The Rome diagnostic criteria for the functional bowel disorders and functional abdominal pain are used widely in research and practice. A committee consensus approach, including criticism from ...multinational expert reviewers, was used to revise the diagnostic criteria and update diagnosis and treatment recommendations, based on research results. The terminology was clarified and the diagnostic criteria and management recommendations were revised. A functional bowel disorder (FBD) is diagnosed by characteristic symptoms for at least 12 weeks during the preceding 12 months in the absence of a structural or biochemical explanation. The irritable bowel syndrome, functional abdominal bloating, functional constipation, and functional diarrhea are distinguished by symptom-based diagnostic criteria. Unspecified FBD lacks criteria for the other FBDs. Diagnostic testing is individualized, depending on patient age, primary symptom characteristics, and other clinical and laboratory features. Functional abdominal pain (FAP) is defined as either the FAP syndrome, which requires at least six months of pain with poor relation to gut function and loss of daily activities, or unspecified FAP, which lacks criteria for the FAP syndrome. An organic cause for the pain must be excluded, but aspects of the patient’s pain behavior are of primary importance. Treatment of the FBDs relies upon confident diagnosis, explanation, and reassurance. Diet alteration, drug treatment, and psychotherapy may be beneficial, depending on the symptoms and psychological features.
Dear Editor, Hereditary Fibrosing Poikiloderma with Tendon Contractures, Myopathy and Pulmonary Fibrosis (POIKTMP MIM 615704) is a recently described autosomal dominant disorder due to missense ...mutations in the FAM111B gene. Key features are early-onset poikiloderma, muscle contractures in particular of the triceps surae, diffuse progressive fatty myopathy, pulmonary fibrosis in adulthood and exocrine pancreatic insufficiency. Dermatological manifestations seem to be constant and early however, a precise description is lacking.
Topical therapy of atopic dermatitis with a focus on pimecrolimus Luger, T.; Paller, A.S.; Irvine, A.D. ...
JEADV. Journal of the European Academy of Dermatology and Venereology/Journal of the European Academy of Dermatology and Venereology,
July 2021, Letnik:
35, Številka:
7
Journal Article
Recenzirano
Odprti dostop
Atopic dermatitis (AD) is a chronic and relapsing, inflammatory skin disease characterized by impaired skin barrier function and immune system dysregulation that results in dryness, skin microbiome ...dysbiosis and intense pruritus. It is highly heterogeneous, and its management is demanding. Patients with AD are at greater risk of comorbidities such as attention‐deficit hyperactivity disorder as well as other atopic diseases. Early‐onset AD cases typically improve or resolve in late childhood; however, it is proposed that the prevalence of persistent or adult‐onset AD is higher than previously thought. Basic therapy consists of emollient application and trigger avoidance, and when insufficient, topical corticosteroids (TCS) are the first‐line treatment. However, corticophobia/steroid aversion and TCS side‐effects, particularly on sensitive skin areas, lead to low compliance and insufficient disease control. Several long‐ and short‐term randomized controlled and daily practice studies have demonstrated that topical calcineurin inhibitors, such as pimecrolimus, have similar anti‐inflammatory effects to low‐to‐medium strength TCS, reduce pruritus and improve the quality of life of patients. In addition, pimecrolimus does not cause skin atrophy, is steroid‐sparing and has a good safety profile, with no evidence for an increased risk of malignancies or skin infections. In general, pimecrolimus cream is well‐accepted and well‐tolerated, encouraging patient adherence and leading to its use by many physicians as a preferred therapy for children and sensitive skin areas.
Background
Atopic dermatitis (AD) is associated with an increased risk for viral infections including those caused by herpes simplex virus and varicella zoster virus.
Objectives
This study examined ...treatment‐emergent (TE) herpes simplex infection including eczema herpeticum (EH), and herpes zoster (HZ), in adult patients with AD receiving ≥1 dose of baricitinib (BARI), an oral selective inhibitor of Janus kinase 1/2.
Methods
We evaluated data from six double‐blinded, randomized, placebo‐controlled (PC) trials and two long‐term extension studies, within three analysis sets: PC, 2–4‐mg BARI extended and All‐BARI‐AD. Frequency, incidence rate (IR)/100 person‐years (PYs) and clinical characteristics of TE‐herpes simplex, EH and HZ were reported.
Results
In the All‐BARI‐AD dataset (n = 2531; 2247 PYs), herpes simplex was reported in 8.9% of patients (n = 224; IR = 10.3). Most herpes simplex events were rated as mild or moderate (93.3%), rarely led to permanent discontinuation (2.2%) and presented mostly as oral/perioral herpes simplex (51.3%). TE‐EH occurred at a low frequency (All‐BARI‐AD 1.7% n = 43; IR = 2.0) and were reported in 0.5%, 0.2% and 1.4% of patients receiving placebo, 2‐mg or 4‐mg BARI respectively. In the All‐BARI‐AD dataset, most events were investigator‐rated as mild/moderate (79.1%), affected ≤2% of the body surface area (74.2%) and occurred as single events (88.4%). Serious TE‐EH (n = 11) occurred exclusively in patients with poor disease control (vIGA‐AD™ score ≥3) at infection onset. TE‐HZ was reported in 2.1% of BARI patients (n = 53; IR = 2.3), without a dose relationship during the PC period (IR = 2.7 and IR = 0.0) or the extended dataset (IR = 3.7 and IR = 1.7) for 2‐ or 4‐mg BARI respectively.
Conclusions
TE‐herpes simplex was common, while occurrence of EH was uncommon. Most events of EH were localized with involvement of a small BSA and were linked to poor disease control. Events of HZ were rare in the PC dataset and without a dose dependent increase in frequency.
Summary
The inherited palmoplantar keratodermas (PPKs) are a heterogeneous group of genodermatoses, characterized by thickening of the epidermis of the palms and soles. No classification system ...satisfactorily unites clinical presentation, pathology and molecular pathogenesis. There are four patterns of hyperkeratosis – striate, focal, diffuse and punctate. Mutations in the desmoglein 1 gene (DSG1), a transmembrane glycoprotein, have been reported primarily in striate, but also in focal and diffuse PPKs. We report seven unrelated pedigrees with dominantly inherited PPK owing to mutations in the DSG1 gene, with marked phenotypic variation. Genomic DNA from each family was isolated, and individual exons amplified by polymerase chain reaction. Sanger sequencing was employed to identify mutations. Mutation analysis identified novel mutations in five families (p.Tyr126Hisfs*2, p.Ser521Tyrfs*2, p.Trp3*, p.Asp591Phefs*9 and p.Met249Ilefs*6) with striate palmar involvement and varying focal or diffuse plantar disease, and the recurrent mutation c.76C>T, p.Arg26*, in two families with variable PPK patterns. We report one recurrent and five novel DSG1 mutations, causing varying patterns of PPK, highlighting the clinical heterogeneity arising from mutations in this gene.
What's already known about this topic?
Twenty‐three mutations in the desmoglein 1 gene (DSG1) have been described in 25 families with palmoplantar keratoderma (PPK).
The majority have striate palmar involvement with focal plantar keratoderma, but isolated focal and diffuse PPKs have been reported.
What does this study add?
DSG1 mutations can present with variable phenotype within the same family.
Environmental factors, such as manual labour, may alter the clinical appearance of PPK.
A lower threshold should be considered for DSG1 screening in nonstriate PPK where an underlying keratin mutation has not been identified.
Summary
Background
Atopic dermatitis (AD) is the most common inflammatory skin disease. It is highly heterogeneous in clinical presentation, treatment response, disease trajectory and associated ...atopic comorbidities. Immune biomarkers are dysregulated in skin and peripheral blood.
Aims
We used noninvasive skin and peripheral biomarkers to observe the effects of real‐world topical corticosteroid (TCS) treatment in infants with AD, by measuring skin and blood biomarkers before and after therapy.
Methods
Seventy‐four treatment‐naïve infants with AD underwent 6 weeks of TCS treatment. Stratum corneum (SC) and plasma blood biomarkers as well as SC natural moisturizing factor (NMF) were measured before and after TCS therapy. Immune markers included innate, T helper (Th)1 and Th2 immunity, angiogenesis, and vascular factors. AD severity was assessed by the Scoring Atopic Dermatitis index, and skin barrier function by transepidermal water loss (TEWL). Twenty healthy infants were recruited as controls.
Results
TCS therapy predictably led to improvement in disease severity. Levels of immune markers in the skin and in the peripheral blood showed significant change from baseline, though most did not reach healthy control levels. The most prominent change from baseline in the SC was in markers of innate immune activation, interleukin (IL)‐18, IL‐8 and IL‐1α, and the Th2 chemokines C‐C motif chemokine (CCL)17 and CCL22. In blood, the largest changes were in Th2‐skewed biomarkers: CCL17, IL‐13, CCL22, IL‐5, and CCL26. TEWL decreased after therapy; no significant changes from baseline were found for NMF.
Conclusions
The profound impact of topical therapy on systemic biomarkers suggests that the skin compartment generates a major component of dysregulated systemic cytokines in infant AD. There may be long‐term beneficial effects of correcting systemic immune dysregulation through topical therapy.
What is already known about this topic?
Atopic dermatitis (AD) is a clinically heterogeneous condition with multiple clinical manifestations and a complex pathogenesis.
Noninvasive sampling of the stratum corneum has yielded significant insights into cytokine profiles of this compartment in AD.
Peripheral blood signatures have distinct cytokine profiles in childhood AD.
What does this study add?
We show the effects of topical corticosteroid (TCS) therapy on both skin‐derived and peripheral blood biomarkers.
TCS therapy had an effect on the cutaneous compartment but also substantially normalized the peripheral blood compartment cytokine signatures.
The long‐term effects of normalizing peripheral immune signatures are unknown but could potentially be beneficial.
What is the translational message?
TCS therapy can normalize systemic immune dysregulation in infant AD.
Different types of memory are thought to rely on different types of synaptic plasticity, many of which depend on the activation of the N-Methyl-D Aspartate (NMDA) subtype of glutamate receptors. ...Accordingly, there is considerable interest in the possibility of using positive allosteric modulators (PAMs) of NMDA receptors (NMDARs) as cognitive enhancers. Here we firstly review the evidence that NMDA receptor-dependent forms of synaptic plasticity: short-term potentiation (STP), long-term potentiation (LTP) and long-term depression (LTD) can be pharmacologically differentiated by using NMDAR ligands. These observations suggest that PAMs of NMDAR function, depending on their subtype selectivity, might differentially regulate STP, LTP and LTD. To test this hypothesis, we secondly performed experiments in rodent hippocampal slices with UBP714 (a GluN2A/2B preferring PAM), CIQ (a GluN2C/D selective PAM) and UBP709 (a pan-PAM that potentiates all GluN2 subunits). We report here, for the first time, that: (i) UBP714 potentiates sub-maximal LTP and reduces LTD; (ii) CIQ potentiates STP without affecting LTP; (iii) UBP709 enhances LTD and decreases LTP. We conclude that PAMs can differentially regulate distinct forms of NMDAR-dependent synaptic plasticity due to their subtype selectivity.
This article is part of the Neuropharmacology Special Issue on ‘Glutamate Receptors – NMDA receptors’.
•NMDAR-dependent STP, LTP and LTD can be dissociated pharmacologically•GluN2A/2B PAM UBP714 potentiates LTP and reduces LTD•GluN2C/D PAM CIQ potentiates STP without affecting LTP•NMDAR pan-PAM UBP709 potentiates LTD and reduces LTP
Re–Os isotope and platinum group elements (PGE) systematics are presented for peridotite xenoliths from N. Lesotho (on-craton), S. Namibia (circum-cratonic), the Vitim volcanic field (Baikhal Rift), ...plus massif peridotites from Beni Bousera, N. Morocco. Mg–Fe variations indicate that these samples have experienced between 5% (Vitim–Beni Bousera) and 50% (Lesotho) melt extraction, providing the opportunity to examine PGE fractionation over a large melting interval. The Namibian xenoliths and Beni Bousera massif peridotites show no variation of iridium group (Ir, Ru, Os; I-PGE) abundances or inter-element fractionations relative to melt depletion indices such as Mg number or Al
2O
3. Lesotho peridotites show large variations in I-PGE abundances (Os range 0.2–13 ppb) at relatively constant Al
2O
3 that are not easily rationalised by melt-extraction models. Despite these abundance variations, there is no significant inter-element fractionation of I-PGE, e.g., (Os/Ir)
n
, showing that these elements are not fractionated by even very large degrees of melting (up to 50% melt extraction). Lesotho peridotites are amongst the most P-PGE (Pt, Pd)-depleted mantle rocks, with highly fractionated chondrite-normalised PGE. PGE systematics for all these peridotite suites allow a relative order of PGE compatibility to be firmly established for mantle melting:
D
solid/melt
Os
∼D
solid/melt
Ir
∼D
solid/melt
Ru
>D
solid/melt
Pt
>D
solid/melt
Pd
.
Vitim peridotite xenoliths have very low Os contents and low Os/Ir (<70% chondritic) compared to the kimberlite-borne xenoliths and massif peridotites. The Vitim low Os/Ir is comparable with other suites of alkali-basalt-borne peridotite xenoliths and may result from syn- or post-eruption sulphide breakdown and alteration. Chondritic (Ru/Ir)
n
and (Os/Ir)
n
ratios in Lesotho and other cratonic peridotites show no evidence of anomalous PGE fractionations in the Archean subcontinental mantle and support the Late Veneer hypothesis. In most of the peridotite suites, (Pd/Ir)
n
values show a strong correlation with Os isotopic composition that is likely the result of melt-residue interaction. The positive variation of both (Ru/Ir)
n
and (Pd/Ir)
n
with bulk rock Al
2O
3 and Os isotopic composition for Beni Bousera and global massif peridotites indicates that these PGE ratios were modified by interaction with melts. Hence, we find no support for the intra-element PGE fractionation in the continental lithospheric mantle (CLM) representing primordial mantle heterogeneity. Highly unradiogenic Os isotope compositions appear characteristic of lithospheric peridotites with the lowest (Pd/Ir)
n
. In these samples, bulk-rock PGE patterns suggest that Os isotope systematics should be dominated by primary, residual, P-PGE-depleted sulphides, and hence, their bulk rock Re-depletion ages should be expected to approximate the melting age of the rock.
A series of polycrystalline cadmium oxide thin films was deposited over a narrow temperature range. Calculating the texture coefficients from the X-ray diffraction peaks highlighted a crystal ...transition from a preferred (111) orientation at temperatures below 310
°C to a randomly oriented thin film above 331
°C. A mechanism for pre-coating of the substrate surface with a thin film of metallic cadmium has been proposed and its likely influence on the crystal orientation transition. The transition takes place in the region of the melting point of cadmium 320.9
°C and it is suggested that the change from a solid to liquid of the metallic cadmium surface influences the nucleation of the CdO film. The (111) oriented films were highly conducting with the best electrical properties;
R
s
=18.0
Ω/sq,
n=1.23×10
20
cm
3
μ=60.0
cm
2/V
s, and
ρ=8.5×10
−04
Ω/cm being achieved for a 500
nm film deposited at 289
°C. The optical bandgap of all films was found to be 2.5
eV with the (111) oriented films yielding the higher transmittance in the visible region.
► Polycrystalline cadmium oxide films were deposited over a narrow temperature range. ► X-ray diffraction peaks highlighted a crystal orientation transition. ► A mechanism is proposed relating to the melting point of cadmium 320.9
°C. ► Electrical properties achieved
R
s
=18.0
Ω/sq,
μ=60.0
cm
2/V
s. ► The (111) oriented films yielded high transmittance in the visible region.
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