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The 1.33-mm survey of protoplanetary discs in the Taurus molecular cloud found annular gaps and rings to be common in extended sources (≳ 55 au), when their 1D visibility distributions were fit parametrically. We first demonstrate the advantages and limitations of non-parametric visibility fits for data at the survey's 0.12-arcsec resolution. Then we use the non-parametric model in Frankenstein (frank) to identify new substructure in three compact and seven extended sources. Among the new features, we identify three trends: a higher occurrence rate of substructure in the survey's compact discs than previously seen, underresolved (potentially azimuthally asymmetric) substructure in the innermost disc of extended sources, and a 'shoulder' on the trailing edge of a ring in discs with strong depletion at small radii. Noting the shoulder morphology is present in multiple discs observed at higher resolution, we postulate it is tracing a common physical mechanism. We further demonstrate how a superresolution frank brightness profile is useful in motivating an accurate parametric model, using the highly structured source DL Tau in which frank finds two new rings. Finally, we show that sparse (u, v) plane sampling may be masking the presence of substructure in several additional compact survey sources. [ABSTRACT FROM AUTHOR]

Large surveys of star-forming regions have unveiled power-law correlations between the stellar mass and the disc parameters, such as the disc mass |$M_{\mathrm{d}} \!-\! {M_{\star }}$| and the accretion rate |$\dot{M} \!-\! {M_{\star }}$|⁠. The observed slopes appear to be increasing with time, but the reason behind the establishment of these correlations and their subsequent evolution is still uncertain. We conduct a theoretical analysis of the impact of viscous evolution on power-law initial conditions for a population of protoplanetary discs. We find that, for evolved populations, viscous evolution enforces the two correlations to have the same slope, λ m =  λ acc, and that this limit is uniquely determined by the initial slopes λ m, 0 and λ acc, 0. We recover the increasing trend claimed from the observations when the difference in the initial values, δ 0 = λ m, 0− λ acc, 0, is larger than 1/2; moreover, we find that this increasing trend is a consequence of a positive correlation between the viscous time-scale and the stellar mass. We also present the results of disc population synthesis numerical simulations, that allow us to introduce a spread and analyse the effect of sampling, which show a good agreement with our analytical predictions. Finally, we perform a preliminary comparison of our numerical results with observational data, which allows us to constrain the parameter space of the initial conditions to λ m, 0 ∈ [1.2, 2.1], λ acc, 0 ∈ [0.7, 1.5]. [ABSTRACT FROM AUTHOR]

Aims: In patients undergoing cardiac implantable electronic device (CIED) intervention, routine pre-procedure antibiotic prophylaxis is recommended. A more powerful antibiotic protocol has been suggested in patients at high risk of infection. Stratification of individual infective risk could guide the prophylaxis before CIED procedure.Methods and Results: Patients undergoing CIED surgery were stratified according to the Shariff score in low and high infective risk. Patients in the 'low-risk' group were treated with only two antibiotic administrations while patients in the 'high-risk' group were treated with a prolonged 9-day protocol, according to renal function and allergies. We followed-up patients for 250 days with clinical outpatient visit and electronic control of the CIED. As primary endpoint, we evaluated CIED-related infections. A total of 937 consecutive patients were enrolled, of whom 735 were stratified in the 'low-risk' group and 202 in the 'high-risk' group. Despite different risk profiles, CIED-related infection rate at 250 days was similar in the two groups (8/735 in 'low risk' vs. 4/202 in 'high risk', P = 0.32). At multivariate analysis, active neoplasia, haematoma, and reintervention were independently associated with CIED-related infection (HR 5.54, 10.77, and 12.15, respectively).Conclusion: In a large cohort of patients undergoing CIED procedure, an antibiotic prophylaxis based on individual stratification of infective risk resulted in similar rate of infection between groups at high and low risk of CIED-related infection. [ABSTRACT FROM AUTHOR]

We present the first ALMA survey of protoplanetary discs at 3 mm, targeting 36 young stellar objects in the Lupus star-forming region with deep observations (sensitivity 20–50  |$\mu$| Jy beam−1) at ∼0.35 arcsec resolution (∼50 au). Building on previous ALMA surveys at 0.89 and 1.3 mm that observed the complete sample of Class II discs in Lupus at a comparable resolution, we aim to assess the level of grain growth in the relatively young Lupus region. We measure 3 mm integrated fluxes, from which we derive disc-averaged 1–3 mm spectral indices. We find that the mean spectral index of the observed Lupus discs is |$\alpha _\mathrm{1-3\, mm}=2.23\pm 0.06$|⁠ , in all cases |$\alpha _\mathrm{1-3\, mm}\lt 3.0$|⁠ , with a tendency for larger spectral indices in the brightest discs and in transition discs. Furthermore, we find that the distribution of spectral indices in Lupus discs is statistically indistinguishable from that of the Taurus and Ophiuchus star-forming regions. Assuming the emission is optically thin, the low values |$\alpha _\mathrm{1-3\, mm}\le 2.5$| measured for most discs can be interpreted with the presence of grains larger than 1 mm. The observations of the faint discs in the sample can be explained without invoking the presence of large grains, namely through a mixture of optically thin and optically thick emission from small grains. However, the bright (and typically large) discs do inescapably require the presence of millimetre-sized grains in order to have realistic masses. Based on a disc mass argument, our results challenge previous claims that the presence of optically thick substructures may be a universal explanation for the empirical millimetre size-luminosity correlation observed at 0.89 mm. [ABSTRACT FROM AUTHOR]

We analyse spatially resolved ALMA observations at 0.9, 1.3, and 3.1 mm for the 26 brightest protoplanetary discs in the Lupus star-forming region. We characterize the discs multiwavelength brightness profiles by fitting the interferometric visibilities in a homogeneous way, obtaining effective disc sizes at the three wavelengths, spectral index profiles, and optical depth estimates. We report three fundamental discoveries: first, the millimetre continuum size–luminosity relation already observed at 0.9 mm is also present at 1.3 mm with an identical slope, and at 3.1 mm with a steeper slope, confirming that emission at longer wavelengths becomes increasingly optically thin. Second, when observed at 3.1 mm the discs appear to be only 9 per cent smaller than when observed at 0.9 mm, in tension with models of dust evolution that predict a starker difference. Third, by forward modelling the sample of measurements with a simple parametric disc model, we find that the presence of large grains (⁠|$a_\mathrm{max}\gt 1\,$| mm) throughout the discs is the most favoured explanation for all discs as it reproduces simultaneously their spectral indices, optical depth, luminosity, and radial extent in the 0.9–1.3 mm wavelength range. We also find that the observations can be alternatively interpreted with the discs being dominated by optically thick, unresolved, substructures made of mm-sized grains with a high scattering albedo. [ABSTRACT FROM AUTHOR]

Recent observations have revealed that most proto-planetary discs show a pattern of bright rings and dark gaps. However, most of the high-resolution observations have focused only on the continuum emission. In this paper, we present high-resolution ALMA band 7 (0.89 mm) observations of the disc around the star CI Tau in the 12CO & 13CO J  = 3–2 and CS J  = 7–6 emission lines. Our recent work demonstrated that the disc around CI Tau contains three gaps and rings in continuum emission, and we look for their counterparts in the gas emission. While we find no counterpart of the third gap and ring in 13CO, the disc has a gap in emission at the location of the second continuum ring (rather than gap). We demonstrate that this is mostly an artefact of the continuum subtraction, although a residual gap still remains after accounting for this effect. Through radiative transfer modelling, we propose this is due to the inner disc shadowing the outer parts of the disc and making them colder. This raises a note of caution in mapping high-resolution gas emission lines observations to the gas surface density – while possible, this needs to be done carefully. In contrast to 13CO, CS emission shows instead a ring morphology, most likely due to chemical effects. Finally, we note that 12CO is heavily absorbed by the foreground preventing any morphological study using this line. [ABSTRACT FROM AUTHOR]

We observed the K7 class III star NO Lup in an ALMA survey of the 1–3 Myr Lupus association and detected circumstellar dust and CO gas. Here we show that the J = 3–2 CO emission is both spectrally and spatially resolved, with a broad velocity width ∼19 km s−1 for its resolved size ∼1 arcsec (∼130 au). We model the gas emission as a Keplerian disc, finding consistency, but only with a central mass of ∼11M⊙, which is implausible given its spectral type and X-Shooter spectrum. A good fit to the data can also be found by modelling the CO emission as outflowing gas with a radial velocity ∼22 km s−1. We interpret NO Lup's CO emission as the first imaged class III circumstellar disc with outflowing gas. We conclude that the CO is continually replenished, but cannot say if this is from the breakup of icy planetesimals or from the last remnants of the protoplanetary disc. We suggest further work to explore the origin of this CO, and its higher than expected velocity in comparison to photoevaporative models. [ABSTRACT FROM AUTHOR]

Dippers are a common class of young variable star exhibiting day-long dimmings with depths of up to several tens of per cent. A standard explanation is that dippers host nearly edge-on (i d ≈ 70°) protoplanetary discs that allow close-in (<1 au) dust lifted slightly out of the mid-plane to partially occult the star. The identification of a face-on dipper disc and growing evidence of inner disc misalignments brings this scenario into question. Thus, we uniformly (re)derive the inclinations of 24 dipper discs resolved with (sub-)mm interferometry from ALMA. We find that dipper disc inclinations are consistent with an isotropic distribution over i d ≈ 0−75°, above which the occurrence rate declines (likely an observational selection effect due to optically thick disc mid-planes blocking their host stars). These findings indicate that the dipper phenomenon is unrelated to the outer (>10 au) disc resolved by ALMA and that inner disc misalignments may be common during the protoplanetary phase. More than one mechanism may contribute to the dipper phenomenon, including accretion-driven warps and 'broken' discs caused by inclined (sub-)stellar or planetary companions. [ABSTRACT FROM AUTHOR]

The Sunyaev–Zel'dovich (SZ) effect can potentially be used to investigate the heating of the circumgalactic medium and subsequent suppression of cold gas accretion on to the host galaxy caused by quasar feedback. We use a deep ALMA observation of HE0515-4414 in band 4, the most luminous quasar known at the peak of cosmic star formation (z  = 1.7), to search for the SZ signal tracing the heating of the galaxy's halo. ALMA's sensitivity to a broad range of spatial scales enables us to disentangle emitting compact sources from the negative, extended SZ signal. We obtain a marginal SZ detection (∼3.3σ) on scales of about 300 kpc (30–40 arcsec), at the 0.2 mJy level, 0.5 mJy after applying a correction factor for primary beam attenuation and flux that is resolved out by the array. We show that our result is consistent with a simulated ALMA observation of a similar quasar in the fable cosmological simulations. We emphasize that detecting an SZ signal is more easily achieved in the visibility plane than in the (inferred) images. We also confirm a marginal detection (3.2σ) of a potential SZ dip on smaller scales (<100 kpc) already claimed by other authors, possibly highlighting the complex structure of the halo heating. Finally, we use SZ maps from the fable cosmological simulations, convolved with ALMA simulations, to illustrate that band 3 observations are much more effective in detecting the SZ signal with higher significance, and discuss the optimal observing strategy. [ABSTRACT FROM AUTHOR]

We present Atacama Large Millimeter/submillimeter Array (ALMA) observations of eight highly excited CO (⁠|${\rm J_{\rm up}}$|  > 8) lines and continuum emission in two z  ∼ 6 quasars: SDSS J231038.88+185519.7 (hereafter J2310), for which CO(8–7), CO(9–8), and CO(17–16) lines have been observed, and ULAS J131911.29+095951.4 (J1319), observed in the CO(14–13), CO(17–16), and CO(19–18) lines. The continuum emission of both quasars arises from a compact region (<0.9 kpc). By assuming a modified blackbody law, we estimate dust masses of log(M dust/M⊙) = 8.75 ± 0.07 and log(M dust/M⊙) = 8.8 ± 0.2 and dust temperatures of T dust = 76 ± 3 K and |$T_{\rm dust}=66^{+15}_{-10}\,{\rm K}$|⁠ , respectively, for J2310 and J1319. Only CO(8–7) and CO(9–8) in J2310 are detected, while 3σ upper limits on luminosities are reported for the other lines of both quasars. The CO line luminosities and upper limits measured in J2310 and J1319 are consistent with those observed in local active galactic nuclei and starburst galaxies, and other z  ∼ 6 quasars, except for SDSS J1148+5251 (J1148), the only quasar at z  = 6.4 with a previous CO(17–16) line detection. By computing the CO spectral line energy distributions normalized to the CO(6–5) line and far-infrared luminosities for J2310, J1319, and J1148, we conclude that different gas heating mechanisms (X-ray radiation and/or shocks) may explain the different CO luminosities observed in these z  ∼ 6 quasar. Future |${\rm J_{\rm up}}$|  > 8 CO observations will be crucial to understand the processes responsible for molecular gas excitation in luminous high- z quasars. [ABSTRACT FROM AUTHOR]

ALMA has observed a plethora of ring-like structures in planet-forming discs at distances of 10–100 au from their host star. Although several mechanisms have been invoked to explain the origin of such rings, a common explanation is that they trace new-born planets. Under the planetary hypothesis, a natural question is how to reconcile the apparently high frequency of gap-carving planets at 10–100 au with the paucity of Jupiter-mass planets observed around main-sequence stars at those separations. Here, we provide an analysis of the new-born planet population emerging from observations of gaps in discs, under the assumption that the observed gaps are due to planets. We use a simple estimate of the planet mass based on the gap morphology, and apply it to a sample of gaps recently obtained by us in a survey of Taurus with ALMA. We also include additional data from recent published surveys, thus analysing the largest gap sample to date, for a total of 48 gaps. The properties of the purported planets occupy a distinctively different region of parameter space with respect to the known exo-planet population, currently not accessible through planet finding methods. Thus, no discrepancy in the mass and radius distribution of the two populations can be claimed at this stage. We show that the mass of the inferred planets conforms to the theoretically expected trend for the minimum planet mass needed to carve a dust gap. Finally, we estimate the separation and mass of the putative planets after accounting for migration and accretion, for a range of evolutionary times, finding a good match with the distribution of cold Jupiters. [ABSTRACT FROM AUTHOR]

Recent observations show that rings and gaps are ubiquitous in protoplanetary discs. These features are often interpreted as being due to the presence of planets; however, the effect of planetary migration on the observed morphology has not been investigated hitherto. In this work, we investigate whether multiwavelength mm/submm observations can detect signatures of planet migration, using 2D dusty hydrodynamic simulations to model the structures generated by migrating planets and synthesizing ALMA continuum observations at |$\rm 850\, \hbox{$\mu $m}$| and |$\rm 3\, mm$|⁠. We identify three possible morphologies for a migrating planet: a slowly migrating planet is associated with a single ring outside the planet's orbit, a rapidly migrating planet is associated with a single ring inside the planet's orbit while a planet migrating at intermediate speed generates one ring on each side of the planet's orbit. We argue that multiwavelength data can distinguish multiple rings produced by a migrating planet from other scenarios for creating multiple rings, such as multiple planets or discs with low viscosity. The signature of migration is that the outer ring has a lower spectral index, due to larger dust grains being trapped there. Of the recent ALMA observations revealing protoplanetary discs with multiple rings and gaps, we suggest that Elias 24 is the best candidate for a planet migrating in the intermediate speed regime. [ABSTRACT FROM AUTHOR]

A correlation between proto-planetary disc radii and sub-mm fluxes has been recently reported. In this letter, we show that the correlation is a sensitive probe of grain growth processes. Using models of grain growth and drift, we have shown in a companion paper that the observed disc radii trace where the dust grains are large enough to have a significant sub-mm opacity. We show that the observed correlation emerges naturally if the maximum grain size is set by radial drift, implying relatively low values of the viscous α parameter ≲0.001. In this case, the relation has an almost universal normalization, while if the grain size is set by fragmentation the flux at a given radius depends on the dust-to-gas ratio. We highlight two observational consequences of the fact that radial drift limits the grain size. The first is that the dust masses measured from the sub-mm could be overestimated by a factor of a few. The second is that the correlation should be present also at longer wavelengths (e.g. 3mm), with a normalization factor that scales as the square of the observing frequency as in the optically thick case. [ABSTRACT FROM AUTHOR]

We present GALARIO, a computational library that exploits the power of modern graphical processing units (GPUs) to accelerate the analysis of observations from radio interferometers like Atacama Large Millimeter and sub-millimeter Array or the Karl G. Jansky Very Large Array. GALARIO speeds up the computation of synthetic visibilities from a generic 2D model image or a radial brightness profile (for axisymmetric sources). On a GPU, GALARIO is 150 faster than standard PYTHON and 10 times faster than serial C++ code on a CPU. Highly modular, easy to use, and to adopt in existing code,GALARIOcomes as two compiled libraries, one for Nvidia GPUs and one for multicore CPUs, where both have the same functions with identical interfaces. GALARIO comes with PYTHON bindings but can also be directly used in C or C++. The versatility and the speed of GALARIO open new analysis pathways that otherwise would be prohibitively time consuming, e.g. fitting high-resolution observations of large number of objects, or entire spectral cubes of molecular gas emission. It is a general tool that can be applied to any field that uses radio interferometer observations. The source code is available online at http://github.com/mtazzari/galario under the open source GNU Lesser General Public License v3. [ABSTRACT FROM AUTHOR]

We present Atacama Large Millimeter/sub-millimeter Array (ALMA) Cycle 2 observations of the 1.3-mm dust continuum emission of the protoplanetary disc surrounding the T Tauri star Elias 24 with an angular resolution of ~0.2 arcsec (~28 au). The dust continuum emission map reveals a dark ring at a radial distance of 0.47 arcsec (~65 au) from the central star, surrounded by a bright ring at 0.58 arcsec (~81 au). In the outer disc, the radial intensity profile shows two inflection points at 0.71 and 0.87 arcsec (~99 and 121 au, respectively). We perform global three-dimensional smoothed particle hydrodynamic gas/dust simulations of discs hosting a migrating and accreting planet. Combining the dust density maps of small and large grains with three-dimensional radiative transfer calculations, we produce synthetic ALMA observations of a variety of disc models in order to reproduce the gap- and ring-like features observed in Elias 24. We find that the dust emission across the disc is consistent with the presence of an embedded planet with a mass of ~0.7MJ at an orbital radius of ~ 60 au. Our model suggests that the two inflection points in the radial intensity profile are due to the inward radial motion of large dust grains from the outer disc. The surface brightness map of our disc model provides a reasonable match to the gap- and ring-like structures observed in Elias 24, with an average discrepancy of ~5 per cent of the observed fluxes around the gap region. [ABSTRACT FROM AUTHOR]

Melanoma is a highly heterogeneous tumor for which recent evidence supports a model of dynamic stemness. Melanoma cells might temporally acquire tumor-initiating properties or switch from a status of tumor-initiating cells (TICs) to a more differentiated one depending on the tumor context. However, factors driving these functional changes are still unknown. We focused on the role of cyto/chemokines in shaping TICs isolated directly from tumor specimens of two melanoma patients, namely Me14346S and Me15888S. We analyzed the secretion profile of TICs and of their corresponding melanoma differentiated cells and we tested the ability of cyto/chemokines to influence TIC self-renewal and differentiation. We found that TICs, grown in vitro as melanospheres, had a complex secretory profile as compared to their differentiated counterparts. Some factors, such as CCL-2 and IL-8, also produced by adherent melanoma cells and melanocytes did not influence TIC properties. Conversely, IL-6, released by differentiated cells, reduced TIC self-renewal and induced TIC differentiation while IL-10, produced by Me15888S, strongly promoted TIC self-renewal through paracrine/autocrine actions. Complete neutralization of IL-10 activity by gene silencing and antibody-mediated blocking of the IL-10Rα was required to sensitize Me15888S to IL-6-induced differentiation. For the first time these results show that functional heterogeneity of melanoma could be directly influenced by inflammatory and suppressive soluble factors, with IL-6 favoring TIC differentiation, and IL-10 supporting TIC self-renewal. Thus, understanding the tumor microenvironment (TME) role in modulating melanoma TIC phenotype is fundamental to identifying novel therapeutic targets to achieve long-lasting regression of metastatic melanoma. S tem C ells 2016;34:2449-2460 [ABSTRACT FROM AUTHOR]

In this paper, we revisit the issue of estimating the 'fossil' disc mass in the circumprimary disc, during the merger of a supermassive black hole binary. As the binary orbital decay speeds up due to the emission of gravitational waves, the gas in the circumprimary disc might be forced to accrete rapidly and could in principle provide a significant electromagnetic counterpart to the gravitational wave emission. Since the luminosity of such flare is proportional to the gaseous mass in the circumprimary disc, estimating such mass accurately is important. Previous investigations of this issue have produced contradictory results, with some authors estimating super-Eddington flares and large disc mass, while others suggesting that the 'fossil' disc mass is very low, even less than a Jupiter mass. Here, we perform simple 1D calculations to show that such very low estimates of the disc mass are an artefact of the specific implementation of the tidal torque in 1D models. In particular, for moderate mass ratios of the binary, the usual formula for the torque used in 1D models significantly overestimates the width of the gap induced by the secondary and this artificially leads to a very small leftover circumprimary disc. Using a modified torque, calibrated to reproduce the correct gap width as estimated by 3D models, leads to fossil disc masses of the order of one solar mass. The rapid accretion of the whole circumprimary disc would produce peak luminosities of the order of 1-20 times the Eddington luminosity. Even if a significant fraction of the gas escapes accretion by flowing out the secondary orbit during the merger (an effect not included in our calculations), we would still predict close to Eddington luminosities that might be easily detected. [ABSTRACT FROM AUTHOR]

The clinical use of endothelial progenitor cells is hampered by difficulties in obtaining an adequate number of functional progenitors. This study aimed to establish whether human thoracic aortas harvested from healthy multiorgan donors can be a valuable source of angiogenic progenitors. Immunohistochemical tissue studies showed that two distinct cell populations with putative stem cell capabilities, one composed of CD34+ cells and the other of c-kit+ cells, are present in between the media and adventitia of human thoracic aortas. Ki-67+ cells with high growth potential were located in an area corresponding to the site of CD34+ and c-kit+ cell residence. We thus isolated cells (0.5 ∼ 2.0 × 104 aortic progenitors per 25 cm2) which, upon culturing, coexpressed molecules of mesenchymal stromal cells (i.e., CD44+, CD90+, CD105+) and showed a transcript expression of stem cell markers (e.g., OCT4, c-kit, BCRP-1, Interleukin-6) and BMI-1. Cell expansion was adequate for use in a clinical setting. A subset of cultured cells acquired the phenotype of endothelial cells in the presence of vascular endothelial growth factor (e.g., increased expression of KDR and von Willebrand factor positivity), as documented by flow cytometry, immunofluorescence, electron microscopy, and reverse transcription-polymerase chain reaction assays. An in vitro angiogenesis test kit revealed that cells were able to form capillary-like structures within 6 hours of seeding. This study demonstrates that thoracic aortas from multiorgan donors yield mesenchymal stromal cells with the ability to differentiate in vitro into endothelial cells. These cells can be used for the creation of an allogenic bank of angiogenic progenitors, thus providing new options for restoring vascularization at ischemic sites. [ABSTRACT FROM AUTHOR]

T-cell-mediated immunoregulation is one of the main mechanisms implicated in induction and maintenance of transplantation tolerance. In this regard, deletion or modulation of xeno/alloantigen-specific T cells, as well as blocking of their interactions with other cell populations, are currently being pursued for tolerance induction in humans as well as nonhuman primates. In order to investigate whether cytotoxic T-lymphocyte antigen-4 (CTLA-4) may represent a suitable target for a T cell depletion approach in nonhuman primate models, we analysed CTLA-4 expression in peripheral blood mononuclear cells (PBMCs) from nonhuman primates and the potential role of two anti-CTLA-4 saporin-conjugated immunotoxins. The analysis was performed in PBMCs from 8 cynomolgus monkeys from Philippines and from Mauritius both at protein level by flow cytometry and at transcriptional level by RT-PCR. In addition, the apoptotic role of the immunotoxins was investigated. The results showed that CTLA-4 was expressed at variable levels depending on the origin of the cynomolgus monkeys and the resting or activated cell condition. CTLA-4 was not expressed on resting Mauritius PBMCs and showed a lower up-regulation upon PMA/PHA activation compared to the Philippines PBMCs that expressed CTLA-4 also before activation. Two CTLA-4 RNA transcripts (672 and 550 bp) were detected with levels variations after cell stimulation. Two anti-CTLA-4 immunotoxins induced in vitro apoptosis of activated PBMCs from both sources of cynomolgus monkeys. This is the first report that documents CTLA-4 expression both at protein and transcriptional level by nonhuman primate PBMCs and provides novel perspectives of xeno/allograft rejection immunotherapy based on CTLA-4 targeting. [ABSTRACT FROM AUTHOR]

Background: Scabies or sarcoptic mange is an infestation of the skin caused by the mite Sarcoptes scabiei. Transmission from animals to humans occurs through close contact. The most common symptoms are papules, erythema, excoriations, hyperkeratosis, and hypotrichosis. In the province of Ferrara (Emilia Romagna, Italy) mange is endemic in wild animals, mostly in foxes, which can act as vectors for domestic animals and humans. Methods: From 2012 to 2020, 564 foxes were surveyed within the Wildlife Health Surveillance Regional Program, including microscopic examination in cases of skin lesions referable to scabies. In 2018, a domestic dog (10-year border collie, male), frequenting an uncultivated area colonized by foxes and located in the outskirts of Ferrara, showed scabby lesions mainly on the nose, around the eyes and on the back. Results: 11 out of 564 foxes resulted positive (1,95%), 6 cases out of 38 being in 2018 (15,8%). The parasite was detected by skin biopsy and direct microscopic examination in the domestic dog. The parasite was transmitted by the dog to the owner and the other two family members. Conclusions: The increased density of dogs and foxes in the Ferrara province, and the attitude of foxes to live near to human settlements, increase the risk of contacts between foxes, domestic animals and humans, even though stray dogs are uncommon. This case illustrates the interdependencies between animal health, human health and environment, a synergy that can enable exacerbation of diseases of zoonotic origin as highlighted by the One Health concept. It is therefore important to increase the investigation on paths as well as vectors of diseases and to find collaborative, multi-sectorial and transversal approaches to ensure quality health outcomes. The control of the disease requires an appropriate monitoring of dogs’ health being skin lesions in both, humans and animals, very similar to allergic dermatitis, which can delay the proper diagnosis of the disease. Key messages: • Sarcoptic mange is a zoonosis still present in Emilia Romagna, Italy. • The One Health approach is key to control the cycle of the zoonotic sarcoptic mange. [ABSTRACT FROM AUTHOR]

Immunotoxins were prepared with several single-chain ribosome-inactivating proteins (RIPs type 1) and with the A-chain of ricin linked to the F(ab')2 fragment of sheep anti-mouse IgG. The cytotoxic activity of these conjugates was tested on human lymphocytes pretreated with an anti-CD3 murine MoAb. The immunotoxins inhibited DNA synthesis in phytohaemagglutinin (PHA)-stimuIated lymphocytes with IC50S (concentrations causing 50% inhibition) ranging from 8.9x10-13 to 5.7 x 10-11M (immunotoxins containing dianthin 32, saporin, pokeweed antiviral protein from seeds (PAP-S), bryodin, momordin, momorcochin, and trichokirin), 1 x 10-8M (immunotoxin containing gelonin) and 5x10-9M (immunotoxin containing ricin A-chain). The immunotoxin containing saporin linked to the anti-mouse IgG F(ab')2 fragment was also highly toxic to human lymphocytes pretreated with anti-CD2, -CD3, -CD5 and -CD45 MoAbs, with IC50S ≤ 10-11M. Immunotoxins were prepared also with saporin linked to MoAbs against various CD antigens. The immunotoxin prepared with the anti-CD3 antibody had the highest specific cytotoxicity to human lymphocytes. [ABSTRACT FROM AUTHOR]

Three monoclonal antibodies (MoAb), named 8A. 8F6 and 62B1. reacting with plasma cell-associated antigens. were characterized. 8A was found to he positive throughout the B cell lineage maturation steps from the immature B-committed CD10+ cell to the plasma cells. 8F6 and 62B1 reactivity is restricted to more mature cells and related lymphoid malignancies. In particular 62B1 appears to be limited to hairy cells and plasma cells. The results show that it is possible to obtain reagents reacting with plasma cells by immunizing mice with cells derived from human multiple myclomas. Furthermore, the obtained results suggest that it is possible to elicit antibodies against antigens which are present throughout all the differentiation steps of the B cell lineage. These new MoAb could help in elucidating the phenotype of the plasma cells and the relationships of multiple myclomas with other B cell proliferative disorders. [ABSTRACT FROM AUTHOR]

BACKGROUND: Injection of DEAE dextran into Lewis rats can produce proteinuria and has been reported as a model of IgA nephropathy. METHODS: Cationic diethyl aminoethyl (DEAE) dextran of molecular weight 500 kDa was injected into male Lewis rats. After a pre-immunization period of 3 weeks, the animals were divided into two groups: group 1 (n = 14) received daily i.v, injections of 3.5 mg of antigen, group 2 (n = 14) was injected with 1.5 mg three times per week for a total period of 6 weeks. I.v. treatment was initiated with gradually increasing doses of DEAE dextran in both groups for 1 week, after which the maintenance dose was reached. RESULTS: We observed the appearance of proteinuria in a nephrotic range after 5 weeks of i.v. injections in group 1 (urinary excretion: 332 +/- 83 mg/24 h, controls: 53 +/- 14 mg/24 h). In group 2, the proteinuria was almost equal to protein excretion of healthy rats of the same weight (67 +/- 20 mg/24 h). The serum and urine creatinine were normal. By light microscopy of kidney biopsies, the presence of focal and segmental proliferation of mesangial cells after 6 weeks of i.v. injections was identified. Immunohistochemistry revealed no deposition of IgA, IgM, IgG, or C3. Using anti-ED1 antibodies, there was no evidence of interstitial infiltration of monocytes/macrophages after 6 weeks of i.v. injections. Staining for proliferating cell nuclear antigen (PCNA) did not show the presence of proliferating cells either in glomeruli or in the interstitium. Staining with FITC-WGA lectin revealed focal and segmental loss of the negative charge in the capillary wall. By electron microscopy there was deposition of dextran in the basal membrane and segmental and focal damage of the podocyte foot processes. As the chemokine RANTES may be involved in glomerular injury, we examined the kidneys of proteinuric and non-proteinuric rats for the presence of RANTES. By indirect immunofluorescence only the proteinuric rats showed RANTES deposition in the mesangium. CONCLUSIONS: Injection of rats with DEAE dextran leads to dose-dependent proteinuria without deposition of immune complexes but with podocyte damage. This is associated with local expression of the chemokine RANTES which may play a role in proteinuria of glomerular disease. [ABSTRACT FROM PUBLISHER]

The monoclonal antibody 8A, which recognizes a human plasma cell-associated antigen, was covalently linked to xanthine oxidase in a conjugate maintaining both immunological and enzymatic properties. A significant degree of target cell lysis was obtained at an enzyme concentration that was ineffective on non-target cells and on myeloid staminal cells (CFU-GM). The cytotoxic activity was abolished by an excess of antibody, by allopurinol and by superoxide dismutase and catalase. A possible use of the conjugate for bone marrow purging in multiple myeloma patients is suggested. [ABSTRACT FROM AUTHOR]

A phenotypic and functional analysis of the circulating natural killer (NK) cell population was carried out in a series of patients with hairy ceil leukaemia (HCL). The overall mean NK activity of both the mononuclear and T cell fractions was reduced compared to that of normal controls (466 lytic units (lu) v 573 lu and 226 lu v 381 lu, respectively), though this difference did not reach statistical significance (P < 0.05), individual analysis of the data showed that in five out of 15 and in seven out of 16 cases the K562 killing by the mononuclear and T cells respectively was below the lowest s.d. limit for normal subjects. This reduced NK function was associated with a decreased ability of the effector cells to bind the target. The NK response lo exogenous human leucocyte interferon was also generally depressed in cases with a low basal NK activity. The functional studies were complemented with the evaluation of the membrane expression of NK associated antigens. The percentage of circulating T cells recognized by the monoclonal antibody (MoAb) Leu-7 was significant higher (P <0.001) in HCL than in normal blood (25.2% ± 10.2 v 11.9 ± 5.9 s.d.). However, the reactivity with two other NK-related MoAb, Leu-11 and AB8.28, was significantly lower (7.1% ± 6.9 and 9.8% ± 8.5; P <0.002) than with Leu-7 and moderately reduced compared with that of normal circulating T cells(11.7% +-6.l & 12%,+ 5.5). These findings suggest that in a proportion of patients with HCL there is an Impairment of the NK compartment, which may contribute towards the occurrence of the infective complications which are the primary cause of death in this disease. [ABSTRACT FROM AUTHOR]

Peripheral blood B lymphocytes, depleted of adherent cells, from 10 patients with multiple myeloma were cultured in the presence of PWM with autologous or donor T lymphocytes. The results show that: (1) co-cultures with allogeneic T lymphocytes produced more plasma cells than those with autologous ones; (2) the k/λ ratio overlapped the values obtained in normal controls, irrespective of the light chain produced by the neoplastic plasma cells and (3) the immunological phenotype of plasma cells obtained from PWM stimulated peripheral B cells (RFA2+, RFA3+, A10+) was clearly different from that one of myelomatous plasma cells (RFA2-, RFA3-, A10+). These data confirm the T cell imbalance already seen in myeloma patients; moreover they show that PWM responsive B cell are functionally normal and phenotypically different from bone marrow myeloma cells. These results support the view that most of the peripheral B lymphocytes, previously identified as monoclonal arc in fact normal cells bearing adherent monoclonal Ig molecules. [ABSTRACT FROM AUTHOR]

The distribution of I lymphocyte subsets was assessed using monoclonal antibodies (MoAbs) in 44 untreated patients with multiple myeloma (MM) subdivided according to the clinical stage of the disease. A significant reduction (P<0.001) of T lymphocytes was observed only in stage II and III patients. The proportion and absolute number of OKT4 positive cells (helper/inducer phenotype) were significantly reduced in all stages of the disease; this quantitative abnormality was more pronounced in advanced disease. While the proportion of OKT8 positive cells (suppressor/cytotoxic phenotype) was increased above normal in all stages, the absolute number (of 0K18 positive cells) was high only in stage I patients; on the contrary in stage Il-Ill patients the total OKT8 count was reduced compared with normal controls. A significantly reduced OKT4/OKT8 ratio was found in both groups of patients (P < 0005). Functional studies, carried out on the unfractionated T cells of patients with MM, demonstrated a consistent helper defect in the ability to induce the differentiation of normal B lymphocytes into antibody producing cells in a pokeweed mitogen driven system. However, the removal of OKT8 positive cells produces a significant increase in helper capacity, suggesting that the reduced helper function of I lymphocytes in toto is probably due to excessive suppressor activity. The possible immunoregulatory role of MM T cell disease is discussed. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Inconsistent information on the prognostic significance of non-small cell lung cancer (NSCLC) isolated tumor cells (ITC) has been reported to date. We sought to evaluate the survival for NSCLC in a group of patients in which the presence of bone marrow isolated tumor cells and their DNA ploidy was assessed. Materials and methods: Seventy patients (58 males [83%]; median age 70 years, range 49–89) with T1–4, N0, M0 clinical staging entered the study; 68 who underwent complete resection, were included in the follow-up. Two patients with clinical stage T2 and T4, N0, M0 were excluded because of pleural carcinosis discovered at thoracotomy. Recruitment ended in 2002. None received neoadjuvant therapy. The rib bone marrow was extracted and assessed for ITC by hematoxylin and eosin (H&E) staining, immunohistochemistry and flow cytometry. The latter was regarded as positive when >10% of cells reacted to pan-cytokeratin antibody MNF116. DNA ploidy was studied by propidium iodide staining. Patient follow-up was with chest X-ray and abdominal US every 6 months, and CT-PET scan every 12 months for at least 5 years after surgery. Causes of death were assessed. Results: Rib bone marrow ITC were documented in 17 patients (25%), 6 with DNA euploidy (p stage: I 4; III 2), and 11 with DNA aneuploidy (p stage: I 5; II 4; III 2) while 51 (75%) patients were free of ITC (p stage: I 32; II 8; III 9; IV 2). The median follow-up was 61 months, 21 patients died from causes unrelated to NSCLC and 12 patients died from causes related to tumor relapse. Significant survival differences were observed according to stage, presence of ITC and DNA aneuploidy. In particular free from recurrence survival was significantly reduced in stage IA and IB patients presenting aneuploid ITC (Wilcoxon (Gehan) test p =0.031). Conclusions: The prognostic role of bone marrow ITC seems to be corroborated by DNA ploidy studies. Patients with bone marrow ITC with abnormal DNA content showed a significantly reduced survival particularly in stage I NSCLC. [Copyright &y& Elsevier]