Granular aluminium nanojunction fluxonium qubit.

Mesoscopic Josephson junctions, consisting of overlapping superconducting electrodes separated by a nanometre-thin oxide layer, provide a precious source of nonlinearity for superconducting quantum circuits. Here we show that in a fluxonium qubit, the role of the Josephson junction can also be played by a lithographically defined, self-structured granular aluminium nanojunction: a superconductor-insulator-superconductor Josephson junction obtained in a single-layer, zero-angle evaporation. The measured spectrum of the resulting qubit, which we nickname gralmonium, is indistinguishable from that of a standard fluxonium. Remarkably, the lack of a mesoscopic parallel plate capacitor gives rise to an intrinsically large granular aluminium nanojunction charging energy in the range of tens of gigahertz, comparable to its Josephson energy. We measure coherence times in the microsecond range and we observe spontaneous jumps of the value of the Josephson energy on timescales from milliseconds to days, which offers a powerful diagnostics tool for microscopic defects in superconducting materials.

[Antithrombotic treatment in acute coronary syndrome and atrial fibrillation]. / Antithrombotische Therapie bei akutem Koronarsyndrom und Vorhofflimmern.

The number of patients with atrial fibrillation (AF) is increasing due to the aging of the population. In addition, the number of patients with AF and indications for oral anticoagulation (OAC) for the prevention of stroke, who need dual antiplatelet treatment (DAPT) with acetylsalicylic acid (ASA) plus a P2Y12 inhibitor because of an acute coronary syndrome (ACS) and/or percutaneous coronary intervention (PCI) is also increasing. In the past these patients received a triple therapy (TT) for 3-12 months. This TT has never been studied for efficacy; however, the rate of bleeding complications in comparison to a simple OAC or DAPT is significantly higher. Registries and smaller trials showed that DAPT with an OAC plus a platelet inhibitor may be sufficient to prevent stroke and stent thromboses/myocardial infarctions. These questions were investigated in various prospective and randomized studies involving all four non-vitamin K oral anticoagulants (NOAC) approved for stroke prevention in AF. The NOACs were tested against vitamin K antagonists (VKA) involving single antiplatelet therapy without using DAPT. The trials with rivaroxaban (PIONEER AF-PCI) and dabigatran (RE-DUAL PCI) have already been published but the investigations involving apixaban (AUGUSTUS) and edoxaban (ENTRUST-AF PCI) are still ongoing. The current status is that a NOAC plus a single antiplatelet agent, mostly clopidogrel, is superior to TT with VKA with respect to bleeding complications without any obvious disadvantage due to increases in stroke cases or cardiac ischemia. The international guidelines already permit treatment without TT in cases where the bleeding risk is prevalent. In this situation it is recommended to prescribe a NOAC plus a single antiplatelet therapy. Thus, TT no longer seems to be indicated for most patients with AF and after ACS or PCI.

Prospective 'real world' registry for the use of the 'PCB only' strategy in small vessel de novo lesions.

BACKGROUND: This prospective registry assessed the safety and efficacy of paclitaxel coated balloon (PCB) angioplasty for small vessel coronary artery disease in Europe and Asia with the intention to treat lesions without additional stenting. The use of PCBs in small vessels seems to be associated with favourable outcomes; however, prospective data for the use of PCBs without stenting are limited. METHODS: The SeQuent Please Small Vessel 'PCB only' Registry was an international, prospective, multicentre registry enrolling patients with de novo lesions of small reference diameters (≥ 2.0 mm, ≤ 2.75 mm). The primary end point was clinically driven target lesion revascularisation (TLR) at 9 months. Secondary end points were acute technical success, in-hospital outcomes, 9-month major adverse cardiac events (MACE) (death, myocardial infarction, or TLR), and the occurrence of definite lesion and vessel thrombosis. RESULTS: A total of 479 patients (66.1 ± 10.9 years, 36.7% diabetics) were enrolled, 105 (23.5%) with an acute coronary syndrome, 41 (9.2%) with ST elevation myocardial infarction (STEMI), and 60 (14.8%) with non-STEMI. The initial procedural success rate was 99.0%; 27 patients (6%) needed additional bare metal stent implantation. TLR at 9.4±1.7 months occurred in 14 patients (3.6%), while three patients (0.6%) had vessel thrombosis in non-target lesions. There was no cardiac death or coronary artery bypass graft surgery. CONCLUSIONS: To date, this is the largest prospective study with PCBs in small vessel de novo lesions in unselected patients. Rates of TLR and MACE were low, suggesting the use of PCBs may be an attractive alternative treatment option to drug eluting stents in small vessels.

[Angiographic assessment of functionally insignificant left main coronary artery stenoses: reliability compared to intracoronary pressure measurement]. / Angiographische Beurteilung funktionell nicht signifikanter Hauptstammstenosen--Zuverlässigkeit im Vergleich zur intrakoronaren Druckmessung.

BACKGROUND AND OBJECTIVE: Left main coronary artery disease (LMCA) is still a widely accepted indication for coronary artery bypass surgery. Intermediate LMCA disease, however, often cannot be evaluated reliably on the basis of clinical and angiographic information alone. The deferral of surgical revascularization based on fractional flow reserve (FFR) measurements has been shown to be safe and feasible when taking an FFR value of (3) 0.75 as cutoff. This study was performed to compare the accuracy of visual angiographic assessment of intermediate LMCA stenoses by experienced interventional cardiologists with functional assessment by FFR in a patient population with excellent long-term outcome after deferral of surgery on the basis of FFR measurements. PATIENTS AND METHODS: 24 of 51 consecutive patients with intermediate LMCA disease were deferred from surgery based on an FFR value of > or = 0.75. Each angiogram was retrospectively reviewed independently by three experienced interventional cardiologists. Reviewers were blinded to initial FFR results, clinical data, and clinical outcome and asked to classify each lesion as SIGNIFICANT (FFR < 0.75), NOT SIGNIFICANT (FFR > or = 0.75), or UNSURE if the observer was unable to make a decision based on the angiogram. RESULTS: Mean follow-up was 29 +/- 13.6 months. No death or myocardial infarction was observed, event-free survival was 69 %. When taking the "unsure" classifications into consideration the individual reviewers achieved correct lesion classification with respect to FFR results on average in 58 % to 82 % of cases. Interobserver variability resulted in only 46 % of cases in concordant lesion classification (3 agreements or 2 agreements and 1 "unsure" evaluation). The number of concordant agreements between the individual pairs of reviewers did not exceed the rate of coincidental agreements that could be expected to result from simple guessing (mean KAPPA coefficient 0.04). More than 50 % of patients with excellent long-term outcome after deferral of surgery would potentially have undergone operative revascularization if consensual decision making had been solely based on angiographic lesion assessment. CONCLUSION: The functional significance of intermediate or equivocal LMCA lesions should not be based on visual assessment alone, even when performed by experienced interventional cardiologists.

Endothelial function in the forearm circulation of patients with the metabolic syndrome--effect of different lipid-lowering regimens.

We compared the effect of statin therapy (either alone or combined with ezetimibe) on the inhibition of cholesterol resorption and endothelial function by measuring forearm blood flow in male patients with the metabolic syndrome. Compared to 40 mg atorvastatin alone, combination therapy with 10 mg ezetimibe and 10 mg atorvastatin for 8 weeks resulted in significantly decreased total serum cholesterol and triglycerides levels (n = 14). Endothelium-dependent, acetylcholine-mediated vasodilation was significantly better with combination therapy (p < 0.05). In contrast, endothelium-independent forearm blood flow response to sodium nitroprusside was comparable in both groups. Our data suggest a more effective restoration of endothelial function with the statin/ezetimibe combination compared to statin monotherapy in patients with the metabolic syndrome.

A functional role of I kappa B-epsilon in endothelial cell activation.

The NF-kappa B inhibitor I kappa B-epsilon is a new member of the I kappa B protein family, but its functional role in regulating NF-kappa B-mediated induction of adhesion molecule expression is unknown. In vascular endothelial cells, I kappa B-epsilon associates predominantly with the NF-kappa B subunit Rel A and to a lesser extent with c-Rel, whereas I kappa B-alpha and I kappa B-beta associate with Rel A only. Following stimulation with TNF-alpha, pyrrolidine dithiocarbamate (PDTC), N-acetylcysteine, and dexamethasone prevented I kappa B kinase-induced I kappa B-alpha, but not I kappa B-beta or I kappa B-epsilon phosphorylation and degradation. Since the activation of NF-kappa B is required for the induction of adhesion molecule expression, we examined the role of I kappa B-epsilon in the transactivation of promoters from VCAM-1, ICAM-1, and E-selectin. Using reporter gene constructs of adhesion molecule promoters, PDTC inhibited VCAM-1 and E-selectin, but to a lesser extent, ICAM-1 promoter activity. Subcloning of kappa B cis-acting elements of VCAM-1, E-selectin, and ICAM-1 into a heterologous promoter construct revealed that PDTC inhibited VCAM-1 and E-selectin, but to a lesser extent, ICAM-1 kappa B promoter activity. By electrophoretic mobility shift assay, NF-kappa B heterodimers containing c-Rel specifically bind to the kappa B motif in the ICAM-1, but not VCAM-1 or E-selectin promoter. Indeed, overexpression of c-Rel induced ICAM-1 kappa B promoter activity to a greater extent than that of E-selectin and overexpression of I kappa B-epsilon inhibited ICAM-1 and VCAM-1 promoter activity in endothelial cells. These findings indicate that c-Rel-associated I kappa B-epsilon is involved in the induction of ICAM-1 expression.

NO reduces PMN adhesion to human vascular endothelial cells due to downregulation of ICAM-1 mRNA and surface expression.

Reperfusion damage is largely due to the adherence of polymorphonuclear leukocytes to the endothelium initiated by adhesion molecule upregulation. The reduced endothelial nitric oxide release during ischemia may be involved in the upregulation of intercellular adhesion molecule 1. In this study, we tested if nitric oxide donors suppress polymorphonuclear leukocyte adherence to activated endothelial cells by inhibition of the intercellular adhesion molecule 1 surface expression. Confluent human umbilical vein endothelial cells were stimulated with tumor necrosis factor alpha (300 U/mL) after preincubation with increasing concentrations of the nitric oxide donors CAS 1609 (0.005-5 mM/L) and 3-(4-morpholinyl)-sydnonimine (0.01-1 mM/L). Intercellular adhesion molecule 1 surface expression was measured in a cell surface enzyme-linked immunosorbent assay, intercellular adhesion molecule 1 mRNA by Northern analysis. Human saphenous vein endothelial cells were transfected with the inducible nitric oxide synthase gene and stimulated with tumor necrosis factor alpha (300 U/mL). Fluorescein green-labeled polymorphonuclear leukocytes adhering to activated human umbilical vein endothelial cells/human saphenous vein endothelial cells were quantified by epifluorescent microscopy. The intercellular adhesion molecule 1 surface expression of activated human umbilical vein endothelial cells/human saphenous vein endothelial cells was significantly diminished to 40 to 60% of the maximum after treatment with CAS 1609, 3-(4-morpholinyl)-sydnonimine, or transfection with the inducible nitric oxide synthase gene. Intercellular adhesion molecule 1 mRNA was diminished by CAS 1609 and 3-(4-morpholinyl)-sydnonimine in the same manner. The functional relevance of our data was shown by reduction of polymorphonuclear leukocyte adherence to activated human umbilical vein endothelial cells/human saphenous vein endothelial cells following treatment with CAS 1609 and 3-(4-morpholinyl)-sydnonimine or transfection with inducible nitric oxide synthase. Tumor necrosis factor-induced polymorphonuclear leukocyte adherence was abolished by blocking antibody against intercellular adhesion molecule 1. Thus, exogenous or endogenous substitution of nitric oxide diminishes the expression of endothelial intercellular adhesion molecule 1 and its mRNA following tumor necrosis factor alpha stimulation. This results in a reduced polymorphonuclear leukocyte adherence to activated endothelium.

Thrombolysis with saruplase versus streptokinase in acute myocardial infarction: five-year results of the PRIMI trial.

BACKGROUND: Short-term safety and efficacy of thrombolysis with saruplase in acute myocardial infarction have been shown in several trials. To assess long-term outcome of patients treated with saruplase or streptokinase for myocardial infarction, a 5-year follow-up of patients included in the Pro-Urokinase in Myocardial Infarction Trial was performed. METHODS AND RESULTS: Follow-up data are available from 8 centers on 255 (92.4%) of 276 included patients. The 5-year mortality rate was comparable with 20.8% of patients in the saruplase group and 16.9% in the streptokinase group (odds ratio 1.29, 95% confidence interval 0.69 to 2.42). In both groups, a considerable number of fatal cardiovascular events occurred more than 1 year after study inclusion. Rates of percutaneous transluminal coronary angioplasty and coronary artery bypass grafting were comparable in both groups. Reinfarction within 5 years occurred in 19.0% of patients in the saruplase group and tended to be less frequent at 10.8% after streptokinase treatment (odds ratio 1.94, 95% confidence interval 0.98 to 3.84). In both groups, the majority of reinfarctions took place more than 3 months after study inclusion. The 5-year stroke rate was 3.6% and 7.2% in the saruplase and streptokinase groups, respectively (odds ratio 0.49, 95% confidence interval 0.16 to 1.47). Subjective symptoms of heart failure and angina pectoris were comparable in both groups. CONCLUSIONS: Our data are consistent with a similar long-term outcome for patients treated with saruplase or streptokinase. Despite the low-risk profile of the patient cohort, there were considerable adverse event rates over a 5-year period.

Anti-inflammatory properties of cytochrome P450 epoxygenase-derived eicosanoids.

The epoxyeicosatrienoic acids (EETs) are products of cytochrome P450 epoxygenases that have vasodilatory properties similar to that of endothelium-derived hyperpolarizing factor. The cytochrome P450 isoform CYP2J2 was cloned and identified as a potential source of EETs in human endothelial cells. Physiological concentrations of EETs or overexpression of CYP2J2 decreased cytokine-induced endothelial cell adhesion molecule expression, and EETs prevented leukocyte adhesion to the vascular wall by a mechanism involving inhibition of transcription factor NF-kappaB and IkappaB kinase. The inhibitory effects of EETs were independent of their membrane-hyperpolarizing effects, suggesting that these molecules play an important nonvasodilatory role in vascular inflammation.

The inhibition of endothelial activation by unsaturated fatty acids.

Dietary long-chain fatty acids (FA) may influence pathological processes involving endothelial activation and leukocyte-endothelial interactions, such as inflammation and atherosclerosis. We previously showed that the n-3 FA docosahexaenoate (22:6n-3, DHA) inhibits cytokine-stimulated expression of endothelial-leukocyte adhesion molecules and soluble cytokines in the range of nutritionally achievable plasma concentrations. More recently we assessed structural determinants of VCAM-1 inhibition by FA. Cultured endothelial cells were incubated first with various saturated, monounsaturated, n-6 or n-3 polyunsaturated FA alone and then together with interleukin-1 or tumor necrosis factor. Saturated FA did not inhibit cytokine-induced endothelial activation, while a progressive increase in inhibitory activity was observed, for the same chain length, with the increase in double bonds accompanying the transition from monounsaturates to n-6 and, further, to n-3 FA. Comparison of various FA indicated no role of the double-bond position or configuration; the greater number of double bonds could explain the greater inhibitory activity of n-3 vs. n-6 FA. In order to ascertain mechanisms for these effects, we demonstrated inhibition of nuclear factor-kappaB (NF-kappaB) activation by DHA in parallel with a reduction in hydrogen peroxide (a critical mediator of NF-kappaB activation) released by endothelial cells either extracellularly or intracellularly. This suggests that a property related to fatty acid peroxidability (the presence of multiple double bonds) is related to inhibitory properties of hydrogen peroxide release and, consequently, of endothelial activation.

Inducible nitric oxide: an autoregulatory feedback inhibitor of vascular inflammation.

Inducible nitric oxide (iNO) is produced at sites of vascular inflammation by resident and nonresident vascular wall cells, but its role in the inflammatory process is not known. In this study, we show that a novel function of iNO is to terminate inflammatory processes. We find that iNO produced by murine macrophage-like cells, RAW264.7, can inhibit cytokine-induced endothelial cell activation in a separated and mixed endothelial-RAW264.7 coculture system. Both iNO production and endothelial VCAM-1 expression were induced simultaneously with bacterial LPS and murine-specific IFN-gamma. Inhibition of iNO synthase (iNOS) activity with N omega-monomethyl-L-arginine in endothelial-RAW264.7 cocultures, stimulated with murine-specific IFN-gamma and LPS, decreased iNO production by 86%, augmented VCAM-1 and iNOS expression in endothelial and RAW264.7 cells, respectively, and increased monocyte adhesion to the endothelial cell surface. Transient transfection studies using various VCAM-1 promoter constructs demonstrated that inhibitory effects of iNO on VCAM-1 gene transcription were mediated, in part, by inhibitory effects of iNO on kappa B cis-acting elements. Immunofluorescence studies using an Ab to the RelA (p65) subunit of nuclear factor-kappa B revealed that iNO inhibited the activation of nuclear factor-kappa B. These studies indicate that iNO attenuates iNOS expression in macrophages and inhibits monocyte adhesion to endothelial cells, and suggest that endogenously derived iNO may be an important autoregulatory inhibitor of vascular inflammation.

Differential regulation of endothelial cell adhesion molecule expression by nitric oxide donors and antioxidants.

Although nitric oxide (NO) and antioxidants inhibit adhesion molecule expression, their inhibitory effects on nuclear factor kappaB (NF-kappaB) activation may differ. The NO donors, but not 8-bromo-cGMP, decreased tumor necrosis factor alpha (TNF-alpha)-induced VCAM-1, ICAM-1, and E-selectin expression by 11-70%. In contrast, NAC completely abolished VCAM-1 and E-selectin expression and decreased ICAM-1 expression by 56%. Gel shift assays demonstrate that NF-kappaB activation was inhibited by both NO and antioxidants. The activation of NF-kappaB involves the phosphorylation and degradation of its cytoplasmic inhibitor IkappaB-alpha by 26S proteasomes. The 26S proteasome inhibitor MG132 prevented the degradation of phosphorylated IkappaB-alpha. NAC inhibited IkappaB kinase (IKK) activity and prevented IkappaB-alpha phosphorylation and degradation. In contrast, NO did not inhibit IKK activity, IkappaB-alpha phosphorylation, or IkappaB-alpha degradation. However, NO, but not antioxidants, induced IkappaB-alpha promoter activity. The inhibitory effects of NO on adhesion molecule expression, therefore, differs from that of antioxidants in terms of the mechanism by which NF-kappaB is inactivated.

Bolus Administration of Saruplase in Europe (BASE), a Pilot Study in Patients with Acute Myocardial Infarction.

To study the safety and efficacy of the thrombolytic agent saruplase as a bolus, the angiographic and clinical outcomes of three bolus regimens were investigated in a pilot study conducted in 192 patients with an acute myocardial infarction and were compared with the standard regimen. Fifty-two patients received a double bolus of 40 mg and 40 mg after 30 minutes, 51 patients a bolus of 80 mg, and 36 patients a bolus of 60 mg. Fifty-three patients received the standard regimen (a bolus of 20 mg and 60 mg IV infusion over 1 hour). At 60 minutes TIMI 2 and 3 flow were, respectively, 9.6% and 61.5% with the 40/40-mg bolus, 15.7% and 51.0% with the 80-mg bolus, 16.7% and 30.6% with the 60-mg bolus, and 7.5% and 54.7% with the standard 20/60-mg infusion. At 90 minutes TIMI 2 and 3 flow improved to 9.6% and 73.1%, 15.7% and 56.9%, 13.9% and 36.1%, and 5.7% and 71.7%, respectively. The primary endpoint, persistent patency (TIMI 2 + 3) at 24-45 hours, was seen in 69.2%, 64.7%, 44.4%, and 67.9% of patients who had no rescue PTCA, respectively. Inclusion in the 60-mg bolus group was prematurely stopped because of their low patency rates. The 40/40-mg bolus group had the highest mortality rate (13.5%), whereas the 60-mg bolus group had no deaths. Other adverse event rates were similar in the four groups. This clinical outcome is highly influenced by rescue PTCA of patients with insufficient TIMI flow. This pilot study indicates that in patients with an acute myocardial infarction, a double bolus of 40/40 mg resulted in the highest patency but also had the highest complication rate. The 80-mg single bolus is an attractive alternative for further evaluation because of its acceptable patency and event profile, and its easy form of administration.

In vitro analysis of synergistic effects of fibrinolytic agents and prostacyclin analogues.

We investigated the in vitro thrombolytic effects of streptokinase, urokinase, alteplase and saruplase, alone or in combination, with the prostacyclin analogues, iloprost and taprostene. Human platelet-rich plasma was stimulated with collagen (1 microgram/ml) to generate thrombi containing platelets and fibrin. Following treatment with fibrinolytic agents, lysis was allowed to proceed for 30 min and was then terminated with aprotinin (2,000 CIU/ml). To evaluate the combinatory effects of fibrinolytic agents and prostacyclin analogues, we used concentrations of fibrinolytic agents which reduced thrombi weight by less than 50%. Neither iloprost nor taprostene alone demonstrated any thrombolytic effects. Furthermore, the thrombolytic efficacies of streptokinase, alteplase and saruplase were not enhanced by prostacyclin analogues. The thrombolytic activities of alteplase and urokinase, however, were additive. Similarly, the combination of urokinase with saruplase had an additive thrombolytic effect in our in vitro model. The effects of alteplase and saruplase were synergistic at a molar ratio of 1:4.7.

Detection of strands in native aortic valves by transesophageal echocardiography.

Prevalence and echocardiographic characteristics of strands on the leaflets of native aortic valves were examined. According to our data, the strands we found in 39% of patients are most likely Lambl's excrescences.

Quantitative assessment of aortic stenosis by three-dimensional echocardiography.

The purpose of this study was to assess the feasibility of three-dimensional echocardiography in aortic stenosis. Planimetric determination of valve area and dynamic volume-rendered display were performed. Three-dimensional echocardiography permits display of any desired plane of the cardiac structure. Thus in the case of aortic stenosis, the plane used for planimetric evaluation can be positioned exactly through the valve orifice. Dynamic volume-rendered display may provide a spatial demonstration of the stenotic valve. In 48 patients aortic valve area was measured by planimetry. The three-dimensional data set was acquired by a workstation in the course of a multiplane transesophageal examination. Results were compared with those obtained by multiplane transesophageal two-dimensional planimetric technique and invasive measurement. A dynamic three-dimensional reconstruction was displayed. Planimetric determination of valve area was possible in 42 (88%) of 48 cases. Statistical analysis of the data acquired showed a good agreement between three-dimensional echocardiography and transesophageal echocardiography (mean difference +0.018 cm2; SD = 0.086) and between three-dimensional echocardiography and the invasive technique (mean difference +0.012 cm2; SD = 0.12). Dynamic volume-rendered display was possible in 42 of 48 cases. Three-dimensional echocardiography permits accurate and reliable determination of aortic valve area. Preoperative spatial recognition of the stenotic valve is possible by dynamic volume-rendered display.

Comparison of saruplase and alteplase in acute myocardial infarction. SESAM Study Group. The Study in Europe with Saruplase and Alteplase in Myocardial Infarction.

Four hundred seventy-three patients with acute myocardial infarction (AMI) were treated with either saruplase (80 mg/hour, n = 236) or alteplase (100 mg every 3 hours, n = 237). Comedication included heparin and acetylsalicylic acid. Angiography was performed at 45 and 60 minutes after the start of thrombolytic therapy. When flow was insufficient, angiography was repeated at 90 minutes. Coronary angioplasty was then performed if Thrombolysis In Myocardial Infarction (TIMI) trial 0 to 1 flow was seen. Control angiography was at 24 to 40 hours. Baseline characteristics were similar. Angiography showed comparable and remarkably high early patency rates (TIMI 2 or 3 flow) in both treatment groups: at 45 minutes, 74.6% versus 68.9% (p = 0.22); and at 60 minutes 79.9% versus 75.3% (p = 0.26). Patency rates at 90 minutes before additional interventions were also comparable (79.9% and 81.4%). Angiographic reocclusion rates were not significantly different: 1.2% versus 2.4% (p = 0.68). After rescue angioplasty, angiographic reocclusion rates of 22.0% and 15.0% were observed. Safety data were similar for both groups. Thus, (1) early patency rates were high for saruplase and alteplase treatment, (2) reocclusion rates for both drugs were remarkably low, and (3) complication rates were similar. Thus, saruplase seems to be as safe and effective as alteplase.

Inhibition of endothelial vascular cell adhesion molecule-1 expression by nitric oxide involves the induction and nuclear translocation of IkappaBalpha.

The induction of vascular cell adhesion molecule-1 (VCAM-1) expression by tumor necrosis factor (TNF)-alpha requires the activation of nuclear factor-kappaB (NF-kappaB) via a process involving the phosphorylation and degradation of its cytoplasmic inhibitor, IkappaBalpha. We have shown that nitric oxide (NO) decreases VCAM-1 expression via inhibition of NF-kappaB activation. To determine how NO inhibits NF-kappaB, we studied the fate of IkappaBalpha following TNF-alpha stimulation in the presence of NO donors S-nitrosoglutathione and sodium nitroprusside. Activation of NF-kappaB by TNF-alpha occurred within 15 min and coincided with rapid degradation of IkappaBalpha. Co-treatment with NO donors did not prevent IkappaBalpha phosphorylation or degradation. However, after 2 h of TNF-alpha stimulation, NO donors inhibited NF-kappaB activation and augmented IkappaBalpha resynthesis and nuclear translocation by 2.5- and 3-fold, respectively. This correlated with a 75% reduction in TNF-alpha-induced VCAM-1 expression. In a time-dependent manner, NO donors alone caused the nuclear translocation of IkappaBalpha. To confirm that NO donors have similar effects as endogenously derived NO, murine macrophage-like cells, RAW264.7, were co-cultured with endothelial cells. Induction of RAW264.7-derived NO inhibited lipopolysaccharide-induced endothelial VCAM-1 expression, which was reversed by the NO synthase inhibitor Nomega-monomethyl-L-arginine. These findings indicate that NO inhibits NF-kappaB activation and VCAM-1 expression by increasing the expression and nuclear translocation of IkappaBalpha.

Quantification of mitral valve stenosis by three-dimensional transesophageal echocardiography.

The aim of this study was the evaluation of the diagnostic potentials of transesophageal 3D- echocardiography in the determination of mitral valve stenosis. 54 patients were investigated by transthoracic and multiplane transesophageal echocardiography. In 41 patients cardiac catheterization was performed. 3D- echocardiographic data acquisition was performed by automatic transducer rotation at 2 degree increments over a span of 180 degrees. The transesophageal probe was linked to an ultrasound unit and to a 3D- workstation capable of ECG- and respiration gated data acquisition, postprocessing and 2D/3D image reconstruction. The mitral valve was visualized in sequential cross-sectional planes out of the 3D data set. The spatial position of the planes was indicated in a reference image. In the cross-sectional plane with the narrowest part of the leaflets the orifice area was measured by planimetry. For topographic information a 3D view down from the top of the left atrium was reconstructed. Measurements were compared to conventional transthoracic planimetry, to Doppler-echocardiographic pressure half time and to invasive data. The mean difference to transthoracic planimetry, pressure half time and to invasive measurements were 0.3 +/- 0.1 cm2, 0.2 +/- 0.1 cm2 and 0.1 +/- 0.1 cm2, respectively. Remarkable differences between the 3D- echocardiographic and the 2D- or Doppler- echocardiographic methods were observed in patients with severe calcification or aortic regurgitation. In 22% of the patients the 3D data set was not of diagnostic quality. New diagnostic information from a 3D view of the mitral valve could be obtained in 69% of the patients. Thus, although image quality is limited, 3D- echocardiography provides new topographic information in mitral valve stenosis. It allows the use of a new quantitative method, by which image plane positioning errors and flow-dependent calculation is avoided.