Bombesin-like peptides as growth factors

Bombesin-like peptides (BN-LP) are involved in the regulation of many important functions, including sensory transmission, regulation of central autonomic pathways, thermoregulation, pituitary, gastric and pancreatic secretion, food intake and satiety. They also stimulate cellular proliferation in a developmental and tissue-specific manner. Their role in pathogenesis appears to be related to their properties as growth factors, especially in the lung, where BN-LP can induce growth of normal and neoplastic epithelial cells. The formulated hypothesis of autocrine control of small cell lung cancer growth by BN-LP will be tested using specific synthetic bombesin antagonists.     

Calcitonin gene-related peptide in patients with and without early reperfusion after acute myocardial infarction.

Plasma concentrations of calcitonin gene-related peptide (CGRP), a potent regulator of vascular tone, creatine kinase, myoglobin, and cardiac troponin T were assessed in 31 patients with acute myocardial infarction. In patients who had sustained acute myocardial infarctions, maximum CGRP concentrations (median, 3.2 pmol/L; interquartile range, 1.5 to 4.8 pmol/L) were markedly elevated as compared with healthy control subjects (n = 23; median, 1.02 pmol/L; p = 0.02). However, no marked differences in CGRP levels were observed between patients with early reperfusion (n = 19; median, 3.5 pmol/L) and patients without early reperfusion (n = 12; median, 2.6 pmol/L; p = 0.96), as well as between those with congestive heart failure (n = 8; median, 3.9 pmol/L) and those without congestive heart failure (n = 23; median, 3.2 pmol/L; p = 0.62). CGRP did not correlate closely with myocardial protein release or hemodynamic parameters (heart rate and blood pressure) or the occurrence of arrhythmias. Therefore we conclude that elevated peripheral venous CGRP concentrations in patients who have sustained an acute myocardial infarction are independent of successful reperfusion and hemodynamic state. Although the cause of CGRP increase is not yet identified, CGRP may play a role in the regulation of coronary vascular tone in patients after acute myocardial infarction.     

Use of the pulmonary artery catheter is not associated with worse outcome in the ICU

STUDY OBJECTIVES: In critically ill patients, the impact of pulmonary artery catheter (PAC) use on outcome is debatable. We investigated the epidemiology of PAC use in European ICUs and its relation to outcome. DESIGN: International cohort, observational study. SETTING: One hundred ninety-eight European ICUs participating in the Sepsis Occurrence in Acutely Ill Patients Study. PATIENTS: All 3,147 adult patients admitted to one of the participating ICUs between May 1, 2002, and May 15, 2002. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: Patients were classified according to whether or not they had a PAC at any time during their ICU stay, and were followed up until death, hospital discharge, or for 60 days. Propensity score case matching was performed, and matched pairs were examined for baseline characteristics and outcome. Of 3,147 patients, 481 patients (15.3%) had a PAC. Patients with a PAC were older, had a higher incidence of heart failure, a lower incidence of cancer, and were more commonly surgical admissions. Fluid balance was comparable between the two groups. ICU and hospital mortality rates were higher in patients with a PAC (28.1% vs 16.8% and 32.5% vs 22.5%, respectively; p < 0.001). However, PAC use was not an independent risk factor for 60-day mortality in multivariate analysis, and in 453 propensity-matched pairs ICU and hospital mortality rates were comparable between groups (26.7% vs 26.3% and 31.4% vs 32.8%, p = not significant). Survival to 60 days was similar between the two matched groups (log rank = 0.02; p = 0.894). CONCLUSIONS: This observational study suggests that PAC use is not associated with increased mortality in this heterogeneous population.     

The Hp, Gc, Gm, Km and beta 2-glycoprotein I genetic variants in hairy cell leukemia: no apparent association

No significant differences could be observed when Hp, Gc, Gm, Km and beta 2-glycoprotein I phenotypes of 50 patients with hairy cell leukemia were compared with healthy unrelated adults.     

Acute phase protein profiles in hairy-cell leukemia. Study in 50 patients. Effects of splenectomy

Serum levels of 15 "positive and negative acute-phase proteins" were measured in 50 patients with hairy-cell leukemia (HCL) and in normal controls. The specific analysis of the protein levels was completed with the combined data of total serum protein and zonal electrophoresis. In HCL patients all electrophoretic globulin fractions were significantly increased, while the albumin fraction was decreased. The changes in albumin levels were more apparent in the nonsplenectomized patients, while the total protein was increased in the splenectomized cases as well as in the total HCL series. Compared with the control groups, in the nonsplenectomized patients both the mean relative increments in the level of some positive acute-phase proteins (such as orosomucoid) and the mean relative decrements in the level of some negative acute-phase proteins (such as alpha 2HS-glycoprotein) were 3 times the values found in the splenectomized patients. The occurrence of elevated values of C-reactive protein was significantly higher in the nonsplenectomized patients than in the splenectomized ones. These differences between the acute-phase proteins of the two subgroups of HCL patients were in agreement with erythrocyte sedimentation rate values. This indicates that the acute-phase protein formula is generally more favorable in splenectomized cases than in nonsplenectomized patients, at least during the first two post-splenectomy years.     

Antithrombin: a new look at the actions of a serine protease inhibitor.

Antithrombin (AT) is a plasma-derived, single-chain glycoprotein with a molecular weight of 58 kDa. It is a serine protease inhibitor (serpin), sharing about 30% homology in amino acid sequence with other serpins. AT is a complex molecule with multiple biologically important properties. It is a potent anticoagulant that has been demonstrated to provide benefit in animal models and small cohorts of patients with coagulation disorders. AT also has remarkable anti-inflammatory properties, several of which result from its actions in the coagulation cascade. Activated coagulation proteases like activated factor X and thrombin contribute to inflammation; for instance, by the release of pro-inflammatory mediators. Inhibition of these proteases by AT prevents their specific interaction with cells and subsequent reactions. Anti-inflammatory properties of AT independent of coagulation involve direct interactions with cells leading to the release of, for instance, prostacyclin. Binding of AT to a recently identified cellular receptor, syndecan-4, leads to the interference with the intracellular signal induced by mediators like lipopolysaccharides and, thereby, to a down-modulation of the inflammatory response. AT has been shown to be effective in prospective and well-controlled small-scale studies of patients with inflammatory conditions, including sepsis. Although AT did not decrease overall patient mortality in a double-blind, placebo-controlled, phase III trial of patients with sepsis, it is important to note that AT improved the survival of individuals in this study not receiving heparin as a prophylactic regimen, which can be explained by the impaired interaction of AT with its cellular receptor in the presence of heparin, resulting in the reduction of the anti-inflammatory properties. Accordingly, the supplementation of AT without concomitant heparin may be beneficial in disorders with inflammatory characteristics, which has to be demonstrated in further clinical studies. Finally, recent results suggest that latent AT can induce apoptosis of endothelial cells by disrupting cell-matrix interactions. Further investigations will have to demonstrate whether latent and/or cleaved AT are physiological means to control angiogenesis. A potential prophylactic or therapeutic use as an anti-angiogenic and antitumor agent merits further exploration, including whether the growth of vessels in tumor tissues or close to tumors can be controlled by latent AT without affecting the formation of blood vessels during wound healing processes.     

Priming of normal human neutrophils by recombinant human growth hormone

Growth hormone (GH) plays an important role in the development, maintenance and function of the immune system. Previous data has demonstrated that GH is also a newly defined macrophage-activating factor. Activation of polymorphonuclear neutrophils (PMN) by GH has not yet been examined. This paper presents studies demonstrating the effects of GH on the migratory behaviour and respiratory burst of PMN. In a modified Boyden chamber chemotaxis assay, GH did not stimulate PMN locomotion when added directly to the cells but potently inhibited formylpeptide-stimulated chemotaxis with effective concentrations in the picomolar range. The migration inhibition observed is known from studies on PMN priming-factors to be due to enhanced adhesiveness of PMN to artificial surfaces such as nitrocellulose, suggesting that GH stimulates PMN adhesiveness. Priming of PMN by GH was confirmed by direct demonstration of a stimulatory effect on reduction of nitroblue tetrazolium. These findings suggest that GH may be involved in the regulation of PMN functions.     

Safety and immunogenicity of concomitant vaccination with the cell-culture based Japanese Encephalitis vaccine IC51 and the hepatitis A vaccine HAVRIX1440 in healthy subjects: A single-blind,randomized, controlled Phase 3 study

In travellers often several pre-departure immunizations are indicated, thus data are needed about possible interactions between vaccines. This Phase 3 study investigated the immunogenicity and safety of IC51 (JE vaccine) and HAVRIX^®1440 (hepatitis A vaccine) when administered alone or concomitantly to healthy subjects. The immune response was compared between single and concomitant vaccination in terms of geometric mean titre (GMT) and seroconversion rate (SCR) on Days 28 and 56. Immunogenicity was comparable for the 2 vaccines whether given together or separately which suggests that travellers to such regions could receive the vaccinations concomitantly.