Cutaneous and hypersensitivity reactions associated with COVID-19 vaccination-a narrative review.

Vaccination against severe acute respiratory syndrome coronavirus type 2 (SARS-CoV­2) has become a major tool in the battle against the coronavirus disease 2019 (COVID-19) pandemic. Numerous products have been developed and more are to come. Vaccination success varies greatly between different countries. There are a number of different vaccine types, such as mRNA, DNA vaccines, adenovirus vector vaccines, and full-length spike protein nanoparticles with a special matrix. The different types may also cause a different spectrum of adverse events. With mass vaccination, post-marketing surveillance for product safety becomes increasingly important. In this review, we discuss possible hypersensitivity and cutaneous adverse events related to SARS-CoV­2 vaccination-from local reactions like COVID arm to systemic and severe reactions like anaphylaxis. Vaccination may also induce or exacerbate preexisting disorders such as herpes zoster infection. This review should provide information to tailor, whenever possible, vaccination to patients' needs. It is a contribution to patient safety as well. There is general consensus that the benefits of SARS-CoV­2 vaccination currently outweigh the risks of possible adverse events.

Can intermittent, time-restricted circadian fasting modulate cutaneous severity of dermatological disorders? Insights from a multicenter, observational, prospective study.

The impact of intermittent circadian fasting (ICF) on skin disorders is far to be plenty deciphered. However, the circadian rhythm seems to exert a modulation on dermatoses severity, drug-response, and drug-related side effects. We aimed to evaluate ICF effect in the daily management of dermatological diseases. In this multicenter, prospective observational study we enrolled patients willing to undergo the 2018 ICF (from May 16 to June 14). Dermatoses severity were evaluated at the beginning of ICF (T0) and at the end of ICF (T1) by two independent board-certified dermatologists. Seventy-two patients suffering from different dermatoses volunteered to take part into the study. They displayed a mean age of 40.38 ± 12.46 years (median 41.0 years), 25 subjects were males (34.7% of the entire sample). The median weight change was 0 kg. The overall ICF effect size was -0.58 ([95% CI -0.83 to -0.33], P < .0001, medium effect size). Since in the present investigation no weight loss occurred, we could speculate that the impact of fasting in terms of improvements in the clinical symptoms could be rather due to the perturbation of the human biological clock. Despite our data remain preliminary, a chronobiological approach should be incorporated in the dermatological armamentarium.

Favorable effect of creams with skimmed donkey milk encapsulated in nanoliposomes on skin physiology.

The use of donkey milk has a long history in external dermal application for cosmetic and medical purposes. The encapsulation of different drugs into nanoliposomes and nutrients may have many benefits for the delivery of the targeted substance. The aim of the present study is to test creams with nanoliposomes encapsulated with skimmed donkey milk, reported in our registered patent, compared with effect of the placebo cream and the untreated skin. To investigate the effect of formulated cream, we have measured the electrical capacitance, transepidermal water loss and the skin pH value. The study included 15 healthy volunteers (11 women and 4 men). The patented creams exhibited satisfactory moisturizing properties very soon after application, while hydration was reached earlier in the spots treated with night cream. Transepidermal water loss slightly decreased only after 4 weeks of treatment in each of the spots assessed. The pH value was similar after each of the treatments. Tested creams may enhance the moisture of skin very soon after application, in this way potentially enable deeper permeation of phospholipids and essential proteins, without changing the pH. It may also contribute to additional anti-aging effects.

Assessment of GC-MS response of selected pesticides in apple matrices related to matrix concentration.

A uniform analyte response is required for GC-MS analysis in order to obtain acceptable quantitative results. The response of pesticides in complex matrices is susceptible to variation due to the interactions of co-extractives, both with pesticides or with GC-MS system. This study was conducted to determine the magnitude of the interactions, called matrix effect, and their behavior with the matrix dilution. The response of pyrimethanil (4,6-dimethyl-N-phenylpyrimidin-2-amine), cyprodinil (4-cyclopropyl-6-methyl-N-phenylpyrimidin-2-amine), trifloxystrobin (methyl-(2Z)-2-methoxyimino-2-[2-[[(E)-1-[3(trifluoromethyl)phenyl]ethylidene amino]oxymethyl]phenyl]acetate) and bifenthrin(2-methyl-3-phenylphenyl)methyl-3-[(Z)-2-chloro-3,3,3-trifluoroprop-1-enyl]-2,2-dimethylcyclopropane-1-carboxylate), used in apple crops protection, was evaluated in different concentrations of peel and flesh extracts of Granny Smith, Golden Delicious and Demi Rouge, selected as representatives of different matrix types. The matrix effect ranged from -0.05 to 146.14%, depending on matrix type and pesticide. The highest response variation was observed in extracts of Granny Smith-an enhancement in flesh and suppression in peel extract. With the dilution, the matrix effect decreased with different magnitudes, but for Granny Smith peel extract an inverted effect was observed. The presence of the matrix effect in GC-MS pesticides analysis was obvious, requiring the application of matrix-matched calibration in quantification procedures for each variety, with calibration standards matched by the matrix concentration.

Oxidative stress, NOx/l-arginine ratio and glutathione/glutathione S-transferase ratio as predictors of 'sterile inflammation' in patients with alcoholic cirrhosis and hepatorenal syndrome type II.

Continuous intake of alcohol leads to liver cirrhosis because of imbalance of oxidative stress/antioxidative defense and chronic 'sterile inflammation'. Hepatorenal syndrome (HRS) is the most severe complication of liver cirrhosis. The aim of our study was to assess: (1) the oxidative stress/antioxidative defense markers such as malondialdehyde (MDA), oxidative glutathione (GSH) and glutathione S-transferase (GST), (2) inflammation [C-reactive protein (CRP)], and (3) nitrate/nitrite levels (NOx) and its substrate L-arginine level. The study enrolled three groups: a group with cirrhosis and HRS (48 patients), a group with cirrhosis without HRS (32 patients), and a control group (40 healthy blood donors). All the patients with cirrhosis and HRS had type II HRS. MDA concentration was significantly higher in the groups with cirrhosis with and without HRS. Significant positive correlation was documented between the MDA level and de Ritis coefficient (AST/ALT), a marker of liver damage severity; between MDA and inflammation (CRP); between MDA and NOx concentration in the groups with cirrhosis with and without HRS. The correlation between MDA and creatinine level was significant in the group with HRS. The levels of GSH and GST were significantly lower in the groups with cirrhosis with and without HRS. The results of the study revealed that an increase in MDA and NOx concentration, along with decreased values of antioxidative defense and L-arginine, may indicate that liver damage can have an influence on progression to renal failure.

Short communication: Effect of commercial or depurinized milk diet on plasma advanced oxidation protein products, cardiovascular markers, and bone marrow CD34+ stem cell potential in rat experimental hyperuricemia.

Cardiovascular repair and myocardial contractility may be improved by migration of bone marrow stem cells (BMSC) and their delivery to the site of injury, a process known as BMSC homing. The aim of our study was to examine the dietary effect of a newly patented depurinized milk (DP) that is almost free of uric acid and purine and pyrimidine compounds compared with a standard commercial 1.5% fat UHT milk diet or allopurinol therapy in rat experimental hyperuricemia. Bone marrow stem cell potential (BMCD34(+), CD34-postive bone marrow cells), plasma oxidative stress parameters [advanced oxidation protein products, AOPP) and thiobarbituric acid reactive substances (TBARS)], myocardial damage markers [creatine phosphokinase (CPK), aspartate aminotransferase (AST), and lactate dehydrogenase (LDH)], plasma cholesterol, and high-density lipoprotein cholesterol were investigated. The DP milk diet significantly increased the number of BMCD34(+) stem cells compared with commercial UHT milk. Allopurinol given alone also increased the number of BMCD34(+). Hyperuricemia caused a significant increase in all plasma enzyme markers for myocardial damage (CPK, LDH, and AST). A cardioprotective effect was achieved with allopurinol but almost equally with DP milk and more than with commercial milk. Regarding plasma AOPP, TBARS, and cholesterol levels, the most effective treatment was DP milk. In conclusion, the protective role of a milk diet on cardiovascular function may be enhanced through the new depurinized milk diet, which may improve cardiovascular system function via increased bone marrow stem cell regenerative potential, decreased plasma oxidative stress parameters, and decreased levels of myocardial damage markers and cholesterol. New dairy technology strategies focused on eliminating harmful milk compounds should be completely nontoxic. Novel milk products should be tested for their ability to improve tissue repair and function.

Oxidative stress and metabolic biomarkers in patients with Psoriasis.

Background: Psoriasis is an autoinflammatory disease that affects not only skin but multiple organs thus being associated with many comorbidities. Oxidative stress and inflammation play the major role in the pathogenesis of this disease. Studies that examined by-products of oxidative stress in psoriasis show discrepant results. Hence, we aimed to examine the oxidative stress, inflammation and metabolic markers and to explore their potential relationship with disease severity in patients with psoriasis. Methods: This case-control study comprised of 35 patients with psoriasis and 35 age, sex and body mass index-matched healthy controls. Metabolic and oxidative stress biomarkers [i.e., malondialdehyde (MDA), advanced oxidation protein products (AOPP), and catalase (CAT)] were measured. The principal component analysis (PCA) was employed to reduce the number of measured variables into smaller number of factors. PCA factors were subsequently used in logistic regression analysis for severe psoriasis prediction.

Impurities in Hyaluronic Acid Dermal Fillers? A Narrative Review on Nonanimal Cross-Linked Fillers.

Importance: Nonanimal cross-linked hyaluronic acid (HA) dermal fillers are among the most versatile tools in minimal invasive esthetic medicine. Filler injections aim to volumize, provide contour, and reduce wrinkles and skinfolds. In the hand of the experienced user, HA fillers have an excellent safety profile. Nevertheless, adverse events have been reported related to poor injection techniques, infection, and immune reactions. Observations: In this review, the focus is on filler impurities. Impurities can originate from the fermentation process, crosslinking, packaging, and contamination. Impurities consist of particular and nonparticular matter. We discuss possible risks for the patient to be treated with HA fillers. Conclusions and Relevance: Impurities of dermal fillers bear a potential risk for patients, such as delayed autoimmune and inflammatory reactions, biofilm formation, and exposure to leachable Endocrine Disrupting Chemicals. Amount and quality of impurities can be considered as one of the quality parameters of commercially fillers. Considering patient safety, filler impurities should be further reduced.

Unusual Clinical Presentation of Giant Extragenital Condyloma.

Dear editor, Condylomata accuminatum (CA) is a human papillomavirus (HPV) related sexually transmitted infection (STI), clinically characterized by solitary or even clustered dark red or pink lesions solely affecting the anogenital area (1). CA involving the extragenital, non-mucosal skin has been sporadically reported (2-4). Diagnosis of CA is usually straightforward when the lesions are located on the anogenital area. However, involvement of extragenital skin may pose a diagnostic challenge. Herein, we report a rare case of giant linear extragenital CA without coexisting genital lesions, diagnosed with a synergic intervention of dermatoscopy and clinics. A 70-year-old Caucasian man was referred to our department for an atypical asymptomatic seborrheic keratosis presenting as a linear verrucous plaque (20 × 2 cm) with few solitary reddish satellite papules on the abdomen (Figure 1, a). No similar lesions were present in both cutaneous and mucosal districts. Medical history was unremarkable, and the patient denied having recent sexual intercourse or any history of condylomas. Remarkably, the patient underwent a diet in the last 8 months that resulted in a loss of 30 kg. We employed dermatoscopy to further assess the lesions, highlighting a finger-like pattern on the main lesion (Figure 1, c), while satellite lesions presented a mosaic pattern (Figure 1, b). The clinical appearance and these dermatoscopic findings were suggestive of condyloma acuminatum (CA), but due to its extraordinary presentation we also performed an incisional biopsy. Histopathological examination reviled features compatible with the diagnosis of CA (Figure 1, d, e). To better characterized the HPV genotype (high-risk and low-risk HPV) a polymerase chain reaction (PCR) from lesional tissue sample was performed and found HPV type 6 positivity. The lesions were successfully removed by electrosurgery. Regular follow-up was scheduled. Sexually transmitted infections (STIs) were also screened, namely syphilis, gonorrhea, chlamydia trachomatis, and HIV status. In addition, laboratory tests and imaging examinations (radiography of the chest and ultrasound examination of the abdomen) revealed no pathological findings. CA involving the extragenital skin has been reported within intertriginous areas, including the inframammary fold, the groin, and the axillary vault, as well as mucosal surface such as intraoral and conjunctival mucosa (1-5). In most cases, extragenital CA coexisted with genital lesions. Staples et al. reported three obese patients with extragenital CA on the skin of the abdominal pannus (3). However, all of the patients had involvement of the inguinal folds, from where the CA had extended. Generally, CA is acquired by genital, oral, or anal sexual contact. Among the wide spectrum of HPV genotypes, types 6 and 11 are responsible of 90% of CA (1). Our paradigmatic case allows us reflect on the concept of transitory immune dysregulation due to a significant amount of weight loss, and the position of the lesions in particular seems to suggest that frictional triggers may disrupt the barrier integrity, leading to higher probability of infection. Dermoscopy is a noninvasive diagnostic tool with a significant role in the assessment of melanocytic and non-melanocytic skin tumors. Furthermore, the utility of dermatoscopy has expanded to the field of inflammatory and infectious skin disease, where dermoscopy enhances the differential diagnosis between them. Seborrheic keratosis, as the most common benign epithelial tumor, can occur anywhere in the skin excluding the palms, soles, and mucosa (6). In the anogenital area, seborrheic keratosis usually resembles CA. However, dermatoscopically, seborrheic keratosis can be immediately identified by the presence of milia-like cysts, comedo-like openings, fissures, finger-print structures, and sharply demarcated borders (6). In contrast, reports of CA dermoscopy suggested four different dermoscopic patterns: fingerlike, mosaic, knoblike, and the most commonly, an unspecific pattern (7). Our case showed that dermoscopy of extragenital CA presented a mosaic pattern in an early stage of CA, while fully developed lesions revealed a fingerlike pattern, as has previously been reported by Dong et al. (7), where two different stages of clinical development of CA exhibit distinctive dermoscopic patterns, which correlates with our case. We did not observe the typical dermoscopic features of seborrheic keratosis. CA arising in an extragenital area is very rare and perhaps also underestimated. Thus, dermatologists should be aware of this unusual presentation even in the absence of genital HPV involvement. Moreover, dermoscopy may facilitate CA recognition in a such uncommon location. To our knowledge, this is the first report of extragenital condyloma acuminatum documented dermoscopically.

DPP-4 inhibition: А novel therapeutic approach to the treatment of pulmonary hypertension?

Pulmonary hypertension (PH) is a progressive disorder characterized by alterations of the vascular structure and function in the lungs. Despite the success in its stabilisation by targeting pulmonary vascular tone and endothelial dysfunction, the prognosis remains poor and new therapeutic approaches via neglected macromolecular targets are needed. In the pathophysiology of PH the early stages of vascular remodelling are considered to be reversible, while endothelial to mesenchymal transition and proliferation/migration of fibroblasts play a critical role in staging the irreversible phase. Dipeptidyl peptidase-4 (DPP-4)/CD26 is present and active in the lungs and is expressed constitutively on lung fibroblasts, on which it exerts proliferative effects. Further, it is a marker of migrating fibroblasts and of their functional activation, including collagen synthesis and inflammatory cytokine secretion. Inhibiting DPP-4 improves the reversible phases of vascular dysfunction in PH, but is also highly likely to attenuate endothelial to mesenchymal transition and decrease the proliferation and migration of fibroblasts, preventing fibrosis and, consequently, should prolong or even inhibit entrance to the potentially irreversible phase of PH. Proposed mechanisms that support the multifaceted aspects of DPP-4 inhibition in terms of improving PH, involve pathways and mediators in pulmonary vascular and connective tissue remodelling. The latter are affected by the inhibition of this protease resulting in the synergistic beneficial antioxidative, anti-inflammatory and antifibrotic effects. We offer here an evidence-supported hypothesis that DPP-4 inhibitors are likely to be effective in the irreversible phase of remodelling in PH. Accordingly, we propose PH as a possible novel therapeutic indication for existing and new DPP-4 inhibitors.

Dietary compounds as potential modulators of microRNA expression in psoriasis.

Nutrigenomic DNA reprogramming in different chronic diseases and cancer has been assessed through the stimulation of gene expression and mRNA synthesis versus DNA silencing by CpG DNA modification (methylation); histone modification (acetylation, methylation) and expression of small noncoding RNAs, known as microRNAs (miRNAs). With regard to the specific nutrigenomic effects in psoriasis, the influence of specific diets on inflammatory cell signaling transcriptional factors such as nuclear factor (NF)-κB and Wnt signaling pathways, on disease-related specific cytokine expression, pro/antioxidant balance, keratinocyte proliferation/apoptosis and on proliferation/differentiation ratio have been documented; however, the influence of dietary compounds on the balance between 'good and bad' miRNA expression has not been considered. This review aims to summarize knowledge about aberrant microRNAs expression in psoriasis and to emphasize the potential impact of some dietary compounds on endogenous miRNA synthesis in experimental conditions in vivo and in vitro. Among the aberrantly expressed miRNAs in psoriasis, one of the most prominently upregulated seems to be miR-21. The beneficial effects of phenolic compounds (curcumin and resveratrol), vitamin D, methyl donors, and omega-3 fatty acids (eicosapentaenoic acid and docosahexaenoic acid) are discussed. Highly expressed miR-155 has been downregulated by flavonoids (through a quercetin-rich diet) and by vitamin D. Quercetin has been effective in modulating miR-146a. On the other hand, downregulated miR-125b expression was restored by vitamin D, Coenzyme Q10 and by microelement selenium. In conclusion, the miRNA profile, together with other 'omics', may constitute a multifaceted approach to explore the impact of diet on psoriasis prevention and treatment.

The Encapsulation of Lycopene in Nanoliposomes Enhances Its Protective Potential in Methotrexate-Induced Kidney Injury Model.

Methotrexate is an antimetabolic drug with a myriad of serious side effects including nephrotoxicity, which presumably occurs due to oxidative tissue damage. Here, we evaluated the potential protective effect of lycopene, a potent antioxidant carotenoid, given in two different pharmaceutical forms in methotrexate-induced kidney damage in rats. Serum biochemical (urea and creatinine) and tissue oxidative damage markers and histopathological kidney changes were evaluated after systemic administration of both lycopene dissolved in corn oil and lycopene encapsulated in nanoliposomes. Similar to previous studies, single dose of methotrexate induced severe functional and morphological alterations of kidneys with cell desquamation, tubular vacuolation, and focal necrosis, which were followed by serum urea and creatinine increase and disturbances of tissue antioxidant status. Application of both forms of lycopene concomitantly with methotrexate ameliorated changes in serum urea and creatinine and oxidative damage markers and markedly reversed structural changes of kidney tissue. Moreover, animals that received lycopene in nanoliposome-encapsulated form showed higher degree of recovery than those treated with free lycopene form. The findings of this study indicate that treatment with nanoliposome-encapsulated lycopene comparing to lycopene in standard vehicle has an advantage as it more efficiently reduces methotrexate-induced kidney dysfunction.

Depurinized milk downregulates rat thymus MyD88/Akt/p38 function, NF-κB-mediated inflammation, caspase-1 activity but not the endonuclease pathway: in vitro/in vivo study.

The aim of this study was the evaluation of 15 days dietary regimen of depurinized (DP) milk (obtained using our patented technological procedures) or 1.5% fat UHT milk instead of standard chow diet, on rat thymus and bone marrow MyD88/Akt/p38, NF-κB, caspase-1 and endonuclease pathways, in relation to peripheral blood cell composition. To determine whether the reduced mass of the thymus is a consequence of the direct effect of DP/UHT milk on apoptosis of thymocytes, in vitro Annexin-V-FITC/PI assay was performed. Significant decreases in the thymus wet weight, thymocyte MyD88, Akt-1/phospho-Akt-1 kinase, p38/phospho-p38, NF-κB, caspase-1 activity and CD4+/CD8+ antigen expression were obtained, especially in the DP milk group. The activity of thymocyte alkaline and acid DNase increased in the DP but not in the UHT milk group. The level of IL-6 significantly decreased in DP milk treated group, while the level of total TGF-ß and IL-6 increased in UHT milk group. Significant differences in hematological parameters were obtained in commercial milk fed group. Observed results about prevention of experimental diabetes in DP pretreated groups may suggest that purine compounds, uric acid and other volatile toxic compounds of commercial milk may suppress oral tolerance, probably via IL-6 and TGF-ß cytokine effects.

Impact of folic acid supplementation on single- and double-stranded RNA degradation in human colostrum and mature milk.

Sufficient intake of folic acid is necessary for normal embryogenesis, fetal, and neonatal development. Folic acid facilitates nucleic acid internalization, and protects cellular DNA from nuclease degradation. Human milk contains enzymes, antimicrobial proteins, and antibodies, along with macrophages, that protect against infections and allergies. However, little to no information is available on the effects of folic acid supplementation on degradation of nucleic acids in human milk. In the present study, we aimed to determine the RNase activity (free and inhibitor-bound) in colostrum and mature milk, following folic acid supplementation. The study design included a total of 59 women, 27 of whom received 400 µg of folic acid daily periconceptionally and after. Folic acid supplementation increased the free RNase and polyadenylase activity following lactation. However, the increased RNase activity was not due to de novo enzyme synthesis, as the inhibitor-bound (latent) RNase activity was significantly lower and disappeared after one month. Folic acid reduced RNase activity by using double-stranded RNA as substrate. Data suggests that folic acid supplementation may improve viral RNAs degradation and mRNA degradation, but not dsRNA degradation, preserving in this way the antiviral defense.