No abstract

Summary:We prospectively evaluated the capacity of serum procalcitonin (PCT), compared with serum levels of Creactive protein (CRP) and endotoxin, to identify children at high risk for mortality from sepsis after BMT. Of 47 pediatric bone marrow transplantation patients studied, 22 had an uneventful course post-transplant (Group 1), 17 survived at least one septic event (Group 2), and eight died from multiorgan failure (MOF) following septic shock (Group 3). Median concentrations of PCT over the course of the study were 1.3, 15.2, and 102.8 ng/ml, respectively, in each of the three groups (Po0.002 for each comparison). Median concentrations of CRP were 91, 213, and 260 mg/l, respectively (Po0.001 for Group 1 vs Group 2 and Group 3; P ¼ NS for Group 2 vs Group 3). Median concentrations of endotoxin were 0.21, 0.30, and 0.93 U/l, respectively (P ¼ NS for each comparison). Median concentrations of PCT, in contrast to serum CRP and endotoxin, correlated with the severity of sepsis (8.2 ng/ml in 'sepsis' and 22.3 ng/ml in 'severe sepsis', P ¼ 0.028) and provided useful prognostic information during septic episodes.

The results indicate that in cardiac fibroblasts AngII via the AT(1)-receptor causes autocrine release of TGFbeta1, which in turn induces biglycan expression and secretion.

Although tightly regulated programmed cell death (apoptosis) possesses great importance for tissue homeostasis, several pathologic processes are associated with organ failure due to adversely activated cell apoptosis. Transient increase in apoptosis has been shown to cause organ damage during fulminant hepatitis B, autoimmune diseases, ischemia-reperfusion injury, sepsis, or allograft rejection. A defined and temporary inhibition of cell apoptosis may therefore be of high clinical relevance. Activation of death receptors results in caspase-8 recruitment to the death-inducing signaling complex, which initiates the apoptotic process through cleavage of caspase-8 and downstream substrates. This initial step may be inhibited by the caspase-8 inhibitor FLIP (FLICE inhibitory protein). To specifically inhibit the initiation of death receptor-mediated apoptosis we constructed a fusion protein containing FLIP fused N-terminally to the human immunodeficiency virus TAT domain. This TAT domain allows the fusion protein to cross the cell membrane and thus makes the Because of severe organ damage due to misregulated apoptosis in various diseases, intense studies have focused on apoptosis signaling pathways triggered by death receptors and their ligands including the Fas ligand, the tumor necrosis factor, and the tumor necrosis factor-related apoptosisinducing ligand (1-3). Fas (APO-1/CD95) surface expression does not necessarily render cells susceptible to Fas ligandinduced apoptosis because of counteracting physiological cellular inhibitors. One of these regulators of death receptormediated apoptosis was termed FLIP 1 (for FLICE inhibitory protein), which is predominantly expressed in lymphoid tissues (4, 5). Cross-linking of Fas-sensitive cells by the Fas ligand or an agonistic antibody induces apoptosis through procaspase-8 recruitment to the Fas-mediated death-inducing signaling complex (DISC), where procaspase-8 is cleaved to initiate apoptosis through a systematic cleavage of downstream substrates. The recruitment of the caspase-8 inhibitor cFLIP into the DISC prevents the cleavage of procaspase-8, resulting in concomitantly reduced apoptosis (6).Multiple splice variants of cFLIP have been reported, but to date only a long and a short form, designated cFLIP L and cFLIP S , respectively, could be detected on a protein level. It has been shown that, in the presence of cFLIP S , procaspase-8 is recruited into the DISC but remains unprocessed (7). Thus FLIP S appears to be a good candidate to block apoptosis in death receptor-mediated caspase-8 dependent pathways.In previous investigations it has been demonstrated that protein transduction is a powerful tool for introducing fulllength proteins into cells without the help of viral or chemical transporters (8,9). The principle of protein transduction originates from the biology of various viruses. In vivo analysis of the transduction properties of the HIV TAT domain demonstrated that almost all cells within the body, even those protected by the blood-brain barrier, were targ...

This study compares the effect of two different strategies to inhibit the renin-angiotensin system in the setting of acute myocardial infarction (MI). Male Wistar rats were treated with placebo, the angiotensin-converting enzyme (ACE) inhibitor ramipril (1 mg/kg/day), or the AT1 receptor antagonist, olmesartan (1 mg/kg/day), both initiated 1 week before induction of MI and continued for 6 weeks after MI. The inflammatory reaction in the heart was investigated 7 days post-MI by determination of macrophage infiltration and the expression of tumor necrosis factor (TNF-alpha), interleukin (IL)-1beta and IL-6 at mRNA and protein levels. Six weeks post-MI, cardiac function was measured following chronic implantation of catheters in the LV and femoral artery, and cardiac morphology and coronary structure were investigated in picrosirius-red stained hearts. In placebo-treated rats, macrophage infiltration was accompanied by upregulation of IL-1beta and IL-6 mRNA in the peri-infarct zone. TNF-alpha and IL-1beta mRNA and protein were also upregulated in the non-infarcted myocardium. Whereas both treatment regimes significantly reduced IL-6 upregulation, olmesartan additionally reduced macrophage infiltration and IL-1beta expression. Six weeks post-MI, placebo-treated MI animals developed an impaired cardiac function with structural remodeling of the myocardium and coronaries. While olmesartan and ramipril both improved cardiac function and reduced infarct size and myocardial/coronary remodeling, olmesartan was more effective not only in increasing vascular perimeter, inner vascular diameter and septal thickness but also in lowering media thickness of coronary arteries, inner left ventricular diameter, left ventricular circumference and left ventricular end-diastolic pressure than ramipril. Thus, following MI the AT1 receptor blocker, olmesartan, attenuated cardiac inflammatory reactions and protected myocardial/coronary structure and function of the failing heart proving to be of similar, in some cases superior effectiveness in this respect than the ACE inhibitor, ramipril.