Defective nitric oxide synthesis: a link between metabolic insulin resistance, sympathetic overactivity and cardiovascular morbidity.

Epidemiological studies demonstrate an association between insulin resistance, hypertension and cardiovascular morbidity. In addition to its metabolic effects, insulin also has important cardiovascular actions. The sympathetic nervous system and the nitric oxide-l-arginine pathway have emerged as central players in the mediation of these actions. Over the past decade, the underlying mechanisms and the factors that may govern the interaction between insulin and these two major cardiovascular regulatory systems have been studied extensively in healthy people and insulin-resistant individuals. Here we summarize the current understanding and gaps in knowledge on these interactions. We propose that a genetic and/or acquired defect of nitric oxide synthesis could represent a central defect triggering many of the metabolic, vascular and sympathetic abnormalities characteristic of insulin-resistant states, all of which may predispose to cardiovascular disease.

Planificació del procés de producció en sèrie d'un silenciós d'escapament per a un turisme de gamma mitjana

A partir d'un disseny d'un silenciós, s'estudien tots els processos i la maquinària necessària per a implantar la fabricació en sèrie del producte, i d'aquesta manera es poden donar unes pautes generals per la fàbrica que haurà d'acollir aquest procés.

Interplay between connexin40 and nitric oxide signaling during hypertension.

Connexins (Cxs) and endothelial nitric oxide synthase (eNOS) contribute to the adaptation of endothelial and smooth muscle cells to hemodynamic changes. To decipher the in vivo interplay between these proteins, we studied Cx40-null mice, a model of renin-dependent hypertension which displays an altered endothelium-dependent relaxation of the aorta because of reduced eNOS levels. These mice, which were either untreated or subjected to the 1-kidney, 1-clip (1K1C) procedure, a model of volume-dependent hypertension, were compared with control mice submitted to either the 1K1C or the 2-kidney, 1-clip (2K1C) procedure, a model of renin-dependent hypertension. All operated mice became hypertensive and featured hypertrophy and altered Cx expression of the aorta. The combination of volume- and renin-dependent hypertension in Cx40-/- 1K1C mice raised blood pressure and cardiac weight index. Under these conditions, all aortas showed increased levels of Cx40 in endothelial cells and of both Cx37 and Cx45 in smooth muscle cells. In the wild-type 1K1C mice, the interactions between Cx40 and Cx37 with eNOS were enhanced, resulting in increased NO release. The Cx40-eNOS interaction could not be observed in mice lacking Cx40, which also featured decreased levels of eNOS. In these animals, the volume overload caused by the 1K1C procedure resulted in increased phosphorylation of eNOS and in a higher NO release. The findings provide evidence that Cx40 and Cx37 play an in vivo role in the regulation of eNOS.

Modern Gamma Knife radiosurgery of vestibular schwannomas: treatment concept, volumetric tumor response, and functional results.

The objective of the present study was longitudinal evaluation of the volumetric tumor response and functional results after Gamma Knife radiosurgery of vestibular schwannomas, performed according to the modern standards of treatment. From October 2003 to September 2007, 133 consecutive patients with vestibular schwannomas were treated according to the concept of robotic Gamma Knife microradiosurgery, which is based on precise irradiation of the lesion, sparing adjacent structures, and delivery of the high radiation energy to the target. Multiple small-sized isocenters located within the border of the neoplasm were applied. The mean marginal dose was 11.5 Gy (range, 11-12 Gy). In total, 126 cases with a minimum posttreatment follow-up of 2 years (range, 2-7 years; median, 4 years) were analyzed. Temporary enlargement was noted in 25 % of tumors at 6 months after radiosurgery. At 3 years of follow-up, tumor shrinkage, stabilization, and increase in volume were marked in 73 %, 23 %, and 4 % of cases, respectively. All progressing lesions spontaneously stabilized later on and did not require additional management. In 3 % of patients, transitory impairment of the facial nerve function was marked; however, neither its permanent dysfunction nor trigeminal neuropathy attributed to radiosurgery was noted. Impairment of hearing compared to its pretreatment level was revealed in 4 %, 12 %, 13 %, and 16 % of patients at 6 months, 1 year, 2 years, and 3 years after radiosurgery, respectively, and this trend was statistically significant (P = 0.0042). Overall, 77 % of patients with serviceable hearing before treatment preserved it 3 years thereafter. In conclusion, modern Gamma Knife radiosurgery provides effective and safe management of vestibular schwannomas. Nevertheless, possible temporary tumor enlargement, delay of its growth arrest, transient dysfunction of the cranial nerves, and gradual deterioration of hearing after irradiation should be always taken into consideration.

Physicochemical characterization of nebulized superparamagnetic iron oxide nanoparticles (SPIONs)

Abstract Background: Aerosol-mediated delivery of nano-based therapeutics to the lung has emerged as a promising alternative for treatment and prevention of lung diseases. Superparamagnetic iron oxide nanoparticles (SPIONs) have attracted significant attention for such applications due to their biocompatibility and magnetic properties. However, information is lacking about the characteristics of nebulized SPIONs for use as a therapeutic aerosol. To address this need, we conducted a physicochemical characterization of nebulized Rienso, a SPION-based formulation for intravenous treatment of anemia. Methods: Four different concentrations of SPION suspensions were nebulized with a one-jet nebulizer. Particle size was measured in suspension by transmission electron microscopy (TEM), photon correlation spectroscopy (PCS), and nanoparticle tracking analysis (NTA), and in the aerosol by a scanning mobility particle sizer (SMPS). Results: The average particle size in suspension as measured by TEM, PCS, and NTA was 9±2 nm, 27±7 nm, and 56±10 nm, respectively. The particle size in suspension remained the same before and after the nebulization process. However, after aerosol collection in an impinger, the suspended particle size increased to 159±46 nm as measured by NTA. The aerosol particle concentration increased linearly with increasing suspension concentration, and the aerodynamic diameter remained relatively stable at around 75 nm as measured by SMPS. Conclusions: We demonstrated that the total number and particle size in the aerosol were modulated as a function of the initial concentration in the nebulizer. The data obtained mark the first known independent characterization of nebulized Rienso and, as such, provide critical information on the behavior of Rienso nanoparticles in an aerosol. The data obtained in this study add new knowledge to the existing body of literature on potential applications of SPION suspensions as inhaled aerosol therapeutics.

The star forming region Monoceros R2 as a gamma-ray source

After the release of the gamma-ray source catalog produced by the Fermi satellite during its first two years of operation, a significant fraction of sources still remain unassociated at lower energies. In addition to well-known high-energy emitters (pulsars, blazars, supernova remnants, etc.), theoretical expectations predict new classes of gamma-ray sources. In particular, gamma-ray emission could be associated with some of the early phases of stellar evolution, but this interesting possibility is still poorly understood. Aims: The aim of this paper is to assess the possibility of the Fermi gamma-ray source 2FGL J0607.5-0618c being associated with the massive star forming region Monoceros R2. Methods: A multi-wavelength analysis of the Monoceros R2 region is carried out using archival data at radio, infrared, X-ray, and gamma-ray wavelengths. The resulting observational properties are used to estimate the physical parameters needed to test the different physical scenarios. Results: We confirm the 2FGL J0607.5-0618c detection with improved confidence over the Fermi two-year catalog. We find that a combined effect of the multiple young stellar objects in Monoceros R2 is a viable picture for the nature of the source.

Very-High-Energy gamma rays from a Distant Quasar: How Transparent Is the Universe?

The atmospheric Cherenkov gamma-ray telescope MAGIC, designed for a low-energy threshold, has detected very-high-energy gamma rays from a giant flare of the distant Quasi-Stellar Radio Source (in short: radio quasar) 3C 279, at a distance of more than 5 billion light-years (a redshift of 0.536). No quasar has been observed previously in very-high-energy gamma radiation, and this is also the most distant object detected emitting gamma rays above 50 gigaelectron volts. Because high-energy gamma rays may be stopped by interacting with the diffuse background light in the universe, the observations by MAGIC imply a low amount for such light, consistent with that known from galaxy counts.

The changing milliarcsecond radio morphology of the gamma-ray binary LS 5039

LS 5039 is one of the few TeV emitting X-ray binaries detected so far. The powering source of its multiwavelength emission can be accretion in a microquasar scenario or wind interaction in a young nonaccreting pulsar scenario. Aims.To present new high-resolution radio images and compare them with the expected behavior in the different scenarios. Methods.We analyze Very Long Baseline Array (VLBA) radio observations that provide morphological and astrometric information at milliarcsecond scales. Results.We detect a changing morphology between two images obtained five days apart. In both runs there is a core component with a constant flux density, and an elongated emission with a position angle (PA) that changes by 12 $\pm$ $3\degr$ between both runs. The source is nearly symmetric in the first run and asymmetric in the second one. The astrometric results are not conclusive. Conclusions.A simple and shockless microquasar scenario cannot easily explain the observed changes in morphology. An interpretation within the young nonaccreting pulsar scenario requires the inclination of the binary system to be very close to the upper limit imposed by the absence of X-ray eclipses.

Controlling the spin of metal atoms adsorbed on oxide surfaces: Ni on regular and defective sites of the MgO(001) surface

We have analyzed the relative energy of nonmagnetic and magnetic low-lying electronic states of Ni atoms adsorbed on regular and defective sites of the MgO(001) surface. To this end cluster and periodic surface models are used within density functional theory. For Ni atoms adsorbed on oxygen vacancies at low coverage, the interaction energy between the metal and the support is much larger than on regular sites. Strong bonding results in a diamagnetic adsorbed species and the energy required to reach the high-spin state increases. Moreover, a correlation appears between the low-spin to high-spin energy difference and the interaction energy hypothesizing that it is possible to prepare the surface to tune the high-spin to low-spin energy difference. Magnetic properties of adsorbed thin films obtained upon increasing coverage are more difficult to interpret. This is because the metallic bond is readily formed and dominates over the effect of the atoms directly bound to the vacancy.

Biphasic response of a tecto-mesencephalic pilocytic astrocytoma after Gamma Knife surgery - A case report.

Biphasic response (shrinkage-regrowth-shrinkage) of tumors has never previously been reported in the postoperative course, neither after microsurgery, nor after Gamma Knife surgery (GKS). We present the case of an adult with dorsal midbrain syndrome resulting from a pilocytic astrocytoma centered on the mesencephalic tectum. The tumor extended to the third ventricle and the thalamus. Initially, due to tumor growth, a biopsy was performed and histology established. Later, a ventriculocisternostomy for obstructive hydrocephalus was performed. Finally, GKS was performed, as the tumor continued to grow. After GKS, the lesion exhibited a biphasic response, with a major shrinkage at 3 months, regrowth within the target volume at 6 and 9 months and a second phase of important shrinkage at 12 months, which persisted for the next two years. The possible mechanisms for this particular response pattern are discussed.

Spectral energy distribution of the gamma-ray microquasar LS 5039

The microquasar LS 5039 has recently been detected as a source of very high energy (VHE) $\gamma$-rays. This detection, that confirms the previously proposed association of LS 5039 with the EGRET source 3EG~J1824$-$1514, makes of LS 5039 a special system with observational data covering nearly all the electromagnetic spectrum. In order to reproduce the observed spectrum of LS 5039, from radio to VHE $\gamma$-rays, we have applied a cold matter dominated jet model that takes into account accretion variability, the jet magnetic field, particle acceleration, adiabatic and radiative losses, microscopic energy conservation in the jet, and pair creation and absorption due to the external photon fields, as well as the emission from the first generation of secondaries. The radiative processes taken into account are synchrotron, relativistic Bremsstrahlung and inverse Compton (IC). The model is based on a scenario that has been characterized with recent observational results, concerning the orbital parameters, the orbital variability at X-rays and the nature of the compact object. The computed spectral energy distribution (SED) shows a good agreement with the available observational data.

Hepatocyte nuclear factor-4 alpha regulates the human apolipoprotein AV gene: Identification of a novel response element and involvement in the control by peroxisome proliferator-activated receptor-gamma coactivator-1 alpha, AMP-activated protein kinase, and mitogen-activated protein kinase pathway

The recently discovered apolipoprotein AV (apoAV) gene has been reported to be a key player in modulating plasma triglyceride levels. Here we identify the hepatocyte nuclear factor-4 (HNF-4 ) as a novel regulator of human apoAV gene. Inhibition of HNF-4 expression by small interfering RNA resulted in down-regulation of apoAV. Deletion, mutagenesis, and binding assays revealed that HNF-4 directly regulates human apoAV promoter through DR1 [a direct repeat separated by one nucleotide (nt)], and via a novel element for HNF-4 consisting of an inverted repeat separated by 8 nt (IR8). In addition, we show that the coactivator peroxisome proliferator-activated receptor- coactivator-1 was capable of stimulating the HNF-4 -dependent transactivation of apoAV promoter. Furthermore, analyses in human hepatic cells demonstrated that AMP-activated protein kinase (AMPK) and the MAPK signaling pathway regulate human apoAV expression and suggested that this regulation may be mediated, at least in part, by changes in HNF-4 . Intriguingly, EMSAs and mice with a liver-specific disruption of the HNF-4 gene revealed a species-distinct regulation of apoAV by HNF-4 , which resembles that of a subset of HNF-4 target genes. Taken together, our data provide new insights into the binding properties and the modulation of HNF-4 and underscore the role of HNF-4 in regulating triglyceride metabolism.

Coronary vasomotor responses to isometric handgrip exercise are primarily mediated by nitric oxide: a noninvasive MRI test of coronary endothelial function.

Endothelial cell release of nitric oxide (NO) is a defining characteristic of nondiseased arteries, and abnormal endothelial NO release is both a marker of early atherosclerosis and a predictor of its progression and future events. Healthy coronaries respond to endothelial-dependent stressors with vasodilatation and increased coronary blood flow (CBF), but those with endothelial dysfunction respond with paradoxical vasoconstriction and reduced CBF. Recently, coronary MRI and isometric handgrip exercise (IHE) were reported to noninvasively quantify coronary endothelial function (CEF). However, it is not known whether the coronary response to IHE is actually mediated by NO and/or whether it is reproducible over weeks. To determine the contribution of NO, we studied the coronary response to IHE before and during infusion of N(G)-monomethyl-l-arginine (l-NMMA, 0.3 mg·kg(-1)·min(-1)), a NO-synthase inhibitor, in healthy volunteers. For reproducibility, we performed two MRI-IHE studies ∼8 wk apart in healthy subjects and patients with coronary artery disease (CAD). Changes from rest to IHE in coronary cross-sectional area (%CSA) and diastolic CBF (%CBF) were quantified. l-NMMA completely blocked normal coronary vasodilation during IHE [%CSA, 12.9 ± 2.5 (mean ± SE, placebo) vs. -0.3 ± 1.6% (l-NMMA); P < 0.001] and significantly blunted the increase in flow [%CBF, 47.7 ± 6.4 (placebo) vs. 10.6 ± 4.6% (l-NMMA); P < 0.001]. MRI-IHE measures obtained weeks apart strongly correlated for CSA (P < 0.0001) and CBF (P < 0.01). In conclusion, the normal human coronary vasoactive response to IHE is primarily mediated by NO. This noninvasive, reproducible MRI-IHE exam of NO-mediated CEF promises to be useful for studying CAD pathogenesis in low-risk populations and for evaluating translational strategies designed to alter CAD in patients.