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This article describes the preparation of hierarchically structured microsieves via a suitable combination of float-casting and inkjet-printing: A mixture of hydrophobized silica particles of 600 nm ± 20 nm diameter, a suitable non-water-soluble nonvolatile acrylic monomer, a nonvolatile photoinitiator, and volatile organic solvents is applied to a water surface. This mixture spontaneously spreads on the water surface; the volatile solvents evaporate and leave behind a layer of the monomer/initiator mixture comprising a monolayer of particles, each particle protruding out of the monomer layer at the top and bottom surface. Photopolymerization of the monomer converts this mixed layer into a solid composite membrane floating on the water surface. Onto this membrane, while still floating on the water surface, a hierarchical reinforcing structure based on a photocurable ink is inkjet-printed and solidified. In contrast to the nonreinforced membrane, the reinforced membrane can easily be lifted off the water surface without suffering damage. Subsequently, the silica particles are removed, and thus, the reinforced composite membrane is converted into a reinforced microsieve of 350 nm ± 50 nm thickness bearing uniform through pores of 465 nm ± 50 nm diameter. This reinforced microsieve is mounted into a filtration unit and used to filter model dispersions: its permeance for water at low Reynolds numbers is in accordance with established theories on the permeance of microsieves and significantly above the permeance of conventional filtration media; it retains particles exceeding the pore size, while letting particles smaller than the pore size pass.

Long-term results of prospective randomized trials comparing triple immunosuppressive strategies combining tacrolimus (TAC) or cyclosporine A (CsA) with mycophenolate mofetil (MMF) and steroids after heart transplantation (HTX) are rarely published. Therefore, we collected long-term follow-up data of an intervention cohort 10 years after randomization.

Background For short-term ventricular and pulmonary support the extracorporeal membrane oxygenation (ECMO) system using the Bio-Medicus centrifugal pump (Medtronic®, Minneapolis, MN, USA) was applied in 108 patients with cardiac low-output.Methods From December 1996 to July 2006 the ECMO was implanted in 108 patients (73 adult, mean age: 49.3±18.0 yrs and 35 children, mean age: 1.3 ± 2.7 yrs) with mostly postcardiotomy cardiac low output. The surgical procedures included congenital heart surgery (n=35), heart transplantation (HTx) (n=21), coronary artery bypass operation (CABG) and/or valvular operation (n=33), other operations (n=6) and 13 patients with ECMO support for bridge to recovery.Results The mean supporting time was 5.1±5.6 days. Overall, 30-day-survival was 40.2%. Best survival rates were seen after congenital heart surgery (24/35, 65.7%) and after HTx (9/21, 42.9%); the worst rates were in the group of CABG and/or valvular operations (5/33, 15.2%), only ECMO support (3/13, 23.1%) and other operations (1/6, 16.7%). Fifty-four patients died while supported by ECMO, 15 were weaned from ECMO but died in hospital, 39 patients were weaned and survived. Causes of death were multi-organ failure (40.6%), bleeding (23.2%), persistent cardiac low output (21.7%), thrombembolic events (8.7%), and graft failure (5.8%). Markers for adverse outcome were identified as older age, high body weight, increased AST/GOT levels, and lower thrombocyte count in adults; and as higher levels of serum creatinine in pediatric patients.Conclusions ECMO support showed best results in pediatric patients after congenital heart surgery and in patients after HTx in contrast to multimorbid, older patients with often irreversible myocardial damage.

The aim of this study was to assess fractional exhaled nitric oxide (FeNO) for the early diagnosis of bronchiolitis obliterans syndrome (BOS) after lung transplantation (LTX). 611 FeNO measurements in 166 consecutive patients were classified depending on BOS stage at the time of assessment and course during minimum follow‐up of 3 months: (1) stable non‐BOS, (2) unstable non‐BOS, (3) stable BOS and (4) unstable BOS. Unstable course was defined as new onset of BOS≥1 or progression of BOS. FeNO before unstable course was significantly increased in comparison to their stable counterparts (non‐BOS: 28.9 ± 1.2 ppb, n = 40 vs. 16.4 ± 0.8 ppb, n = 131 and BOS: 32.5 ± 1.3 ppb, n = 35 vs. 15.3 ± 0.8 ppb, n = 26; p = 0.01 each). Average time from FeNO reading to onset of deterioration was 117 ± 9 days in non‐BOS and 136 ± 9 days in BOS patients. The positive and negative predictive value of FeNO >20 ppb for BOS was 69.0% and 96.9%, respectively. Serial measurements demonstrated significantly lower mean individual variation in stable recipients as compared to stable patients switching to unstable course (3.2 ± 0.3 ppb vs. 12.7 ± 1.4 ppb, p = 0.02). In particular, the excellent negative predictive value of persistently low FeNO readings for future BOS make FeNO assessments a useful tool for continuous risk stratification after LTX.

The aim of this study was to assess fractional exhaled nitric oxide (FeNO) for the early diagnosis of bronchiolitis obliterans syndrome (BOS) after lung transplantation (LTX). 611 FeNO measurements in 166 consecutive patients were classified depending on BOS stage at the time of assessment and course during minimum follow-up of 3 months: (1) stable non-BOS, (2) unstable non-BOS, (3) stable BOS and (4) unstable BOS. Unstable course was defined as new onset of BOS≥1 or progression of BOS. FeNO before unstable course was significantly increased in comparison to their stable counterparts (non-BOS: 28.9 ± 1.2 ppb, n = 40 vs. 16.4 ± 0.8 ppb, n = 131 and BOS: 32.5 ± 1.3 ppb, n = 35 vs. 15.3 ± 0.8 ppb, n = 26; p = 0.01 each). Average time from FeNO reading to onset of deterioration was 117 ± 9 days in non-BOS and 136 ± 9 days in BOS patients. The positive and negative predictive value of FeNO >20 ppb for BOS was 69.0% and 96.9%, respectively. Serial measurements demonstrated significantly lower mean individual variation in stable recipients as compared to stable patients switching to unstable course (3.2 ± 0.3 ppb vs. 12.7 ± 1.4 ppb, p = 0.02). In particular, the excellent negative predictive value of persistently low FeNO readings for future BOS make FeNO assessments a useful tool for continuous risk stratification after LTX.

Pharmacokinetics of mycophenolate mofetil (MMF) show large interindividual variability. Concentration-controlled dosing of MMF based on routine therapeutic drug monitoring, which requires area under the concentration-time curve (mycophenolic acid [MPA]-AUC0-12h) determinations, is uncommon. Dose adjustments are based on predose concentrations (C0h) or side effects. The aim of this study was to compare C0hwith postdose concentrations (C0.5h-C12h) and to develop practical methods for estimation of MPA-AUCs on the basis of a limited sampling strategy (LSS) in heart transplant recipients under MMF and tacrolimus maintenance immunosuppression. Full MPA-AUC0-12hprofiles were generated by high-performance liquid chromatography in 28 patients. Statistical analysis for MPA-AUC0-12hwas performed by a case resampling bootstrap method. Bland and Altmann analysis was performed to test agreement between “predicted AUC” and “measured AUC.” C1hprovided the highest coefficient of determination (r2= 0.57) among the concentrations determined during the 12-hour interval, which were correlated with AUC. All other MPA levels were better surrogates of the MPA-AUC0-12hwhen compared with C0h(r2= 0.14). The best estimation of MPA-AUC0-12hwas achieved with four sampling points with the algorithm AUC = 1.25*C1h+ 5.29*C4h+ 2.90*C8h+ 3.61*C10h(r2= 0.95). Since LSS with four time points appeared unpractical, the authors prefer models with three or two points. To optimize practicability, LSS with sample points within the first 2 hours were evaluated resulting in the algorithms: AUC = 1.09*C0.5h+ 1.19*C1h+ 3.60*C2h(r2= 0.84) and AUC = 1.65*C0.5h+ 4.74*C2h(r2= 0.75) for three and two sample points, respectively. The results provide strong evidence for the use of either LSS or the use of time points other than C0hfor therapeutic drug monitoring of MMF. Using the algorithms for the estimation of MPA-AUC0-12hbased on LSS within the first 2 hours after MMF dosing may help to optimize treatment with MMF by individualization of dosing.

Bronchiolitis obliterans syndrome (BOS) is the major problem after lung and heart-lung transplantation (LTx/HLTx). Sirolimus (Sir) and Mycophenolate (MMF) showed a promising efficacy in the treatment of BOS in animal models. The first clinical experience in converting LTx/HLTx-recipients with BOS from calcineurin inhibitor-(CNI)-based immunosuppression to a Sir-MMF based immunosuppression is reported herein.

Calcineurin-inhibitor (CNI)-related renal failure is a common problem after cardiac transplantation (HTx). The aim of this study was to introduce a CNI-free immunosuppressive regimen to HTx recipients with late posttransplant renal impairment and to evaluate the impact of conversion to this new immunosuppression (mycophenolate mofetil MMF and sirolimus Sir) treatment on renal function.

The role of cardiac sympathetic nerves in the regulation of myocardial metabolism is not well defined. Owing to the presence of incomplete reinnervation, heart transplant recipients provide a unique model to study the effects of efferent sympathetic innervation. Using this model, we sought to determine the influence of cardiac sympathetic signals on substrate utilisation and overall oxidative metabolism. In 21 transplant recipients, positron emission tomography was applied to determine sympathetic innervation with the noradrenaline analogue carbon-11 hydroxyephedrine, oxidative metabolism with carbon-11 acetate (n=14), and glucose utilisation with fluorine-18 fluorodeoxyglucose (n=7). The reinnervated area comprised 22%±20% of the left ventricle. Oxidative metabolism was similar in denervated and reinnervated myocardium [0.06±0.01 vs 0.06±0.01/min for k(mono)], while glucose uptake was significantly higher in denervated myocardium (6.9±6.6 vs 6.0±6.2 µmol/min/100 g; P=0.03). Reinnervation mainly occurred in the territory of the left anterior descending artery, where retention of 11C-hydroxyephedrine (6.8±2.7%/min) was higher compared with territories of the left circumflex (4.1±1.7%/min; P<0.01) and right coronary (3.8±1.1%/min; P<0.01) arteries. Oxidative metabolism was similar in all three territories, but compared with the reinnervated territory of the left anterior descending artery (53%±16% of maximum), relative FDG uptake was higher in territories of the left circumflex (76%±6%, P<0.01) and right coronary (67%±10%, P<0.05) arteries. Similar degrees of regional heterogeneity were not observed in normals. Thus, while overall energy production through oxidative metabolism remains unaffected, cardiac utilisation of glucose in the fasting state is increased in the absence of catecholamine uptake sites. Innervated myocardium, however, may preferentially utilise free fatty acids, suggesting a role for sympathetic tone in substrate utilisation.

Abstract Endothelial dysfunction precedes and predicts transplant vasculopathy. We investigated the relationship between endothelial dysfunction and the vasoactive mediators nitric oxide and endothelin, 33.7 ± 2.0 days after heart transplantation. Coronary flow was measured in 18 patients to determine the endothelial microvascular vasomotor response to acetylcholine. Endomyocardial biopsies were taken to determine the levels of gene expression of isozymes of endothelin and nitric oxide synthases (NOS). Blood samples from the coronary sinus and aorta were withdrawn for measurement of endothelin, nitrite and cytokines. Five patients (30 %) showed an impaired coronary flow reserve response to acetylcholine, significantly higher inducible NOS gene expression and significant transcardiac nitrite production. Plasma nitrite correlated with tumour necrosis factor-alpha levels in coronary sinus and a transcardiac net extraction of endothelin was noted in all patients. In conclusion, 30 % of patients develop endothelial dysfunction early after heart transplantation; this correlates with the expression and activation of vasoactive and immunomodulatory mediators, which may predict the development of transplant vasculopathy.

AbstractEndothelial dysfunction precedes and predicts transplant vasculopathy. We investigated the relationship between endothelial dysfunction and the vasoactive mediators nitric oxide and endothelin, 33.7 ± 2.0 days after heart transplantation. Coronary flow was measured in 18 patients to determine the endothelial microvascular vasomotor response to acetylcholine. Endomyocardial biopsies were taken to determine the levels of gene expression of isozymes of endothelin and nitric oxide synthases (NOS). Blood samples from the coronary sinus and aorta were withdrawn for measurement of endothelin, nitrite and cytokines. Five patients (30 %) showed an impaired coronary flow reserve response to acetylcholine, significantly higher inducible NOS gene expression and significant transcardiac nitrite production. Plasma nitrite correlated with tumour necrosis factor‐alpha levels in coronary sinus and a transcardiac net extraction of endothelin was noted in all patients. In conclusion, 30 % of patients develop endothelial dysfunction early after heart transplantation; this correlates with the expression and activation of vasoactive and immunomodulatory mediators, which may predict the development of transplant vasculopathy.