LIF: not just a leukemia inhibitory factor

Increasingly it seems that many cytokines are pleiotropic, and individual molecules may have critical roles in several different organ systems. LIF exemplifies this phenomenon: it influences embryogenesis, bone and lipid metabolism, and hematopoietic and nervous system function. Many of LIF's effects are reminiscent of those of IL-1, TNF, and TGF-beta. Further, even within a single system, LIF can display totally different effects, i.e. induction of differentiation of one leukemic cell line vs. stimulation of proliferation of another. The corollary to these observations is that there appears to be many parallels in developmental systems. For instance, in the case of neuronal "lineage commitment," the events that relate to migration of neural crest cells along various pathways and their ultimate arrest in different locales demonstrate sufficient analogies to hematopoietic lineage commitment phenomena that, in a provocative review, Anderson coined the term "neuropoiesis". This type of analogy becomes even more intriguing when one realizes that some of the same molecules are regulating neuronal and hematopoietic "lineage" proliferation and differentiation. In this respect, several interleukins in addition to LIF are important in neuronal development, and nerve growth factor turns out to also be a hematopoietic regulatory molecule. Similar parallels are enacted in other organ systems as well. The mediation of identical effects by distinct cytokines bound to unique receptors could conceivably be explained by receptor transmodulation or by overlapping signaling sequences. It is nevertheless also unclear how a single cytokine attached to a single receptor can accomplish varied and opposing effects, although divergent intracellular signaling mechanisms could account for some of these phenomena. Yet another enigma relates to how cells from one system can be properly influenced by a pleiotropic molecule such as LIF without significant "cross-effects" on other potentially responsive systems. Cytokine production that is restricted to certain developmental stages, or very localized distribution and spheres of influence within a microenvironment, could be explanatory. The findings of Rathjan and colleagues, i.e. that LIF exists as both a diffusible molecule and as a molecule incorporated into the extracellular matrix, is of special interest in relation to the above questions. Indeed, the distinctions between the roles of diffusible and immobilized signaling molecules could be crucial to the multiplicity of LIF's actions. Diffusible regulatory factors allow communication between spatially separated cells. Cellular responsiveness to such factors is dictated by the presence of appropriate receptors and postreceptor machinery.(ABSTRACT TRUNCATED AT 400 WORDS)     

Psychological Response of Firefighters to a Chemical Fire

Abstract

Samples of firefighter subjects (n = 80) and a comparison group (n = 15) were contrasted on a number of postincident psychological distress measures in the aftermath of a polyvinyl chloride (PVC) fire. Using a structured, self-administered questionnaire, firefighter subjects were found to be more psychologically distressed on demoralization, specific emotional distress, and perceived threat to physical health. After controlling for baseline characteristics on which subjects and the comparison group differed, these between-group effects remained significant. The three outcome scales, while correlated, measure different components of psychological distress.     

Cardiac contractility modulation: a novel approach for the treatment of heart failure

Heart failure is a major health problem worldwide and, despite effective therapies, is expected to grow by almost 50 % over the next 15 years. Five-year mortality remains high at 50 % over 5 years. Because of the economic burden and large impact on quality of life, substantial effort has focused on treatments with multiple medical (beta-blockers, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers (ARB), aldosterone antagonists, and combination of ARB/neprilysin blockers, ivabradine) and device therapies (ICD, CRT) which have been implemented to reduce disease burden and mortality. However, in the past decade only two new medical therapies and no devices have been approved by the US FDA for the treatment of heart failure. This review highlights the preclinical and clinical literature, and the implantation procedure, related to a relatively new therapeutic device for heart failure; cardiac contractility modulation (CCM). CCM delivers a biphasic high-voltage bipolar signal to the RV septum during the absolute refractory period, eliciting an acute increase in global contractility, and chronically producing a sustained improvement in quality of life, exercise tolerance, and heart failure symptoms. The technology is used commercially in Europe with nearly 3000 patients implanted worldwide. Indications include patients with reduced EF and normal or slightly prolonged QRS duration, thus filling an important therapeutic gap among the 2/3 of patients with heart failure who do not meet criteria for CRT. The mechanism by which CCM provides benefit can be seen at the cellular level where improved calcium handling (phosphorylation of phospholamban, upregulation of SERCA-2A), reversal of the fetal myocyte gene program associated with heart failure, and reverse remodeling are observed. Recent retrospective studies indicate a long-term mortality benefit. A pivotal randomized controlled study is currently being completed in the USA. CCM appears to be an effective, safe technology for the treatment of heart failure with reduced ejection fraction.     

Stimulation of myelopoiesis in a patient with congenital neutropenia: biology and nature of response to recombinant human granulocyte-macrophage colony-stimulating factor

To stimulate granulopoiesis, we gave recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF; 120 microgram/m2/d) to a patient with congenital neutropenia. The treatment resulted in marked increases in white blood cell counts (maximum, 17,400/microL), consisting mainly of eosinophils (maximum, 13,050/microL) and monocytes (maximum, 1305/microL), rather than neutrophils (maximum, 798/microL). Circulating phagocytes (97% eosinophils) derived after GM-CSF treatment were less effective in chemotaxis, slower but equally effective in phagocytosis, and more effective in H2O2 production compared with normal control neutrophils, but comparable in chemotaxis and H2O2 production to control eosinophils. Before GM-CSF treatment, the bone marrow showed a maturation defect in the neutrophilic series that persisted after treatment despite marked increases in mature cells of other lineages. In vitro agar culture of bone marrow cells before GM-CSF treatment showed a normal number of granulocyte colonies; however, maturation was limited to the metamyelocyte stage. Although the absolute number and cycling rates of myeloid colony forming cells (predominantly eosinophils) increased after treatment, the maturation defect in the neutrophilic series persisted. The finding that GM-CSF induced stimulation of proliferation, which was coupled with maturation in the eosinophilic and monocytic but not the neutrophilic components, suggests that this patient had an intrinsic cellular or humoral defect in neutrophil maturation.     

Avicins, a family of triterpenoid saponins from Acacia victoriae (Bentham), suppress H-ras mutations and aneuploidy in a murine skin carcinogenesis model

We tested the ability of avicins, a family of triterpenoid saponins obtained from Acacia victoriae (Bentham) (Leguminosae: Mimosoideae), to inhibit chemically induced mouse skin carcinogenesis. Varying doses of avicins were applied to shaved dorsal skin of SENCAR mice 15 min before application of 100 nmol of 7,12-dimethylbenz[a]anthracene (DMBA) twice a week for 4 weeks (complete carcinogenesis model). The dorsal skin of a second group of mice was treated with one dose of 10 nmol of DMBA. Avicins were then applied 15 min before repetitive doses of 2 microg of phorbol 12-tetradecanoate 13-acetate (TPA) twice a week for 8 weeks (initiation/promotion model). At 12 weeks, avicins produced a 70% decrease in the number of mice with papillomas and a greater than 90% reduction in the number of papillomas per mouse in both protocols. We also observed a 62% and 74% reduction by avicins in H-ras mutations at codon 61 in the DMBA and DMBA/TPA models, respectively, as well as a significant inhibition of the modified DNA base formation (8-OH-dG) in both protocols. Marked suppression of aneuploidy occurred with treatment at 16 weeks in the initiation/promotion experiment. These findings, when combined with the proapoptotic property of these compounds and their ability to inhibit hydrogen peroxide (H(2)O(2)) generation, nuclear factor-kappaB (NF-kappaB) activation, and inducible nitric oxide synthase (iNOS) induction reported elsewhere, suggest that avicins could prove exciting in reducing oxidative and nitrosative stress and thereby suppressing the development of human skin cancer and other epithelial malignancies.     

Recombinant interferon gamma in hairy cell leukemia, multiple myeloma, and Waldenstrom's macroglobulinemia

Fifteen patients with multiple myeloma, five with hairy cell leukemia, and five with Waldenstrom's macroglobulinemia were treated with recombinant interferon gamma (rINF-gamma) to determine the antitumor activity of this agent. The rIFN-gamma was administered by daily intramuscular injection at doses ranging from 0.125 to 0.5 mg/m2. No responses were observed in patients with multiple myeloma, although in one patient the disease has remained stable for over 16 months. Minimal improvement in some hematologic indexes were observed in three of five patients with hairy cell leukemia. One partial remission and one minor response were documented in two of the five patients with Waldenstrom's macroglobulinemia. In five patients, an increase in normal serum immunoglobulins was observed. These results suggest that there is only minimal activity of rIFN-gamma as a single agent in neoplasms of B-cell origin.     

Expression of c-abl in Philadelphia-positive acute myelogenous leukemia

The identical cytogenetic marker, t(9;22)(q34;q11) (Philadelphia [Ph] translocation), is found in approximately 90%, 20%, and 2% of adult patients with chronic myelogenous leukemia (CML), acute lymphoblastic leukemia (ALL), and acute myelogenous leukemia (AML), respectively. In CML, the molecular events resulting from the Ph translocation include a break within the bcr locus on chromosome 22, transfer of the c-abl protooncogene from chromosome 9 to 22, and formation of an aberrant 210- kD bcr-abl fusion protein (p210bcr-abl). Recently, the absence of bcr rearrangement and expression of a distinct aberrant 190-kd abl protein (p190c-abl) has been described in Ph-positive ALL, with the suggestion that the two abl variants may be pathogenetically associated with myeloid v lymphoid leukemogenesis. Here we report that the genomic configuration and translation product of Ph-positive AML can be similar to that of Ph-positive ALL: the break at 22q11 may occur outside the 5.8 kb bcr region and result in expression of a 190-kD abl protein lacking these bcr sequences. Phosphokinase enzymatic activity, a fundamental property of p210bcr-abl, was also associated with AML- derived p190c-abl. Our current observations indicate that p190c-abl can be found in cells of lymphoid or myeloid lineage and is therefore unlikely to play a specific role in the development of lymphoid leukemias. Formation of p190c-abl instead of p210bcr-abl appears to be a characteristic of the acute rather than the chronic Ph-positive leukemic state.     

Regulation of the human coronary microcirculation

Atherosclerosis of conduit epicardial arteries is the principal culprit behind the complications of coronary heart disease, but a growing body of literature indicates that the coronary microcirculation also contributes substantially to the pathophysiology of cardiovascular disease. An understanding of mechanisms regulating microvascular function in humans is an essential foundation for understanding the role in disease, especially since these regulatory mechanisms vary substantially across species and vascular beds. In fact all subjects whose coronary tissue was used in the studies described have medical conditions that warrant cardiac surgery, thus relevance to the normal human must be inferential and is based on tissue from subjects without known arteriosclerotic disease. This review will focus on recent advances in the physiological and pathological mechanisms of coronary microcirculatory control, describing a robust plasticity in maintaining endothelial control over dilation, including mechanisms that are most relevant to the human heart. This article is part of a Special Issue entitled "Coronary Blood Flow".