Prognostic value of erythrocyte sedimentation rate in ST segment elevation myocardial infarction: interaction with hyperglycaemia

OBJECTIVES: Many inflammatory markers are associated with an adverse prognosis after ST segment elevation myocardial infarction (STEMI). Hyperglycaemia may exacerbate this inflammatory response. We investigated whether the erythrocyte sedimentation rate (ESR) was associated with an adverse prognosis and whether this was mediated by glucose levels. RESEARCH DESIGN AND METHODS: It concerns a post hoc analysis of a prospective randomised trial. In 346 patients with STEMI treated with reperfusion therapy, we investigated long-term outcome. Patients with ESR in the upper quartile (>14 mm h(-1)) were compared to patients with a normal ESR. Hyperglycaemia was defined as admission glucose >or=7.8 mmol L(-1). Median follow up was 7.4 years (range: 5.7-8.3). MAIN OUTCOME MEASURES: All cause mortality, cardiovascular mortality, sudden death, death as a result of heart failure. RESULTS: Both elevated ESR and hyperglycaemia were associated with a worse prognosis and increased mortality. Elevated ESR was particularly associated with an increased risk of sudden death (OR: 3.3, 17% vs. 6%, P < 0.01) whereas hyperglycaemia was especially associated with an increased risk of death because of heart failure (OR: 6.5, 8% vs. 1%, P < 0.01). There was no association between increased ESR and elevated glucose levels. Multivariate analysis did reveal that both elevated ESR and admission glucose were independent predictors of long-term mortality. CONCLUSIONS: Elevated ESR and admission glucose are independent predictors of mortality in STEMI patients treated with reperfusion therapy. There is no association or interaction between glucose levels and the inflammatory response as reflected by ESR.     

Gastric Emptying of Solid Meal in Male Chronic Alcoholics

Nausea and vomiting are common complaints in chronic alcoholics. Autonomic neuropathy and esophageal motor abnormalities are frequently observed in chronic alcoholics, but gastric emptying has not been studied in these patients. Gastric emptying of a solid meal was measured, using 99mTc-sulfur colloid cooked in a scrambled egg, in 10 male chronic alcoholics with upper gastrointestinal complaints of nausea and vomiting. All patients were adequately nourished, recently drinking, but just over withdrawal and free of clinical peripheral neuropathy. Gastric emptying in 10 alcoholics was similar to 5 normal controls (t 1/2 115 +/- 12 versus 107 +/- 8 min). These data suggest that upper gastrointestinal symptoms in chronic alcoholics are not related to gastric motor dysfunction.     

Evidence that large granular lymphocytes from B-CLL patients with hypogammaglobulinemia down-regulate B-cell immunoglobulin synthesis [published erratum appears in Blood 1989 Jun;73(8):2232]

B-chronic lymphocytic leukemia (CLL) patients frequently suffer from moderate to severe hypogammaglobulinemia. This complication is a serious cause of morbidity and mortality in this disorder. There is recent evidence that natural killer (NK) cells modulate B-cell immunoglobin (Ig) synthesis/secretion. The authors therefore evaluated the circulating NK cells from B-CLL patients on their ability to regulate mitogen-induced B-cell Ig synthesis. Blood, NK cells (CD16+, CD3-) from three B-CLL patients with hypogammaglobulinemia were able to clearly down-regulate the pokeweed mitogen (PWM)-induced-B-cell Ig secretion. In contrast, CD16+, CD3- cells from age-sex-matched controls or B-CLL patients with normal Ig were either nonregulatory or enhanced mitogen-induced B-cell Ig secretion. An alternative explanation for hypogammaglobulinemia in B-CLL patients is the immunomodulation of B- cell Ig production/secretion by CD16+, CD3- blood cells.     

High resolution of heterogeneity among human neutrophil granules: physical, biochemical, and ultrastructural properties of isolated fractions

Previous studies on the fractionation of human neutrophil granules have identified two major populations: myeloperoxidase (MPO)-containing azurophil, or primary, granules and MPO-deficient specific, or secondary, granules. Peripheral blood neutrophils from individual donors were lysed in sucrose-free media by either hypotonic shock or nitrogen cavitation. Using a novel two-gradient Percoll density centrifugation system, the granule-rich postnuclear supernatant was rapidly (ten minutes) and reproducibly resolved into 13 granule fractions (L1 through L8 and H1 through H5). Granule flotation and recentrifugation experiments on both continuous, self-generated and multiple-step gradients using individual and mixed isolated fractions demonstrated that the banding patterns were isopycnic and nonartifactual. Isolated granules were intact based on the findings that biochemical latency of several granule enzymes was greater than 95%, and thin-sectioned electron micrographs demonstrated intact granule profiles. Biochemical analyses of the granule marker proteins MPO, beta-glucuronidase, lysozyme, and lactoferrin indicated that a number of the fractions were related to the major azurophil and specific granule populations. Lactoferrin was found in ten of 13 fractions (L1 through L8, H1 to H2), whereas MPO was found in every fraction. Consistent with these biochemical data, all fractions exhibited varying degrees of heterogeneity based on ultrastructural morphology and cytochemistry, including diaminobenzidine (DAB) reactivity for peroxidase and periodate-thiocarbohydrazide-silver proteinate (PA-TCH-SP) staining for complex glycoconjugates. A variable but significant percentage (23% to 70%) of the granules in fractions L1 through L8 and H1 and H2 showed DAB reactivity, while about 90% of the granules in fractions H3 through H5 were peroxidase positive. These results demonstrated that DAB-reactive granules spanned the entire range of granule size and density. Ultrastructural PA-TCH-SP staining of isolated granule fractions revealed patterns similar to those of granules in intact neutrophils at different stages of development. Granules from human acute promyelocytic leukemia cells (HL-60) exhibited a surprisingly low density compared with typical azurophil granules from normal, mature neutrophils. The data suggest that both functional and maturational differences contribute to granule heterogeneity, and provide a new practical and conceptual framework for further defining the phenomenon of neutrophil granule heterogeneity.     

Nucleotide metabolic mismatches in mammalian hearts: implications for transplantation

Introduction

Human donor organ shortages have led surgeons and scientists to explore the use of animals as alternative organ sources. Acute thrombovascular rejection (AVR) is the main hurdle in xenotransplantation. Disparities in nucleotide metabolism in the vessels of different species may contribute significantly to the microvascular component of AVR.

Methods

We evaluated the extent of nucleotide metabolism mismatch in selected organs and endothelial cells of different mammals with particular focus on the changes in activity of ecto-5’-nucleotidase (E5’N) elicited by exposure of porcine hearts or endothelial cells to human blood (ex vivo) or human plasma (in vitro).

Results

E5’N activity in the rat heart was significantly higher than in other species. We noted a significant difference (p<0.001) in E5’N activity between human and pig endothelial cell lines. Initial pig aortic endothelial E5’N activity decreased in vitro after a three-hour exposure to human and porcine plasma while remaining constant in controls. Ex vivo perfusion with fresh human blood for four hours resulted in a significant decrease of E5’N activity in both wild type and transgenic pig hearts overexpressing human decay accelerating factor (p<0.001).

Conclusions

This study provides evidence that mismatches in basal mammalian metabolic pathways and humoral immunity interact in a xenogeneic environment. Understanding the role of nucleotide metabolism and signalling in xenotransplantation may identify new targets for genetic modifications and may lead to the development of new therapies extending graft survival.     

Predictive mathematical models of cancer signalling pathways

Complex intracellular signalling networks integrate extracellular signals and convert them into cellular responses. In cancer cells, the tightly regulated and fine-tuned dynamics of information processing in signalling networks is altered, leading to uncontrolled cell proliferation, survival and migration. Systems biology combines mathematical modelling with comprehensive, quantitative, time-resolved data and is most advanced in addressing dynamic properties of intracellular signalling networks. Here, we introduce different modelling approaches and their application to medical systems biology, focusing on the identifiability of parameters in ordinary differential equation models and their importance in network modelling to predict cellular decisions. Two related examples are given, which include processing of ligand-encoded information and dual feedback regulation in erythropoietin (Epo) receptor signalling. Finally, we review the current understanding of how systems biology could foster the development of new treatment strategies in the context of lung cancer and anaemia.