Local excitation black blood imaging at 3T: application to the carotid artery wall.

A novel approach for imaging large sections of the carotid artery wall at isotropic spatial resolution is presented. Local excitation by means of 2D excitation pulses was combined with a diffusion-prepared segmented steady-state black-blood gradient echo technique enabling the assessment of the carotid arterial wall over a range of up to 15 cm. The carotid arteries of five healthy volunteers were imaged with the proposed technique. Signal-to-noise ratio (SNR), wall-lumen contrast-to-noise ratio (CNR), and vessel dimensions were assessed and compared to conventional excitation techniques. In all experiments black-blood contrast could be realized over the covered carotid arteries with similar SNR and CNR as the conventional technique covering the region of the bulbus only. The proposed technique enables the time-efficient coverage of the carotid arteries without compromising wall-lumen CNR and geometrical accuracy. Furthermore, the proposed technique appears to be less sensitive to motion and swallowing artifacts due to the local character of the excitation.

Interleukin-1beta stimulates acute phase response and C-reactive protein synthesis by inducing an NFkappaB- and C/EBPbeta-dependent autocrine interleukin-6 loop.

Cytokines interleukin-1beta (IL-1beta) and interleukin-6 (IL-6) are involved in acute phase response (APR). C-reactive protein (CRP), the prototype acute phase protein, may represent an important component in the pathogenesis of arteriosclerosis and may also be a target for drug development. Inhibition of CRP synthesis is one potential strategy. Understanding CRP synthesis, however, is a prerequirement for the development of CRP-inhibitors. From studies in hepatoma cell lines, IL-1beta and IL-6 were considered as equal inductors of APR and CRP. We investigated IL-1beta- and IL-6-effects on primary human hepatocytes (PHH) and Hep3B-cells. Kupffer cell contamination in PHH preparations was <3%. In PHH, several APP like CRP, haptoglobin (HP), lipopolysaccharide-binding protein (LBP) or hepcidin (HAMP) were regulated similarly by IL-1beta and IL-6, though signal transduction pathways of these cytokines are different. In Hep3B-cells, APP were regulated exclusively by IL-6. IL-1beta induced IL-6-synthesis in PHH but not in Hep3B-cells. C/EBPbeta-overexpression in Hep3B-cells reconstituted IL-1beta-mediated IL-6/CRP inducibility. In PHH and in C/EBPbeta-overexpressing Hep3B-cells, neutralizing anti-IL-6-antibodies blocked IL-1beta-mediated APR. Inhibition of protein synthesis and NFkappaB-signalling blocked IL-1beta- but not IL-6-mediated CRP-expression in PHH, whereas Janus-Kinase-1-inhibition blocked IL-1beta- and IL-6-mediated APR. IL-1beta induces APR in PHH via an NFkappaB- and C/EBPbeta-dependent autocrine IL-6-loop. These findings partly reconcile the understanding of APR and may help to design a transcriptional suppressor of CRP for the treatment of cardiovascular disease.

Sirolimus inhibits key events of restenosis in vitro/ex vivo: evaluation of the clinical relevance of the data by SI/MPL- and SI/DES-ratios.

BACKGROUND: Sirolimus (SRL, Rapamycin) has been used successfully to inhibit restenosis both in drug eluting stents (DES) and after systemic application. The current study reports on the effects of SRL in various human in vitro/ex vivo models and evaluates the theoretical clinical relevance of the data by SI/MPL- and SI/DES-ratio's. METHODS: Definition of the SI/MPL-ratio: relation between significant inhibitory effects in vitro/ex vivo and the maximal plasma level after systemic administration in vivo (6.4 ng/ml for SRL). Definition of the SI/DES-ratio: relation between significant inhibitory effects in vitro/ex vivo and the drug concentration in DES (7.5 mg/ml in the ISAR drug-eluting stent platform). Part I of the study investigated in cytoflow studies the effect of SRL (0.01-1000 ng/ml) on TNF-alpha induced expression of intercellular adhesion molecule 1 (ICAM-1) in human coronary endothelial cells (HCAEC) and human coronary smooth muscle cells (HCMSMC). Part II of the study analysed the effect of SRL (0.01-1000 ng/ml) on cell migration of HCMSMC. In part III, IV, and V of the study ex vivo angioplasty (9 bar) was carried out in a human organ culture model (HOC-model). SRL (50 ng/ml) was added for a period of 21 days, after 21 and 56 days cell proliferation, apoptosis, and neointimal hyperplasia was studied. RESULTS: Expression of ICAM-1 was significantly inhibited both in HCAEC (SRL > or = 0.01 ng/ml) and HCMSMC (SRL > or = 10 ng/ml). SRL in concentrations > or = 0.1 ng/ml significantly inhibited migration of HCMSMC. Cell proliferation and neointimal hyperplasia was inhibited at day 21 and day 56, significance (p < 0.01) was achieved for the inhibitory effect on cell proliferation in the media at day 21. The number of apoptotic cells was always below 1%. CONCLUSION: SI/MPL-ratio's < or = 1 (ICAM-1 expression, cell migration) characterize inhibitory effects of SRL that can be theoretically expected both after systemic and local high dose administration, a SI/MPL-ratio of 7.81 (cell proliferation) represents an effect that was achieved with drug concentrations 7.81-times the MPL. SI/DES-ratio's between 10-6 and 10-8 indicate that the described inhibitory effects of SRL have been detected with micro to nano parts of the SRL concentration in the ISAR drug-eluting stent platform. Drug concentrations in DES will be a central issue in the future.

Low-dose irradiation stimulates TNF-alpha-induced ICAM-1 mRNA expression in human coronary vascular cells.

BACKGROUND: Low-dose irradiation (LDI) is employed to extend the irradiation area in vascular brachytherapy to minimize the edge effect. Stimulation of adhesion molecule 1 (ICAM-1) is one of many mechanisms important in the early stages of atherosclerosis and restenosis. This study investigates the effect of gamma-irradiation on mRNA expression of ICAM-1 in human coronary vascular cells. MATERIAL/METHODS: Human coronary endothelial cells (HCAECs), human umbilical endothelial cells (HUVECs), and human coronary smooth muscle cells (HCMSMCs) were cultured and identified. Twenty-four hours after seeding, gamma-irradiation at doses of 0.5 Gy, 1 Gy, 10 Gy, 20 Gy, and 30 Gy (Linac Philips FL 75/20) was carried out. Twenty hours after irradiation, ICAM-1 expression was stimulated for 6 h with TNF-alpha (20 ng/ml). In Northern blot assays, 10 microg of RNA were used. The relative band density of ICAM-1 mRNA of irradiated and stimulated cells were compared with that of non-irradiated cells after TNF-alpha stimulus only. RESULTS: In HCAECs and HCMSMCs, stimulation of ICAM-1 mRNA was detected after irradiation, no matter which dose was applied. After low-dose irradiation (0.5 Gy and 1 Gy) the stimulating effect was pronounced, significant differences being found in HCAECs after irradiation with 1 Gy. CONCLUSIONS: Stimulation of ICAM-1 mRNA expression after LDI of human coronary vascular cells may be one of the many mechanisms that trigger the edge effect in vivo. If these results are confirmed by further studies and if anti-inflammatory treatment strategies cannot inhibit the stimulatory effects, a major problem exists for the future of vascular brachytherapy.

Septic shock caused by Streptococcus pneumoniae in a post-splenectomy patient successfully treated with recombinant human activated protein C.

We present a case of severe sepsis due to Streptococcus pneumoniae, serotype 22F treated with recombinant human activated protein C (drotrecogin alpha activated) (DrotAA). APACHE II score at admission was 34 with a predicted mortality of 81%. A wide range of cytokines, chemokines and receptors was measured before and after DrotAA treatment. Soon after infusion of 24 microg DrotAA per kg bodyweight and h (microg/kg/h) over a period of 96 h, cytokine levels fell markedly. The patient survived and was discharged after 6 weeks of hospitalization. In conclusion, administration of DrotAA in a case of Streptococcus pneumoniae-induced septic shock was followed by dramatic changes in serum levels of immuno-regulatory cytokines.

Intracoronary beta-irradiation with a rhenium-188-filled balloon catheter: a randomized trial in patients with de novo and restenotic lesions.

BACKGROUND: Restenosis requiring reintervention is the main limitation of coronary angioplasty. Intracoronary irradiation reduces neointimal proliferation. We studied the efficacy of a self-centering liquid rhenium-188-filled balloon catheter for coronary beta-brachytherapy. METHODS AND RESULTS: After successful coronary angioplasty with or without stenting, 225 patients (71% de novo lesions) were randomly assigned to receive 22.5 Gy intravascular beta-irradiation in 0.5-mm tissue depth (n=113) or to receive no additional intervention (n=112). Clinical and procedural data did not differ between the groups except a higher rate of stenting in the control group (63%) compared with the rhenium-188 group (45%, P<0.02). After 6 months of follow-up, late loss was significantly lower in the irradiated group compared with the control group, both of the target lesion (0.11+/-0.54 versus 0.69+/-0.81 mm, P<0.0001) and of the total segment (0.22+/-0.67 versus 0.70+/-0.82 mm, P<0.0001). This was also evident in the subgroup of patients with de novo lesions and independent from stenting. Binary restenosis rates were significantly lower at the target lesion (6.3% versus 27.5%, P<0.0001) and of the total segment (12.6% versus 28.6%, P<0.007) after rhenium-188 brachytherapy compared with the control group. Target vessel revascularization rate was significantly lower in the rhenium-188 (6.3%) compared with the control group (19.8%, P=0.006). CONCLUSIONS: Intracoronary beta-brachytherapy with a rhenium-188 liquid-filled balloon is safe and efficiently reduces restenosis and revascularization rates after coronary angioplasty.