Thrombopoietin stimulates megakaryocytopoiesis, myelopoiesis, and expansion of CD34+ progenitor cells from single CD34+Thy-1+Lin- primitive progenitor cells

Thrombopoietin (TPO) or MpI ligand is known to stimulate megakaryocyte (MK) proliferation and differentiation. To identify the earliest human hematopoietic cells on which TPO acts, we cultured single CD34+Thy- 1+Lin- adult bone marrow cells in the presence of TPO alone, with TPO and interleukin-3 (IL-3), or with TPO and c-kit ligand (KL) in the presence of a murine stromal cell line (Sys1). Two distinct growth morphologies were observed: expansion of up to 200 blast cells with subsequent differentiation to large refractile CD41b+ MKs within 3 weeks or expansion to 200-10,000 blast cells, up to 25% of which expressed CD34. The latter blast cell expansions occurred over a 3- to 6-week period without obvious MK differentiation. Morphological staining, analysis of surface marker expression, and colony formation analysis revealed that these populations consisted predominantly of cells committed to the myelomonocytic lineage. The addition of IL-3 to TPO-containing cultures increased the extent of proliferation of single cells, whereas addition of KL increased the percentage of CD34+ cells among the expanding cell populations. Production of multiple colony- forming unit-MK from single CD34+Thy-1+Lin- cells in the presence of TPO was also demonstrated. In limiting dilution assays of CD34+Lin- cells, TPO was found to increase the size and frequency of cobblestone areas at 4 weeks in stromal cultures in the presence of leukemia inhibitory factor and IL-6. In stroma-free cultures, TPO activated a quiescent CD34+Lin-Rhodamine 123lo subset of primitive hematopoietic progenitor cells into cycle, without loss of CD34 expression. These data demonstrate that TPO acts directly on and supports division of cells more primitive than those committed to the MK lineage.     

Quality of diabetes care predicts the development of cardiovascular events: results of the QuED study

Background and aimIn the context of the QuED Study we assessed whether a quality of care summary score was able to predict the development of cardiovascular (CV) events in patients with type 2 diabetes.Methods and resultsThe score was calculated using process and intermediate outcome indicators (HbA_1c, blood pressure, low-density lipoprotein cholesterol, microalbuminuria) and ranged from 0 to 40. Overall, 3235 patients were enrolled, of whom 492 developed a CV event after a median follow-up of 5 years. The incidence rate (per 1000 person-years) of CV events was 62.4 in patients with a score ≤10, 54.8 in those with a score between 15 and 20, and 39.8 in those with a score >20. In adjusted multilevel regression models, the risk to develop a CV event was 89% greater in patients with a score of ≤10 (rate ratio [RR] = 1.89; 95% confidence interval [CI] 1.43–2.50) and 43% higher in those with a score between 10 and 20 (RR = 1.43; 95% CI 1.14–1.79), as compared to those with a score >20. A difference between centers of 5 points in the mean quality score was associated with a difference of 16% in CV event risk (RR = 0.84; 95% CI 0.72–0.98).ConclusionOur study documented for the first time a close relationship between a score of quality of diabetes care and long-term outcomes.     

Impact of physicians' beliefs and practices on cholesterol levels in patients with type 2 diabetes: a longitudinal assessment

Background

Clinical trials demonstrate significant benefit from cholesterol management for patients with type 2 diabetes. The aim of this work was to explore the correlates of lipid management in patients with type 2 diabetes, including the subjective beliefs of physicians, setting of care, and patient-related factors.

Methods

This longitudinal outcomes research study involved 2359 patients with type 2 diabetes recruited by 111 general practitioners and 214 physicians practicing in diabetes clinics. Physicians' beliefs were assessed through a questionnaire administered when the study started in 1998. Main outcome measures were total cholesterol (TC) and LDL cholesterol (LDL-C) levels over 3 years and the proportion of patients treated with lipid-lowering drugs (LLDs).

Results

Less than one-third of the physicians (27%) stated that they routinely started pharmacologic therapy for TC values ≥200 mg/dL (more aggressive), whereas 46% considered a TC level ≥240 mg/dL as the threshold for the initiation of treatment (less aggressive). During 3 years of observation, mean TC and LDL-C levels decreased from 215 ± 40 mg/dL to 203 ± 37 mg/dL and from 135 ± 36 mg/dL to 126 ± 35 mg/dL respectively, while the proportion of patients treated with LLDs increased from 13.2% to 24.6%; in particular, among individuals cared for by the more aggressive physicians, 30.0% were taking LLDs after 3 years, while only 17.7% of those followed by the less aggressive physicians and 18.1% of those followed by >1 physician were being treated with LLDs. Multilevel analysis showed that physicians' beliefs were an independent predictor of TC levels over the 3-year period. In patients treated with LLDs, TC levels decreased on average by 14%, and LDL-C levels decreased by 20%.

Conclusion

Our data show that physicians' beliefs in more aggressive management strategies will result in better mean TC values over a 3-year period.     

Long-term protection of hematopoiesis against the cytotoxic effects of multiple doses of nitrosourea by retrovirus-mediated expression of human O6-alkylguanine-DNA-alkyltransferase

A human O6-alkylguanine-DNA-alkyltransferase (ATase) cDNA-containing retrovirus was used to infect murine long-term primary bone marrow cultures. High levels of ATase expression were obtained, and colony- forming cells of the granulocyte-macrophage lineage from the cultures transduced with the human ATase retrovirus were three times more resistant to the alkylating agent, N-methyl-N-nitrosourea (MNU), than control cultures. Furthermore, expression of the human ATase protected long-term hematopoiesis, measured as the output of progenitor cells to the nonadherent fraction of the culture, against the cytotoxic effects of repeated exposures to MNU. These results clearly show that a human ATase cDNA-containing retrovirus can be used to infect long-term primary bone marrow cultures and that this attenuates their sensitivity to nitrosoureas.     

Using ecological frameworks to advance a field of research, practice, and policy on aging-in-place initiatives

Initiatives to promote aging in place have emerged rapidly in the United States across various health care settings (e.g., acute care hospitals, skilled nursing facilities) and broader community settings (e.g., public social service agencies). Moreover, recent federal policies include a growing number of provisions for local efforts to promote aging in place. Despite emerging bodies of research that have described singular initiatives in their own right, there has been very little scholarship that forges conceptual linkages across this increasingly vast domain of research, practice, and policy. Integrative theory development is critical to ensure that aging-in-place initiatives do not become fragmented from each other. This article uses insights from ecological frameworks-specifically Urie Bronfenbrenner's bioecological systems theory and M. Powell Lawton's general ecological model of aging-to conceptualize a range of programs as aging-in-place initiatives and for describing their similarities and differences, particularly in terms of the features through which they intend to promote aging in place. Theoretically derived dimensions along which to characterize aging-in-place initiatives include environment-focused aspects (e.g., the types of social systems and structures that the initiatives target for change) and person-focused aspects (e.g., the extent to which the initiatives target particular subgroups of older adults). The article concludes with a discussion on how these theoretically derived dimensions can be used to advance and integrate research, practice, and policy to systematically develop and expand aging-in-place initiatives.     

Review of Substance Use Disorder Treatment Research in Indian Country: Future Directions to Strive toward Health Equity

Background: American Indians and Alaska Natives (AI/ANs) have disproportionately high rates of substance use disorders (SUDs). Effective treatment can help to reduce these disparities. Objective: To review and summarize the AI/AN SUD treatment research literature. Methods: The literature between 1965 and 2011 was reviewed to identify AI/AN SUD treatment articles. Results: Twenty-four unique studies were identified. Earlier treatment research focused on clinical ratings of improvement; later studies employed formal assessment measures. Poor outcomes were attributed to psychosocial factors. Where treatment outcomes appeared to be similar to comparison samples, interpretation was hampered by methodological concerns. Conclusions: The research has improved across the decades, as has the inclusion of cultural adaptations. Future research should examine factors that influence treatment effectiveness and improve retention to bolster confidence in findings. Scientific Significance: AI/ANs experience SUD-related health disparities. Understanding what factors contribute to positive treatment outcomes can help to address these disparities.     

Comorbidities,Treatment and Ensuing Survival in Men with Prostate Cancer

Background  

Comorbidity is poorly integrated into prostate cancer decision making.