Optimization of a 3D dynamic culturing system for in vitro modeling of Frontotemporal Neurodegeneration-relevant pathologic features

Frontotemporal lobar degeneration (FTLD) is a severe neurodegenerative disorder that is diagnosed with increasing frequency in clinical setting. Currently, no therapy is available and in addition the molecular basis of the disease are far from being elucidated. Consequently, it is of pivotal importance to develop reliable and cost-effective in vitro models for basic research purposes and drug screening. To this respect, recent results in the field of Alzheimer’s disease have suggested that a tridimensional (3D) environment is an added value to better model key pathologic features of the disease. Here, we have tried to add complexity to the 3D cell culturing concept by using a microfluidic bioreactor, where cells are cultured under a continuous flow of medium, thus mimicking the interstitial fluid movement that actually perfuses the body tissues, including the brain. We have implemented this model using a neuronal-like cell line (SH-SY5Y), a widely exploited cell model for neurodegenerative disorders that shows some basic features relevant for FTLD modeling, such as the release of the FTLD-related protein progranulin (PRGN) in specific vesicles (exosomes). We have efficiently seeded the cells on 3D scaffolds, optimized a disease-relevant oxidative stress experiment (by targeting mitochondrial function that is one of the possible FTLD-involved pathological mechanisms) and evaluated cell metabolic activity in dynamic culture in comparison to static conditions, finding that SH-SY5Y cells cultured in 3D scaffold are susceptible to the oxidative damage triggered by a mitochondrial-targeting toxin (6-OHDA) and that the same cells cultured in dynamic conditions kept their basic capacity to secrete PRGN in exosomes once recovered from the bioreactor and plated in standard 2D conditions. We think that a further improvement of our microfluidic system may help in providing a full device where assessing basic FTLD-related features (including PRGN dynamic secretion) that may be useful for monitoring disease progression over time or evaluating therapeutic interventions

Star formation in disk galaxies driven by primordial H_2

We show that gaseous \HI disks of primordial composition irradiated by an external radiation field can develop a multiphase medium with temperatures between 10^2 and 10^4 K due to the formation of molecular hydrogen. For a given \HI column density there is a critical value of the radiation field below which only the cold \HI phase can exist. Due to a time decreasing quasar background, the gas starts cooling slowly after recombination until the lowest stable temperature in the warm phase is reached at a critical redshift $z=z_{cr}$. Below this redshift the formation of molecular hydrogen promotes a rapid transition towards the cold \HI phase. We find that disks of protogalaxies with 10^{20}\simlt N_{HI}\simlt 10^{21} cm^{-2} are gravitationally stable at $T\sim 10^4$ K and can start their star formation history only at z \simlt z_{cr}\sim 2, after the gas in the central portion of the disk has cooled to temperatures T\simlt 300 K. Such a delayed starbust phase in galaxies of low gas surface density and low dynamical mass can disrupt the disks and cause them to fade away. These objects could contribute significantly to the faint blue galaxy population.Comment: 16 pages (LaTeX), 2 Figures to be published in Astrophysical Journal Letter

The effects of an ionizing background on the HI column density distribution in the local Universe

Using data on the HI column density distribution in the local Universe, f(N_{HI}), we show how to determine g(N_{H}), the distribution of the total gas (HI+HII) column density. A simple power law fit to f(N_{HI}) fails due to bendings in the distributions when N_{HI}<10^{20} cm^{-2} and H is no longer fully neutral. If an ultraviolet background is responsible for the gas ionization, and g(N_{H}) is proportional N_{H}^{-alpha}, we find the values of alpha and of the intensity of the background radiation which are compatible with the present data. These best fitting values, however, depend upon the scaling law of the the gas volume densities with N_{H} and cannot be determined unambiguously. We examine in detail two models: one in which the average gas volume density decreases steadily with N_H, while in the other it stays constant at low column densities. The former model leads to a steep power law fit for g(N_{H}), with alpha of order 3.3 +- 0.4 and requires an ultraviolet flux larger than what the QSOs alone produce at z=0. For the latter alpha is 1.5 +- 0.1 and a lower ionizing flux is required. The ambiguities about the modelling and the resulting steep or shallow N_{H} distribution can be resolved only if new 21-cm observations and QSOs Lyman limit absorbers searches will provide more data in the HI-HII transition region at low redshifts. Using the best fit obtained for higher redshift data we outline two possible scenarios for the evolution of gaseous structures, compatible with the available data at z=0.Comment: 12 pages, 2 figures, ApJ in press (2002, vol. 567

A warped disk model for M33 and the 21-cm line width in spiral galaxies

To determine the actual HI distribution and the velocity field in the outermost disk of the spiral galaxy M33, a tilted-ring model is fitted to 21-cm line data taken with the Arecibo Telescope. Since M33 is one of the main calibrators for the extragalactic distance scale derived through the Tully-Fisher relation, the outer disk warping is of interest for a correct determination and deprojection of the galaxy's line width. Even though our best model predicts small effects on the observed line width of M33, we show that similar outer disk warping in galaxies oriented differently along our line of sight could affect the widths considerably. Therefore there may be systematic effects in the determination of the rotation velocities and dynamic masses of spiral galaxies, whose exact value depends also on which method is used for measuring the galaxy's total line width.Comment: 27 pages, ps files only, ApJ in pres

The impact on disability of initial treatment with methotrexate in patients with rheumatoid arthritis: results from the MARI study

The study aimed to assess in a population of subjects with rheumatoid arthritis (RA) treated with methotrexate (MTX) how the initial approach to the treatment influenced subsequent disability. We performed a cross-sectional analysis of data collected during the baseline visit of the MARI study, a multicenter observational study on patients with RA on treatment with MTX for at least 12 months. Subjects who fulfilled the Health Assessment Questionnaire (HAQ) were included in the evaluation. For every patient we retrospectively evaluated the disease duration, the duration of symptoms before the diagnosis, the time elapsed before first MTX treatment, the initial MTX dose, and the concomitant medications in the first six months of therapy. Disability was defined as a DI-HAQ score ≥1. The study population included 1015 subjects. Patients with a DI-HAQ score ≥1 had a longer duration of symptoms before diagnosis, a higher delay in treatment initiation, a lower initial dose of MTX and a more frequent co-treatment with symptomatic drugs. Disability was found less frequently in subjects treated with other concomitant disease modifying anti-rheumatic drugs (DMARDs) but not with biological agents. Logistic regression analysis identified as significant predictors of disability: older age, female sex, a longer time to complete diagnosis, a delay in starting MTX treatment higher than 6 months, and a concomitant treatment with symptomatic drugs, while a combination therapy with other DMARDs was associated with a lower risk of disability. A late diagnosis and a delay in starting a treatment with MTX are associated with poorer functional outcomes in patients with RA

the influence of nanoscale morphology on the resistivity of cluster assembled nanostructured metallic thin films

We have studied in situ the evolution of the electrical resistivity of Fe, Pd, Nb, W and Mo cluster-assembled films during their growth by supersonic cluster beam deposition. We observed resistivity of cluster-assembled films several orders of magnitude larger than the bulk, as well as an increase in resistivity by increasing the film thickness in contrast to what was observed for atom-assembled metallic films. This suggests that the nanoscale morphological features typical of ballistic films growth, such as the minimal cluster?cluster interconnection and the evolution of surface roughness with thickness, are responsible for the observed behaviour

Radial HI Profiles at the Periphery of Galactic Disks: The Role of Ionizing Background Radiation

Observations of neutral hydrogen in spiral galaxies reveal a sharp cutoff in the radial density profile at some distance from the center. Using 22 galaxies with known HI distributions as an example, we discuss the question of whether this effect can be associated exclusively with external ionizing radiation, as is commonly assumed. We show that before the surface density reaches $\sigma_{\textrm{HI}}\le 0.5 {\cal M}_\odot/{\textrm {pc}}^2$(the same for galaxies of different types), it is hard to expect the gas to be fully ionized by background radiation. For two of 13 galaxies with a sharp drop in the HI profile, the "steepening" can actually be caused by ionization. At the same time, for the remaining galaxies, the observed cutoff in the radial HI profile is closer to the center than if it was a consequence of ionization by background radiation and, therefore, it should be caused by other factors.Comment: 15 pages, 6 figure

The Herschel Virgo Cluster Survey: IV. Resolved dust analysis of spiral galaxies

We present a resolved dust analysis of three of the largest angular size spiral galaxies, NGC 4501 and NGC 4567/8, in the Herschel Virgo Cluster Survey (HeViCS) Science Demonstration field. Herschel has unprecedented spatial resolution at far-infrared wavelengths and with the PACS and SPIRE instruments samples both sides of the peak in the far infrared spectral energy distribution (SED).We present maps of dust temperature, dust mass, and gas-to-dust ratio, produced by fitting modified black bodies to the SED for each pixel. We find that the distribution of dust temperature in both systems is in the range ~19 - 22 K and peaks away from the centres of the galaxies. The distribution of dust mass in both systems is symmetrical and exhibits a single peak coincident with the galaxy centres. This Letter provides a first insight into the future analysis possible with a large sample of resolved galaxies to be observed by Herschel.Comment: Letter accepted for publication in A&A (Herschel special issue

Early onset of hypertension and serum electrolyte changes as potential predictive factors of activity in advanced hcc patients treated with sorafenib: results from a retrospective analysis of the HCC-AVR group

Hypertension (HTN) is frequently associated with the use of angiogenesis inhibitors targeting the vascular endothelial growth factor pathway and appears to be a generalized effect of this class of agent. We investigated the phenomenon in 61 patients with advanced hepatocellular carcinoma (HCC) receiving sorafenib. Blood pressure and plasma electrolytes were measured on days 1 and 15 of the treatment. Patients with sorafenib-induced HTN had a better outcome than those without HTN (disease control rate: 63.4% vs. 17.2% (p=0.001); progression-free survival 6.0 months (95% CI 3.2-10.1) vs. 2.5 months (95% CI 1.9-2.6) (p<0.001) and overall survival 14.6 months (95% CI9.7-19.0) vs. 3.9 months (95% CI 3.1-8.7) (p=0.003). Sodium levels were generally higher on day 15 than at baseline (+2.38, p<0.0001) in the group of responders (+4.95, p <0.0001) compared to patients who progressed (PD) (+0.28, p=0.607). In contrast, potassium was lower on day 14 (-0.30, p=0.0008) in the responder group (-0.58, p=0.003) than in those with progressive disease (-0.06, p=0.500). The early onset of hypertension is associated with improved clinical outcome in HCC patients treated with sorafenib. Our data are suggestive of an activation of the renin-angiotensin system in patients with advanced disease who developed HTN during sorafenib treatmen

The far-infrared view of M87 as seen by the Herschel Space Observatory

The origin of the far-infrared emission from the nearby radio galaxy M87 remains a matter of debate. Some studies find evidence of a far-infrared excess due to thermal dust emission, whereas others propose that the far-infrared emission can be explained by synchrotron emission without the need for an additional dust emission component. We observed M87 with PACS and SPIRE as part of the Herschel Virgo Cluster Survey (HeViCS). We compare the new Herschel data with a synchrotron model based on infrared, submm and radio data to investigate the origin of the far-infrared emission. We find that both the integrated SED and the Herschel surface brightness maps are adequately explained by synchrotron emission. At odds with previous claims, we find no evidence of a diffuse dust component in M87.Comment: 4 pages, 2 figures, proceedings IAU Symposium 275 (Jets at all scales