Microblading reaction as a manifestation of systemic sarcoidosis: two case reports and a review of the literature.

BACKGROUND: Sarcoidosis is a multisystemic disease characterized by granulomatous inflammation. Sarcoidosis often poses a diagnostic challenge owing to its nonspecific or mild clinical features. In 20-35% of cases, sarcoidosis initially presents on skin. However, skin lesions commonly mimic dermatological conditions. Therefore, it is important to not underestimate the skin manifestations and perform histopathological examinations to make a timely diagnosis. CASE PRESENTATION: We present two cases of 33-year-old Caucasian female patients with orange-red macules and plaques that developed in the eyebrow area 1 and 6 years after microblading, respectively. Histopathological examination confirmed a diagnosis of sarcoidosis. The lymph nodes and lungs were also affected in both patients. CONCLUSION: Our two reports suggest that an esthetic procedure involving dermal or subcutaneous injection of foreign materials can trigger the development of cutaneous and systemic sarcoidosis. However, this relationship has not been described yet. Physicians should, therefore, be aware of this complication to properly evaluate and treat such patients in a timely manner.

Evaluation of corticophobia in patients with atopic dermatitis and psoriasis using the TOPICOP© score.

INTRODUCTION: Atopic dermatitis (AD) and psoriasis (PS) are skin diseases that have a significant impact on the quality of life. The correct application of corticosteroids in topical treatment is highly effective and safe for patients. Excessive and irrational fear of these drugs based on incorrect information is increasingly observed at dermatological clinics. METHODS: To assess the extent of corticophobia, we conducted a single-center cross-sectional survey using the TOPICOP© questionnaire. RESULTS: The study included 57 patients (56% female) with AD and 58 patients (60% female) with PS. The combined TOPICOP© score averaged around 44, showing no significant difference between the two skin conditions. However, consistently higher scores were observed among female participants compared to males. CONCLUSIONS: The prevalence of corticophobia was comparable to that reported in other similar studies and was higher among female patients, which replicates previous findings. Patients with AD, who were younger on average than patients with PS, often relied on friends, acquaintances, family members, and the internet as their main information sources. Providing correct and reliable information to patients is crucial for ensuring treatment adherence.

Proposal of Slovenian guidelines for the diagnosis of neonatal erythroderma with a case report of Omenn syndrome.

Diagnosing and treating neonatal and infantile erythroderma can be challenging due to the wide variety of potential causes. Neonatal erythroderma is rare and is associated with a high mortality rate due to complications of erythroderma itself and potential life-threatening underlying diseases. Prolonged erythroderma should always be a warning sign and an indication for referral to a hospital where a multidisciplinary team approach is possible. The role of a pediatric dermatologist is to keep in mind the wide spectrum of differential diagnoses that could be causing the condition and the determination of the final diagnosis. To avert a delay in establishing the correct diagnosis, we suggest adhering to specific guidelines. We reviewed available guidelines and adapted a step-by-step approach for use in Slovenia. We also discuss a case of a neonate with erythroderma to illustrate the applicability of the proposed guidelines. Our patient presented with persistent erythroderma, pustules on the trunk and limbs, and intertriginous dermatitis. Despite local corticosteroid treatment, the skin redness persisted. After the exclusion of a systemic infection and additional tests, Omenn syndrome was diagnosed as the underlying cause.

Killing Two Birds with One Stone: Potential Therapies Targeting Psoriasis and Atherosclerosis at the Same Time.

Psoriasis is a chronic systemic inflammatory disease. Due to systemic inflammation, it is associated with many comorbidities. Among them, cardiovascular diseases represent the most common causes of morbidity and mortality in this population. Therefore, physicians treating patients with psoriasis should keep in mind that, as important as the treatment of psoriasis, awareness of cardiovascular risk deserves additional attention. Thus, in parallel with psoriasis treatment, a cardiovascular risk assessment must also be performed and addressed accordingly. In addition to encouraging non-pharmacologic strategies for a healthy lifestyle, physicians should be familiar with different pharmacologic options that can target psoriasis and reduce cardiovascular risk. In the present article, we present the pathophysiological mechanisms of the psoriasis and cardiometabolic interplay, our view on the interaction of psoriasis and cardiovascular disease, review the atherosclerotic effect of therapeutic options used in psoriasis, and vice versa, i.e., what the effect of medications used in the prevention of atherosclerosis could be on psoriasis.

Hereditary benign telangiectasia: a case report.

Hereditary benign telangiectasia is an autosomal dominant inherited dermatosis with typical presentation of telangiectasia of the skin and lips. The cause is still unknown. It is a primary telangiectasia that develops during childhood without systemic symptoms. Clinically round, oval, dendritic, or punctate telangiectasias are present, mostly asymptomatic, and they may cause only aesthetic problems. Because a similar clinical picture can be seen in several other skin diseases that may manifest not only with vascular lesions of the skin but also with systemic involvement and possible serious complications, we must be aware of all differential diagnostic possibilities. We present the case of a 37-year-old patient with hereditary benign telangiectasia to emphasize the importance of establishing the correct diagnosis and presenting proper information about the disease in a patient with telangiectasia of the skin.

Acquired epidermodysplasia verruciformis in a renal transplant patient: a case report.

Acquired epidermodysplasia verruciformis is a rare disease. It can develop in immunocompromised patients due to infection with human papillomaviruses. Because such patients are at high risk of developing cutaneous squamous cell carcinoma, timely diagnosis and regular monitoring of the patient is essential. Here we present the case of a 46-year-old male patient with acquired epidermodysplasia verruciformis occurring 5 years after a kidney transplantation. A skin biopsy detected human papillomavirus genotype 20 with low oncogenic potential. Accordingly, a follow-up interval of 1 year was determined. He was instructed to follow strict photoprotection and to visit earlier if atypical lesions appeared. Overall, our case emphasizes the consideration of possible squamous cell carcinoma in such patients and the importance of appropriate preventive measures.

A case of a 4-year-old boy with difficult-to-diagnose skin infection with nontuberculous mycobacteria.

Nontuberculous mycobacteria infections have become increasingly common in recent years and have even been confirmed in children. In addition to other organs, they can even affect the skin; nevertheless, in children lymphadenitis is the most common manifestation of the infection. The diagnosis of mycobacterial skin infection is based on patient history, clinical picture, histopathological changes, and tuberculin test result. Evidence of the causative agent in the lesion is confirmed with cultivation and PCR, two of the main tests that help determine the type of the causative mycobacteria. Here we report the case of a 4-year-old boy that presented with a few pink-to-livid papules and one plaque with a central crust on the skin of the left knee and an enlarged popliteal lymph node, highly suspicious of nontuberculous mycobacteria infection. Among the laboratory results, only a positive QuantiFERON and Mantoux test stood out. In addition, in the histopathological report, superficial and deep inflammatory elements were described, which could be due to an infection with nontuberculous mycobacteria. Despite negative cultivation and PCR, in agreement with a pediatric pulmonologist we decided to introduce antibiotic therapy for 6 months. Treatment was successful, we achieved regression of the skin lesions, and lymphadenitis was no longer present.

Challenges in the treatment of psoriasis in childhood.

Psoriasis is a chronic, immune-mediated, inflammatory skin disease that affects up to 1.2% of children and adolescents. The treatment possibilities for pediatric psoriasis are usually based on the same principles as in adults. Most information on safety and efficacy has been derived from adult studies, but only some of the frequently used treatments have approval for use in children. Treatment options for psoriasis in children and adolescents are mostly off-label, with little available data on efficacy and safety, and so the treatment of pediatric psoriasis remains a challenge. In the future, new pediatric clinical trials should be undertaken to expand the therapeutic spectrum for psoriasis in children and adolescents.

A traumatized melanocytic nevus with atypical clinical and dermoscopic features: a case report and review of the literature.

We report the case of an adolescent girl that presented with an atypical melanocytic lesion on the left gluteal region, suspicious for melanoma. She was healthy with no associated diseases, and there was no history of skin cancer in the family. The nevus had been present for several years, but she had noted a change and growth of it in the last few months. She reported that the nevus was injured about 2 years earlier and it had appeared different ever since. Although dermoscopic examination showed the lesion to be highly suspicious for melanoma and it was therefore surgically excised on the same day, pathohistological examination showed a compound melanocytic nevus with extensive dermal fibrosis/regression and overlying atypical junctional hyperplasia of melanocytes consistent with pseudomelanoma, also known as recurrent melanocytic nevus.

Hard-to-treat psoriasis in a child developing neutralizing anti-drug antibodies against adalimumab during Streptococcus pyogenes throat infection: a case report.

We report a case of a child with severe psoriasis vulgaris that developed neutralizing anti-drug antibodies against the biologic agent adalimumab 3 months after the first administration of the drug during Streptococcus pyogenes infection of the throat. After replacement of biologic agent, she was unsuccessfully treated with etanercept. Treatment with ustekinumab was the last option and initially it also appeared ineffective, but as we shortened the interval and doubled the dosage our patient's skin condition finally improved.

Papular eruption on UV-exposed skin in a 7-year-old boy caused by Enterobius vermicularis infection.

Enterobiasis is the most common parasite infestation in children; it is often asymptomatic and may rarely be a cause of skin eruption. We present the case of a 7-year-old boy with sudden onset of pruritic erythemato-squamous confluent papules and plaques on UV-exposed skin, caused by proven enterobiasis. To our understanding, this is the first case of photodermatosis-like dermatitis caused by enterobiasis reported in the literature.

Drug survival of biological therapy is showing class effect: updated results from Slovenian National Registry of psoriasis.

BACKGROUND: Drug survival is an important measure of successful treatment of patients with chronic diseases such as psoriasis. Therefore, the objective was to calculate drug survival and examine safety profile of biologics and immunomodulators (adalimumab, apremilast, etanercept, ixekizumab, infliximab, secukinumab, and ustekinumab) from the Slovenian National Registry of patients with moderate-to-severe psoriasis. METHODS: Data about the patients with moderate-to-severe plaque psoriasis treated with biologics were collected from 2005 until July 2018. Kaplan-Meier survival curves and Cox regression were used to calculate drug survival, where ustekinumab was selected as a reference. RESULTS: Overall, 1,606 patients were analyzed within 2,241 treatment episodes; adalimumab N = 831, apremilast N = 94, etanercept N = 101, ixekizumab N = 98, infliximab N = 164, secukinumab N = 340, and ustekinumab N = 613, respectively. Loss of efficacy was the most frequent reason for treatment discontinuation (contributing to 66.1% of all discontinuations). Ustekinumab was associated with the highest drug survival, meanwhile apremilast was the drug with the lowest survival rate compared to all others. Both IL-17 inhibitors, secukinumab and ixekizumab, showed similar survival rate. CONCLUSIONS: Ustekinumab was associated with the highest drug survival and most favorable safety profile compared to other biologics. Drug survival rates can be associated with the class effect of biological targets. Highest survival rate was observed for IL-12/23 inhibitor, followed by IL-17 and TNF-α inhibitors, and last by an immunomodulator such as apremilast. Adverse events occurred most frequently with TNF-α inhibitors.

Toll-like receptor 4 senses oxidative stress mediated by the oxidation of phospholipids in extracellular vesicles.

Oxidative stress produced in response to infection or sterile injury activates the innate immune response. We found that extracellular vesicles (EVs) isolated from the plasma of patients with rheumatoid arthritis or secreted from cells subjected to oxidative stress contained oxidized phospholipids that stimulated cells expressing Toll-like receptor 4 (TLR4) in a manner dependent on its co-receptor MD-2. EVs from healthy subjects or reconstituted synthetic EVs subjected to limited oxidation gained the ability to stimulate TLR4-expressing cells, whereas prolonged oxidation abrogated this property. Furthermore, we found that 15-lipoxygenase generated hydro(pero)xylated phospholipids that stimulated TLR4-expressing cells. Molecular modeling suggested that the mechanism of activation of TLR4 by oxidized phospholipids in EVs was structurally similar to that of the TLR4 ligand lipopolysaccharide (LPS). This was supported by experiments showing that EV-mediated stimulation of cells required MD-2, that mutations that block LPS binding to TLR4 abrogated the stimulatory effect of EVs, and that EVs induced TLR4 dimerization. On the other hand, analysis of gene expression profiles showed that genes encoding factors that resolve inflammation were more abundantly expressed in responses to EVs than in response to LPS. Together, these data suggest that EVs act as an oxidative stress-induced endogenous danger signal that underlies the pervasive role of TLR4 in inflammatory diseases.

N-acylated peptides derived from human lactoferricin perturb organization of cardiolipin and phosphatidylethanolamine in cell membranes and induce defects in Escherichia coli cell division.

Two types of recently described antibacterial peptides derived from human lactoferricin, either nonacylated or N-acylated, were studied for their different interaction with membranes of Escherichia coli in vivo and in model systems. Electron microscopy revealed striking effects on the bacterial membrane as both peptide types induced formation of large membrane blebs. Electron and fluorescence microscopy, however demonstrated that only the N-acylated peptides partially induced the generation of oversized cells, which might reflect defects in cell-division. Further a different distribution of cardiolipin domains on the E. coli membrane was shown only in the presence of the N-acylated peptides. The lipid was distributed over the whole bacterial cell surface, whereas cardiolipin in untreated and nonacylated peptide-treated cells was mainly located at the septum and poles. Studies with bacterial membrane mimics, such as cardiolipin or phosphatidylethanolamine revealed that both types of peptides interacted with the negatively charged lipid cardiolipin. The nonacylated peptides however induced segregation of cardiolipin into peptide-enriched and peptide-poor lipid domains, while the N-acylated peptides promoted formation of many small heterogeneous domains. Only N-acylated peptides caused additional severe effects on the main phase transition of liposomes composed of pure phosphatidylethanolamine, while both peptide types inhibited the lamellar to hexagonal phase transition. Lipid mixtures of phosphatidylethanolamine and cardiolipin revealed anionic clustering by all peptide types. However additional strong perturbation of the neutral lipids was only seen with the N-acylated peptides. Nuclear magnetic resonance demonstrated different conformational arrangement of the N-acylated peptide in anionic and zwitterionic micelles revealing possible mechanistic differences in their action on different membrane lipids. We hypothesized that both peptides kill bacteria by interacting with bacterial membrane lipids but only N-acylated peptides interact with both charged cardiolipin and zwitterionic phosphatidylethanolamine resulting in remodeling of the natural phospholipid domains in the E. coli membrane that leads to defects in cell division.

Interactions of archaeal chromatin proteins Alba1 and Alba2 with nucleic acids.

BACKGROUND: Architectural proteins have important roles in compacting and organising chromosomal DNA. There are two potential histone counterpart peptide sequences (Alba1 and Alba2) in the Aeropyrum pernix genome (APE1832.1 and APE1823). METHODOLOGY/PRINCIPAL FINDINGS: THESE TWO PEPTIDES WERE EXPRESSED AND THEIR INTERACTIONS WITH VARIOUS DNAS WERE STUDIED USING A COMBINATION OF VARIOUS EXPERIMENTAL TECHNIQUES: surface plasmon resonance, UV spectrophotometry, circular dichroism-spectropolarimetry, gel-shift assays, and isothermal titration calorimetry. CONCLUSIONS/SIGNIFICANCE: Our data indicate that there are significant differences in the properties of the Alba1 and Alba2 proteins. Both of these Alba proteins can thermally stabilise DNA polynucleotides, as seen from UV melting curves. Alba2 and equimolar mixtures of Alba1/Alba2 have greater effects on the thermal stability of poly(dA-dT).poly(dA-dT). Surface plasmon resonance sensorgrams for binding of Alba1, Alba2, and equimolar mixtures of Alba1/Alba2 to DNA oligonucleotides show different binding patterns. Circular dichroism indicates that Alba2 has a less-ordered secondary structure than Alba1. The secondary structures of the Alba proteins are not significantly influenced by DNA binding, even at high temperatures. Based on these data, we conclude that Alba1, Alba2, and equimolar mixtures of Alba1/Alba2 show different properties in their binding to various DNAs.

Production of recombinant antimicrobial peptides in bacteria.

Large quantities of antimicrobial peptides are required for investigations and clinical trials, therefore suitable production method alternative to traditional chemical synthesis is necessary. Production of recombinant antimicrobial peptides in prokaryotic systems has successfully demonstrated the viability of this approach. Production of antimicrobial peptides in Escherichia coli is potentially limited due to their toxicity to host cells and susceptibility to proteolytic degradation, which can be avoided using fusion protein approach. We describe antimicrobial peptide production in E. coli based on forcing antimicrobial peptides into inclusion bodies, which is affective for the production of large quantities of antimicrobial peptides. Chemical reagents for cleaving peptide bond between antimicrobial peptides and fusion proteins such as cyanogen bromide and diluted acid are selective and provide antimicrobial peptides for biological studies in short time.

Expression, purification and structural studies of a short antimicrobial peptide.

We have produced a small antimicrobial peptide PFWRIRIRR in bacteria utilizing production in the form of insoluble fusion protein with ketosteroid isomerase. The recombinant peptide was rapidly and efficiently isolated by acidic cleavage of the fusion protein based on the acid labile Asp-Pro bond at the N-terminus of the peptide. The peptide has antibacterial activity and neutralizes macrophage activation by LPS. The selectivity of the peptide against bacteria correlates with preferential binding to acidic phospholipid vesicles. Solution structure of the peptide in SDS and DPC micelles was determined by NMR. The peptide adopts a well-defined structure, comprising a short helical segment. Cationic and hydrophobic clusters are segregated along the molecular axis of the short helix, which is positioned perpendicular to the membrane plane. The position of the helix is shifted in two micellar types and more nonpolar surface is exposed in anionic micelles. Overall structure explains the advantageous role of the N-terminal proline residue, which forms an integral part of the hydrophobic cluster.

Alexidine and chlorhexidine bind to lipopolysaccharide and lipoteichoic acid and prevent cell activation by antibiotics.

OBJECTIVES: Many antibiotics used to treat infections cause release of immunostimulatory cell wall components from bacteria. Therefore, a combination of antimicrobial and endotoxin-neutralizing activity is desired to prevent inflammation induced by destroyed bacteria. Chlorhexidine and alexidine are amphipathic bisbiguanides and could neutralize bacterial membrane components as stimulators of Toll-like receptors (TLRs). METHODS: Binding of chlorhexidine and alexidine to lipopolysaccharide (LPS) and lipoteichoic acid (LTA) was determined by fluorescence displacement assay and isothermal calorimetric titration. Neutralization of the biological effect of LPS and LTA on TLR-activated cellular activation was determined by NF-kappaB reporter luciferase activation on cells transfected with specific TLRs and NO production of murine macrophages in the presence of isolated agonists and antibiotic-treated bacteria. RESULTS: Alexidine and chlorhexidine bind not only to LPS but also to LTA from Gram-positive bacteria. Alexidine has a higher affinity than chlorhexidine for both compounds. Calorimetric titration shows an initial endothermic contribution indicating participation of hydrophobic interactions in LPS binding, while binding to LTA displayed initial exothermic contribution. Both compounds prevent cell activation of TLR4 and TLR2 by LPS and LTA, respectively. The addition of both compounds suppressed NO production by macrophages in the presence of bacteria treated with different types of antibiotics. CONCLUSIONS: Chlorhexidine and alexidine suppress bacterial membrane-induced cell activation at concentrations two orders of magnitude lower than that used in topical applications. Combining biocides with different types of antibiotics prevented macrophage activation in the presence of bacteria and demonstrated the potential of chlorhexidine and alexidine to suppress inflammatory responses caused by activation of TLRs.