Dnmt3a regulates myeloproliferation and liver-specific expansion of hematopoietic stem and progenitor cells

DNMT3A mutations are observed in myeloid malignancies, including myeloproliferative neoplasms (MPN), myelodysplastic syndromes (MDS), and acute myeloid leukemia (AML). Transplantation studies have elucidated an important role for Dnmt3a in stem cell self-renewal and in myeloid differentiation. Here we investigated the impact of conditional hematopoietic Dnmt3a loss on disease phenotype in primary mice. Mx1-Cre-mediated Dnmt3a ablation led to the development of a lethal, fully penetrant myeloproliferative neoplasm with myelodysplasia (MDS/MPN) characterized by peripheral cytopenias and by marked, progressive hepatomegaly. We detected expanded stem/progenitor populations in the liver of Dnmt3a-ablated mice. The MDS/MPN induced by Dnmt3a ablation was transplantable, including the marked hepatomegaly. Homing studies showed that Dnmt3a-deleted bone marrow cells preferentially migrated to the liver. Gene expression and DNA methylation analyses of progenitor cell populations identified differential regulation of hematopoietic regulatory pathways, including fetal liver hematopoiesis transcriptional programs. These data demonstrate that Dnmt3a ablation in the hematopoietic system leads to myeloid transformation in vivo, with cell autonomous aberrant tissue tropism and marked extramedullary hematopoiesis (EMH) with liver involvement. Hence, in addition to the established role of Dnmt3a in regulating self-renewal, Dnmt3a regulates tissue tropism and limits myeloid progenitor expansion in vivo

Somatically ill persons’ self-nominated quality of life domains: review of the literature and guidelines for future studies

OBJECTIVE: To review which domains somatically ill persons nominate as constituting their QoL. Specific objective is to examine whether the method of enquiry affect these domains. METHODS: We conducted two literature searches in the databases PubMed/Medline, CINAHL and Psychinfo for qualitative studies examining patients' self-defined QoL domains using (1) SEIQoL and (2) study-specific questions. For each database, two researchers independently assessed the eligibility of the retrieved abstracts and three researchers subsequently classified all QoL domains. RESULTS: Thirty-six eligible papers were identified: 27 studies using the SEIQoL, and nine presenting data derived from study-specific questions. The influence of the method of enquiry on patients' self-nominated QoL domains appears limited: most domains were presented in both types of studies, albeit with different frequencies. CONCLUSIONS: This review provides a comprehensive overview of somatically ill persons' self-nominated QoL domains. However, limitations inherent to reviewing qualitative studies (e.g., the varying level of abstraction of patients' self-defined QoL domains), limitations of the included studies and limitations inherent to the review process, hinder cross-study comparisons. Therefore, we provide guidelines to address shortcomings of qualitative reports amenable to improvement and to stimulate further improvement of conducting and reporting qualitative research aimed at exploring respondents' self-nominated QoL domains

New Options for Iron Supplementation in Maintenance Hemodialysis Patients

End-stage renal disease results in anemia caused by shortened erythrocyte survival, erythropoietin deficiency, hepcidin-mediated impairment of intestinal absorption and iron release, recurrent blood loss, and impaired responsiveness to erythropoiesis-stimulating agents (ESAs). Iron malabsorption renders oral iron products generally ineffective, and intravenous (IV) iron supplementation is required in most patients receiving maintenance hemodialysis (HD). IV iron is administered at doses far exceeding normal intestinal iron absorption. Moreover, by bypassing physiologic safeguards, indiscriminate use of IV iron overwhelms transferrin, imposing stress on the reticuloendothelial system that can have long-term adverse consequences. Unlike conventional oral iron preparations, ferric citrate has recently been shown to be effective in increasing serum ferritin, hemoglobin, and transferrin saturation values while significantly reducing IV iron and ESA requirements in patients treated with HD. Ferric pyrophosphate citrate is a novel iron salt delivered by dialysate; by directly reaching transferrin, its obviates the need for storing administered iron and increases transferrin saturation without increasing serum ferritin levels. Ferric pyrophosphate citrate trials have demonstrated effective iron delivery and stable hemoglobin levels with significant reductions in ESA and IV iron requirements. To date, the long-term safety of using these routes of iron administration in patients receiving HD has not been compared to IV iron and therefore awaits future investigations