Prorenin and the heart : the Mannose 6-phosphate connection

The knowledge concerning the formation of angiotensins at cardiac tissue sites in relation to the presence and origin of cardiac renin, angiotensinogen and ACE is evaluated in chapter 2. To gain insight in the functional importance of locally generated angiotensin 11, the response of human forearm blood flow to infusion of either angiotensin I or angiotensin 11 was investigated (Chapter 3). To extend our results in the perfused isolated rat heart,31 experiments were performed to detect de novo synthesis of RAS components by neonatal rat cardiomyocytes and -fibroblasts under basal conditions and after stretch (Chapter 4). In addition, we characterized the binding and activation of human recombinant prorenin via mannose 6- phosphate/IGF11 receptors on the surface of human endothelial cells, and neonatal rat cardiomyocytes and -fibroblasts (Chapters 5 and 6). To validate our results obtained with human recombinant prorenin, neonatal rat cardiomyocytes were also incubated with human (pro)renin- containing body fluids (Chapter 7). The latter studies also addressed the importance of soluble mannose 6-phosphate/IGF11 receptors. Finally, since 1) under certain conditions man nose 6-phosphate/IGF11 receptor activation initiates transcellu\ar signaling pathways,'2 and 2) renin binding to glomerular mesangial cells leads to plasminogen activator inhibitor type-1 release and an increase in 3H-thymidine incorporation,25 we investigated whether prorenin binding and/or uptake by rat cardiomyocytes, in the presence or absence of angiotensinogen, resulted in a cellular response (Chapter 8). In these latter studies we also investigated intra- and extracellular angiotensin 11 generation and compared the effects of prorenin with those obtained with angiotensin II in parallel experiments

Remote monitoring for better management of LVAD patients: the potential benefits of CardioMEMS

Left ventricular assist devices (LVAD) are frequently used in the treatment of end-stage heart failure (HF), and due to the shortage of heart donors and destination programs, it is likely to keep on growing. Still, LVAD therapy is not without complications and morbidity and rehospitalization rates are high. New ways to improve LVAD care both from the side of the patient and the physician are warranted. Remote monitoring could be a tool to tailor treatment in these patients, as no feedback exists at all about patient functioning on top of the static pump parameters. We aim to provide an overview and evaluation of the novel remote monitoring strategies to optimize LVAD management and elaborate on the opportunities of remote hemodynamic monitoring with CardioMEMS, at home in these patients as the next step to improve care

A new formulation of Kapila\xe2\x80\x99s five-equation model for compressible two-fluid flow, and its numerical treatment

A new formulation of Kapila’s five-equation model for inviscid, non-heat-conducting, compressible two-fluid flow is derived, together with an appropriate numerical method. The new formulation uses flow equations based on conservation laws and exchange laws only. The two fluids exchange momentum and energy, for which exchange terms are derived from physical laws. All equations are written as a single system of equations in integral form. No equation is used to describe the topology of the two-fluid flow. Relations for the Riemann invariants of the governing equations are derived, and used in the construction of an Osher-type approximate Riemann solver. A consistent finite-volume discretization of the exchange terms is proposed. The exchange terms have distinct contributions in the cell interior and at the cell faces. For the exchange-term evaluation at the cell faces, the same Riemann solver as used for the flux evaluation is exploited. Numerical results are presented for two-fluid shock-tube and shock-bubble-interaction problems, the former also for a two-fluid mixture case. All results show good resemblance with reference results

Conditions for superdecoherence

Decoherence is the main obstacle to quantum computation. The decoherence rate perqubit is typically assumed to be constant. It is known, however, that quantum registers coupling to a single reservoir can show a decoherence rate per qubit that increases linearly with the number of qubits. This effect has been referred to as superdecoherence, and has been suggested to pose a threat to the scalability of quantum computation. Here, we show that superdecoherence is absent when the spectrum of the single reservoir is continuous, rather than discrete. The reason of this absence, is that, as the number of qubits is increased, a quantum register inevitably becomes susceptible to an ever narrower bandwidth of frequencies in the reservoir. Furthermore, we show that for superdecoherence to occur in a reservoir with a discrete spectrum, one of the frequencies in the reservoir has to coincide exactly with the frequency the quantum register is most susceptible to. We thus fully resolve the conditions that determine the presence or absence of superdecoherence. We conclude that superdecoherence is easily avoidable in practical realizations of quantum computers

The role of intestinal epithelium in inflammatory bowel disease and inflammation related intestinal cancer

The intestinal epithelial cells(IEC) are indispensable factors in the host protection against the harmful luminal content. In this thesis we aimed to gain further insight in the role of IEC in the Inflammatory Bowel Disease(IBD) aetiology, since it is an important mediator between the already known factors that give onset of IBD. To investigate the IEC involvement in IBD we stimulated freshly isolated biopsies from CD patients with PXR ligands to inhibit the NF-κB(inflammatory key regulator) signalling. We have found that the presence of PXR was more important than the actual PXR activation to inhibit the NF-κB activity. It becomes increasingly clear that the function of PXR goes beyond its primary function in the xenobiotic detoxification pathways. We found that high PXR expression is present exclusively in the neoplastic intestinal epithelium, whereas no PXR protein could be detected in normal or inflamed intestinal tissue. In vitro experiments uncovered that this high PXR expression reduces the growth speed of the cells but increases the high cell density survival. Proper functioning IEC are depending on correctly folded (inside the endoplasmic reticulum(ER)) and expressed proteins. We postulate that inflammation related conditions affect ER-dependent proteins in expression, e.g. ABCG2 and initiate ER-stress. As such, ABCG2 expression and function is impeded due to ER-protein folding difficulties. Besides, ER stress in Paneth cells is found in a subset of CD patients carrying an ATG16L1 risk allele(G). This indicates that multiple factors IBD related factors can provoke protein-folding difficulties. Overall we conclude that, the intestinal epithelium has a distinct function in the aetiology of IBD patients on many disease-associated factors. This thesis justifies the extensive investigation of IEC driven therapeutic approaches for IBD patients

Tailored-therapy of ACE-inhibitors in Coronary Artery Disease: Pharmacogenetic Profiling of Treatment Benefit

To optimally treat patients, and to develop ways to guide ACE-inhibitor treatment, it remains essential to identify those patients most likely to benefit from therapy. New research to elucidate such heterogeneity is necessary. If feasible, guided-therapy of ACE-inhibitors will have a large impact on clinical practice by increasing patient's benefit of drug prescriptions and reducing healthcare costs: to get the right drug to the right patient. The quest for the Holy Grail: tailoring drug therapies to individual patients. The purpose of this thesis was to investigate a new approach to guide ACE-inhibitor therapy using patient specific genetic characteristics (19). We studied the feasibility of pharmacogenetic profiling of the treatment benefit of ACE-inhibitor therapy. We focused on the common genetic variation in the candidate genes of the direct pharmacodynamic pathway of ACE-inhibitors: the renin-angiotensin-system and kallikrein-bradykinin system. These studies were conducted within the randomized placebo-controlled EUROPA-trial studying the ACE-inhibitor perindopril versus placebo in ten thousand patients with stable coronary artery disease. The main research questions we examined were as follows: - Is the treatment benefit (reduction of cardiovascular events) of ACE-inhibitor therapy modified by genetic variation between patients? - Is the level of blood pressure and blood pressure reduction by ACE-inhibitor therapy modified by genetic variation between patients? - Can we develop a pharmacogenetic profile to individualize ACE-inhibitor therapy and optimize patients' benefit in stable coronary artery disease

Comparative Study of IGFBP Properties in Toad and Rat Sera

The levels ofIGF-Ihave been simultaneously measured byradioimmunoassayin samples of the toadBufo arenarumand of normal male Wistar rats. In addition, the different fractions of IGF-I binding proteins (IGFBP) and their binding properties have been identified by ligand blot and Scatchard analysis in the serum of both species. In the toad, we have measured levels of IGF-I (2.78 ± 0.48 ng/ml) similar to those previously reported in amphibians but far below those found in rats. IGFBP levels were estimated at 129 ± 23 and 4249 ± 321 pg/ml in toad and rat serum samples. Two main IGFBP fractions of 30-34 kDa, accompanied by a minor component of 24 kDa and seldom by another of 40 kDa, were identified in toad serum. In rat serum—as already reported—three bands of 40, 30, and 24 kDa were identified, the first being the main component and the last the minor one. The Scatchard analysis of a competitive binding assay showed two types of binding sites in toad serum: one of high affinity-low capacity (Ka1= 1.6 × 1010M-1;R1= 1.2 × 10-11M) and another with low affinity-high capacity (Ka2= 1.9 × 108M-1;R2= 1.9 × 10-10M). The percentage fraction of these binding sites occupied by IGF-I was 13.5%. The figures for K1and K2were lower and those for R1and R2were higher in rat than in toad serum. The percentage fraction of occupied ratIGFbinding sites was 3.6%. The IGF carrier levels (IGFBP5) estimated in our laboratory in samples of rat and toad serum gave figures that were almost 33 times lower in the latter than in the former. Hence, the fraction of free and bound IGF-I in toad and rat blood might be different. Our results provide new evidence of the presence and the properties of IGFBP in amphibians, confirming the wide distribution of this carrier among different species and its possible role as modulator of IGF-I biological effects

Remote monitoring of pulmonary artery pressures with cardiomems in patients with chronic heart failure and nyha class III: First experiences in the Netherlands

We report the first patient experiences with the CardioMEMS device in the Erasmus MC Thorax Center in the Netherlands. In line with clinical trial evidence, the device is applicable in patients with chronic heart failure in functional New York Heart Association class III with at least 1 admission for heart failure in the past 12 months. CardioMEMS has been shown to be safe and reliable, and effective in reducing the number of hospitalisations for heart failure by guided therapy based on pulmonary artery pressures