Brynjar Foss

Stress in obesity: Cause or consequence?

Obesity is a global public health challenge that increases the risk of various diseases including type 2 diabetes mellitus, hypertension and cancer, and will in the future cause further increases in the incidence of chronic disease. Understanding the mechanisms of obesity is critical if we are to prevent and treat this pandemic challenge. Diet and physical activity have traditionally been the major tasks in preventing and treating obesity. However, other mechanisms are now also being considered in the quest for knowledge and understanding of obesity, including the bodys stress system and cortisol release. While it seems evident that stress is a cause of obesity, whether stress is also a consequence of obesity has up to now only briefly been discussed. The aim of this article is to elucidate how stress and obesity might be linked and discuss the cause/consequence relationship between the stress response and obesity. Our hypothesis is that stress and obesity interfere by positive feedback. This may be an important issue in both our understanding and coping of obesity.

In Vitro Culture of Acute Myelogenous Leukemia Blasts: A Comparison of Four Different Culture Media

Proliferative responses and cytokine secretion were compared when AML blasts were cultured in the three serum-free media, X-Vivo 10, X-Vivo 15, and defined serum-free medium (IMDM with mercaptoethanol, low-density lipoprotein, albumin, and transferrin) and in media containing 10% inactivated fetal bovine serum (FBS). The following AML blast functions were investigated: (a) constitutive cytokine secretion, (b) autonomous and cytokine-dependent proliferation, and (c) accessory cell function during T cell activation. Constitutive cytokine secretion and accessory cell function differed markedly when using different culture media. For the constitutive AML blast secretion of IL-1beta, IL-6, and tumor necrosis factor (TNF)-alpha, no qualitative differences were seen, but quantitative differences were observed with decreased cytokine levels for cells cultured in X-Vivo 10 and X-Vivo 15. The accessory cell function of AML blasts was also decreased in the X-Vivo media, whereas differences were less pronounced when comparing AML blast proliferation. Our results clearly demonstrate that a well-characterized culture system is essential for in vitro studies of AML blast functions.

Platelet functions and clinical effects in acute myelogenous leukemia

Platelets interact with normal peripheral blood cells via adhesion as well as soluble mediators, and platelet released mediators can affect hematopoietic stem and progenitor cells. Interactions may also be involved between platelets and circulating malignant cells, which is suggested by the effects platelets seem to have on metastasis and the various platelet abnormalities observed in various malignant disorders, including acute myelogenous leukemia (AML) and other leukemias. It is only recently that the interactions between platelets and AML cells have been characterized in detail, and studies show that; i) platelets and AML blasts can affect functional characteristic of each other, ii) chemotherapeutic drugs frequently used in AML therapy can alter several platelet functions, iii) the systemic levels of various cytokines are enhanced during AML chemotherapy, including cytokines known to affect both leukemic blasts and platelet activation, and iv) platelet secretion of growth factors are clearly detected in peripheral blood stem cells autografts. In this review we describe platelet interactions with normal leukocytes, normal hematopoietic and leukemic cells and the possible clinical relevance of these interactions in AML.

Effects of vascular endothelial growth factor on acute myelogenous leukemia blasts.

Vascular endothelial growth factor (VEGF) and its specific receptors are expressed by various malignant cells, including acute myelogenous leukemia (AML) blasts. In this study we performed a detailed characterization of VEGF effects on native human AML blasts derived from a large group of consecutive AML patients with high blast counts in peripheral blood. Exogenous VEGF had divergent effects on spontaneous proliferation and cytokine-dependent (GM-CSF, G-CSF, IL-3) proliferation. Increased, decreased, or unaltered proliferation was observed in the presence of VEGF for various patients, and the VEGF effect differed even in the same patient depending on which exogenous cytokine being present together with VEGF. Similarly, increased, decreased or unaltered interleukin-1beta (IL-1beta) and IL-6 secretion was detected when VEGF was added, and for certain patients the effect of VEGF differed between IL-1beta and IL-6. Exogenous VEGF could also modulate proliferation and differentiation of clonogenic AML progenitors. Constitutive AML blast secretion of VEGF was detected for 40% of patients. Leptin, Flt3-L, IL-4, IL-10, and IL-13 had divergent effects on VEGF release by AML blasts. These results suggest that VEGF can modulate AML blast functions in vivo for a subset of patients. Furthermore, the detection of VEGF in peripheral blood stem cell (PBSC) autografts suggests that VEGF may influence the proliferation and possibly also the survival of contaminating AML cells in PBSC autografts. We conclude that VEGF may influence the functional characteristics of AML cells. Our results suggest that VEGF is important in leukemic hematopoiesis, and the detection of VEGF in PBSC autografts indicates that VEGF may influence the functional phenotype of contaminating AML cells in these grafts.

Autologous Stem Cell Transplantation As Post-Remission Therapy in Adult Acute Myelogenous Leukemia: Does Platelet Contamination of Peripheral Blood Mobilized Stem Cell Grafts Influence the Risk of Leukemia Relapse?

Conventional chemotherapy of acute myelogenous leukemia (AML) results in an overall long-term disease-free survival of less than 50%, but for selected subsets of younger patients the prognosis can be improved by allogeneic stem cell transplantation. The use of autologous stem cell transplantation is now investigated as an alternative to allotransplantation due to its lower risk of serious complications. However, autotransplantation is associated with a relatively high risk of post-transplant AML relapse that can be derived from contaminating leukemia cells in the autograft. Peripheral blood mobilized stem cell (PBSC) grafts usually contain a higher number of platelets. The degree of platelet contamination is determined by the peripheral blood platelet count at the time of harvesting, and the platelets become activated and release soluble mediators during the ex vivo handling of PBSC grafts. Many of these platelet-derived mediators can bind to specific receptors expressed by AML blasts, and the platelet contamination may then alter AML blast survival and thereby influence the risk of post-transplant leukemia relapse. Therefore, we conclude that the platelet contamination of autologous stem cell grafts is possibly of clinical importance, but the effect of this nonstandardized parameter is difficult to predict in individual patients because the number of graft-contaminating platelets, the degree of platelet activation, and the effects of platelet-derived mediators on AML blasts differ between patients.

Connexin-based signaling in acute myelogenous leukemia (AML)

Normal and malignant hematopoiesis are regulated by intercellular communication in the hematopoietic microenvironments, and both soluble mediators as well as direct cell-cell contact play important functional roles. Gap junctions are complex membrane structures that transfer molecules between neighboring cells and thereby alter intracellular signaling and metabolism. The gap junction building blocks, the connexins, are also involved in gap junction-independent intercellular communication by forming hemichannels that transfer substances between the intra- and extracellular spaces. Connexins are furthermore involved in cell regulation as single molecules by modulating intracellular pathways and possibly gene transcription. The role of connexins in leukemogenesis and leukemic cell functions are not well characterized. In this review, we describe the known effects of gap junctions and connexins in acute myelogenous leukemia and the diverse potential of connexins in acute myelogenous leukemia chemosensitivity, intracellular signaling and cell death regulation.

Platelet-released supernatants enhance hematopoietic stem cell proliferation in vitro.

Peripheral blood stem cell transplantation (PBSCT) is used to reconstitute normal hematopoiesis after myeloablative chemotherapy. The hematopoietic stem cells are collected from the blood by apheresis machines using density gradient centrifugation. Because of density similarities the grafts contain high levels of leukocytes and platelets that release various mediators into the grafts. The collected hematopoietic stem cells are therefore exposed to platelet released mediators including platelet-derived growth factor, transforming growth factor-β, vascular endothelial growth factor and platelet factor-4. To investigate whether platelet activation and secretion can affect hematopoietic stem cells during PBSCT, we cultured (i) normal cord blood stem cells and (ii) mobilized peripheral blood stem cells from autografts together with the total secretion product of thrombin activated platelets (i.e. platelet released supernatants). Platelet released supernatants enhanced the cell proliferation of both peripheral blood stem cell (PBSC) autograft and normal cord blood CD34+ cells. Our study shows that platelet secretion in PBSCT autografts affect the hematopoietic stem cell function and possibly thereby the hematopoietic reconstitution after PBSCT.

Medication calculation: the potential role of digital game-based learning in nurse education.

Medication dose calculation is one of several medication-related activities that are conducted by nurses daily. However, medication calculation skills appear to be an area of global concern, possibly because of low numeracy skills, test anxiety, low self-confidence, and low self-efficacy among student nurses. Various didactic strategies have been developed for student nurses who still lack basic mathematical competence. However, we suggest that the critical nature of these skills demands the investigation of alternative and/or supplementary didactic approaches to improve medication calculation skills and to reduce failure rates. Digital game-based learning is a possible solution because of the following reasons. First, mathematical drills may improve medication calculation skills. Second, games are known to be useful during nursing education. Finally, mathematical drill games appear to improve the attitudes of students toward mathematics. The aim of this article was to discuss common challenges of medication calculation skills in nurse education, and we highlight the potential role of digital game-based learning in this area.

Connexin expression in human acute myeloid leukemia cells: Identification of patient subsets based on protein and global gene expression profiles

Bone marrow stromal cells support both normal and malignant hematopoiesis. Τhis support is mediated through the local cytokine network and by direct cell-cell interactions mediated via adhesion molecules and the formation of gap junctions by connexins. Previous studies on connexins in human acute myeloid leukemia (AML) have mainly focused on the investigation of leukemia cell lines. In the present study, we therefore investigated the expression of various connexins at the protein (i.e., cell surface expression) and mRNA level in primary human AML cells. The cell surface expression of the connexins, Cx26, Cx32, Cx37, Cx43 and Cx45, varied considerably between patients, and detectable levels were observed only for subsets of patients. On the whole, Cx43 and Cx45 showed the highest cell surface expression. Connexin expression was dependent on AML cell differentiation, but showed no association with cytogenetic abnormalities or mutations of the fms-related tyrosine kinase 3 (FLT3) or nucleophosmin (NPM)‑1 genes. By contrast, only Cx45 showed a significant variation between patients at the mRNA level. A high Cx45 expression was associated with the altered regulation of the mitogen-activated protein kinase (MAPK) pathway and the release of pro-inflammatory cytokines [interleukin (IL)-17, tumor necrosis factor (TNF), interferon-γ], whereas a low Cx45 expression was associated with the altered regulation of protein functions (i.e., ligase activity, protein folding and catabolism). There was no significant correlation observed between the connexin mRNA and protein levels. Thus, differences in connexin expression can be used to subclassify AML patients. Differences in connexin cell surface expression profiles are not reflected at the mRNA level and have to be directly examined, whereas variations in Cx45 mRNA expression are associated with differences in cell signaling and the regulation of protein functions.

Digital Game-Based Learning: A Supplement for Medication Calculation Drills in Nurse Education

Student nurses, globally, appear to struggle with medication calculations. In order to improve these skills among student nurses, the authors developed The Medication Game – an online computer game that aims to provide simple mathematical and medical calculation drills, and help students practise standard medical units and expressions. The aim of this study was to examine whether baccalaureate student nurses who played The Medication Game as a supplement to lectures and task-solving during a medication calculation course improved their examination results compared to a control group who used lectures and task-solving only. The authors used a randomised controlled design to study 201 students enrolled in medication calculation courses. The main measures were examination results, gaming high scores, the number of gaming self-tests and gaming time. There was no significant difference between groups in examination pass rates: 56% of the control group and 67% of the gamers passed. However, gamers who passed the examination had higher gaming high scores (p < .01) and used the gaming self-tests more frequently (p < .01) than gamers who failed the examination. The authors concluded that The Medication Game did not significantly improve examination results, but that using the game frequently appeared to influence the examination outcome positively.