ETFAD/EADV Eczema task force 2020 position paper on diagnosis and treatment of atopic dermatitis in adults and children.

Atopic dermatitis (AD) is a highly pruritic, chronic inflammatory skin disease. The diagnosis is made using evaluated clinical criteria. Disease activity and burden are best measured with a composite score, assessing both objective and subjective symptoms, such as SCORing Atopic Dermatitis (SCORAD). AD management must take into account clinical and pathogenic variabilities, the patient's age and also target flare prevention. Basic therapy includes hydrating and barrier-stabilizing topical treatment universally applied, as well as avoiding specific and unspecific provocation factors. Visible skin lesions are treated with anti-inflammatory topical agents such as corticosteroids and calcineurin inhibitors (tacrolimus and pimecrolimus), which are preferred in sensitive locations. Topical tacrolimus and some mid-potency corticosteroids are proven agents for proactive therapy, which is defined as the long-term intermittent anti-inflammatory therapy of frequently relapsing skin areas. Systemic anti-inflammatory or immunosuppressive treatment is a rapidly changing field requiring monitoring. Oral corticosteroids have a largely unfavourable benefit-risk ratio. The IL-4R-blocker dupilumab is a safe, effective and licensed, but expensive, treatment option with potential ocular side-effects. Other biologicals targeting key pathways in the atopic immune response, as well as different Janus kinase inhibitors, are among emerging treatment options. Dysbalanced microbial colonization and infection may induce disease exacerbation and can justify additional antimicrobial treatment. Systemic antihistamines (H1R-blockers) only have limited effects on AD-related itch and eczema lesions. Adjuvant therapy includes UV irradiation, preferably narrowband UVB or UVA1. Coal tar may be useful for atopic hand and foot eczema. Dietary recommendations should be patient-specific, and elimination diets should only be advised in case of proven food allergy. Allergen-specific immunotherapy to aeroallergens may be useful in selected cases. Psychosomatic counselling is recommended to address stress-induced exacerbations. Efficacy-proven 'Eczema school' educational programmes and therapeutic patient education are recommended for both children and adults.

European task force on atopic dermatitis position paper: treatment of parental atopic dermatitis during preconception, pregnancy and lactation period.

Atopic dermatitis (AD) is a common inflammatory skin disease that affects both children and adults, including a large number of adults of reproductive age. Several guidelines for the treatment of AD exist, yet specific recommendations for the treatment of pregnant or lactating women and for adults planning to have a child are often lacking. This position paper from the European Task force on Atopic Dermatitis (ETFAD) is based on up-to-date scientific literature on treating pregnant and lactating women as wells as adults with AD planning to have a child. It is based on the expert opinions of members of the ETFAD and on existing safety data on the proposed treatments, many of which are derived from patients with other inflammatory diseases or from transplantation medicine. For treating future parents, as well as pregnant and lactating women with AD, the use of topical treatments including moisturizers, topical corticosteroids, tacrolimus, antiseptics such as chlorhexidine, octenidine, potassium permanganate and sodium hypochlorite (bleach) is deemed to be safe. Ultraviolet (UV) therapy may also be used. Systemic treatment should be prescribed only after careful consideration. According to the opinion of the ETFAD, treatment should be restricted to systemic corticosteroids and cyclosporine A, and, in selected cases, azathioprine.

ETFAD/EADV Eczema task force 2015 position paper on diagnosis and treatment of atopic dermatitis in adult and paediatric patients.

Atopic dermatitis (AD) is a clinically defined, highly pruritic, chronic inflammatory skin disease of children and adults. The diagnosis is made using evaluated clinical criteria. Disease activity is best measured with a composite score assessing both objective signs and subjective symptoms, such as SCORAD. The management of AD must consider the clinical and pathogenic variabilities of the disease and also target flare prevention. Basic therapy includes hydrating topical treatment, as well as avoidance of specific and unspecific provocation factors. Anti-inflammatory treatment of visible skin lesions is based on topical glucocorticosteroids and the topical calcineurin inhibitors tacrolimus and pimecrolimus. Topical calcineurin inhibitors are preferred in sensitive locations. Tacrolimus and mid-potent steroids are proven for proactive therapy, which is long-term intermittent anti-inflammatory therapy of the frequently relapsing skin areas. Systemic anti-inflammatory or immunosuppressive treatment is indicated for severe refractory cases. Biologicals targeting key mechanisms of the atopic immune response are promising emerging treatment options. Microbial colonization and superinfection may induce disease exacerbation and can justify additional antimicrobial treatment. Systemic antihistamines (H1R-blockers) may diminish pruritus, but do not have sufficient effect on lesions. Adjuvant therapy includes UV irradiation, preferably UVA1 or narrow-band UVB 311 nm. Dietary recommendations should be patient specific and elimination diets should only be advised in case of proven food allergy. Allergen-specific immunotherapy to aeroallergens may be useful in selected cases. Psychosomatic counselling is recommended to address stress-induced exacerbations. 'Eczema school' educational programmes have been proven to be helpful for children and adults.

TIRC7 and HLA-DR axis contributes to inflammation in multiple sclerosis.

BACKGROUND AND OBJECTIVE: Interactions between TIRC7 (a novel seven-transmembrane receptor on activated lymphocytes) and its ligand HLA-DR might be involved in the inflammatory process in multiple sclerosis (MS). METHODS: Methods comprised immunohistochemistry and microscopy on archival MS autopsies, proliferation-, cytokine-, and surface-staining assays using peripheral blood lymphocytes (PBLs) from MS patients and an in vitro model. RESULTS: TIRC7 was expressed in brain-infiltrating lymphocytes and strongly correlated with disease activity in MS. TIRC7 expression was reduced in T cells and induced in B cells in PBLs obtained from MS patients. After ex vivo activation, T cell expression of TIRC7 was restored in patients with active MS disease. The interaction of TIRC7(+) T lymphocytes with cells expressing HLA-DR on their surface led to T cell proliferation and activation whereas an anti-TIRC7 mAb preventing interactions with its ligand inhibited proliferation and Th1 and Th17 cytokine expression in T cells obtained from MS patients and in myelin basic protein-specific T cell clone. CONCLUSION: Our findings suggest that TIRC7 is involved in inflammation in MS and anti-TIRC7 mAb can prevent immune activation via selective inhibition of Th1- and Th17-associated cytokine expression. This targeting approach may become a novel treatment option for MS.

Coralline algal barium as indicator for 20th century northwestern North Atlantic surface ocean freshwater variability.

During the past decades climate and freshwater dynamics in the northwestern North Atlantic have undergone major changes. Large-scale freshening episodes, related to polar freshwater pulses, have had a strong influence on ocean variability in this climatically important region. However, little is known about variability before 1950, mainly due to the lack of long-term high-resolution marine proxy archives. Here we present the first multidecadal-length records of annually resolved Ba/Ca variations from Northwest Atlantic coralline algae. We observe positive relationships between algal Ba/Ca ratios from two Newfoundland sites and salinity observations back to 1950. Both records capture episodical multi-year freshening events during the 20th century. Variability in algal Ba/Ca is sensitive to freshwater-induced changes in upper ocean stratification, which affect the transport of cold, Ba-enriched deep waters onto the shelf (highly stratified equals less Ba/Ca). Algal Ba/Ca ratios therefore may serve as a new resource for reconstructing past surface ocean freshwater changes.

Patient-Oriented SCORAD (PO-SCORAD): a new self-assessment scale in atopic dermatitis validated in Europe.

BACKGROUND: Patient-oriented medicine is an emerging concept, encouraged by the World Health Organization, to greater involvement of the patient in the management of chronic diseases. The Patient-Oriented SCORing Atopic Dermatitis (PO-SCORAD) index is a self-assessment score allowing the patient to comprehensively evaluate the actual course of atopic dermatitis (AD), using subjective and objective criteria derived mainly from the SCORAD, a validated AD severity clinical assessment tool. OBJECTIVES: To validate the PO-SCORAD index in a large European population of patients exhibiting all forms of AD severity by assessing its correlation with the SCORAD index. PATIENTS/METHODS: Four hundred and seventy-one patients (185 adults, 286 children) consulting for AD in hospitals from 9 European countries were recruited. The investigators and the patients used the SCORAD and PO-SCORAD scales, respectively, to assess AD severity at inclusion (D0) and 28 ± 7 days later (D28). RESULTS: Patient-Oriented SCORing Atopic Dermatitis and SCORAD scores were significantly correlated at D0 [r = 0.67 (95% CI: 0.62; 0.72), P < 0.0001]. Consistency was confirmed at D28, with a stronger linear correlation between both scales [r = 0.79 (95% CI: 0.75; 0.83), P < 0.0001]. Absolute changes from baseline in SCORAD and PO-SCORAD scores were also significantly correlated [r= 0.71 (95% CI: 0.64; 0.76), P < 0.0001]. Although no specific intervention was investigated, AD improved over the study, with a decrease of PO-SCORAD and SCORAD scores from D0 to D28 by -19.19% and -24.39%, respectively. The consistency of the correlations was similar in the adult and children groups. CONCLUSIONS: This study validated the use of PO-SCORAD to self-assess AD severity and demonstrated its good correlation with SCORAD.

High-dose intravenous interferon beta in patients with neutralizing antibodies (HINABS): a pilot study.

BACKGROUND: Neutralizing antibodies (NABs) against interferon beta (IFNbeta) are associated with a loss of IFNbeta bioactivity and clinical effectiveness. To date, there are no anti-NAB strategies available. The primary objective of this trial was to investigate whether intravenous IFNbeta-1b can restore bioactivity in NAB-positive patients with MS. METHODS: NAB-positive patients with MS were treated with 8 MIU IFNbeta-1b s.c., 8 MIU i.v., and 16 MIU i.v. Each application was preceded by a wash-out period of 1 week. Blood samples were collected before, 3, 12, and 24 h after each administration. Myxovirus protein A (MxA) RNA and protein levels were determined. The study has been approved by the local ethics committee. RESULTS: Five patients completed the study. NAB titers ranged from 42 to 4482 neutralizing units. Median MxA protein (1821, range 12-3234) and RNA (2186, range 114-7525) area under the curve levels for the four measurements at each IFNbeta injection were significantly higher after i.v. application of 16 MIU as compared with both 8-MIU dosages, which were 743 (0-2709) for MxA protein after 8 MIU i.v. and 254 (0-1200) after s.c., and 1763 (25-7188) for MxA RNA after 8 MIU i.v., and 557 (5-2265) after s.c. applications. NAB titers decreased significantly and transiently after infusion of 16 MIU IFNbeta-1b but not after both forms of 8 MIU applications. Typical side effects could be controlled by paracetamol. No allergic reaction was observed. DISCUSSION: The results indicate that i.v. administration of IFNbeta can restore bioavailability of IFNbeta in patients with NABs.

Treatment of patients with atopic dermatitis using wet-wrap dressings with diluted steroids and/or emollients. An expert panel's opinion and review of the literature.

BACKGROUND: The use of dampened bandages to reduce inflamed eczema (synonyme dermatitis) is an old remedy. In order to evaluate the current indications for so-called wet-wrap treatment (WWT) for atopic dermatitis (AD), and to compare the different currently recognized methods, a group of experts critically reviewed their own expertise on WWT in respect to the existing literature on the subject. RESULTS: WWT is well tolerated in eczema due to the cooling effect on the skin and the rapid improvement in skin inflammation. It has been shown to be an extremely effective treatment for acute erythrodermic dermatitis, therapy-resistant AD and intolerable pruritus. Advantages of WWT include rapid response to therapy, reduction in itch and sleep disturbance, and potential for reduction in usage of topical corticosteroids (TCS). However, disadvantages include high cost, the necessity for special training in usage, potential for increased TCS absorption, increased cutaneous infections and folliculitis, and poor tolerability. Precautions to reduce the risks of long-term treatment should include education, monitoring of weight and height and, if necessary, serum cortisol levels. In adolescents the risk of striae from TCS absorption around puberty is high, and WWT with TCS in this age group should be used as a short-term therapy only and with extreme caution. To reduce risks, dilutions of steroids may be used ranging from 5 to 10%. In the maintenance phase this treatment can be rotated with the use of emollients only. Low potency TCS should be used on the face (with a mask). CONCLUSION: WWT using diluted steroids is a relatively safe addition to the therapeutic treatment options for children and adults with severe and/or refractory AD. Explanation and education is extremely important in the treatment of AD and WWT should only be employed by practitioners trained in its use. Specialized nursing care is essential, especially when using WWT for prolonged periods.

Interferon-beta antibodies have a higher affinity in patients with neutralizing antibodies compared to patients with non-neutralizing antibodies.

In this study, we investigated the affinity, determined by a relative affinity assay, using increasing concentrations of sodium-isothiocyanate to disrupt the antigen antibody binding of neutralizing and non-neutralizing antibodies against interferon-beta (IFNbeta)-1a and -1b in 73 serum samples of MS patients treated with IFNbeta-1a or -1b. Relative affinity values were significantly higher in NAB-positive compared to NAB-negative samples and in samples of IFNbeta-1a-treated patients compared to IFNbeta-1b. A significant positive correlation between relative affinity values and therapy duration indicates affinity maturation as another qualitative factor in IFNbeta neutralization.

[Positioning of the premaxilla in cases of bilateral cleft lip, alveolus and palate using Latham's appliance]. / Positionierung der Oberkieferelemente mit der Latham-Appartur bei Patienten mit Lippen-Kiefer-Gaumen-Spalten.

UNLABELLED: SUBJECT MATTER: In cases of bilateral cleft lip, alveolus and palate, preoperative positioning of the premaxilla using Latham's appliance has been described. This method is controversial, since it may cause growth defects. PATIENTS AND METHODS: From 1992 to 2000, Latham's appliance was inserted preoperatively into 20 patients with bilateral lip, alveolus and palate clefts with extreme premaxillary protrusion. Pin fixation ensued at the age of 3 months. After adjustment of the premaxilla, the soft palate was closed and bilateral lip adhesion as well as bilateral gingivoperiosteoplasty were performed directly after the removal of the appliance. Final lip closure took place 4-6 weeks later. At the age of 2 years, the hard palate was closed. Evaluation was based on combined face-maxilla models, standard photographs and, when available, lateral skull x-rays showing the relative position of the segments, the influence of Latham's appliance on the nasal septum and the relation of the upper jaw to the skull base and mandibula. RESULTS: In all cases, a satisfactory alveolar alignment was achieved; thickening and curvature of the nasal septum occurred but receded. Neither growth disturbances nor dental germ damage were seen. In two cases, complications arose from suture dehiscence of the lip adhesion: in one patient, a screw defect caused a loosening of the appliance and there was also a transmigration of the postpremaxillary pin. CONCLUSIONS: On the basis of our experience, the use of Latham's appliance, combined with consistent orthodontic supervision and, if necessary, treatment, represents a practical option for the treatment of bilateral cleft lip, alveolus and palate, especially in cases with extreme protrusion of the premaxilla.

A pervaporation-bio-hybridreactor (PBHR) for improved aroma biosynthesis with submerged culture of Ceratocystis fimbriata.

In the present study a Pervaporation-bio-hybridreactor was investigated for the improved biotechnological production of volatile flavour compounds. The mixture of esters and alcohols produced by the fungus Ceratocystis fimbriata had a fruity, banana-like odour and can legally be defined as "natural flavour". Increasing consumer demand and high market prices make the production of bioflavours an attractive alternative to chemical synthesises. However, the yield of biotechnological flavour production is often very low due to product inhibition. In situ product-removal processes can yield higher productivities by preventing product inhibition. A bioreactor with an integrated pervaporation membrane was used to determine the effects of in-situ product removal on the metabolic productivity of C. fimbriata. Fed-batch fermentations with and without integrated product removal were conducted and the performance of the processes in terms of productivities was compared. Improved productivities were observed for all products. Figure 1a and 1b show the increased amount of product gained through the application of the PBHR with fed-batch fermentation.

[Kasabach-Merritt syndrome in giant hemangioma of the liver. A case report]. / Kasabach-Merritt-Syndrom bei Riesenhämangiom der Leber. Ein Fallbericht.

Kasabach-Merritt-syndrome is rare coagulation disorder with consumption coagulopathy caused by vascular malformations. We report the case of a 44-year-old woman with repeated severe bleeding complications after small and medium sized operations with normal results in the tests of plasmatic coagulation. After discovery of a giant hemangioma of the liver the diagnosis was established. Activation of coagulation was stopped preoperatively by i.v.-heparinization and curative treatment by right-sided hemihepatectomy followed.

Positive and negative roles of the trans-acting T cell factor-1 for the acquisition of distinct Ly-49 MHC class I receptors by NK cells.

Members of the Ly-49 gene family code for class I MHC-specific receptors that regulate NK cell function. Due to a combinatorial distribution of Ly-49 receptors, NK cells display considerable clonal heterogeneity. The acquisition of one Ly-49 receptor, Ly-49A is strictly dependent on the transcriptional trans-acting factor T cell-specific factor-1 (TCF-1). Indeed, TCF-1 binds to two sites in the Ly-49a promoter and regulates its activity, suggesting that the Ly-49a gene is a direct TCF-1 target. TCF-1 deficiency resulted in the altered usage of additional Ly-49 receptors. We show in this study, using TCF-1 beta(2)-microglobulin double-deficient mice, that these repertoire alterations are not due to Ly-49/MHC class I interactions. Our findings rather suggest a TCF-1-dependent, cell autonomous effect on the acquisition of multiple Ly-49 receptors. Besides reduced receptor usage (Ly-49A and D), we also observed no effect (Ly-49C) and significantly expanded (Ly-49G and I) receptor usage in the absence of TCF-1. These effects did not in all cases correlate with the presence of TCF binding sites in the respective proximal promoter. Therefore, besides TCF-1 binding to the proximal promoter, Ly-49 acquisition may also be regulated by TCF-1 binding to more distant cis-acting elements and/or by regulating the expression of additional trans-acting factors. Consistent with the observed differential, positive or negative role of TCF-1 for Ly-49 receptor acquisition, reporter gene assays revealed the presence of an inducing as well as a repressing TCF site in certain proximal Ly-49 promoters. These findings reveal an important role of TCF-1 for the formation of the NK cell receptor repertoire.

Test-retest-reliability and validity of the Kinesiology muscle test.

OBJECTIVES: To assess the test-retest-reliability and validity of the Health Kinesiology muscle test. PATIENTS: Seven patients with clinically and allergologically confirmed wasp venom allergy. DESIGN: Four Health Kinesiology-examiners tested each patient in a random order for 10 verum and 10 placebo bottles. All examiners used the anterior deltoid as indicator muscle. Patients and examiners were completely blinded. OUTCOME MEASURES: Weak muscle holds were rated as 'sensitivity' towards the test substance, stable holding as normal (not sensitive). RESULTS: An overall kappa of 0.03 (95%-CI: -0.02-0.07) indicates the test is not reliable. Individual kappas do not substantially vary from examiner to examiner. Sensitivity and specificity were estimated at 40% and 60%. CONCLUSIONS: The results suggest that the use of Health Kinesiology as a diagnostic tool is not more useful than random guessing. This should at least be true in patients with insect venom allergy that are tested by examiners with average skills.

DNA damage-induced mutation: tolerance via translesion synthesis.

Translesion synthesis (TLS) appears to be required for most damage-induced mutagenesis in the yeast Saccharomyces cerevisiae, whether the damage arises from endogenous or exogenous sources. Thus, the production of such mutations seems to occur primarily as a consequence of the tolerance of DNA lesions rather than an error-prone repair mechanism. Tolerance via TLS in yeast involves proteins encoded by members of the RAD6 epistasis group for the repair of ultraviolet (UV) photoproducts, in particular two non-essential DNA polymerases that catalyse error-free or error-prone TLS. Homologues of these RAD6 group proteins have recently been discovered in rodent and/or human cells. Furthermore, the operation of error-free TLS in humans has been linked to a reduced risk of UV-induced skin cancer, whereas mutations generated by error-prone TLS may increase the risk of cancer. In this article, we review and link the evidence for translesion synthesis in yeast, and the involvement of nonreplicative DNA polymerases, to recent findings in mammalian cells.

Impaired natural killing of MHC class I-deficient targets by NK cells expressing a catalytically inactive form of SHP-1.

NK cell function is negatively regulated by MHC class I-specific inhibitory receptors. Transduction of the inhibitory signal involves protein tyrosine phosphatases such as SHP-1 (SH2-containing protein tyrosine phosphatase-1). To investigate the role of SHP-1 for NK cell development and function, we generated mice expressing a catalytically inactive, dominant-negative mutant of SHP-1 (dnSHP-1). In this paper we show that expression of dnSHP-1 does not affect the generation of NK cells even though MHC receptor-mediated inhibition is partially impaired. Despite this defect, these NK cells do not kill syngeneic, normal target cells. In fact dnSHP-1-expressing NK cells are hyporesponsive toward MHC-deficient target cells, suggesting that non-MHC-specific NK cell activation is significantly reduced. In contrast, these NK cells mediate Ab-dependent cell-mediated cytotoxicity and prevent the engraftment with beta2-microglobulin-deficient bone marrow cells. A similar NK cell phenotype is observed in viable motheaten (mev) mice, which show reduced SHP-1 activity due to a mutation in the Shp-1 gene. In addition, NK cells in both mouse strains show a tendency to express more inhibitory MHC-specific Ly49 receptors. Our results demonstrate the importance of SHP-1 for the generation of functional NK cells, which are able to react efficiently to the absence of MHC class I molecules from normal target cells. Therefore, SHP-1 may play an as-yet-unrecognized role in some NK cell activation pathways. Alternatively, a reduced capacity to transduce SHP-1-dependent inhibitory signals during NK cell development may be compensated by the down-modulation of NK cell triggering pathways.