Transfer of Direct and Moiré Patterns by Reactive Ion Etching Through Ex Situ Fabricated Nanoporous Polymer Masks.

We present a conceptually simple approach to nanolithographic patterning utilizing ex situ fabricated nanoporous masks from block copolymers. The fabricated block copolymer (BC) masks show predictable morphology based on the correlation between BC composition and bulk properties, independent of substrates' surface properties. The masks are prepared by microtoming of prealigned nanoporous polymer monoliths of hexagonal morphology at controlled angles; they appear as 30-60 nm thick films of typical dimensions 100 µm × 200 µm. Masks cut perpendicular to the cylindrical axis show monocrystalline hexagonal packing of 10 nm pores with a principal period of 20 nm. We demonstrate the transfer of the hexagonal pattern onto silicon by means of reactive ion etching through the masks. In addition, patterns of elliptic and slit-like holes on silicon are obtained by utilizing masks cut at 45° relative to the cylinder axis. Finally, we demonstrate the first transfer of moiré patterns from block copolymer masks to substrate. The nanoporous masks prepared ex situ show outstanding long-range order and can be applied directly onto any flat substrate, eliminating the need for topographic and chemical surface modification, which are essential prerequisites for the conventional procedure of block copolymer directed self-assembly. The demonstrated elliptic and moiré pattern transfers prove that the proposed ex situ procedure allows us to realize nanolithographic patterns that are difficult to realize by the conventional approach alone.

Inhaled nitric oxide versus aerosolized iloprost for the treatment of pulmonary hypertension with left heart disease.

OBJECTIVE: To determine the effects of inhaled nitric oxide (NO) and aerosolized iloprost on pulmonary hemodynamics and lung edema formation in a rat model of pulmonary hypertension due to congestive heart failure (CHF). DESIGN: Prospective, randomized, controlled study. SETTING: Research laboratory. SUBJECTS: One hundred sixty male Sprague-Dawley rats. INTERVENTIONS: CHF was induced by supracoronary aortic banding whereas sham-operated rats served as controls. CHF rats or controls inhaled NO, aerosolized iloprost, or 0.9% NaCl for 3 minutes each. Additional CHF groups received intravenous infusions of iloprost, sodium nitroprusside, or 0.9% NaCl. For prolonged drug administration over 150 minutes, NO was inhaled continuously whereas aerosolized iloprost was administered for 3 minutes each at 45-minute intervals. MEASUREMENTS AND MAIN RESULTS: Dose-response relations in rats with CHF showed a maximal pulmonary-selective reduction in blood pressure at 20 ppm NO and 2.5 microg/mL aerosolized iloprost, with iloprost therapy resulting in a greater decrease in pulmonary arterial pressure (PAP). At these doses, both vasodilators decreased pulmonary vascular resistance and increased venous oxygen saturation (Svo2) in the absence of systemic hemodynamic effects. No pulmonary or systemic effects were detected in rats with CHF inhaling 0.9% NaCl or in control rats inhaling NO or iloprost. Intravenous infusion of iloprost or sodium nitroprusside not only reduced pulmonary but also systemic vascular resistance. During prolonged inhalation, NO caused a stable reduction in PAP, whereas PAP decreased even further during repetitive iloprost inhalations. After 150 minutes, iloprost-treated rats had a higher Svo2 and lesser edema as compared with animals with CHF inhaling NO or untreated rats with CHF, although differences in wet/dry weight ratio did not reach statistical significance (p < 0.06). CONCLUSIONS: Inhaled vasodilators may offer an effective, safe, and pulmonary-selective strategy for the treatment of pulmonary hypertension in left heart disease, and inhaled iloprost may be superior to NO in this condition.

Inhalation of the phosphodiesterase-3 inhibitor milrinone attenuates pulmonary hypertension in a rat model of congestive heart failure.

BACKGROUND: Most patients with congestive heart failure (CHF) develop pulmonary venous hypertension, but right ventricular afterload is frequently further elevated by increased pulmonary vascular resistance. To investigate whether inhalation of a vasodilatory phosphodiesterase-3 inhibitor may reverse this potentially detrimental process, the authors studied the effects of inhaled or intravenous milrinone on pulmonary and systemic hemodynamics in a rat model of CHF. METHODS: In male Sprague-Dawley rats, CHF was induced by supracoronary aortic banding, whereas sham-operated rats served as controls. Milrinone was administered as an intravenous infusion (0.2-1 microg.kg body weight.min) or by inhalation (0.2-5 mg/ml), and effects on pulmonary and systemic hemodynamics and lung water content were measured. RESULTS: In CHF rats, intravenous infusion of milrinone reduced both pulmonary and systemic arterial blood pressure. In contrast, inhalation of milrinone predominantly dilated pulmonary blood vessels, resulting in a reduced pulmonary-to-systemic vascular resistance ratio. Repeated milrinone inhalations in 20-min intervals caused a stable reduction of pulmonary artery pressure. No hemodynamic effects were detected when 0.9% NaCl was administered instead of milrinone or when milrinone was inhaled in sham-operated rats. No indications of potentially adverse effects of milrinone inhalation in CHF, such as left ventricular volume overload, were detected. Moreover, lung edema was significantly reduced by repeated milrinone inhalation. CONCLUSION: If these results can be confirmed in humans, inhalation of nebulized milrinone may present a novel, effective, safe, and pulmonary selective strategy for the treatment of pulmonary venous hypertension in CHF.

Inhaled aerosolized iloprost in the evaluation of heart transplant candidates--experiences with 45 cases.

PURPOSE: Pulmonary hypertension represents a significant predictor of postoperative right heart insufficiency and increased mortality in patients undergoing orthotopic heart transplantation. As the use of intravenous vasodilators is limited by their systemic effects, we evaluated the pulmonary and systemic hemodynamic effects of inhaled aerosolized iloprost in heart transplant candidates with elevated pulmonary vascular resistance. METHODS: Forty-five male heart transplant candidates with dilated or ischemic cardiomyopathy were included in the study. After assessing baseline hemodynamics, 20 microg of aerosolized iloprost was administered by ultrasonic inhalation. All patients were breathing spontaneously. RESULTS: Inhalation of iloprost reduced pulmonary vascular resistance index (395 +/- 205 vs 327 +/- 222 dyne.s.cm(-5).m(-2); P < 0.05) and mean pulmonary arterial pressure (28.7 +/- 10 vs 24.3 +/- 10 mm Hg; P < 0.05). An additional improvement of ventricular performance with an increase of cardiac index (2.7 +/- 0.7 vs 3.0 +/- 0.8 L.min(-1).m(-2); P < 0.05) and a decrease of pulmonary capillary wedge pressure (16.6 +/- 7.7 vs 13.4 +/- 7.3 mm Hg; P < 0.05) was accompanied by a slight decrease of systemic vascular resistance (1280 +/- 396 vs 1172 +/- 380 dyne.s.cm(-5); P < 0.05). However, the mean arterial pressure remained uninfluenced. CONCLUSIONS: Inhaled aerosolized iloprost effectively reduces mean pulmonary arterial pressure and also induces an increase in cardiac index. Further advantages of iloprost inhalation are the lack of adverse reactions and ease of administration. Iloprost represents a useful drug to screen for vascular reactivity in cardiac transplantation patients.

Heparin-level-based anticoagulation management during cardiopulmonary bypass: a pilot investigation on the effects of a half-dose aprotinin protocol on postoperative blood loss and hemostatic activation and inflammatory response.

UNLABELLED: Cardiac surgery involving cardiopulmonary bypass (CPB) leads to activation of the hemostatic/inflammatory system. We compared the influence of a half-dose aprotinin regimen on postoperative blood loss and the activation of the hemostatic/inflammatory system during CPB, when used during a heparin-level-based heparin management for cardiac surgery. Two-hundred patients (n = 100 in each group) were enrolled in this randomized prospective study. In Group I only heparin was given according to the results of the Hepcon HMS Plus. In Group II aprotinin was added with a bolus of 1 x 10(6) kallikrein inhibiting units (KIU) for the patient immediately before initiation of CPB, 1 x 10(6) KIU in the priming solution of the CPB, and a continuous infusion of 250,000 KIU/h during CPB. Postoperative blood loss was determined after 12 h. Heparin and antithrombin activity were evaluated by an anti-Xa assay and measurement of antithrombin III activity. Hemostatic activation was evaluated by adenosine diphosphate-stimulated platelet aggregometry and by measurements of the generation/release of beta-thromboglobulin (beta-TG), soluble P-selectin (sPS), thrombin (TAT), prothrombin 1 and 2 fragments (PTF1+2), factor XIIa (FXIIa), plasmin (PAP), and D-dimers. Inflammatory response was evaluated by measuring complement factors 5b-9 (C5b-9), interleukin (IL)-6, and neutrophil elastase (NE). There were no differences in the pre-CPB values or duration of CPB between the two groups. There were no differences in the post-CPB values for platelet count, platelet aggregation, beta-TG, sPS, TAT, PTF1+2, C5b-9, NE, or IL-6. The additional use of aprotinin resulted in a significant decrease of PAP, D-dimers, and 12 h postoperative blood loss, whereas generation of the contact factor XIIa was increased. The administration of aprotinin significantly reduced postoperative blood loss after cardiac surgery and CPB. This most likely has to be attributed to the antifibrinolytic effects of aprotinin. No effects on thrombin generation, platelet activation, inflammatory response, or clinical outcome were noted. IMPLICATIONS: The use of half-dose aprotinin and heparin-level-based anticoagulation management during cardiopulmonary bypass leads to a significant reduction of postoperative blood loss after cardiac surgery. This effect can most likely be attributed to the antifibrinolytic effects of aprotinin, as we did not observe effects on other variables of activation of the hemostatic/inflammatory system.

Iloprost improves hemodynamics in patients with severe chronic cardiac failure and secondary pulmonary hypertension.

PURPOSE: Significant pulmonary hypertension is a predictor of postoperative right heart insufficiency and increased mortality in patients undergoing orthotopic heart transplantation. Since the use of iv vasodilators is limited by their systemic effects, we evaluated the pulmonary and systemic hemodynamic effects of inhaled aerosolized iloprost (IP) in heart transplant candidates with elevated pulmonary vascular resistance (PVR). METHODS: Twenty-nine male heart transplant candidates because of dilated or ischemic cardiomyopathy with elevated PVR were included in the study. After assessing baseline hemodynamics, 50 micro g aerosolized IP were administered by inhalation. RESULTS: Inhalation of iloprost reduced PVR index (PVRI; 416 +/- 180 vs 349 +/- 173 dyn x sec(-1) x m(-2) x cm(-5); P < 0.01) and mean pulmonary artery pressure (MPAP; 28.6 +/- 9 vs 24.2 +/- 9.1 mmHg; P < 0.01), but did not affect blood pressure or systemic vascular resistance. An additional improvement of ventricular performance with an increase of cardiac index (CI; 2.8 +/- 0.7 vs 2.6 +/- 0.7 L x min(-1) x m(-2); P < 0.05) and a decrease of pulmonary capillary wedge pressure (PCWP; 15.6 +/- 6.8 vs 12.8 +/- 7.1 mmHg; P < 0.01) was observed after inhalation of IP. CONCLUSIONS: Inhaled aerosolized iloprost effectively reduces MPAP and is accompanied by an increase in CI and stroke index. Further advantages of iloprost inhalation are the lack of adverse reactions and ease of administration. Iloprost may be a useful drug to screen for vascular reactivity in cardiac transplantation patients.

Hemodynamic effects of inhaled aerosolized iloprost and inhaled nitric oxide in heart transplant candidates with elevated pulmonary vascular resistance.

OBJECTIVE: An elevated pulmonary vascular resistance (PVR) is described as a predictor of postoperative right heart failure and increased mortality in patients undergoing orthotopic heart transplantation. The use of intravenous vasodilators is limited by their systemic effects. We evaluated the pulmonary and systemic hemodynamic effects of inhaled nitric oxide (NO) and inhaled aerosolized iloprost (IP) in heart transplant candidates with elevated PVR. METHODS: Fourteen male heart transplant candidates due to dilative or ischemic cardiomyopathia with elevated PVR (> or = 180 dyn s cm(-5)) were included in the study. Increasing concentrations of NO (5, 10 and 30 ppm) and 50 microg aerosolized IP were administered by inhalation. Hemodynamic measurements preceded and followed administration of each agent. RESULTS: Inhalation of IP, 10, and 30 ppm NO reduced PVR and mean pulmonary artery pressure (MPAP), but did not affect blood pressure or systemic vascular resistance. Comparing the effectiveness of 10 ppm NO and IP, we found a significant higher reduction of MPAP in patients treated with IP. An increase of cardiac index and stroke index could only be shown with IP-inhalation. CONCLUSIONS: Inhaled iloprost induces pulmonary vasodilation which is significantly greater than the effects of 10 and 30 ppm NO. The results of our study show, that inhaled iloprost induces a reliable hemodynamic response in the evaluation of heart transplant candidates. Further advantages of iloprost inhalation are the lack of adverse reactions and toxic side effects and an easier administration. Due to this facts we recommend iloprost as a routine screening drug for vascular reactivity in HTx-candidates. Based on our results it would be of great interest to investigate the role of iloprost in management of postoperative right heart insufficiency following cardiac transplantation.