Epinephrine induces a late thromboxane-dependent platelet shape change and enhances synergistically the shape change induced by other platelet agonists

Epinephrine is the only physiological platelet activator which induces platelet aggregation without a preceding change in platelet shape. The reason why epinephrine cannot induce this shape change is not known. Electron microscopically, we could show that during the first phase of epinephrine-induced platelet aggregation, the platelet aggregate is composed of discoid platelets, lying in rather loose contact with neighbouring platelets. During the second wave of epinephrine-induced aggregation (this is when thromboxane (TX)A(2) production has taken place), platelets have completely lost their discoid shape and are very tightly bound. In EDTA-platelet rich plasma (PRP), we could demonstrate a clear synergistic action of epinephrine 10-20 μM on the first phase of shape change (disc-to-sphere transformation), induced by low concentrations of arachidonic acid (AA), collagen, adenosine diphosphate (ADP) and platelet activating factor (PAF). In combination with moderate concentrations of AA or collagen, epinephrine induced a clear aggregation-independent secretion of platelet granules, which in the absence of epinephrine, only takes place with higher inducer concentrations. All these synergistic actions could be demonstrated in the aggregometer and electron microscopically. To explain these findings, we hypothesize that the inability of epinephrine to induce a shape change that precedes aggregation is due to slow generation of TXA(2) which is only formed as a positive feedback mechanism of aggregation. This TXA(2) will bind to its own receptor and produce a shape change coinciding with the second wave of epinephrine-induced aggregation. Collagen, in contrast, induces very rapid TXA(2) generation, causing Ca(2+) mobilization and myosin light chain-phosphorylation, leading to shape change, clearly before aggregation starts.     

The Research Board of the European Dialysis and Transplantation Nurses Association/European Renal Care Association (EDTNA/ERCA)

The Research Board (RB) of EDTNA/ERCA is a multidisciplinary group, established by the participation of renal care centres all around Europe. The RB also works with the association's Special Interest Groups (SIGs) on developing guidelines for implementing safe renal clinical practice. It is composed of six permanent members, with co-opted experts from specific fields. This article describes how the RB works and the projects implemented since 1996.     

European study on epidemiology and the management of HCV in the haemodialysis population--Part 1: centre policy

Haemodialysis patients are known to be at risk of infection of Hepatitis C Virus (HCV) through nosocomial spread. This paper presents the first part of a study on epidemiology and management of HCV, in a haemodialysis population, conducted by the EDTNA/ERCA Research Board. Data on HCV management and infection control procedures was collected from 136 European centres using an electronic questionnaire. The study identifies a number of possible risk factors for transmission of the virus: failing to disinfect devices between patients, sharing of single-use vials to prepare drugs or infusions for different patients, inadequate sterilisation or cleaning of machines between dialysis sessions, unsatisfactory environmental cleaning and distance less than one metre between chairs.     

Genetic variants of coagulation factor XIII,postmenopausal estrogen therapy,and risk of nonfatal myocardial infarction

We hypothesized that possession of either of 2 functional coagulation factor XIII polymorphisms, one within subunit A (Val34Leu) and one within subunit B (His95Arg), might modulate the prothrombotic effects of estrogen and help to explain the variation in incidence of arterial thrombotic events among postmenopausal women using hormone replacement therapy. In a population-based case-control study of 955 postmenopausal women, we assessed the associations of factor XIII genotypes and their interactions with estrogen therapy on risk of nonfatal myocardial infarction (MI). The presence of the factor XIIIA Leu34 allele was associated with a reduced risk of MI (odds ratio [OR] = 0.70, 95% confidence interval [95% CI] = 0.51-0.95). The presence of the factor XIIIB Arg95 allele had little association with MI risk. Neither factor XIII polymorphism alone significantly modified the association between the risk of MI and current estrogen use. In exploratory analyses, however, there was a significant factor XIII subunit gene-gene interaction. Compared to women homozygous for both common factor XIII alleles, the Arg95 variant was associated with a reduced risk of MI in the presence of the Leu34 variant (OR = 0.36, 95% CI = 0.17-0.75) but not in the absence of the Leu34 variant (OR = 1.11, 95% CI = 0.69-1.79). Moreover, among women who had at least 2 copies of the variant factor XIII alleles and were current estrogen users, the risk of MI was reduced by 70% relative to estrogen nonusers with fewer than 2 factor XIII variant alleles (P value for interaction =.03). If confirmed, these findings may permit a better assessment of the cardiovascular risks and benefits associated with postmenopausal estrogen therapy.     

Concentrations of 5-ASA and Ac-5-ASA in human ileocolonic biopsy homogenates after oral 5-ASA preparations.

Intramucosal 5-aminosalicylic acid (5-ASA) and acetylated 5-ASA (Ac-5-ASA) concentrations were determined in ileocolonic biopsy specimens from 61 patients with irritable bowel syndrome treated for one week with near equimolar doses of different slow release preparations of 5-ASA (Claversal, Asacol, or Pentasa) or azo-bound drugs (Salazopyrin, Dipentum). The transit time in these patients was accelerated by a laxative, metoclopramide, and colonic lavage. The presence of 5-ASA in the mucosa was confirmed by autofluorescence. The highest concentrations of 5-ASA were obtained after Asacol (mean (SEM), 298.5 (37.3) ng/mg wet wt), followed by Claversal 500 mg (108.8 (11.7) ng/mg wet wt) and Pentasa (25.7 (2.2) ng/mg wet wt). Very low concentrations only were observed after Claversal 250 mg (0.3 (0.03) ng/mg wet wt), Salazopyrine (1.2 (0.1) ng/mg wet wt), and Dipentum (11.0 (3.2) ng/mg wet wt). The results for Ac-5-ASA were similar but the concentrations were generally lower. Serum concentration-time curves over eight hours were obtained from 34 healthy volunteers after a single oral dose of 400 to 500 mg of the different drugs. For the slow release forms, an apparently inverse relationship was found between the area under the curve of the serum concentrations and the intramucosal concentrations, supporting the importance of the local availability of the drug. This inverse relationship was absent for the azo-bound drugs. Colonic washout induced mechanical removal of intraluminal 5-ASA with a secondary disturbance in absorption resulting in a rapid decline in the serum concentrations. However, only for Dipentum did this result in significantly lower 5-ASA mucosal concentrations. This is the first reported attempt to evaluate the mucosal availability of 5-ASA after different oral preparations. It shows that where transit time is accelerated higher mucosal concentrations occur after slow release preparations (except for Claversal 250 mg) than after azo-bound drugs. Additional studies are necessary to correlate these concentrations with clinical effects.     

Early detection of left ventricular diastolic dysfunction using conventional and speckle tracking echocardiography in a large animal model of metabolic dysfunction

Left ventricular (LV) diastolic dysfunction is one of the important mechanisms responsible for symptoms in patients with heart failure. The aim of the current study was to identify parameters that may be used to detect early signs of LV diastolic dysfunction in diabetic pigs on a high fat diet, using conventional and speckle tracking echocardiography. The study population consisted of 16 healthy Göttingen minipigs and 18 minipigs with experimentally induced metabolic dysfunction. Echocardiography measurements were performed at baseline and 3-month follow-up. The ratio of peak early (E) and late filling velocity (E/A ratio) and the ratio of E and the velocity of the mitral annulus early diastolic wave (E/Em ratio) did not change significantly in both groups. Peak untwisting velocity decreased in the metabolic dysfunction group (? 30.1?±?18.5 vs. ? 23.4?±?15.5 °/ms) but not in controls (? 38.1?±?23.6 vs. ? 42.2?±?23.0 °/ms), being significantly different between the groups at the 3-month time point (p?<?0.05). In conclusion, whereas E/A ratio and E/Em ratio did not change significantly after 3 months of metabolic dysfunction, peak untwisting velocity was significantly decreased. Hence, peak untwisting velocity may serve as an important marker to detect early changes of LV diastolic dysfunction.