The Cytokine Flt3-Ligand in Normal and Malignant Hematopoiesis

The cytokine Fms-like tyrosine kinase 3 ligand (FL) is an important regulator of hematopoiesis. Its receptor, Flt3, is expressed on myeloid, lymphoid and dendritic cell progenitors and is considered an important growth and differentiation factor for several hematopoietic lineages. Activating mutations of Flt3 are frequently found in acute myeloid leukemia (AML) patients and associated with a poor clinical prognosis. In the present review we provide an overview of our current knowledge on the role of FL in the generation of blood cell lineages. We examine recent studies on Flt3 expression by hematopoietic stem cells and its potential instructive action at early stages of hematopoiesis. In addition, we review current findings on the role of mutated FLT3 in leukemia and the development of FLT3 inhibitors for therapeutic use to treat AML. The importance of mouse models in elucidating the role of Flt3-ligand in normal and malignant hematopoiesis is discussed

Selective Expression of Flt3 within the Mouse Hematopoietic Stem Cell Compartment

The fms-like tyrosine kinase 3 (Flt3) is a cell surface receptor that is expressed by various hematopoietic progenitor cells (HPC) and Flt3-activating mutations are commonly present in acute myeloid and lymphoid leukemias. These findings underscore the importance of Flt3 to steady-state and malignant hematopoiesis. In this study, the expression of Flt3 protein and Flt3 mRNA by single cells within the hematopoietic stem cell (HSC) and HPC bone marrow compartments of C57/BL6 mice was investigated using flow cytometry and the quantitative reverse transcription polymerase chain reaction. Flt3 was heterogeneously expressed by almost all of the populations studied, including long-term reconstituting HSC and short-term reconstituting HSC. The erythropoietin receptor (EpoR) and macrophage colony-stimulating factor receptor (M-CSFR) were also found to be heterogeneously expressed within the multipotent cell compartments. Co-expression of the mRNAs encoding Flt3 and EpoR rarely occurred within these compartments. Expression of both Flt3 and M-CSFR protein at the surface of single cells was more commonly observed. These results emphasize the heterogeneous nature of HSC and HPC and the new sub-populations identified are important to understanding the origin and heterogeneity of the acute myeloid leukemias

The positioning of moral leadership in primary education: perspectives and contextual understandings of school principals in Ireland

In the study reported here, we explore the positioning of moral leadership in primary education through critical scrutiny of a select literature and the contextual understandings and perspectives of a purposive sample of 103 primary school principals in Ireland. The cultural context is unique in Europe given that primary education is a largely state funded system of denominational education with almost 90% of schools under the patronage of the Catholic Church. We draw from a number of theoretical perspectives as a critical feminist heuristic device to broaden the problem beyond any reductionist view of exchange value and to advocate for educational leadership as an emancipatory and transformative practice. Data analysis involved policy analysis of four reform documents and critical scrutiny of an empirical dataset, a regional survey and twelve indepth interviews with school principals. The findings reveal tensions and contradictions between policy documents mandating the uncritical adoption of a model of distributive leadership and the perspectives of school principals advocating for servant leadership. The study has implications beyond Ireland for educational and moral leader-ship in primary education and is presented here as a hypothesis worthy of further research and consideration</p

The Summer Wind

The four musicians on this tract have completed the Master of Music jazz programme and are highly regarded on the Irish jazz scene. The performers are Ciaran Wilde (saxonphone), Gediminas Karkauskas (piano), Gary Grand (drums) and Dave Mooney (bass)

Diurnal cycle of precipitation over the British Isles in a 0.44° WRF multiphysics regional climate ensemble over the period 1990–1995

The diurnal cycle of precipitation is an important and fundamental cycle in Earth’s climate system, yet many aspects of this cycle remain poorly understood. As a result climate models have struggled to accurately simulate the timing of the peak and the amplitude of the cycle. This has led to a large number of modelling studies on the diurnal cycle of precipitation which have focussed mainly on the influence of grid spacing and/or convective parameterizations. Results from these investigations have shown that, while grid spacing and convective parameterizations are important factors in the diurnal cycle, it cannot be fully explained by these factors and it must also be subject to other factors. In this study, we use the weather research and forecasting (WRF) model to investigate four of these other factors, namely the land surface model (LSM), microphysics, longwave radiation and planetary boundary layer in the case of the diurnal cycle of precipitation over the British Isles. We also compare their impact with the effect of two different convective schemes. We find that all simulations have two main problems: (1) there is a large bias (too much precipitation) in both summer and winter (+19 and +38 % respectively for the ensemble averages), and (2) WRF summer precipitation is dominated by a diurnal (24-h) component (~28 % of the mean precipitation) whereas the observations show a predominantly semidiurnal (12-h) component with a much smaller amplitude (~10 % of mean precipitation). The choice of LSM has a large influence on the simulated diurnal cycle in summer with the remaining physics schemes showing very little effect. The magnitude of the LSM effect in summer is as large as 35 % on average and up to 50 % at the peak of the cycle. While neither of the two LSMs examined here capture the harmonic content of the diurnal cycle of precipitation very well, we find that use of the RUC LSM results in better agreement with the observations compared with Noah

Is travel distance a barrier to veterans' use of VA hospitals for medical surgical care?

Lengthy travel distances may explain why relatively few veterans in the United States use VA hospitals for inpatient medical/surgical care. We used two approaches to distinguish the effect of distance on VA use from other factors such as access to alternatives and veterans' characteristics. The first approach describes how disparities in travel distance to the VA are related to other characteristics of geographic areas. The second approach involved a multivariate analysis of VA use in postal zip code areas (ZCAs). We used several sources of data to estimate the number of veterans who had priority access to the VA so that use rates could be estimated. Access to hospitals was characterized by estimated travel distance to inpatient providers that typically serve each ZCA. The results demonstrate that travel distance to the VA is variable, with veterans in rural areas traveling much farther for VA care than veterans in areas of high population density. However, Medicare recipients also travel farther in areas of low population density. In some areas veterans must travel lengthy distances for VA care because VA hospitals which were built over the past few decades are not located close to areas in which veterans reside in the 1990s. The disparities in travel distance suggest inequitable access to the VA. Use of the VA decreases with increases in travel distance only up to about 15 miles, after which use is relatively insensitive to further increases in distance. The multivariate analyses indicate that those over 65 are less sensitive to distance than younger veterans, even though those over 65 are Medicare eligible and therefore have inexpensive access to alternatives. The results suggest that proximity to a VA hospital is only one of many factors determining VA use. Further research is indicated to develop an appropriate response to the needs of the small but apparently dedicated group of VA users who are traveling very long distances to obtain VA care.Veterans Hospitalization Distance