Erythrokeratodermia Variabilis-like Phenotype in Patients Carrying ABCA12 Mutations.

Erythrokeratodermia variabilis (EKV) is a rare genodermatosis characterized by well-demarcated erythematous patches and hyperkeratotic plaques. EKV is most often transmitted in an autosomal dominant manner. Until recently, only mutations in connexins such as GJB3 (connexin 31), GJB4 (connexin 30.3), and occasionally GJA1 (connexin 43) were known to cause EKV. In recent years, mutations in other genes have been described as rare causes of EKV, including the genes KDSR, KRT83, and TRPM4. Features of the EKV phenotype can also appear with other genodermatoses: for example, in Netherton syndrome, which hampers correct diagnosis. However, in autosomal recessive congenital ichthyosis (ARCI), an EKV phenotype has rarely been described. Here, we report on seven patients who clinically show a clear EKV phenotype, but in whom molecular genetic analysis revealed biallelic mutations in ABCA12, which is why the patients are classified in the ARCI group. Our study indicates that ARCI should be considered as a differential diagnosis in EKV.

S3 Guideline Atopic dermatitis: Part 1 - General aspects, topical and non-drug therapies, special patient groups.

This S3 guideline was created based on the European S3 guideline, with special consideration of the medical conditions in the German-speaking region and incorporating additions from the previous German-language version. The interdisciplinary guideline commission consisted of representatives from the German Dermatological Society, the Professional Association of German Dermatologists, the Austrian Society of Dermatology and Venereology, the Swiss Society of Dermatology and Venereology, the German Society for Allergology and Clinical Immunology, the German Society for Pediatric and Adolescent Medicine, the Professional Association of Pediatricians and Adolescent Medicine, the Society for Pediatric Allergology and Environmental Medicine, the German Society for Pediatric Rehabilitation and Prevention, the German Society for Psychosomatic Medicine and Medical Psychotherapy, the German Network for Health Services Research, the German Eczema Association and the German Allergy and Asthma Association. This first part of the guideline focuses on the definition and diagnostic aspects of atopic dermatitis (AD), addressing topical therapy as well as non-pharmacological treatment approaches such as UV therapy, psychoeducational therapy, dietary interventions for AD, allergen immunotherapy for AD, and complementary medicine. This part of the guideline also covers specific aspects of AD in children and adolescents, during pregnancy and lactation, and in the context of family planning. Additionally, it addresses occupational aspects of AD and highlights the perspective of the patients. The second part of the guideline, published separately, addresses the systemic therapy of AD.

Incontinentia pigmenti Stage 1 is not simply vesiculo-bullous but vesiculo-pustular.

Incontinentia pigmenti (IP) is a rare X-linked dominant, male-lethal disorder characterized by pathognomic skin lesions. As described in the literature the typical cutaneous changes follow the pattern of Blaschko's lines and develop in four stages that usually start at birth. Stage 1 is called vesicular, bullous or inflammatory. The vesicles are rapidly filled with eosinophils and thus turn into pustules. Thus, the term "pustular" is relevant to the first phase of IP, and the stage can be considered as "vesiculopustular/inflammatory" to be more precise than "vesicular" or "bullous."

S3 guideline Atopic dermatitis: Part 2 - Systemic treatment.

The present S3 guideline was created based on the European English-language S3 guideline, with special consideration given to the medical conditions in the German-speaking region, and with additions from the previous German-language version, in accordance with the criteria of the AWMF. This second part of the guideline addresses the systemic therapy of atopic dermatitis (AD). It covers topics such as the indication for systemic therapy in children, adolescents, and adult patients with AD. Furthermore, it addresses all medications approved for AD, such as the biologics dupilumab and tralokinumab, the Janus kinase inhibitors abrocitinib, baricitinib, and upadacitinib, as well as conventional immunosuppressive therapies with systemic glucocorticosteroids and ciclosporin. Additionally, it discusses systemic off-label therapies. The first part of the guideline, published separately, includes the definition and diagnostic aspects of AD, describes topical therapy, non-drug therapy approaches, and addresses aspects related to special patient groups.

Exploring the Interplay between Nutrients, Bacteriophages, and Bacterial Lipases in Host- and Bacteria-mediated Pathogenesis.

BACKGROUND AND AIMS: Pathogenic bacteria and host cells counteract or neutralize each other's effect in two fundamental ways: Direct invasion and secretion of various substances. Among these, lipases secreted by pathogenic bacteria and host cell lysozyme are key actors. Secreted lipases from pathogenic bacterial are suggested as a key player in the pathogen-host interaction. Among the gut microbial energy sources, glucose and fats have been referred to as one of the best inducers and substrates for bacterial lipases. Enrichment of bacterial growth medium with extra glucose or oil has been shown to induce lipase production in pathogenic bacteria. More recently, research has focused on the role of human gut phage alterations in the onset of dysbiosis because the bacteria-phage interactions can be dramatically affected by the nutrient milieu of the gut. However, the reciprocal role of bacterial lipases and phages in this context has not been well studied and there is no data available about how high glucose or fat availability might modulate the cellular milieu of the pathogenic bacteria-phageeukaryotic host cell interface. The purpose of this study was to evaluate the immunologic outcome of pathogenic bacteria-phage interaction under normal, high glucose, and high butter oil conditions to understand how nutrient availability affects lipase activity in pathogenic bacteria and, ultimately, the eukaryotic host cell responses to pathogenic bacteria-phage interaction. MATERIALS AND METHODS: 10 groups of co-cultured T84 and HepG2 cells were treated with Pseudomonas aeruginosa strain PAO1 (P.a PAO1) in the presence and absence of its KPP22 phage and incubated in three different growth media (DMEM, DMEM + glucose and DMEM + butter oil). Structural and physiological (barrier function and cell viability), inflammatory (IL-6 and IL-8), metabolic (glucose and triglycerides), and enzymatic (lipases and lysozyme) parameters were determined. RESULTS: Excess glucose or butter oil enhanced additively extracellular lipase activity of P.a PAO1. Excess glucose or butter oil treatments also magnified P. a PAO1- induced secretion of inflammatory signal molecules (IL-1ß, IL-6) from co-cultured cells, concomitant with the enhancement of intracellular triglycerides in co-cultured HepG2 cells, these effects being abolished by phage KPP22. CONCLUSION: The results of the present study imply that KPP22 phage influences the interplay between food substances, gut bacterial lipases, and the gut cellular milieu. This can be applied in two-way interaction: by affecting the microbial uptake of excess free simple sugars and fats from the gut milieu leading to decreased bacterial lipases and by modulating the immune system of the intestinal -liver axis cells. Further studies are needed to see if the biological consequences of these effects also occur in vivo.

Short anagen hair syndrome: association with mono- and biallelic variants in WNT10A and a genetic overlap with male pattern hair loss.

BACKGROUND: Short anagen hair (SAH) is a rare paediatric hair disorder characterized by a short anagen phase, an inability to grow long scalp hair and a negative psychological impact. The genetic basis of SAH is currently unknown. OBJECTIVES: To perform molecular genetic investigations in 48 individuals with a clinical phenotype suggestive of SAH to identify, if any, the genetic basis of this condition. METHODS: Exome sequencing was performed in 27 patients diagnosed with SAH or with a complaint of short, nongrowing hair. The cohort was screened for variants with a minor allele frequency (MAF) < 5% in the general population and a Combined Annotation Dependent Depletion (CADD) score > 15, to identify genes whose variants were enriched in this cohort. Sanger sequencing was used for variant validation and screening of 21 additional individuals with the same clinical diagnosis and their relatives. Genetic association testing of SAH-related variants for male pattern hair loss (MPHL) was performed using UK Biobank data. RESULTS: Analyses revealed that 20 individuals (42%) carried mono- or biallelic pathogenic variants in WNT10A. Rare WNT10A variants are associated with a phenotypic spectrum ranging from no clinical signs to severe ectodermal dysplasia. A significant association was found between WNT10A and SAH, and this was mostly observed in individuals with light-coloured hair and regression of the frontoparietal hairline. Notably, the most frequent variant in the cohort [c.682T>A;p.(Phe228Ile)] was in linkage disequilibrium with four common WNT10A variants, all of which have a known association with MPHL. Using UK Biobank data, our analyses showed that c.682T>A;p.(Phe228Ile) and one other variant identified in the SAH cohort are also associated with MPHL, and partially explain the known associations between WNT10A and MPHL. CONCLUSIONS: Our results suggest that WNT10A is associated with SAH and that SAH has a genetic overlap with the common phenotype MPHL. The presumed shared biologic effect of WNT10A variants in SAH and MPHL is a shortening of the anagen phase. Other factors, such as modifier genes and sex, may also play a role in the clinical manifestation of hair phenotypes associated with the WNT10A locus.

The immunological and structural epidermal barrier dysfunction and skin microbiome in atopic dermatitis-an update.

Atopic dermatitis (AD) is a common, chronic and relapsing inflammatory skin disease with various clinical presentations and combinations of symptoms. The pathophysiology of AD is complex and multifactorial. There are several factors involved in the etiopathogenesis of AD including structural and immunological epidermal barrier defect, imbalance of the skin microbiome, genetic background and environmental factors. Alterations in structural proteins, lipids, proteases, and their inhibitors, lead to the impairment of the stratum corneum which is associated with the increased skin penetration and transepidermal water loss. The elevated serum immunoglobulin E levels and blood eosinophilia have been shown in the majority of AD patients. Type 2 T-helper cell immune pathway with increased expression of interleukin (IL)-4, IL-5, and IL-13, has an important role in the etiopathogenesis of AD. Both T cells and keratinocytes contribute to epidermal barrier impairment in AD via a dynamic interaction of cytokines and chemokines. The skin microbiome is another factor of relevance in the etiopathogenesis of AD. It has been shown that during AD flares, Staphylococcus aureus (S. aureus) colonization increased, while Staphylococcus epidermidis (S. epidermidis) decreased. On the contrary, S. epidermidis and species of Streptococcus, Corynebacterium and Propionibacterium increased during the remision phases. However, it is not clear whether skin dysbiosis is one of the symptoms or one of the causes of AD. There are several therapeutic options, targeting these pathways which play a critical role in the etiopathogenesis of AD. Although topical steroids are the mainstay of the treatment of AD, new biological therapies including IL-4, IL-13, and IL-31 inhibitors, as well as Janus kinase inhibitors (JAKi), increasingly gain more importance with new advances in the therapy of AD. In this review, we summarize the role of immunological and structural epidermal barrier dysfunction, immune abnormalities, impairment of lipids, filaggrin mutation and skin microbiome in the etiopathogenesis of AD, as well as the therapeutic options for AD and their effects on these abnormalities in AD skin.

Miscellaneous annular diseases.

Annular lesions represent a unique macro-morphologic pattern in various skin disorders that may be found in pityriasis rotunda, elastosis perforans serpiginosa, subacute nodular migratory panniculitis, keratolysis exfoliativa, neutrophilic eccrine hidradenitis, hemophagocytic lymphohistiocytosis, and intentionally induced annular lesions. This group is highly heterogenous and variable in clinical presentation. Whereas some are benign self-limiting disorders like pityriasis rotunda, others such as hemophagocytic lymphohistiocytosis follow a chronic course or have a potential of being life-threatening. Epidemiology, pathogenesis, histopathology, clinical presentation and diagnosis, differential diagnosis, and treatment are discussed.

Effects of Early Emollient Use in Children at High Risk of Atopic Dermatitis: A German Pilot Study.

Several small studies have indicated that daily emollient use from birth might delay, suppress or prevent atopic dermatitis (AD). Two larger trials did not confirm this; however, a recent smaller study indicated a protective effect if daily emollient use is used in the first 2 months of life. Further research is needed to evaluate the effect of emollient use on development of AD. The current study randomly assigned 50 newborns who were at high risk of developing AD (1:1) to receive general infant skin-care advice (control group), or skin-care advice plus emollient with advice to apply emollient at least once daily until 1 year of age (intervention group). Repeated skin examinations, skin physiology measurements and skin microbiome profiling were performed. Of the children in the intervention and control groups, 28% and 24%, respectively, developed AD (adjusted Relative Risk (RR) 1.19, p = 0.65, adjusted risk difference 0.05). Skin pH decreased and transepidermal water loss and stratum corneum hydration increased over time in both groups with no significant differences. In the intervention group skin microbiome alpha diversity increased earlier, and the abundance of Streptococcus and Staphylococcus species were significantly reduced at month 1. Daily early emollient use in children with high risk of AD was safe, but it did not significantly reduce the risk of developing AD or impact skin physiology development.

IgE Depletion with Ligelizumab Does Not Significantly Improve Clinical Symptoms in Patients with Moderate-to-Severe Atopic Dermatitis.

BACKGROUND: The value, if any, of anti-IgE approaches in the treatment of atopic dermatitis has not been fully clarified. Studies using the anti-IgE omalizumab have yielded conflicting results. OBJECTIVE: Antibodies with an IgE-suppressive capacity stronger than omalizumab might be more efficacious. STUDY DESIGN: We assessed the safety and efficacy of the high-affinity anti-IgE antibody ligelizumab (280 mg, subcutaneous, every other week) in 22 adult patients with moderate-to-severe atopic dermatitis in a placebo and active (cyclosporine A) controlled, randomized, multicenter, double-blind clinical trial for 12 weeks. RESULTS: We found that ligelizumab treatment resulted in either complete (patients with baseline IgE < 1,500 IU/ml) or partial (baseline IgE > 1,500 IU/ml) suppression of serum and cell-bound IgE as well as of allergic skin prick tests. On the other hand, ligelizumab-as opposed to cyclosporine A-was not significantly superior to placebo in inducing Eczema Area and Severity Index 50 response or significantly reducing pruritus and sleep disturbance. Interestingly though, patients with high baseline IgE exhibited a slightly but not significantly better treatment response than those with low baseline IgE. CONCLUSION: Our study shows that an immunologically efficacious anti-IgE approach is not clearly superior to placebo in treating atopic dermatitis. Larger studies are needed to determine whether certain patient subgroups may benefit from this strategy. TRIAL REGISTRATION: The study was registered in 2011 at clinicaltrialsregister.eu, EudraCT Number 2011-002112-84.

Endogenous Ethanol-producing Bacteria Interference in Pathogen-host Crosstalk.

BACKGROUND AND AIMS: The host micronutrient milieu is a compilation of factors of both endogenous and exogenous origin. This milieu shapes the host's immune responses and can control the inflammatory response of the host when infected. Among vitamins, B12 plays a key role in the defense process because there is intense competition for it between pathogenic invaders and infected host cells. Alcoholic beverages and antibiotics can cause biological (in vivo) interferences that affect pathogenhost crosstalk. Ethanol is known to interfere with the absorption, distribution, and excretion of vitamin B12 in men and animals. However, the molecular mechanisms underlying this backdrop are not fully understood. Here, we explored how Gram-positive ethanol-producing and Gram-negative vitamin B12- producing microbes of the infected milieu interact to influence biomarkers of host cell defense responses in absorbing, digesting, and defensive cells. MATERIAL AND METHODS: We investigated two different cell types of colon and liver origin, hepatic-like Huh7 cells and HT- 29/B6 colon cells. To assess the ability of secreted factors from bacteria to exert influence on co-cultured cell's secretion of host-defense markers in response to invading pathogens, cocultured human colonic HT-29/B6 and human hepatic Huh-7 (hereafter Huh7) cells were stimulated or not with Klebsiella pneumoniae 52145 for 24 h in the presence or absence of either Weissella confusa strain NRRL-B-14171 (as a Gram-positive producer of ethanol), Limosilactobacillus reuteri 20016 (as a Gram-positive producer of vitamin B12), or Pseudomonas nitroreducens 1650 (as a Gram-negative producer of vitamin B12). After stimulation, molecular functional biomarkers of host cell defense responses including total MMP-1, lysozyme activity, ALP, and IL-25 were measured. RESULTS: While simultaneously reducing IL-25 secretion, Kp52145 alone significantly elicited MMP-1, lysozyme, and ALP secretion from co-cultured cells, as compared to no treatment. When compared with Kp 52145 stimulation alone, Pn1650 significantly potentiated MMP-1 and lysozyme secretions from Kp 52145-stimulated co-cultured cells by 29.7% and 67.4%, respectively. Simultaneously, a potentiated suppression (an overall decrease of 77.3%) in IL-25 secretion occurred 24 hours after Kn52145 plus Pn1650 administration. Compared to Kp52145-stimulation alone, treatment with W. confusa NRRL-B-14171 and Kp52145-stimulated co-cultured cells was associated with significant additive induction of MMP-1 and lysozyme secretions. However, compared to Kp52145-stimulation alone, W. confusa NRRL-B-14171 treatment significantly potentiated Kp52145-induced suppression of IL-25. Using the same condition as mentioned above and compared to Kp52145-stimulation alone, L. reuteri 20016 treatment altered the secretion pattern in response to Kp52145: L. reuteri 20016-treated cells displayed less aversive responses towards Kp52145, suggesting that L. reuteri 20016 modulation may act differently on Kp52145 - induced signaling. CONCLUSION: Gram-negative and Gram-positive vitamin B12- producing bacteria differently affect the secretion of key immune biomarkers in co-cultured HT-29/B6 and Huh7 cells following exposure to Kp52145. Ethanol-producing bacteria additively potentiate pathogenicity and inflammatory responses upon infection. To confirm the biological consequences of these effects on human gut microbiota and health, further studies are warranted, incorporating ex vivo studies of human colon samples and host biomarkers such as cytohistological, molecular, or biochemical measurements.

Oral Mucosal In Vitro Cell Culture Model to Study the Effect of Fructilactobacillus Phage on the Interplay between Food Components and Oral Microbiota.

BACKGROUND AND AIMS: Dietary habits, food, and nutrition-associated oral dysbiosis lead to the formation of microbial biofilm, which affects the overall health of an individual by promoting systemic diseases like cardiovascular disease, immunological disorders, and diabetes. Today's diets contain a variety of fermentable carbohydrates, including highly processed starch and novel synthetic carbohydrates such as oligofructose, sucralose, and glucose polymers. These constitute risk factors in the initiation and progression of oral dysbiosis. Oral, lung and gut microbiomes are interlinked with each other via direct and indirect ways. It is unknown whether or not lactobacilli and Lactobacillus phages are able to rescue dysbiotic effects by decreasing the uptake into the cells of excess simple sugars and their derivatives present within the digestive tract. MATERIALS AND METHODS: Using transwell cell culture plate inserts, six groups of in vitro co-cultured TR146 and HepG2 cells, grown in DMEM medium either with or without sucrose (10 % v/v), were treated with 1) PBS, 2) Fructilactobacillus sanfranciscensis (F.s) H2A, 3) F.s H2A and sucrose, 4) F.s H2A plus sucrose plus phage EV3 lysate, 5) F.s H2A plus sucrose plus phage EV3 supernatant, and 6) F.s H2A plus sucrose plus phage EV3 particles. The pH of the culture medium (indicating lactic acid production) and key oral biomarkers, including cytokines (IL-1ß and IL-6), inflammatory chemokines (e.g., CXCL8 and CCL2), and homeostatic chemokines (e.g., CXCL4 and CCL18) were measured. RESULTS: Excess sucrose significantly enhanced inflammatory signal molecules (e.g., IL-1ß, IL-6, and CCL2) secretion, concomitant with the enhancement of intracellular triglycerides in co-cultured HepG2 cells. Co-culture with F.s H2A decreased the sucrose-induced release of inflammatory signal molecules from co-cultured cells, these effects being abolished by F.s phage EV3. CONCLUSION: This study shows that Lactobacillus phages apparently influence the interplay between food components, oral microbiota, and the oral cellular milieu, at least in part by affecting the microbial uptake of excess free simple sugars from the oral milieu. To confirm the biological consequences of these effects on human oral microbiota and health, further studies are warranted, incorporating ex vivo studies of human dental plaque biofilms and host biomarkers, such as cytohistological, molecular, or biochemical measurements.