volving several other kinases as well as small GTP The cytokine tumor necrosis factor (TNF) a was binding proteins (For review see 1-3).found to stimulate the p38 mitogen activated protein Recently, two homologues of p38 MAP kinase have (MAP) kinase signalling cascade in human umbilical been identified in human monocytes by the use of a vein endothelial cells. TNFa increased the activity of class of pyridinyl imidazoles (4). These drugs inhibit the p38 substrate MAP kinase-activated-protein (MAP-the production of interleukin-1b and tumor necrosis KAP) kinase 2 and the subsequent phosphorylation of factor (TNF) by stimulated monocytes. The pyridinyl the small heat shock protein Hsp27 about two to three imidazole SB203580 specifically inhibits p38 MAP ki- expression of the intercellular cell adhesion molecule-1 (ICAM-1). The biological functions of these adhesion molecules are distinct. ICAM-1 binds leukocytes via their b2 integrins and can therefore serve to recruit both granulocytes and monocytes from the bloodstream Under conditions of cellular stress, such as heat to sites of tissue injury, whereas VCAM-1 binds monoshock, UV radiation and osmotic stimulation, as well cytes and lymphocytes expressing the integrins a4b1 as subsequent to cytokine treatment at least two and a4b7 specifically supporting the recruitment of members of the superfamily of mitogen-activated chronic inflammatory cells (10,11). In this paper we protein (MAP) kinases are rapidly activated. These have investigated whether there is a direct connection enzymes, which are distinct from the extra-cellularly between the p38 MAP kinase cascade and the expresregulated kinase (Erk)-1 and Erk2 stimulated by sion of the endothelial adhesion molecules. By the use growth factors, are p38 MAP kinase/reactivating kiof the inhibitor SB203580 we demonstrate that the exnase (RK) and c-jun amino terminal kinase (JNK)/ pression of VCAM-1, but not ICAM-1, is likely regustress-activated protein (SAP) kinase. Like Erk1/2 lated by the p38 MAP kinase at the post-transcripthese enzymes are activated through a cascade intional level.

The objectives of the study were to determine regional changes in body composition, energy expenditure by means of doubly labeled water, and net energy balance during exposure to high and extreme altitudes (5,300-8,848 m). This study focuses on a subset of subjects who consumed the doubly labeled water (three base camp personnel and seven climbers). Regional body composition was determined by measuring skinfold thicknesses and circumferences at 10 different sites on the body. Energy expenditure was measured by doubly labeled water excretion. Discrepancies between actual energy expenditure and data obtained from diet records and body weight changes suggested a chronic underreporting of dietary energy intake, especially by those subjects who reached the highest altitudes. This underreporting may be due in part to diminished cognition or to a preferential focus on survival, rather than on filling out diet records accurately. Mean adjusted dietary intakes were 10.50 +/- 0. 65 MJ/d (2510 +/- 155 kcal/d) for those who remained at base camp, and 20.63 +/- 6.56 MJ/d (4931 +/- 1568 kcal/d) for those who climbed above base camp. Energy expenditure averaged 2.5-3.0 times sea level resting energy expenditure. Differential changes in regional body composition suggested a preferential loss of fat mass and a relative sparing of muscle mass, despite insufficient energy intake to maintain body weight.

Background The purpose of this pilot study was to identify biological risk factors for restenosis after percutaneous transluminal coronary angioplasty (PTCA) to predict the long-term outcome of PTCA before treatment.

The plasma level of fibrinogen is associated with the risk of ischaemic heart disease (IHD) and the severity of atherosclerosis. It has been suggested that an increased plasma level of fibrinogen is a coronary risk indicator because it reflects the inflammatory condition of the vascular wall. An inflamed vascular wall may increase the production of the cytokines interleukin 6 (IL6), interleukin l/3 (ILl,@, and tumour necrosis factor c( (TNFcc), which have a major role in the regulation of synthesis in the liver of acute phase proteins, including fibrinogen. Smoking has also been reported to increase the levels of fibrinogen and C-reactive protein (CRP). This may indicate that smoking induces an inflammatory reaction, probably of the pulmonary bronchi and alveolae. Therefore, we anticipated that with both types of inflammation the levels of acute phase proteins and cytokines would be related. We have investigated the contribution of inflammation to the plasma levels of fibrinogen in 34 patients with severe coronary artery disease (CAD) and 30 healthy controls comparable for age and smoking habits. We did not find a parallel in the effects of smoking and ischaemic heart disease on the plasma levels of fibrinogen, CRP, IL6, ILlD and TNFc(. Cardiovascular disease had its most important effect on the plasma fibrinogen level, while smoking appeared to increase the CRP levels, while both CAD and smoking seemed to affect the IL6 levels. Our results indicate that both smoking and CAD induce an inflammatory condition but that the increase of plasma levels of different inflammatory markers is complex. Although the acute phase reaction is the main regulatory mechanism of fibrinogen, the increase of fibrinogen in our group of CAD patients could not be fully explained by increased inflammation.

The present study was undertaken to investigate the hypothesis that multiple oxygen radical generating systems contribute to the tumor necrosis factor (TNF) alpha-stimulated transcriptional activation of the vascular cell adhesion molecule (VCAM)-1 in endothelial cells. Experimental evidence has implicated the cytochrome P450 monooxygenase and a phagocyte type NADPH-oxidase as a source of oxygen radicals in these cells. We show here that endothelial cells exhibit cytochrome P450 activity by measuring the O-dealkylation of the exogenous substrate 7-ethoxyresorufin, but components of the phagocyte-type NADPH oxidase could not be demonstrated in endothelial cells. In that latter respect it was surprising that the NADPH oxidase inhibitor apocynin completely prevented the accumulation of VCAM-1 mRNA. However, we found that apocynin also acts as an inhibitor of cytochrome P450 activity in endothelial cells. Therefore the inhibitory effect of apocynin on the induction of VCAM-1 may no longer be used to demonstrate a role for the NADPH oxidase in this process. Furthermore, different cytochrome P450 inhibitors Co2+, metyrapone, SKF525a decreased the endothelial VCAM-1 expression stimulated by TNFalpha. Also under hypoxic conditions the expression of VCAM-1 was reduced. On this basis we assume that the oxygen dependent step in the intracellular signalling cascade underlying the TNFalpha stimulated transcriptional activation of VCAM-1 resides in the activity of a cytochrome P450 dependent monooxygenase. The finding that the phospholipase A2 inhibitor bromophenacylbromide inhibited the expression of VCAM-1 may indicate that arachidonic acid serves as a substrate for the cytochrome P450 monooxygenase reaction, but further research is needed to elucidate the particular cytochrome P450 family member mediating the expression of VCAM-1.