Despite the relevant research efforts, the causes of amyotrophic lateral sclerosis (ALS) are still unknown and no effective cure is available. Many authors suggest that ALS is a multi-system disease ...caused by a network failure instead of a cell-autonomous pathology restricted to motoneurons. Although motoneuronal loss is the critical hallmark of ALS given their specific vulnerability, other cell populations, including muscle and glial cells, are involved in disease onset and progression, but unraveling their specific role and crosstalk requires further investigation. In particular, little is known about the plastic changes of the degenerating motor system. These spontaneous compensatory processes are unable to halt the disease progression, but their elucidation and possible use as a therapeutic target represents an important aim of ALS research. Genetic animal models of disease represent useful tools to validate proven hypotheses or to test potential therapies, and the conception of novel hypotheses about ALS causes or the study of pathogenic mechanisms may be advantaged by the use of relatively simple
models recapitulating specific aspects of the disease, thus avoiding the inclusion of too many confounding factors in an experimental setting. Here, we used a neurotoxic model of spinal motoneuron depletion induced by injection of cholera toxin-B saporin in the gastrocnemius muscle to investigate the possible occurrence of compensatory changes in both the muscle and spinal cord. The results showed that, following the lesion, the skeletal muscle became atrophic and displayed electromyographic activity similar to that observed in ALS patients. Moreover, the changes in muscle fiber morphology were different from that observed in ALS models, thus suggesting that some muscular effects of disease may be primary effects instead of being simply caused by denervation. Notably, we found plastic changes in the surviving motoneurons that can produce a functional restoration probably similar to the compensatory changes occurring in disease. These changes could be at least partially driven by glutamatergic signaling, and astrocytes contacting the surviving motoneurons may support this process.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
ABP 501 is a biosimilar to the anti-tumor necrosis factor-alfa monoclonal antibody adalimumab and despite its effectiveness and safety in the treatment of psoriasis was demonstrated in randomized ...clinical trials, no real-life data are available, in particular in patients undergoing non-medical switch from originator to biosimilar.
We retrospectively searched our clinical records for all patients receiving ABP 501 between March 10, 2019 and September 7, 2019 at our Department. Therefore, we identified 94 patients, 46 patients underwent non-medical switch from adalimumab reference product to ABP 501.
In originator-naïve patients, mean PASI significantly improved from baseline to week 24 (
< .0001) in both Pso and PsA cohorts. In these patients, mean DAS-28 ESR improved with no significant differences from baseline. In patients undergoing non-medical switch from adalimumab reference product to ABP 501, no significant difference in PASI or DAS-28 ESR were observed from week 16 before switch to week 24 after switch.
AB- 501 is an effective treatment for plaque-type psoriasis and psoriatic arthritis regardless if patients are originator-naïve or if they were switched from the reference product.
During the eruption of Eyjafjallajökull in April–May 2010 multi-wavelength Raman lidar measurements were performed at the CNR-IMAA Atmospheric Observatory (CIAO), whenever weather conditions ...permitted observations. A methodology both for volcanic layer identification and accurate aerosol typing has been developed. This methodology relies on the multi-wavelength Raman lidar measurements and the support of long-term lidar measurements performed at CIAO since 2000. The aerosol mask for lidar measurements performed at CIAO during the 2010 Eyjafjallajökull eruption has been obtained. Volcanic aerosol layers were observed in different periods: 19–22 April, 27–29 April, 8–9 May, 13–14 May and 18–19 May. A maximum aerosol optical depth of about 0.12–0.13 was observed on 20 April, 22:00 UTC and 13 May, 20:30 UTC. Volcanic particles were detected at low altitudes, in the free troposphere and in the upper troposphere. Occurrences of volcanic particles within the PBL were detected on 21–22 April and 13 May. A Saharan dust event was observed on 13–14 May: dust and volcanic particles were simultaneously detected at CIAO at separated different altitudes as well as mixed within the same layer. Lidar ratios at 355 and 532 nm, the Ångström exponent at 355/532 nm, the backscatter-related Ångström exponent at 532/1064 nm and the particle linear depolarization ratio at 532 nm measured inside the detected volcanic layers are discussed. The dependence of these quantities on relative humidity has been investigated by using co-located microwave profiler measurements. The measured values of these intensive parameters indicate the presence of volcanic sulfates/continental mixed aerosol in the volcanic aerosol layers observed at CIAO. In correspondence of the maxima observed in the volcanic aerosol load on 19–20 April and 13 May, different values of intensive parameters were observed. Apart from the occurrence of sulfate aerosol, these values indicate also the presence of some ash which is affected by the aging during transport over Europe.
Summary
Background
Adherence is an overall marker of treatment success, and it depends on multiple factors including efficacy and safety. Despite the wide use of tumour necrosis factor (TNF)‐α ...blockers in the treatment of plaque‐type psoriasis, few data regarding treatment adherence in routine clinical practice are available.
Objectives
To estimate the long‐term survival rate of anti‐TNF‐α therapy in a cohort of patients with psoriasis in routine clinical practice; to evaluate the reasons for and predictors of treatment discontinuation.
Methods
The Outcome and Survival rate Concerning Anti‐TNF Routine treatment (OSCAR) study was based on a retrospective analysis to estimate the long‐term survival rate of the first anti‐TNF‐α treatment in patients with psoriasis, from three Italian academic referral centres. Adult patients (n = 650) with plaque psoriasis treated with a first course of adalimumab, etanercept or infliximab for ≥ 3 months were included.
Results
Global adherence to anti‐TNF‐α treatments after 28·9 ± 15·4 months (867 ± 462 days) of observation was 72·6%. Etanercept showed a longer survival (mean 51·4 months, 1565 days; P < 0·001) compared with infliximab (36·8 months, 1120 days) and adalimumab (34·7 months, 1056 days). Treatment discontinuation due to primary and secondary inefficacy was observed in 5·2% and 14·5% of patients, respectively, whereas discontinuation due to adverse events was reported in 29 subjects (4·5%). Independent predictors of treatment withdrawal were female gender hazards ratio (HR) 1·3, treatment with adalimumab or infliximab compared with etanercept (HR 2·7 and 1·7, respectively), and the concomitant use of traditional systemic treatment, as a rescue therapy, compared with monotherapy (HR 1·9).
Conclusions
Overall survival of anti‐TNF‐α agents in psoriasis is elevated, with drug discontinuation mostly due to inefficacy. Etanercept showed a longer adherence compared with adalimumab and infliximab.
What's already known about this topic?
Very few studies have analysed long‐term efficacy and safety of antitumour necrosis factor (anti‐TNF)‐α agents in plaque psoriasis.
Treatment adherence is an overall marker of treatment success, and it depends on multiple factors including efficacy, safety, patients’ satisfaction and dermatologists’ confidence with the treatment.
Survival rate is a standardized method for estimating treatment adherence.
What does this study add?
Adherence to anti‐TNF‐α agents after 2 years was > 70%.
The risk of drug discontinuation was significantly higher in women than in men, in case of treatment with adalimumab and infliximab compared with etanercept, and in patients who required a traditional systemic treatment as a rescue therapy, compared with patients treated exclusively with TNF‐α blockers.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Abstract
We present an optical/near-IR survey of 11 variable young stars (EXors and EXor candidates) aimed at deriving and monitoring their accretion properties. About 30 optical and near-infrared ...spectra (
R
∼
1500
–
2000
) were collected between 2014 and 2019 with the Large Binocular Telescope (LBT). From the spectral analysis we have derived the accretion luminosity (
L
acc
) and mass accretion rate (
M
̇
acc
), the visual extinction (
A
V
), the temperature and density of the permitted line formation region (
T
,
n
H
), and the signature of the outflowing matter. Two sources (ASASSN-13db and iPTF15afq) have been observed in outburst and quiescence, three during a high level of brightness (XZ Tau, PV Cep, and NY Ori), and the others in quiescence. These latter have
L
acc
and
M
̇
acc
in line with the values measured in classical T Tauri stars of similar mass. All sources observed more than once present
L
acc
and
M
̇
acc
variability. The most extreme case is ASASSN-13db, for which
M
̇
acc
decreases by two orders of magnitude from the outburst peak in 2015 to quiescence in 2017. Also, in NY Ori
L
acc
decreases by a factor 25 in one year. In 80% of the sample we detect the O
i
6300 Å line, a tracer of mass loss. From the variability of the H
α
/O
i
6300 Å ratio, we conclude that mass accretion variations are larger than mass loss variations. From the analysis of the H
i
recombination lines, a correlation is suggested between the density of the line formation region, and the level of accretion activity of the source.
Context.
V1118 Ori is a classical EXor source whose light curve has been monitored, although not continuously, over the past 30 years. This source underwent a powerful outburst in 2005, followed by ...10 years of quiescence and a less intense outburst in 2015. In 2019, a new intense brightness increase was observed (Δ
g
∼ 3 mag).
Aims.
This new accretion episode offers the opportunity to compare the photometric and spectroscopic properties of multiple outbursts of the same source. This allows us to highlight the differences and similarities among various events by removing any possible bias related to the intrinsic properties of the star-disk system.
Methods.
We discovered the 2019 V1118 Ori outburst by examining the
g
-band light curve acquired by the Zwicky Transient Facility and followed the declining phase with the Rapid Eye Mount telescope in the
griz
bands. Two near-infrared spectra were also acquired at different brightness stages with the Large Binocular Telescope.
Results.
The last event shows the following characteristics: (1) an amplitude similar to that of 2015 and lower than that of 2005; (2) a duration of less than one year as in previous events; (3) a increasing (decreasing) speed of 0.018 (0.031) mag day
−1
, which is different from previous cases; (4) a gradually blueing of the
g
−
r
color is observed over time, while the
r
−
i
color remains roughly unchanged; (5) with few exceptions, the near-infrared lines (mainly H
I
recombination) are the same as those observed in 2015; and (6) the mass accretion rate peaks at
Ṁ
acc
∼ 10
−7
M
⊙
yr
−1
and decreases in about a month down to a few 10
−8
M
⊙
yr
−1
.
Conclusions.
Our analysis shows that the comparison of data from different outbursts of the same source is a nontrivial exercise, which allows us to obtain important clues that are useful to drive theoretical efforts toward a better understanding of the EXor phenomenon.
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FMFMET, NUK, UL, UM, UPUK
Sonic hedgehog (Shh) signaling is a key pathway within the central nervous system (CNS), during both development and adulthood, and its activation via the 7-transmembrane protein Smoothened (Smo) may ...promote neuroprotection and restoration during neurodegenerative disorders. Shh signaling may also be activated by selected glucocorticoids such as clobetasol, fluocinonide and fluticasone, which therefore act as Smo agonists and hold potential utility for regenerative medicine. However, despite its potential role in neurodegenerative diseases, the impact of Smo-modulation induced by these glucocorticoids on adult neural stem cells (NSCs) and the underlying signaling mechanisms are not yet fully elucidated. The aim of the present study was to evaluate the effects of Smo agonists (i.e., purmorphamine) and antagonists (i.e., cyclopamine) as well as of glucocorticoids (i.e., clobetasol, fluocinonide and fluticasone) on NSCs in terms of proliferation and clonal expansion. Purmorphamine treatment significantly increased NSC proliferation and clonal expansion via GLI-Kruppel family member 1 (Gli1) nuclear translocation and such effects were prevented by cyclopamine co-treatment. Clobetasol treatment exhibited an equivalent pharmacological effect. Moreover, cellular thermal shift assay suggested that clobetasol induces the canonical Smo-dependent activation of Shh signaling, as confirmed by Gli1 nuclear translocation and also by cyclopamine co-treatment, which abolished these effects. Finally, fluocinonide and fluticasone as well as control glucocorticoids (i.e., prednisone, corticosterone and dexamethasone) showed no significant effects on NSCs proliferation and clonal expansion. In conclusion, our data suggest that Shh may represent a druggable target system to drive neuroprotection and promote restorative therapies.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
This study investigates the degree of consistency and fungibility of micro and macro sources of global value chain (GVC) data. We combine two datasets for selected European countries over the period ...2001–2014: the European Union-European Firms in a Global Economy (EU-EFIGE) firm-level dataset (integrated with panel balance sheet data from Amadeus) and the World Input–Output Database (WIOD) at the country and sectoral level. Although the two datasets come from different sources and are based on different assumptions, we find that (i) the WIOD-based country and sectoral GVC indicators are positively correlated with firm-level proxies based on EFIGE data; and (ii) the GVC indicators from both sources are positively correlated with firm-level labor productivity. These outcomes are robust to various empirical tests and specifications, as well as to controlling for firm, sector, and country heterogeneity. Our results hold relevance for scholars by demonstrating that the available inter-country input–output (ICIO) data can be used to compensate for the scarcity of firm-level data for evidence-based GVC analyses.
•We contribute to the applied literature by making methodological advances in GVC data use.•We combine the available micro and macro GVC data for four European countries.•We demonstrate that GVC measures computed from the two data sources are highly consistent.•We advocate utilizing the available ICIO data sources for evidence-based GVC analyses.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Confirmatory data on the long-term effectiveness and safety of ixekizumab in psoriatic patients from real-world studies are needed.
The primary aim was to evaluate the 3-year drug survival of ...ixekizumab in the treatment of patients with moderate-to-severe plaque psoriasis, in a multicenter real-world setting. The secondary aim was to assess the influence of predictive factors on the drug survival of ixekizumab.
A retrospective analysis was performed on a cohort of patients with chronic plaque psoriasis, who received at least one dose of ixekizumab before December 2018. The drug survival analysis was performed and descriptively analyzed using Kaplan-Meier survival curves. Multivariable Cox regression analyses were carried out including variables considered to be of clinical importance.
A total of 306 patients were enrolled. The overall drug survival at 12, 24, and 36 months of treatment with ixekizumab was 92.11%, 83.85%, and 80.19%, respectively. A higher probability (HR 2.34) of drug withdrawal was found among patients who had already received an anti-IL-17 agent compared with bio-naive patients (p 0.017).
We found that ixekizumab is a biological agent characterized by long-term effectiveness, not influenced by several clinical factors and associated with a good safety profile.
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