This guideline was developed as a joint interdisciplinary European project, including physicians from all relevant disciplines as well as patients. It is a consensus‐based guideline, taking available ...evidence from other guidelines, systematic reviews and published studies into account. This first part of the guideline covers methods, patient perspective, general measures and avoidance strategies, basic emollient treatment and bathing, dietary intervention, topical anti‐inflammatory therapy, phototherapy and antipruritic therapy, whereas the second part covers antimicrobial therapy, systemic treatment, allergen‐specific immunotherapy, complementary medicine, psychosomatic counselling and educational interventions. Management of AE must consider the individual clinical variability of the disease; highly standardized treatment rules are not recommended. Basic therapy is focused on treatment of disturbed barrier function by hydrating and lubricating topical treatment, besides further avoidance of specific and unspecific provocation factors. Topical anti‐inflammatory treatment based on glucocorticosteroids and calcineurin inhibitors is used for flare management and for proactive therapy for long‐term control. Topical corticosteroids remain the mainstay of therapy, whereas tacrolimus and pimecrolimus are preferred in sensitive skin areas and for long‐term use. Topical phosphodiesterase inhibitors may be a treatment alternative when available. Adjuvant therapy includes UV irradiation, preferably with UVB 311 nm or UVA1. Pruritus is targeted with the majority of the recommended therapies, but some patients may need additional antipruritic therapy. Antimicrobial therapy, systemic anti‐inflammatory treatment, immunotherapy, complementary medicine and educational intervention will be addressed in part II of the guideline.
This guideline was developed as a joint interdisciplinary European project, including physicians from all relevant disciplines as well as patients. It is a consensus‐based guideline, taking available ...evidence from other guidelines, systematic reviews and published studies into account. This second part of the guideline covers antimicrobial therapy, systemic treatment, allergen‐specific immunotherapy, complementary medicine, psychosomatic counselling and educational interventions, whereas the first part covers methods, patient perspective, general measures and avoidance strategies, basic emollient treatment and bathing, dietary intervention, topical anti‐inflammatory therapy, phototherapy and antipruritic therapy. Management of AE must consider the individual clinical variability of the disease. Systemic immunosuppressive treatment with cyclosporine, methotrexate, azathioprine and mycophenolic acid is established option for severe refractory cases, and widely available. Biologicals targeting the T helper 2 pathway such as dupilumab may be a safe and effective, disease‐modifying alternative when available. Oral drugs such as JAK inhibitors and histamine 4 receptor antagonists are in development. Microbial colonization and superinfection may cause disease exacerbation and can require additional antimicrobial treatment. Allergen‐specific immunotherapy with aeroallergens may be considered in selected cases. Psychosomatic counselling is recommended especially in stress‐induced exacerbations. Therapeutic patient education (‘Eczema school’) is recommended for children and adult patients. General measures, basic emollient treatment, bathing, dietary intervention, topical anti‐inflammatory therapy, phototherapy and antipruritic therapy have been addressed in the first part of the guideline.
Summary
Peripheral T‐cell lymphomas (PTCL) comprise a heterogeneous group of aggressive lymphoproliferative disorders almost all of which are associated with poor clinical outcomes. ...Angioimmunoblastic T‐cell lymphoma (AITL) and some peripheral T‐cell lymphoma, not otherwise specified (PTCL‐NOS) have similarities to normal CD4+ T‐cell subsets in their gene expression profiles. A cell of origin model is, therefore, emerging and is likely to be refined in the future. Follicular helper (Tfh) T cells are now established as the cell of origin of AITL and about 20% of PTCL‐NOS. Sequencing studies have identified recurrent genetic alterations in epigenetic modifiers, T‐cell receptor signalling pathway intermediates or RHOA, most commonly a specific mutation leading to RHOA G17V. While PTCL‐NOS remains a diagnosis of exclusion, advances in genomics have identified subgroups expressing transcription factors TBX 21 (Th1‐like origin) and GATA3 (Th2‐like origin). These findings suggest new biomarkers and new therapeutic avenues including the hypomethylating agent azacytidine, or inhibitors of proximal T‐cell receptor (TCR) signalling and potentially certain monoclonal antibodies. The advances over the past few years, therefore, prompt stratified medicine approaches to test biologically based treatments and determine the clinical utility of the new disease classifications.
Bcl2 is an important pro-survival protein that has an essential function in normal immunity and whose constitutive expression leads to the development of lymphomas. Although transcriptional control ...of Bcl2 has been reported, increasing evidence suggests an important component of Bcl2 regulation is post-transcriptional. Phosphorylation of Bcl2 has been shown to enhance activity to allow response to extracellular growth-factor-mediated signals. Bcl2 mRNA contains regulatory elements in both its 5'- and 3'-UTRs (untranslated regions). An IRES (internal ribosome entry sequence) in the 5'-UTR permits continued translation in the presence of cellular stresses that reduce cap-dependent translation. The 3'-UTR of Bcl2 mRNA is 5.2 kb in length and contains multiple predicted miRNA (microRNA) and RNA-BP (RNA-binding protein)-binding sites. miR-15a and miR-16-1 have been found to inhibit Bcl2 expression in B-cells, whereas the RNA-BP nucleolin has been shown to increase Bcl2 expression by binding to the 3'-UTR and enhancing mRNA stability. Both decreased expression of miR-15a and miR-16-1 and increased nucleolin have been shown to be associated with increased Bcl2 expression and resistance to apoptosis in the common human disease, chronic lymphocytic leukaemia. miRNA-based therapeutic approaches to treat cancer are emerging. Bcl2 is highly regulated by miRNAs and is therefore an excellent candidate for such approaches.
We present the first detailed elemental abundances in the ultra-faint Magellanic satellite galaxies Carina II (Car II) and Carina III (Car III). With high-resolution Magellan/MIKE spectroscopy, we ...determined the abundances of nine stars in Car II, including the first abundances of an RR Lyrae star in an ultra-faint dwarf galaxy (UFD), and two stars in Car III. The chemical abundances demonstrate that both systems are clearly galaxies and not globular clusters. The stars in these galaxies mostly display abundance trends matching those of other similarly faint dwarf galaxies: enhanced but declining /Fe ratios, iron-peak elements matching the stellar halo, and unusually low neutron-capture element abundances. One star displays a low outlying Sc/Fe = −1.0. We detect a large Ba scatter in Car II, likely due to inhomogeneous enrichment by low-mass asymptotic giant branch star winds. The most striking abundance trend is for Mg/Ca in Car II, which decreases from +0.4 to −0.4 and indicates clear variation in the initial progenitor masses of enriching core-collapse supernovae. So far, the only UFDs displaying a similar Mg/Ca trend are likely satellites of the Large Magellanic Cloud. We find two stars with Fe/H ≤ −3.5 whose abundances likely trace the first generation of metal-free Population III stars and are well fit by Population III core-collapse supernova yields. An appendix describes our new abundance uncertainty analysis that propagates line-by-line stellar parameter uncertainties.
Developmental stage-specific regulation of BCL2 occurs during B-cell maturation and has a role in normal immunity. CD40 signaling promotes proliferation and rescues B-cells from apoptosis, partly ...through induction of BCL2L1 and BCL2A1 and repression of BCL2. We previously showed that a stromal cell/CD40 ligand (CD154) culture system reproduced this switch in survival protein expression in primary human leukemic B-cells and we employed this model system to investigate BCL2 repression. BCL2 was post-transcriptionally regulated and the repressed BCL2 mRNA was associated with non-polysomal, but dense fractions on sucrose density gradients. Microarrays identified a set of miRNA that were induced by culture conditions and potentially able to bind to the BCL2 3′-UTR. Luciferase reporter assays demonstrated that miR-125b and miR-155 repressed BCL2 mRNA but while stromal cell contact alone was sufficient to induce strongly miR-125b this did not cause BCL2 repression. miR-155, which is the most abundant miRNA under basal conditions, specifically required CD154 for further induction above a threshold to exert its full repressive effects. Anti-miR-125b and anti-miR-155 prevented CD154-mediated repression of BCL2 and reduced CD154-mediated proliferation in the MEC1 B-cell line. We suggest that miR-155 and miR-125b, which are induced by CD154 and stromal cell signals, contribute to regulating proliferation and that BCL2 is one of their target mRNAs.
Background: BCL2 repression occurs in normal and leukemic B-lymphocytes in lymph nodes.
Results: miR-155 and miR-125b repress BCL2 translation and, in part, mediate the proliferative response to CD40 ligand (CD154).
Conclusion: miR-155 and miR-125b contribute to proliferative responses to CD154 and one of their targets is BCL2.
Significance: CD154 drives proliferation of mature B-cell malignancies and abrogating the effects of miRNA induced by CD154 may be therapeutically useful.
Abstract
We report the discovery of Pegasus IV, an ultra-faint dwarf galaxy found in archival data from the Dark Energy Camera processed by the DECam Local Volume Exploration Survey. Pegasus IV is a ...compact, ultra-faint stellar system (
r
1
/
2
=
41
−
6
+
8
pc;
M
V
= −4.25 ± 0.2 mag) located at a heliocentric distance of
90
−
6
+
4
kpc
. Based on spectra of seven nonvariable member stars observed with Magellan/IMACS, we confidently resolve Pegasus IV’s velocity dispersion, measuring
σ
v
=
3.3
−
1.1
+
1.7
km s
−1
(after excluding three velocity outliers); this implies a mass-to-light ratio of
M
1
/
2
/
L
V
,
1
/
2
=
167
−
99
+
224
M
⊙
/
L
⊙
for the system. From the five stars with the highest signal-to-noise spectra, we also measure a systemic metallicity of Fe/H =
−
2.63
−
0.30
+
0.26
dex, making Pegasus IV one of the most metal-poor ultra-faint dwarfs. We tentatively resolve a nonzero metallicity dispersion for the system. These measurements provide strong evidence that Pegasus IV is a dark-matter-dominated dwarf galaxy, rather than a star cluster. We measure Pegasus IV’s proper motion using data from Gaia Early Data Release 3, finding (
μ
α
*
,
μ
δ
) = (0.33 ± 0.07, −0.21 ± 0.08) mas yr
−1
. When combined with our measured systemic velocity, this proper motion suggests that Pegasus IV is on an elliptical, retrograde orbit, and is currently near its orbital apocenter. Lastly, we identify three potential RR Lyrae variable stars within Pegasus IV, including one candidate member located more than 10 half-light radii away from the system’s centroid. The discovery of yet another ultra-faint dwarf galaxy strongly suggests that the census of Milky Way satellites is still incomplete, even within 100 kpc.
The existing evidence for treatment of atopic eczema (atopic dermatitis, AE) is evaluated using the national standard Appraisal of Guidelines Research and Evaluation. The consensus process consisted ...of a nominal group process and a DELPHI procedure. Management of AE must consider the individual symptomatic variability of the disease. Basic therapy is focused on hydrating topical treatment, and avoidance of specific and unspecific provocation factors. Anti‐inflammatory treatment based on topical glucocorticosteroids and topical calcineurin inhibitors (TCI) is used for exacerbation management and more recently for proactive therapy in selected cases. Topical corticosteroids remain the mainstay of therapy, but the TCI tacrolimus and pimecrolimus are preferred in certain locations. Systemic immune‐suppressive treatment is an option for severe refractory cases. Microbial colonization and superinfection may induce disease exacerbation and can justify additional antimicrobial treatment. Adjuvant therapy includes UV irradiation preferably with UVA1 wavelength or UVB 311 nm. Dietary recommendations should be specific and given only in diagnosed individual food allergy. Allergen‐specific immunotherapy to aeroallergens may be useful in selected cases. Stress‐induced exacerbations may make psychosomatic counselling recommendable. ‘Eczema school’ educational programs have been proven to be helpful. Pruritus is targeted with the majority of the recommended therapies, but some patients need additional antipruritic therapies.
The existing evidence for treatment of atopic eczema (atopic dermatitis, AE) is evaluated using the national standard Appraisal of Guidelines Research and Evaluation. The consensus process consisted ...of a nominal group process and a DELPHI procedure. Management of AE must consider the individual symptomatic variability of the disease. Basic therapy is focused on hydrating topical treatment, and avoidance of specific and unspecific provocation factors. Anti‐inflammatory treatment based on topical glucocorticosteroids and topical calcineurin inhibitors (TCI) is used for exacerbation management and more recently for proactive therapy in selected cases. Topical corticosteroids remain the mainstay of therapy, but the TCI tacrolimus and pimecrolimus are preferred in certain locations. Systemic immune‐suppressive treatment is an option for severe refractory cases. Microbial colonization and superinfection may induce disease exacerbation and can justify additional antimicrobial treatment. Adjuvant therapy includes UV irradiation preferably with UVA1 wavelength or UVB 311 nm. Dietary recommendations should be specific and given only in diagnosed individual food allergy. Allergen‐specific immunotherapy to aeroallergens may be useful in selected cases. Stress‐induced exacerbations may make psychosomatic counselling recommendable. ‘Eczema school’ educational programs have been proven to be helpful. Pruritus is targeted with the majority of the recommended therapies, but some patients need additional antipruritic therapies.
Abstract
We report the discovery of six ultra-faint Milky Way satellites identified through matched-filter searches conducted using Dark Energy Camera (DECam) data processed as part of the second ...data release of the DECam Local Volume Exploration (DELVE) survey. Leveraging deep Gemini/GMOS-N imaging (for four candidates) as well as follow-up DECam imaging (for two candidates), we characterize the morphologies and stellar populations of these systems. We find that these candidates all share faint absolute magnitudes (
M
V
≥ −3.2 mag) and old, metal-poor stellar populations (
τ
> 10 Gyr, Fe/H < −1.4 dex). Three of these systems are more extended (
r
1/2
> 15 pc), while the other three are compact (
r
1/2
< 10 pc). From these properties, we infer that the former three systems (Boötes V, Leo Minor I, and Virgo II) are consistent with ultra-faint dwarf galaxy classifications, whereas the latter three (DELVE 3, DELVE 4, and DELVE 5) are likely ultra-faint star clusters. Using data from the Gaia satellite, we confidently measure the proper motion of Boötes V, Leo Minor I, and DELVE 4, and tentatively detect a proper-motion signal from DELVE 3 and DELVE 5; no signal is detected for Virgo II. We use these measurements to explore possible associations between the newly discovered systems and the Sagittarius dwarf spheroidal, the Magellanic Clouds, and the Vast Polar Structure, finding several plausible associations. Our results offer a preview of the numerous ultra-faint stellar systems that will soon be discovered by the Vera C. Rubin Observatory and highlight the challenges of classifying the faintest stellar systems.
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