Early Treatment with Fumagillin, an Inhibitor of Methionine Aminopeptidase-2, Prevents Pulmonary Hypertension in Monocrotaline-Injured Rats

Pulmonary Hypertension (PH) is a pathophysiologic condition characterized by hypoxemia and right ventricular strain. Proliferation of fibroblasts, smooth muscle cells, and endothelial cells is central to the pathology of PH in animal models and in humans. Methionine aminopeptidase-2 (MetAP2) regulates proliferation in a variety of cell types including endothelial cells, smooth muscle cells, and fibroblasts. MetAP2 is inhibited irreversibly by the angiogenesis inhibitor fumagillin. We have previously found that inhibition of MetAP2 with fumagillin in bleomycin-injured mice decreased pulmonary fibrosis by selectively decreasing the proliferation of lung myofibroblasts. In this study, we investigated the role of fumagillin as a potential therapy in experimental PH. In vivo, treatment of rats with fumagillin early after monocrotaline injury prevented PH and right ventricular remodeling by decreasing the thickness of the medial layer of the pulmonary arteries. Treatment with fumagillin beginning two weeks after monocrotaline injury did not prevent PH but was associated with decreased right ventricular mass and decreased cardiomyocyte hypertrophy, suggesting a direct effect of fumagillin on right ventricular remodeling. Incubation of rat pulmonary artery smooth muscle cells (RPASMC) with fumagillin and MetAP2-targeting siRNA inhibited proliferation of RPASMC in vitro. Platelet-derived growth factor, a growth factor that is important in the pathogenesis of PH and stimulates proliferation of fibroblasts and smooth muscle cells, strongly increased expression of MetP2. By immunohistochemistry, we found that MetAP2 was expressed in the lesions of human pulmonary arterial hypertension. We propose that fumagillin may be an effective adjunctive therapy for treating PH in patients

Approximate analytic expressions using Stokes model for tokamak polarimetry and their range of validity

The analysis of the polarimetry measurements has the aim of validating models (De Marco and Segre 1972 Plasma Phys. 14 245), with a careful attention to the clarification of their limits of application. In this paper a new approximation method is introduced, the so-called special constant Omega direction (SCOD), which gives an analytical solution to the polarimetry exact Stokes model equations. The available approximate solutions (including SCOD) of the polarimetry propagation equations are presented, compared and their application limits determined, using a reference tokamak configuration, which is a simplified equilibrium for a circular tokamak. The SCOD approximation is compared successfully to the Stokes model in the context also of equilibria evaluated for two JET discharges. The approximation methods are analytical or very simple mathematical expressions which can also be used in equilibrium codes for their optimization

Energetic ion losses 'channeling' mechanism and strategy for mitigation

Results from two different sets of JET experiments are presented. In experiments in which toroidicity-induced Alfven eigenmodes (TAEs) localized at different radial locations had the same frequencies and toroidal mode numbers, the occurrence of enhanced losses after the excitation of TAEs in the core of the plasma was observed. On the contrary, enhanced losses were not observed if the TAEs localized at different radial locations had different frequencies and toroidal mode numbers. Numerical modeling indicates that, in the first set of experiments, the enhanced losses were caused by a combined effect of the TAEs localized at different radial locations. The TAEs localized in the plasma core transported energetic ions from the core to outer regions of the plasma. Then, the TAEs localized in outer regions of the plasma interacted with these ions just transported by the core-localized TAEs causing a further radial displacement of the ions to the plasma edge. This process eventually ends up causing the loss of the resonant ions. In the second set of experiments, it was found that TAEs localized in the plasma core and in outer regions did not interact with the same ions and so no enhanced losses were measured. Sheared profiles of the safety factor combined with flat mass density profiles lead to larger differences on the frequencies of the TAEs localized at different radial locations, eventually avoiding loss of energetic ions through the described mechanism

Modification of the Alfven wave spectrum by pellet injection

Alfven eigenmodes driven by energetic particles are routinely observed in tokamak plasmas. These modes consist of poloidal harmonics of shear Alfven waves coupled by inhomogeneity in the magnetic field. Further coupling is introduced by 3D inhomogeneities in the ion density during the assimilation of injected pellets. This additional coupling modifies the Alfven continuum and discrete eigenmode spectrum. The frequencies of Alfven eigenmodes drop dramatically when a pellet is injected in JET. From these observations, information about the changes in the ion density caused by a pellet can be inferred. To use Alfven eigenmodes for MHD spectroscopy of pellet injected plasmas, the 3D MILD codes Stellgap and AE3D were generalised to incorporate 3D density profiles. A model for the expansion of the ionised pellet plasmoid along a magnetic field line was derived from the fluid equations. Thereby, the time evolution of the Alfven eigenfrequency is reproduced. By comparing the numerical frequency drop of a toroidal Alfven eigenmode (TAE) to experimental observations, the initial ion density of a cigar-shaped ablation region of length 4cm is estimated to be n(*) = 6.8 x 10(22) m(-3) at the TAE location (r/a approximate to 0.75). The frequency sweeping of an Alfven eigenmode ends when the ion density homogenises poloidally. Modelling suggests that the time for poloidal homogenisation of the ion density at the TAE position is tau(h) = 18 +/- 4 ms for inboard pellet injection, and tau(h) = 26 +/- 2 ms for outboard pellet injection. By reproducing the frequency evolution of the elliptical Alfven eigemnode (EAE), the initial ion density at the EAE location (r/a approximate to 0.9) can be estimated to be n(*) = 4.8 x 10(22) m(-3). Poloidal homogenisation of the ion density takes 2.7 times longer at the EAE location than at the TAE location for both inboard and outboard pellet injection

Role of fast ion pressure in the isotope effect in JET L-mode plasmas

This paper presents results of JET ITER-like wall L-mode experiments in hydrogen and deuterium (D) plasmas, dedicated to the study of the isotope dependence of ion heat transport by determination of the ion critical gradient and stiffness by varying the ion cyclotron resonance heating power deposition. When no strong role of fast ions in the plasma core is expected, the main difference between the two isotope plasmas is determined by the plasma edge and the core behavior is consistent with a gyro-Bohm scaling. When the heating power (and the fast ion pressure) is increased, in addition to the difference in the edge region, also the plasma core shows substantial changes. The stabilization of ion heat transport by fast ions, clearly visible in D plasmas, appears to be weaker in H plasmas, resulting in a higher ion heat flux in H with apparent anti-gyro-Bohm mass scaling. The difference is found to be caused by the different fast ion pressure between H and D plasmas, related to the heating power settings and to the different fast ion slowing down time, and is completely accounted for in non-linear gyrokinetic simulations. The application of the TGLF quasi-linear model to this set of data is also discussed

Long-lived coupled peeling ballooning modes preceding ELMs on JET

In some JET discharges, type-I edge localised modes (ELMs) are preceded by a class of low-frequency oscillations (Perez et al 2004 Nucl. Fusion 44 609). While in many cases the ELM is triggered during the growth phase of this oscillation, it is also observed that this type of oscillation can saturate and last for several tens of ms until an ELM occurs. In order to identify the nature of these modes, a wide pre-ELM oscillation database, including detailed pedestal profile information, has been assembled and analysed in terms of MHD stability parameters. The existence domain of these pre-ELM oscillations and the statistical distribution of toroidal mode numbers (n) up to n = 16 have been mapped in ballooning alpha (alpha(ball)) and either edge current density (J(edge)) or pedestal collisionality (nu(ee,ped)*) coordinates and compared to linear MHD stability predictions. The pre-ELM oscillations are reliably observed when the J/alpha ratio is high enough for the pedestal to access the coupled peeling-ballooning (PB) domain (aka stability nose). Conversely, when the pedestal is found to be in or near the high-n ballooning domain (which is at low J/alpha ratio), ELMs are usually triggered promptly, i.e. with no detectable pre-ELM oscillations, or with pre-ELM oscillations only observable on ECE whose n appears to be too high to be resolved by the magnetics. Individual discharges can sometimes exhibit a fairly wide range of pre-ELM mode numbers, but for a wider database, the statistical n-number domains are found to be well ordered along the J - alpha stability boundary and behave as expected from PB theory: the higher the J/alpha ratio, the lower the mode's measured n tends to be. Within the measurement uncertainties, the measured n is usually found to be compatible with the most unstable n predicted by the linear stability code MISHKA1. These results confirm the earlier hypothesis that these modes are coupled peeling-ballooning modes, and extend and generalise to higher-mode numbers the work by Huysmans et al (1998 Nucl. Fusion 38 179), who identified the lowest n modes as pure external kink modes. Since the destabilisation of PB modes is widely accepted to give rise to ELMs, the mode saturation and delayed ELM triggering that is sometimes observed is rather unexpected. Possibilities to reconcile the extended lifetime of these modes with current ELM models are briefly discussed, but will require further investigation