Reducing Elevated Heart Rates in Patients with Multiple Organ Dysfunction Syndrome with The If (Funny Channel Current) Inhibitor Ivabradine.

Introduction: A heart rate higher than 90 beats/min indicates an unfavorable prognosis for patients with multiple organ dysfunction syndrome (MODS). We sought to investigate the effect of the pacemaker current (If) inhibitor ivabradine on heart rate, hemodynamics, and disease severity among patients with MODS.

Patients And Methods: In this prospective, controlled, randomized, open-label, two-arm phase II trial, 70 patients with MODS, a sinus rhythm of at least 90 beats/min, and contraindications to β-blocker therapy were randomly assigned to receive the standard treatment ± ivabradine (5 mg twice daily) for 96 h via the enteral route.

Staphylococcus aureus α-toxin triggers the synthesis of B-cell lymphoma 3 by human platelets.

The frequency and severity of bacteremic infections has increased over the last decade and bacterial endovascular infections (i.e., sepsis or endocarditis) are associated with high morbidity and mortality.

Hemodynamic effects of eating and prolonged supine position in healthy subjects studied under clinical-pharmacological test conditions.

The influences of both being in a supine position for a prolonged period and food intake on cardiovascular variables were studied under clinical-pharmacological test conditions. In a randomized crossover design study without drug or placebo administration, 6 healthy male volunteers received a light standard meal before and during test A and fasted in test B. In both tests, while they were continuously supine for more than 8 h, a synchronous recording of cardiovascular variables was done at 24, 26 and 28 min after starting the supine position (first recordings) and 25 times from 2 to 480 min after the first recordings.

Medication adherence, self-care behaviour and knowledge on heart failure in urban South Africa: the Heart of Soweto study.

Background: There is a paucity of data on treatment adherence in patients with chronic heart failure (CHF) in Africa.

Methods: We examined the pattern of treatment adherence, self-care behaviour and treatment knowledge in 200 consecutive patients with CHF attending the Chris Hani Baragwanath Hospital, Soweto, South Africa via a combination of questionnaire (100%, n = 200) and pill count (41%, n = 82).

Results: Mean age was 56 +/- 14 years, 157 were black African (79%) and 109 (55%) were male.

Glycation of PDGF results in decreased biological activity.

Advanced glycation end products (AGEs) are formed by the non-enzymatic glycation of proteins by reducing carbohydrates or alpha-oxo-aldehydes such as glyoxal and methylglyoxal and further rearrangements, eliminations and oxidations. AGE-modifications alter peptide structure, function and stability and accumulate under several pathophysiological conditions such as diabetes and are considered a biomarker of ageing. PDGF is a major regulator of wound healing, which is impaired in hyperglycaemia and ageing.

Influence of systemically given placebo, trapidil and isosorbide dinitrate on norepinephrine-evoked hand vein constriction in healthy subjects.

Since trapidil (CAS 15421-84-8) is able to dilate human hand veins after local intravenous administration, four studies were carried out in healthy male volunteers using the dorsal hand vein compliance technique to test the influence of common systemic single doses of trapidil (200 mg orally, 100 mg intravenously) and isosorbide dinitrate (CAS 87-33-2, 20 mg orally) on norepinephrine (CAS 51-41-2)-evoked hand vein constriction in comparison with oral placebo. Oral placebo and oral trapidil were studied in a randomized double-blind cross-over design in 10 subjects aged 20 to 30 years, and oral isosorbide dinitrate and intravenous trapidil, in a randomized open cross-over design in 8 subjects aged 22 to 29 years. In the three similar studies with oral medications dose-response curves for venoconstriction by locally infused norepinephrine were established before and 1 h, 2 h and 3 h after oral medication and ED50 values of norepinephrine were calculated.

Effect of locally applied trapidil on norepinephrine- and dinoprost-evoked hand vein constriction in healthy men.

Objective: In this study the effect of locally administered trapidil on human hand veins was examined.

Subjects: 10 healthy male volunteers aged 20 - 30 years were included.

Method: The dorsal hand vein compliance technique was used.

P2Y12 ADP receptor-dependent tyrosine phosphorylation of proteins of 27 and 31 kDa in thrombin-stimulated human platelets.

In thrombin-stimulated human platelets several proteins undergo rapid and transient changes in tyrosine phosphorylation. We demonstrate that a set of proteins of 27, 29, 31, 34, and 39 kDa is affected by released ADP and P2Y12 receptor signaling during platelet activation. AR-C69931MX, an antagonist of the Gi(2)-coupled P2Y12 ADP receptor, inhibits initial tyrosine phosphorylation of p27 and p31 and prevents subsequent dephosphorylation of p29, p34, and p39.

[Differential influence of immune therapy on relapses and progression in multiple sclerosis: interpretation and therapeutic consequences].

It is well established that relapses can be suppressed by different substances in patients with relapsing-remitting multiple sclerosis (MS). In contrast, patients with progressive forms of MS do hardly respond to immune therapy. Therefore, start of immune therapy after the first relapse has been proposed, especially in order to prevent degeneration and disability.

ADP secretion and subsequent P2Y12 receptor signalling play a crucial role in thrombin-induced ERK2 activation in human platelets.

Stimulating human platelets with thrombin induces the activation of the extracellular signal-regulated kinase 2 (ERK2). We demonstrate that this effect is highly dependent on ADP secretion and P2Y12 receptor signalling. AR-C69931MX (10 microM), a specific antagonist of the Gi-coupled P2Y12 ADP receptor, inhibits ERK2 activation induced by thrombin.

The inflammatory action of CD40 ligand (CD154) expressed on activated human platelets is temporally limited by coexpressed CD40.

Recently, we have demonstrated that human platelets carry preformed CD40 ligand (CD154) molecules, which rapidly appear on the platelet surface following stimulation by thrombin. Once on the surface, platelet CD154 induces an inflammatory reaction of CD40-bearing endothelial cells. This study shows that strong platelet agonists other than thrombin also lead to the expression of CD154 on the platelet surface.

Biomarkers of genetic damage and inflammation in blood and bronchoalveolar lavage fluid among former German uranium miners: a pilot study.

Former East German uranium miners who are known to have been exposed to radon are estimated to be at high risk for lung carcinogenesis. Among these miners over 200 occupationally caused lung cancer cases are expected to occur each year, resulting in a total of 7,000-24,000 excess lung cancer cases in the coming years. It is still unknown whether there is a correlation between biomarkers and the exposure of the uranium miners to ionizing radiation that might enable us to trace those miners with high lung cancer risk.

Serum ras (p21) as a marker for occupationally derived lung cancer?

Certain subsets of the population are especially sensitive to carcinogens, and this can be determined using molecular biological methods. In the literature there has been evidence presented for the use of p21ras (ras) as a tumor marker for human carcinogenic substances such as asbestos, polycyclic aromatic hydrocarbons, and vinyl chloride in the workplace. In this study we have examined whether serum ras could serve as a biomarker for the early detection of occupationally derived lung cancer, with an emphasis on Schneeberger (radon-induced) lung cancer.

Protein-tyrosine-phosphatase-mediated epidermal growth factor (EGF) receptor transinactivation and EGF receptor-independent stimulation of mitogen-activated protein kinase by bradykinin in A431 cells.

Transactivation of the epidermal growth factor (EGF) receptor (EGFR) has been proposed to represent an essential link between G-protein-coupled receptors and the mitogen-activated protein kinase (MAPK) pathway in various cell types. In the present work we report, in contrast, that in A431 cells bradykinin transinactivates the EGFR and stimulates MAPK activity independently of EGFR tyrosine phosphorylation. Both effects of bradykinin are mediated by a pertussis-toxin-insensitive G-protein.

A key role of adenosine diphosphate in the irreversible platelet aggregation induced by the PAR1-activating peptide through the late activation of phosphoinositide 3-kinase.

Although adenosine diphosphate (ADP), per se, is a weak platelet agonist, its role as a crucial cofactor in human blood platelet functions has now been clearly demonstrated in vitro and in vivo. The molecular basis of the ADP-induced platelet activation is starting to be understood since the discovery that 2 separate P2 purinergic receptors may be involved simultaneously in the activation process. However, little is known about how ADP plays its role as a cofactor in platelet activation and which signaling pathway initiated by a specific agonist can be modulated by the released ADP.

Serum levels of pantropic p53 protein and EGF-receptor, and detection of anti-p53 antibodies in former uranium miners (SDAG Wismut).

Background: The oncogene product EGF-receptor (EGF-R), the tumor suppressor gene product p53, and anti-p53 antibodies are detectable in serum of certain cancer patients. Increased levels of some of these products were reported in lung cancer patients after occupational asbestos exposure, after exposure to polycyclic aromatic hydrocarbons or vinyl chloride. This molecular epidemiological study investigated the use of serum EGF-R, p53-protein, and anti-p53 antibodies as biomarkers for detection of effects of radon and its decay products.

p53 protein, EGF receptor, and anti-p53 antibodies in serum from patients with occupationally derived lung cancer.

The oncogene product epidermal growth factor receptor (EGF-R), the tumour suppressor gene product p53 and anti-p53 antibodies are detectable in the serum of certain cancer patients. Increased levels of some of these products were reported in lung cancer patients after occupational asbestos exposure and after exposure to polycyclic aromatic hydrocarbons or vinylchloride. In the first step, this study investigated the possible diagnostic value of serum EGF-R, p53-protein and anti-p53 antibodies, measured by an enzyme-linked immunosorbent assay, in lung tumour patients.

Secreted ADP plays a central role in thrombin-induced phospholipase D activation in human platelets.

Thrombin and other agonists that induce secretion and aggregation in human platelets also activate phospholipase D (PLD), but the signaling cascade leading to activation of PLD in human platelets is not yet clear. We have determined that apyrase, which scavenges ADP secreted during platelet activation, is able to block or reduce the PLD activation stimulated by low (0.1 U/ml or less) or high (0.

Identification of phosphorylated proteins from thrombin-activated human platelets isolated by two-dimensional gel electrophoresis by electrospray ionization-tandem mass spectrometry (ESI-MS/MS) and liquid chromatography-electrospray ionization-mass spectrometry (LC-ESI-MS).

Two-dimensional polyacrylamide gel electrophoresis (2-D PAGE) is a powerful tool to separate complex protein mixtures including whole cell lysates. In combination with immunoblotting techniques or radioactive labeling techniques it is a fast and convenient way to demonstrate the presence of certain proteins or protein modifications. With the development of extremely sensitive analytical techniques such as matrix-assisted laser desorption/ionization-mass spectrometry (MALDI-MS) or electrospray ionization (ESI)-MS, it has become possible to use 2-D gels not only as an analytical but also as a preparative tool.

Platelet phospholipase D is activated by protein kinase C via an integrin alpha IIb beta 3-independent mechanism.

Blood platelets contain phospholipase D (PLD) that is rapidly activated following platelet stimulation. It is currently unclear, however, where PLD fits into the signalling cascade that leads to aggregation and secretion. Therefore we investigated the mechanism of activation of PLD in human platelets, using the formation of the PLD-specific product phosphatidylethanol as a measure of PLD activity.

Rapid protein tyrosine phosphorylation in the cytoskeleton of stimulated human platelets.

Upon activation platelets show elevated protein tyrosine phosphorylation, and translocation of the protein tyrosine kinase pp60c-src from the plasma membrane to the cytoskeleton occurs. We therefore investigated whether tyrosine phosphorylation also increases in the cytoskeletal compartment. Here we show that almost identical patterns of phosphotyrosine-containing proteins are detectable in the cytoskeleton after platelet stimulation with compounds that directly (phorbol 12-myristate, 13-acetate) or indirectly (thrombin, vasopressin, collagen, ADP) activate protein kinase C.

The protein tyrosine kinase pp60c-src is activated upon platelet stimulation.

Stimulation of human platelets causes a dramatic increase in phosphorylation of various proteins at tyrosine residues. The abundance of protein tyrosine kinases of the src-family in platelets, particularly pp60c-src, suggests an important role of these kinases in response to stimulation events. We have shown that pp60c-src is activated on agonist-induced platelet stimulation with respect to its substrate affinity.