Summary
Background
Pyoderma gangrenosum (PG) is a rare skin disease characterized clinically by ulcers with undermined borders, and histologically by neutrophil‐rich infiltrates. PG may occur alone, ...in syndromic forms or associated with systemic diseases, such as inflammatory bowel disease and haematological or rheumatological disorders.
Objectives
To determine a specific genetic background related to autoinflammation for PG.
Methods
We assessed autoinflammation by evaluating the cytokine profile and genes involved in classic autoinflammatory diseases in 13 patients with PG and in seven patients with the syndromic form, known as PASH (pyoderma gangrenosum, acne and suppurative hidradenitis).
Results
In skin samples, the expression of interleukin (IL)‐1β and its receptors, IL‐17 and its receptor, and tumour necrosis factor‐α and its receptors were significantly higher in both PG (P = 0·001) and in PASH (P < 0·001) than in controls. The chemokines IL‐8; chemokine (C‐X‐C motif) ligand 1/2/3; chemokine (C‐X‐C motif) ligand 16; and RANTES (regulated on activation, normal T‐cell‐expressed and secreted) were also overexpressed. Cases of PG and PASH showed mutations in the autoinflammatory genes MEFV, NLRP3, NLRP12, NOD2, LPIN2 and PSTPIP1.
Conclusions
Overexpression of cytokines/chemokines, along with genetic changes, supports the hypothesis that PG and its syndromic form, PASH, are a spectrum of polygenic autoinflammatory conditions.
What's already known about this topic?
Pyoderma gangrenosum (PG) is a prototypic neutrophilic dermatosis manifesting as skin ulcers. It may also occur in the context of syndromes like PAPA (pyogenic arthritis, pyoderma gangrenosum and acne) and PASH (pyoderma gangrenosum, acne and suppurative hidradenitis).
Although an autoinflammatory origin has been demonstrated for its syndromic forms, to date a specific genetic background related to autoinflammation has not been proven for pyoderma gangrenosum.
What does this study add?
The clear‐cut increase in skin expression of interleukin (IL)‐1β and IL‐17 and the presence of mutations in the main genes involved in autoinflammation indicate that PG is a polygenic autoinflammatory condition, as previously demonstrated in PASH.
The involvement of proinflammatory cytokines could address the use of biological drugs blocking IL‐1 or IL‐17 in patients with refractory PG and in patients with PASH.
Context. Mergers of two stellar-origin black holes are a prime source of gravitational waves and are under intensive investigation. One crucial ingredient in their modeling has been neglected: ...pair-instability pulsation supernovae with associated severe mass loss may suppress the formation of massive black holes, decreasing black-hole-merger rates for the highest black-hole masses. Aims. We demonstrate the effects of pair-instability pulsation supernovae on merger rate and mass using populations of double black-hole binaries formed through the isolated binary classical evolution channel. Methods. The mass loss from pair-instability pulsation supernova is estimated based on existing hydrodynamical calculations. This mass loss is incorporated into the StarTrack population synthesis code. StarTrack is used to generate double black-hole populations with and without pair-instability pulsation supernova mass loss. Results. The mass loss associated with pair-instability pulsation supernovae limits the Population I/II stellar-origin black-hole mass to 50 M⊙, in tension with earlier predictions that the maximum black-hole mass could be as high as 100 M⊙. In our model, neutron stars form with mass 1−2 M⊙. We then encounter the first mass gap at 2−5 M⊙ with the compact object absence due to rapid supernova explosions, followed by the formation of black holes with mass 5−50 M⊙, with a second mass gap at 50−135 M⊙ created by pair-instability pulsation supernovae and by pair-instability supernovae. Finally, black holes with masses above 135 M⊙ may potentially form to arbitrarily high mass limited only by the extent of the initial mass function and the strength of stellar winds. Suppression of double black-hole-merger rates by pair-instability pulsation supernovae is negligible for our evolutionary channel. Our standard evolutionary model, with the inclusion of pair-instability pulsation supernovae and pair-instability supernovae, is fully consistent with the Laser Interferometric Gravitational-wave Observatory (LIGO) observations of black-hole mergers: GW150914, GW151226, and LVT151012. The LIGO results are inconsistent with high (≳ 400 km s-1) black hole (BH) natal kicks. We predict the detection of several, and up to as many as ~60, BH-BH mergers with a total mass of 10−150 M⊙ (most likely range: 20−80 M⊙) in the forthcoming ~60 effective days of the LIGO O2 observations, assuming the detectors reach the optimistic target O2 sensitivity.
Reticulohistiocytoses: a revision of the full spectrum Bonometti, A.; Berti, E.
Journal of the European Academy of Dermatology and Venereology,
August 2020, 2020-Aug, 2020-08-00, 20200801, Letnik:
34, Številka:
8
Journal Article
Recenzirano
Odprti dostop
Reticulohistiocytoses (RH) are rare and clinically heterogeneous histiocytic disorders of dermatological interest. Three clinical entities with superimposable histopathological features are currently ...considered, namely solitary reticulohistiocytoma, diffuse/generalized reticulohistiocytosis and multicentric reticulohistiocytosis. Although in the last decade, RH studies have only minimally progressed, histiocytosis research has advanced considerably: the prognostic and therapeutic importance of the clinical subclassification of histiocytosis patients as well as of the detection of genetic alterations in the genes of the ERK pathway has been highlighted. According to these insights, we previously reported the presence of molecular alteration RH and described a subset of patients with disseminated multisystem involvement lacking arthritis. In the present review, we aim to update and revise the knowledge regarding RH. We first reviewed their histopathological, immunophenotypical and ultrastructural features, discussed their histopathological differential diagnosis with other conditions characterized by infiltrates made of oncocytic or epithelioid cells (with special regard to Destombes–Rosai–Dorfman disease) and finally summarized the molecular landscape of RH. We therefore tried to adjust the clinical subclassification of Langerhans cell histiocytosis to the clinical phenotypes of RH, outlining five clinically different groups of patients. Finally, we reconsidered the clinical workflow to the evaluation of RH patients, in light of the 5 different clinical groups and discussed the different therapeutic approaches and the possible role of target inhibitors.
Atopic dermatitis (AD) is a common chronic multifactorial dermatosis that can occur through different clinical phenotypes although all exhibit identical pathogenetic mechanisms such as the prurigo ...nodularis (PN)-like phenotype.
Here, we described 11 patients with PN-like AD treated with dupilumab, a human monoclonal IgG4 antibody that inhibits interleukin-4 (IL-4) and interleukin-13 (IL-13). Efficacy outcomes were performed at baseline, at first and fourth month after starting treatment. We collected different scores such as NRSi as well as IGA. At the same time, patient subjective benefits were analyzed through DLQI, POEM, and HADS scores. Quality of sleep was also recorded by NRSS. All patients showed rapid clinical improvement of cutaneous lesions and no other new lesions were reported during treatment. Reduction of daily itching was referred already after the first month of treatment.
These results show the effectiveness of dupilumab in this clinical setting of AD, supporting this treatment as a valid therapeutic approach in difficult-to-treat-PN-like clinical presentation of AD.
All ten LIGO/Virgo binary black hole (BH-BH) coalescences reported following the O1/O2 runs have near-zero effective spins. There are only three potential explanations for this. If the BH spin ...magnitudes are large, then: (i) either both BH spin vectors must be nearly in the orbital plane or (ii) the spin angular momenta of the BHs must be oppositely directed and similar in magnitude. Then there is also the possibility that (iii) the BH spin magnitudes are small. We consider the third hypothesis within the framework of the classical isolated binary evolution scenario of the BH-BH merger formation. We test three models of angular momentum transport in massive stars: a mildly efficient transport by meridional currents (as employed in the Geneva code), an efficient transport by the Tayler-Spruit magnetic dynamo (as implemented in the MESA code), and a very-efficient transport (as proposed by Fuller et al.) to calculate natal BH spins. We allow for binary evolution to increase the BH spins through accretion and account for the potential spin-up of stars through tidal interactions. Additionally, we update the calculations of the stellar-origin BH masses, including revisions to the history of star formation and to the chemical evolution across cosmic time. We find that we can simultaneously match the observed BH-BH merger rate density and BH masses and BH-BH effective spins. Models with efficient angular momentum transport are favored. The updated stellar-mass weighted gas-phase metallicity evolution now used in our models appears to be key for obtaining an improved reproduction of the LIGO/Virgo merger rate estimate. Mass losses during the pair-instability pulsation supernova phase are likely to be overestimated if the merger GW170729 hosts a BH more massive than 50
M
⊙
. We also estimate rates of black hole-neutron star (BH-NS) mergers from recent LIGO/Virgo observations. If, in fact. angular momentum transport in massive stars is efficient, then any (electromagnetic or gravitational wave) observation of a rapidly spinning BH would indicate either a very effective tidal spin up of the progenitor star (homogeneous evolution, high-mass X-ray binary formation through case A mass transfer, or a spin- up of a Wolf-Rayet star in a close binary by a close companion), significant mass accretion by the hole, or a BH formation through the merger of two or more BHs (in a dense stellar cluster).
Pyoderma gangrenosum (PG) is a rare, immune-mediated inflammatory skin disease presenting with painful ulcers having undermined edges. Less commonly, bullous and vegetative variants exist. Histology ...consists of a neutrophil-rich dermal infiltrate. We characterized immunohistochemically the infiltrate in different variants of PG and in another neutrophilic dermatosis as Sweet's syndrome. We studied 21 patients with PG, eight with Sweet's syndrome and 20 controls, evaluating skin immunoreactivity for inflammatory cell markers (CD3, CD163 and myeloperoxidase), cytokines tumour necrosis factor (TNF)-α, interleukin (IL)-8 and IL-17, metalloproteinases (MMP-2 and MMP-9) and vascular endothelial growth factor (VEGF). Immunoreactivities of CD3, CD163, myeloperoxidase, TNF-α, IL-8, IL-17, MMP-2, MMP-9 and VEGF were significantly higher in both PG and Sweet's syndrome than in controls (P = 0·0001). Myeloperoxidase (neutrophil marker), IL-8 (cytokine chemotactic for neutrophils) and MMP-9 (proteinase-mediating tissue damage) were expressed more significantly in both ulcerative and bullous PG than in vegetative PG as well as in Sweet's syndrome (P = 0·008-P = 0·0001). In ulcerative PG, the expression of CD3 (panT cell marker) and CD163 (macrophage marker) were significantly higher in wound edge than wound bed (P = 0·0001). In contrast, the neutrophil marker myeloperoxidase was expressed more significantly in wound bed than wound edge (P = 0·0001). Our study identifies PG as a paradigm of neutrophil-mediated inflammation, with proinflammatory cytokines/chemokines and MMPs acting as important effectors for the tissue damage, particularly in ulcerative and bullous PG where damage is stronger. In ulcerative PG, the wound bed is the site of neutrophil-recruitment, whereas in the wound edge activated T lymphocytes and macrophages pave the way to ulcer formation.
The Large Hadron Collider forward (LHCf) experiment is designed to use the LHC to verify the hadronic-interaction models used in cosmic-ray physics. Forward baryon production is one of the crucial ...points to understand the development of cosmic-ray showers. We report the neutron-energy spectra for LHC s=7 TeV proton–proton collisions with the pseudo-rapidity η ranging from 8.81 to 8.99, from 8.99 to 9.22, and from 10.76 to infinity. The measured energy spectra obtained from the two independent calorimeters of Arm1 and Arm2 show the same characteristic feature before unfolding the detector responses. We unfolded the measured spectra by using the multidimensional unfolding method based on Bayesian theory, and the unfolded spectra were compared with current hadronic-interaction models. The QGSJET II-03 model predicts a high neutron production rate at the highest pseudo-rapidity range similar to our results, and the DPMJET 3.04 model describes our results well at the lower pseudo-rapidity ranges. However, no model perfectly explains the experimental results over the entire pseudo-rapidity range. The experimental data indicate a more abundant neutron production rate relative to the photon production than any model predictions studied here.
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