Discovery and pharmacological development of cyclosporine was conducted by Jean Borel and colleagues in the 1970s. Cyclosporine is the first compound to inhibit the lymphocytes specifically and ...reversibly, and represents the prototype of a new generation of immunosuppressive drugs: the calcineurine inhibitors. Historical chronology of successes in clinical application of cyclosporine and development of solid-organ transplantation are retraced here, underscoring the converging timelines of this drug and these interventions. In 1978-79 the first successful results of the use of cyclosporine in kidney were reported. Cyclosporine was the first single drug able to control rejection. In 1982-83 first trials demonstrated the benefit from treatment with cyclosporine in kidney recipients compared to azathioprine and steroids. In the 1980s solid-organ transplantation entered the cyclosporine era with unhoped-for results in heart transplantation. The present review focuses also on cyclosporine-based regimen of immunosuppression, adverse side effects and safety in pregnancy in subjects under treatment with cyclosporine.
ABSTRACT
The SEDIGISM (Structure, Excitation and Dynamics of the Inner Galactic Interstellar Medium) survey used the APEX telescope to map 84 deg2 of the Galactic plane between ℓ = −60° and +31° in ...several molecular transitions, including 13CO (2 – 1) and C18O (2 – 1), thus probing the moderately dense (∼103 cm−3) component of the interstellar medium. With an angular resolution of 30 arcsec and a typical 1σ sensitivity of 0.8–1.0 K at 0.25 km s−1 velocity resolution, it gives access to a wide range of structures, from individual star-forming clumps to giant molecular clouds and complexes. The coverage includes a good fraction of the first and fourth Galactic quadrants, allowing us to constrain the large-scale distribution of cold molecular gas in the inner Galaxy. In this paper, we provide an updated overview of the full survey and the data reduction procedures used. We also assess the quality of these data and describe the data products that are being made publicly available as part of this First Data Release (DR1). We present integrated maps and position–velocity maps of the molecular gas and use these to investigate the correlation between the molecular gas and the large-scale structural features of the Milky Way such as the spiral arms, Galactic bar and Galactic Centre. We find that approximately 60 per cent of the molecular gas is associated with the spiral arms and these appear as strong intensity peaks in the derived Galactocentric distribution. We also find strong peaks in intensity at specific longitudes that correspond to the Galactic Centre and well-known star-forming complexes, revealing that the 13CO emission is concentrated in a small number of complexes rather than evenly distributed along spiral arms.
ABSTRACT
The processes that regulate star formation are essential to understand how galaxies evolve. We present the relation between star formation rate density, ΣSFR , and hydrostatic mid-plane ...pressure,Ph, for 4260 star-forming regions of kpc size located in 96 galaxies included in the EDGE-CALIFA survey covering a wide range of stellar masses and morphologies. We find that these two parameters are tightly correlated, showing a smaller scatter in comparison to other star-forming relations. A power law, with a slightly sublinear index, is a good representation of this relation. Its residuals show a significant anticorrelation with both stellar age and metallicity whereas the total stellar mass may also play a secondary role in shaping the ΣSFR–Ph relation. For actively star-forming regions, we find that the effective feedback momentum per unit stellar mass (p*/m*), measured from thePh/ΣSFR ratio increases withPh. The median value of this ratio for all the sampled regions is larger than the expected momentum just from supernovae explosions. Morphology of the galaxies, including bars, does not seem to have a significant impact in the ΣSFR–Ph relation. Our analysis indicates that local ΣSFR self-regulation comes mainly from momentum injection to the interstellar medium from supernovae explosions. However, other mechanisms in disc galaxies may also play a significant role in shaping the ΣSFR at kpc scales. Our results also suggest thatPh is the main parameter that modulates star formation at kpc scales, rather than individual components of the baryonic mass.
ABSTRACT
Expansion of (sub)millimetre capabilities to high angular resolution offered with interferometers allows to resolve giant molecular clouds (GMCs) in nearby galaxies. This enables us to place ...the Milky Way in the context of other galaxies to advance our understanding of star formation in our own Galaxy. We, thus, remap 12CO (1–0) data along the Perseus spiral arm in the outer Milky Way to a fixed physical resolution and present the first spiral arm data cube at a common distance as it would be seen by an observer outside the Milky Way. To achieve this goal, we calibrated the longitude–velocity structure of 12CO gas of the outer Perseus arm based on trigonometric distances and maser velocities provided by the BeSSeL survey. The molecular gas data were convolved to the same spatial resolution along the whole spiral arm and regridded on to a linear scale map with the coordinate system transformed to the spiral arm reference frame. We determined the width of the Perseus spiral arm to be 7.8 ± 0.2 km s−1 around the kinematic arm centre. To study the large-scale structure, we derived the 12CO gas mass surface density distribution of velocities, shifted to the kinematic arm centre, and arm length. This yields a variation of the gas mass surface density along the arm length and a compression of molecular gas mass at linear scale. We determined a thickness of ∼63 pc on average for the Perseus spiral arm and a centroid of the molecular layer of 8.7 pc.
Context. The different theoretical models concerning the formation of high-mass stars make distinct predictions regarding their progenitors, which are the high-mass pre-stellar cores. However, no ...conclusive observation of such objects has been made to date. Aims. We aim to study the very early stages of high-mass star formation in two infrared-dark massive clumps. Our goal is to identify the core population that they harbour and to investigate their physical and chemical properties at high spatial resolution. Methods. We obtained Atacama Large Millimeter/submillimeter Array (ALMA) Cycle 6 observations of continuum emission at 0.8 mm and of the ortho-H2D+ transition at 372 GHz towards the two clumps. We used the SCIMES algorithm to identify substructures (i.e. cores) in the position-position-velocity space, finding 16 cores. We modelled their observed spectra using a Bayesian fitting approach in the approximation of local thermodynamic equilibrium. We derived the centroid velocity, the line width, and the molecular column density maps. We also studied the correlation between the continuum and molecular data, which in general do not present the same structure. Results. We report, for the first time, the detection of ortho-H2D+ in high-mass star-forming regions performed with an interferometer. The molecular emission shows narrow and subsonic lines, suggesting that locally, the temperature of the gas is below 10 K. From the continuum emission, we estimated the cores’ total masses and compare them with the respective virial masses. We also computed the volume density values, which are found to be higher than 106 cm−3. Conclusions. Our data confirm that ortho-H2D+ is an ideal tracer of cold and dense gas. Interestingly, almost all the H2D+-identified cores are less massive than ≈13 M⊙, with the exception of one core in AG354, which could be as massive as 39 M⊙ under the assumption of low dust temperature (5 K). Furthermore, most of them are sub-virial and larger than their Jeans masses. These results are hence difficult to explain in the context of the turbulent accretion models, which predict massive and virialised pre-stellar cores. However, we cannot exclude that the cores are still in the process of accreting mass and that magnetic fields are providing enough support for the virialisation. ALMA could also be seeing only the innermost parts of the cores, and hence the cores’ total masses could be higher than inferred in this work. Furthermore, we note that the total masses of the investigated clumps are below the average for typical high-mass clumps, and thus studies of more massive sources are needed.
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ABSTRACT
The current generation of (sub)mm-telescopes has allowed molecular line emission to become a major tool for studying the physical, kinematic, and chemical properties of extragalactic ...systems, yet exploiting these observations requires a detailed understanding of where emission lines originate within the Milky Way. In this paper, we present 60 arcsec (∼3 pc) resolution observations of many 3 mm band molecular lines across a large map of the W49 massive star-forming region (∼100 pc × 100 pc at 11 kpc), which were taken as part of the ‘LEGO’ IRAM-30m large project. We find that the spatial extent or brightness of the molecular line transitions are not well correlated with their critical densities, highlighting abundance and optical depth must be considered when estimating line emission characteristics. We explore how the total emission and emission efficiency (i.e. line brightness per H2 column density) of the line emission vary as a function of molecular hydrogen column density and dust temperature. We find that there is not a single region of this parameter space responsible for the brightest and most efficiently emitting gas for all species. For example, we find that the HCN transition shows high emission efficiency at high column density (1022 cm−2) and moderate temperatures (35 K), whilst e.g. N2H+ emits most efficiently towards lower temperatures (1022 cm−2; <20 K). We determine $X_{\mathrm{CO} (1-0)} \sim 0.3 \times 10^{20} \, \mathrm{cm^{-2}\, (K\, km\, s^{-1})^{-1}}$, and $\alpha _{\mathrm{HCN} (1-0)} \sim 30\, \mathrm{M_\odot \, (K\, km\, s^{-1}\, pc^2)^{-1}}$, which both differ significantly from the commonly adopted values. In all, these results suggest caution should be taken when interpreting molecular line emission.
ABSTRACT
We use the 13CO (2–1) emission from the SEDIGISM (Structure, Excitation, and Dynamics of the Inner Galactic InterStellar Medium) high-resolution spectral-line survey of the inner Galaxy, to ...extract the molecular cloud population with a large dynamic range in spatial scales, using the Spectral Clustering for Interstellar Molecular Emission Segmentation (scimes) algorithm. This work compiles a cloud catalogue with a total of 10 663 molecular clouds, 10 300 of which we were able to assign distances and compute physical properties. We study some of the global properties of clouds using a science sample, consisting of 6664 well-resolved sources and for which the distance estimates are reliable. In particular, we compare the scaling relations retrieved from SEDIGISM to those of other surveys, and we explore the properties of clouds with and without high-mass star formation. Our results suggest that there is no single global property of a cloud that determines its ability to form massive stars, although we find combined trends of increasing mass, size, surface density, and velocity dispersion for the sub-sample of clouds with ongoing high-mass star formation. We then isolate the most extreme clouds in the SEDIGISM sample (i.e. clouds in the tails of the distributions) to look at their overall Galactic distribution, in search for hints of environmental effects. We find that, for most properties, the Galactic distribution of the most extreme clouds is only marginally different to that of the global cloud population. The Galactic distribution of the largest clouds, the turbulent clouds and the high-mass star-forming clouds are those that deviate most significantly from the global cloud population. We also find that the least dynamically active clouds (with low velocity dispersion or low virial parameter) are situated further afield, mostly in the least populated areas. However, we suspect that part of these trends may be affected by some observational biases (such as completeness and survey limitations), and thus require further follow up work in order to be confirmed.
Abstract Objective Assessing the frequency of Wearing-Off (WO) in Parkinson's disease (PD) patients, and its impact on Quality of Life (QoL). Methods Consecutive ambulatory patients, who were on ...dopaminergic treatment for ≥1 year, were included in this multicentre, observational cross-sectional study. In a single visit, WO was diagnosed based on neurologist assessment as well as using the validated Italian version of a patient self-rated 19-question Wearing-Off Questionnaire (WOQ-19); WO was defined for scores ≥ 2. QoL was evaluated by the 8-item Parkinson's Disease Questionnaire (PDQ-8). Results 617 subjects were included, with a mean anti-Parkinson treatment duration of 6.6 ± 4.6 years, 87.2% were on levodopa treatment. Neurologists identified presence of WO in 351 subjects (56.9%), whereas 415 subjects (67.3%) were identified by the self-administered WOQ-19. In patients with a <2.5 years disease duration, WO was diagnosed in 12 subjects (21.8%) by neurologists and in 23 subjects (41.8%) by the WOQ-19. The most frequent WO symptoms, as identified by WOQ-19, were “slowness of movements” (55.8%) and “reduced dexterity” (48.8%). Younger age, female gender, Unified Parkinson's Disease Rating Scale (UPDRS) part II score and duration of anti-Parkinson treatment were found significantly associated with WO. The number of motor ( p < 0.0001) and non-motor ( p < 0.0001) WO symptoms correlated with PDQ-8 total score. Conclusions WO is common already at the early stages of PD and is underestimated by routine neurological clinical evaluation. The number of WO symptoms, both motor and non motor, increases along with disease duration and has a negative impact on patients QoL.
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Context.
Star formation in the outer Galaxy is thought to be different from that in the inner Galaxy, as it is subject to different environmental parameters such as metallicity, interstellar ...radiation field, or mass surface density, which all change with galactocentric radius. Extending our star formation knowledge, from the inner to the outer Galaxy, helps us to understand the influences of the change of the environment on star formation throughout the Milky Way.
Aims.
We aim to obtain a more detailed view on the structure of the outer Galaxy, determining physical properties for a large number of star forming clumps and understanding star formation outside the solar circle. As one of the largest expanding Galactic super-shells is present in the observed region, a unique opportunity is taken here to investigate the influence of such an expanding structure on star formation as well.
Methods.
We used pointed
12
CO(2–1) observations conducted with the APEX telescope to determine the velocity components towards 830 dust clumps identified from 250
μ
m
Herschel
/Hi-GAL SPIRE emission maps in the outer Galaxy between 225° <
ℓ
< 260°. We determined kinematic distances from the velocity components, in order to analyze the structure of the outer Galaxy and to estimate physical properties such as dust temperatures, bolometric luminosities, clump masses, and H
2
column densities for 611 clumps. For this, we determined the dust spectral energy density distributions from archival mid-infrared to submillimeter (submm) emission maps.
Results.
We find the identified CO clouds to be strongly correlated with the highest column density parts of the H
I
emission distribution, spanning a web of bridges, spurs, and blobs of star forming regions between the larger complexes, unveiling the complex three-dimensional structure of the outer Galaxy in unprecedented detail. Using the physical properties of the clumps, we find an upper limit of 6% (40 sources) capable of forming high-mass stars. This is supported by the fact that only two methanol Class II masers, or 34 known or candidate H
II
regions, are found in the whole survey area, indicating an even lower fraction that are able to form high-mass stars in the outer Galaxy. We fail to find any correlation of the physical parameters of the identified (potential) star forming regions with the expanding supershell, indicating that although the shell organizes the interstellar material into clumps, the properties of the latter are unaffected.
Conclusions.
Using the APEX telescope in combination with publicly available Hi-GAL, MSX, and Wise continuum emission maps, we were able to investigate the structure and properties of a region of the Milky Way in unprecedented detail.
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•An XFEM coupled hydro-mechanical model with a non-regularized cohesive zone constitutive law is developed.•A Lagrange multiplier formulation is considered to stabilize the fracture propagation and ...the fluid exchanges.•The competition mechanisms between fluid-driven fractures are investigated.
The present work focuses on a new numerical model for the fully coupled hydro-mechanical analysis of groundwater flows through poroelastic saturated media. In particular, the presence and eventual propagation of fluid-driven fractures is accounted for within a non-regularized cohesive zone model. In this paper, the fracture propagation is considered as a reactivation process: the fracture already exists and evolves (i.e. opens or closes) on a pre-defined path initially constrained. The Talon-Curnier constitutive law is considered for the fracture interfaces and its expression has been adapted to the hydro-mechanical coupling related to the fracture evolution. The fluid pressure inside the fracture is governed by the lubrication equation. The momentum-stress balance equations involving fluid flow and deformation of the solid porous matrix are derived within the framework of the generalized Biot theory. The extended finite element method (XFEM) is preferred to a standard finite element spatial discretization in order to easily handle the presence and evolution of discontinuities in the porous medium. A set of four Lagrange multipliers is introduced to prevent spurious oscillations of the numerical solution at the interface. Comparisons between numerical results and theoretical solution assess the validity of the model presented in this paper. In addition, the hydro-mechanical interactions between neighboring fractures and the effects of the permeability of the porous medium are investigated. We also demonstrate the capability of our model to handle non-planar fracture paths.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
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