: thallium workers (those who work directly with thallium or its compounds) and general workers; and compared to the background level. Bayesian linear mixed effects modelling was used to investigate factors affecting urinary thallium concentration and the efficacy of creatinine correction for the determination of urinary thallium.

Results

The reference background urinary thallium level is 0.27 μmol/mol creatinine (creatinine-corrected) or 0.40 μg/l (uncorrected). Median values were 0.11 μmol/mol creatinine or 0.17 μg/l for non-occupationally exposed people, 0.12 μmol/mol creatinine or 0.20 μg/l for general workers and 0.19 μmol/mol creatinine or 0.41 μg/l for thallium workers. Variation was lower in creatinine-corrected models. Nine per cent of samples from general workers and 39 % of samples from thallium workers exceeded the creatinine-corrected background level. By 2010, 90 % of all workers had urinary thallium levels below the 95th percentile reference background level.

Conclusions

Urinary thallium concentrations were higher in thallium workers than non-occupationally exposed people and general workers. Creatinine correction is appropriate.