The Role of the Neutrophilic Network in the Pathogenesis of Psoriasis.

One role of neutrophils, the most abundant innate immune sentinels, is neutrophil extracellular trap (NET) formation, which plays a significant role in immune surveillance. However, NET operation is bidirectional. Recent studies report that NETs may contribute to the development of autoimmune diseases such as psoriasis. The participation of neutrophils in the pathogenesis of that disease is dependent on an autoinflammatory feedback loop between neutrophils, lymphocytes, dendritic cells and keratinocytes. Our aim was to clarify the field of NET research in psoriasis and highlight the main factors required for NET generation, which may be a target of new therapies. This article presents a comphrehensive review concerning studies addressing the participation of neutrophils in the pathogenesis of psoriasis. Based on the available English-language literature, we discuss original papers presenting significant research findings which may help to understand and interpret the NET formation process in psoriasis, as well as the newest systematic reviews on PubMed. Next, the comparison, synthesis and summary of reported results were performed to clearly indicate the specific component of the NET which participates in the development of psoriasis.

The Analysis of a Genome-Wide Association Study (GWAS) of Overweight and Obesity in Psoriasis.

There is evidence that the concomitance of psoriasis and obesity may originate from the interplay between multiple genetic pathways and involve gene−gene interactions. The aim of this study was to compare the genetic background related to obesity among psoriatic patients versus healthy controls by means of a Genome-Wide Association Study (GWAS). A total of 972 psoriatic patients and a total of 5878 healthy donors were enrolled in this study. DNA samples were genotyped for over 500,000 single nucleotide polymorphisms (SNPs) using Infinium CoreExome BeadChips (Illumina, San Diego, CA, USA). Statistical analysis identified eleven signals (p < 1 × 10−5) associated with BMI across the study groups and revealed a varying effect size in each sub-cohort. Seven of the alternative alleles (rs1558902 in the FTO gene, rs696574 in the CALCRL gene, as well as rs10968110, rs4551082, rs4609724, rs9320269, and rs2338833,) are associated with increased BMI among all psoriatic patients and four (rs1556519 in the ITLN2 gene, rs12972098 in the AC003006.7 gene, rs12676670 in the PAG1 gene, and rs1321529) are associated with lower BMI. The results of our study may lead to further insights into the understanding of the pathogenesis of obesity among psoriatic patients.

The effect of therapy on TRM in psoriatic lesions.

Introduction: The course of psoriasis is associated with recurrence of the lesions at the same location despite effective treatment. It is due to the presence of TRM (tissue-resident memory cells) in the seemingly healthy skin, which may initiate an inflammatory cascade. Aim: The assessment of TRM in psoriatic lesions prior to and after 12 weeks of systemic therapy with methotrexate (MTX) or secukinumab (SEC) or ixekizumab (IXE) or adalimumab (ADA). Material and methods: TRM markers (CD4, CD8, CD103, CD69, CD49, CXCR6) and the tissue expression of cytokines (IL-17, IL-22) in the psoriatic lesions obtained from 13 patients compared to 10 healthy skin samples were evaluated with immunohistochemistry. Biopsy specimens were collected three times from the same psoriatic plaque before and after 4 and 12 weeks of therapy. Results: The expression of TRM markers in the lesions decreased at three time points (W0, W4, W12), revealing the diminished intensity of fluorescence over time with each therapy. The most rapid response was observed with anti-IL-17 therapy at W4 of treatment, while with MTX and ADA at W12. Conclusions: The decreased expression of TRM markers occurring predominantly in the lesional dermis and not in the epidermis over 12 weeks of observation may be due to the poorer penetration of systemic drugs to the epidermis, or the process of psoriatic lesion regression in the epidermis is secondary to the reduction of inflammation in the skin, or TRM in the epidermis may be more resistant to therapy.

D-chiro-inositol as a treatment in plaque psoriasis: A randomized placebo-controlled clinical trial.

Cyclitols are widely available natural sugars which do not exert toxic effects. Their anti-inflammatory and antioxidant properties may be used in the treatment of psoriasis. The aim of this placebo-controlled, double-blind study was to evaluate the clinical effects of D-chiro-inositol (DCI) in mild plaque psoriasis (46 psoriatic patients and 10 healthy volunteers). Three stable psoriatic plaques were selected for evaluation in every patient. Different samples were applied on each lesion twice a day: vehiculum without an active agent, containing 1% DCI and 0.25% DCI. The lesions were assessed using the PSI, VAS scale, and the objective measurement of hydration, transepidermal water loss (TEWL), elasticity, and thickness (DermaLab Combo) at 0, 3, and 6 weeks. PSI and VAS were improved in all groups without significant statistical differences. 1% DCI sample presented the highest statistically significant increase in the hydration of 50%, but it was still significantly lower than in healthy controls. TEWL increased for 1% DCI, which was a statistically significant difference compared to 0.25% DCI and still higher than in controls. An improvement in elasticity was observed in all lesions-it was statistically significant for 1% DCI. The thickness of the lesion decreased for 1% DCI, but the change was not statistically significant. Subepidermal low-echogenic band showed a decreasing tendency in all groups, but it was not statistically significant. Favorable 1% DCI sample results indicate that it may be used as an adjuvant to the local treatment of psoriasis.

Detection of mephedrone and its metabolites in fingerprints from a controlled human administration study by liquid chromatography-tandem mass spectrometry and paper spray-mass spectrometry.

The use of synthetic stimulants, including designer cathinones, remains a significant concern worldwide. Thus, the detection and identification of synthetic cathinones in biological matrices is of paramount importance for clinical and forensic laboratories. In this study, distribution of mephedrone and its metabolites was investigated in fingerprints. Following a controlled human mephedrone administration (100 mg nasally insufflated), two mass spectrometry-based methods for fingerprint analysis have been evaluated. The samples deposited on triangular pieces of chromatography paper were directly analysed under ambient conditions by paper spray-mass spectrometry (PS-MS) while those deposited on glass cover slips were extracted and analysed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The LC-MS/MS method was 5-6 times more sensitive than PS-MS but required sample preparation and longer analysis time. Mephedrone was detected in 62% and in 38% of all post-administration samples analysed by LC-MS/MS and PS-MS, respectively. Nor-mephedrone was the only metabolite detected in 3.8% of all samples analysed by LC-MS/MS. A large inter- and intra-subject variation was observed for mephedrone which may be due to several factors, such as the applied finger pressure, angle and duration of contact with the deposition surface and inability to control the 'amount' of collected fingerprint deposits. Until these limitations are addressed, we suggest that the sole use of fingerprints can be a useful diagnostic tool in qualitative rather than quantitative analysis, and requires a confirmatory analysis in a different biological matrix.

Adalimumab and methotrexate affect the concentrations of regulatory cytokines (interleukin-10, transforming growth factor-ß1, and interleukin-35) in patients with plaque psoriasis.

Dysfunctional regulatory T lymphocytes are important for the pathogenesis of psoriasis and atherosclerosis. We analyzed the severity of atherosclerosis and the concentration of regulatory cytokines in patients with psoriasis who were administered methotrexate or adalimumab for 12 weeks. We included 34 patients with psoriasis (17 each, administered methotrexate or adalimumab) and eight healthy volunteers. BMI, psoriasis area and severity index (PASI), body surface area (BSA), and at least 75% and 90% improvements in PASI were observed. The 10-year risk of fatal cardiovascular disease was estimated using Systematic Coronary Risk Evaluation charts. The plasma interleukin (IL)-10, IL-35, and transforming growth factor ß1 (TGF-ß1) levels were determined using enzyme-linked immunosorbent assay before and after the 12-week treatment regimen. PASI (P = .0006) and BSA (P = .0001) were positively correlated with the BMI, IL-35 (-0.38), and IL-10 (0.48) levels. Baseline IL-35 concentrations were the highest in healthy volunteers; the IL-10 and TGF-ß1 level were the highest in the methotrexate group. IL-10 concentration decreased in both treatment groups (P = .02 for the methotrexate and P = .09 for adalimumab group), and IL-35 decreased in the adalimumab group (P = .019), consistent with skin lesion recovery. Thus, this study demonstrates the dysregulated secretion of regulatory cytokines in psoriatic patients under systemic treatment.

Sex- and season-dependent differences in the expression of adiponectin and adiponectin receptors (AdipoR1 and AdipoR2) in the hypothalamic-pituitary-adrenal axis of the Eurasian beaver (Castor fiber L.).

Adiponectin, a product of the Adipoq gene, is an adipocyte-derived protein hormone of the cytokine family and the most abundantly expressed adipokine. Adiponectin and its receptors AdipoR1 and AdipoR2 (collectively referred to as the adiponectin system) are widely expressed in the central nervous system and other tissues, which suggests that this hormone has pleiotropic effects. Adiponectin could also play a role in the modulation of the hypothalamic-pituitaryadrenal (HPA) hormonal regulatory axis. There is a general scarcity of data on the adiponectin system in wild animals where annual changes in reproductive activity are linked with fluctuations in the activity of the HPA axis. The Eurasian beaver (Castor fiber L.) could be an interesting and suitable model for investigating the above processes. We hypothesized that the expression of the adiponectin system in the tissues of the beaver HPA axis is sex- and season-dependent. The study was performed on adult animals harvested during three different stages of reproductive activity: April ('breeding'), July ('post-breeding') and November ('pre-breeding'). The expression of the adiponectin system was confirmed in all branches (mediobasal hypothalamus, pituitary, adrenal cortex) of the HPA axis in both sexes and during all periods of reproductive activity. The expression of Adipoq, AdipoR1 and AdipoR2 was generally dependent on sex and the period of the reproductive season. The expression of adiponectin system genes was particularly pronounced in the adrenal cortex. These findings suggest that the adiponectin system in the Eurasian beaver could link reproductive processes with stress responses and energy metabolism.

Methotrexate and Adalimumab Decrease the Serum Levels of Cardiovascular Disease Biomarkers (VCAM-1 and E-Selectin) in Plaque Psoriasis.

Background and objectives: The shared pathogenesis of psoriasis and atherosclerosis may be determined by assaying the levels of endothelial activation molecules. This study aimed at evaluating vascular cell adhesion molecule 1 (VCAM-1) and E-selectin serum concentrations, and atherosclerosis severity in patients with plaque psoriasis. It also aimed to determine the effects of methotrexate/adalimumab treatment for 12 weeks on the plasma levels of the aforementioned molecules. Materials and Methods: The study included 34 psoriasis patients (17 treated with methotrexate and 17 treated with adalimumab) and eight controls. The 10-year risk of a fatal cardiovascular disease, body mass index, Psoriasis Area and Severity Index, and body surface area were calculated for each subject. VCAM-1 and E-selectin levels were determined via an enzyme-linked immunosorbent assay at baseline and after 12 weeks. Results: Baseline E-selectin and VCAM-1 levels were higher in the adalimumab group than in the methotrexate and control groups. VCAM-1 levels decreased in the adalimumab (p = 0.02) and methotrexate groups (p = 0.008), while E-selectin levels decreased in the methotrexate group (p = 0.004). Conclusions: The results indicate a correlation between systemic psoriasis treatment and E-selectin and VCAM-1 plasma concentrations, which may be associated with the risk of cardiovascular disease development.

Effect of methotrexate treatment on the expression of epidermal-fatty acid-binding protein (E-FABP) and apolipoproteins in patients with psoriasis.

INTRODUCTION: Epidermal-fatty acid-binding protein (E-FABP) is a marker of transiently amplifying cells which are formed from stem cells in epidermis. Their role is an uptake of fatty acids and metabolism. Psoriatic keratinocytes overexpress E-FABPs, which leads to acanthosis and may explain the lipid's disturbances in psoriasis. AIM: Assessment of FABP and apolipoprotein expression in patients treated with methotrexate (MTX). MATERIAL AND METHODS: FABP expression in the lesional and perilesional psoriatic skin from 11 male patients compared to 5 healthy skin samples were evaluated by immunohistochemistry. FABP, apolipoprotein A1 (ApoA1) and B (ApoB) serum levels were assessed by ELISA. These parameters were evaluated before and after treatment with subcutaneous MTX (15 mg/wk for 12 weeks). RESULTS: Expression of E-FABP was lower in the control group than in the lesional and perilesional psoriatic skin, before and after treatment. After treatment the expression decreased in the lesional and perilesional skin. Serum E-FABP was higher in the control group (482.855 ±240.550 pg/ml) compared to patients, but not statistically significantly. After MTX treatment, a statistically significant reduction was observed in psoriatic patients. ApoA1 levels did not differ in the control and patients groups, both before and after treatment. In contrast, ApoB levels did not differ statistically between the control group (1447.126 ±311.11 ng/ml) and patients before treatment, while they were the lowest after treatment (1081.67 ±117.83 ng/ml vs. 808.306 ±103.72 ng/ml; p < 0.01). CONCLUSIONS: Our study confirms the beneficial effect of MTX, not only as an anti-proliferative effect, but also reducing the cardiovascular risk by decreasing atherogenic ApoB.

Evaluation of selected mechanisms of immune tolerance in psoriasis.

INTRODUCTION: Psoriasis is an autoimmune disease with an excessively aberration of the Th17/Treg balance and deficiency of anti-inflammatory cytokines. AIM: Evaluation of Treg markers expression in the lesional and perilesional psoriatic skin and serum anti-inflammatory cytokines in male psoriatic patients compared to healthy men. MATERIAL AND METHODS: Treg markers (FoxP3+, CD4, CTLA-4, CD25/IL-2R, CD39/ENTPD1, IL-7R/CD127, CD3) and tissue expression of protective cytokines (IL-10, IL-35, TGF-ß) in the lesional and perilesional psoriatic skin from 33 male patients compared to 6 healthy skin samples were evaluated by immunohistochemistry. ELISA was used to assess serum IL-10, IL-35 and TGF-ß levels. RESULTS: The serum levels of IL-35, IL-10 and TGF-ß1 were higher in psoriatic patients than in controls but without any statistically significant relationship with PASI. The expressions of IL-35, CD4, IL-10, TGF-ß1, CD3, FOXP3 and CD25/IL-2R were varied in different experimental groups (p < 0.05). The level of IL-35 was the lowest in psoriatic lesions (p < 0.05) compared to perilesional skin and to controls. CD4, IL-10 and TGF-ß1 expressions were higher (p < 0.05) in perilesional skin than in lesions. TGF-ß1 expression was decreased in psoriatic lesions compared to controls (p < 0.05). CD25/IL2R expression was increased in healthy skin compared to psoriatic skin (p < 0.05). FOXP3 expression was elevated in psoriatic skin compared to healthy and perilesional one. There was no difference between experimental groups in CTLA-4, IL7R/CD127 and CD39/ENTPD1 expression. CONCLUSIONS: The differences between the levels of protective cytokines and expression of Treg markers might explain the inflammation development in psoriasis.

Orexin receptor expression in the hypothalamic-pituitary-adrenal and hypothalamic-pituitary-gonadal axes of free-living European beavers (Castor fiber L.) in different periods of the reproductive cycle.

Orexins are hypothalamic neuropeptides acting via two G protein-coupled receptors in mammals: orexin receptor 1 (OX1R) and orexin receptor 2 (OX2R). In European beavers, which are seasonally breeding animals, the presence and functions of orexins and their receptors remain unknown. Our study aimed to determine the expression of OXR mRNAs and the localization of OXR proteins in hypothalamic-pituitary-adrenal/gonadal (HPA/HPG) axes in free-living beavers. The expression of OXR genes (OX1R, OX2R) and proteins was found in all analysed tissues during three periods of beavers' reproductive cycle (April, July, November). The expression of OXR mRNAs in the beaver HPA axis varied seasonally (P<0.05). The levels of OX1R mRNA also differed between the sexes (P<0.05). In the mediobasal hypothalamus, OX1R transcript content increased in pregnant females in April (P<0.05) and OX2R expression increased in males in July (P<0.05). In the pituitary and adrenals, OX1R mRNA levels were relatively constant in females and peaked in July in males (P<0.05), whereas the OX2R was most highly expressed in males in November and in females in April (P<0.05). In gonads, OX1R expression did not fluctuate between seasons or sexes, but transcript levels were elevated in the testes in November and in the ovaries in July (P<0.05). In turn, OX2R mRNA levels varied between the sexes (P<0.05) and were higher in females (July and November) than in males (P<0.05). The circannual variations in OXR mRNA levels in HPA and HPG axes suggest that the expression of these receptors is associated with sex-specific changes in beavers' reproductive activity and their environmental adaptations.

Plasma-Glucocorticoids and ACTH Levels During Different Periods of Activity in the European Beaver (Castor fiber L.).

Glucocorticoids (GCs) and adrenocorticotropic hormone (ACTH) are major components of the classic endocrine stress response. Free-living vertebrates are characterized by circannual changes in the baseline and/or stress-induced secretion of GCs and ACTH. In mammalian species, GC and ACTH levels vary seasonally but there is no consensus to the season in which animals have elevated GC and ACTH levels. The aim of our study was to determine, for the first time, the type and amount of glucocorticoids produced in free-living beaver (Castor fiber L.)--the largest rodent in Eurasia, and to find out whether stress-induced plasma GC and ACTH levels show seasonal variations. Blood samples were obtained from animals under general anesthesia in April (pregnancy in females), July (offspring rearing) and November (preparing for the winter). The adrenals of beavers produce both cortisol and corticosterone, and plasma cortisol levels were higher than corticosterone. In the current experiment, plasma cortisol concentrations in beavers were affected by the season. The highest stress-associated cortisol levels were noted in males in July during offspring rearing. Corticosterone and ACTH concentrations in beavers remained generally constant, regardless of the season and sex. In conclusion, seasonal changes were observed only in relation to stress-induced plasma cortisol levels in the beaver.

Expression of adiponectin receptors 1 and 2 in the ovary and concentration of plasma adiponectin during the oestrous cycle of the pig.

The aim of this study was to compare the expression levels of adiponectin receptor 1 and adiponectin receptor 2 mRNAs and proteins in porcine ovaries during four stages (days 2 to 3, 10 to 12, 14 to 16, 17 to 19) of the oestrous cycle and to measure adiponectin plasma concentrations during the same phases of the cycle. Higher mRNA expression of adiponectin receptor 1 was detected in porcine granulosa cells than in corpora lutea and theca cells (P < 0.01). In contrast, higher gene expression of adiponectin receptor 2 occurred in newly developed and mature corpora lutea (P < 0.01). The adiponectin receptor 1 protein content was the highest in corpora lutea isolated on days 2 to 3 of the cycle and was the lowest in theca interna cells (P < 0.01). The profile of adiponectin receptor 2 protein was similar to that of adiponectin receptor 1. Adiponectin plasma concentrations were significantly higher throughout the luteal phase than in the follicular phase (P < 0.01). In conclusion, the presence of adiponectin receptor 1 and adiponectin receptor 2 mRNAs and proteins in the porcine ovary suggests that adiponectin may directly affect ovarian functions through its own specific receptors. The expression of both receptors and adiponectin plasma concentration were dependent on hormonal status related to the stage of the cycle.

The Effect of the Long-Term Calcipotriol/Betamethasone Dipropionate Local Therapy on Tissue Resident Memory Cells Markers in Psoriatic Eruptions.

BACKGROUND: The natural course of psoriasis is characterized by the long-term persistence of lesions and a predilection for relapse in the same area. It is caused by the inherence of TRM (tissue resident memory T cells) in apparently healthy skin. These cells are able to initiate an inflammatory cascade and induce relapse of the disease. These cells are characterized by high resistance to damaging factors and apoptosis, which determines their longevity. AIM: The aim of our study was to evaluate the presence of TRM in psoriatic plaques before, during and after 12 weeks of therapy in patients treated with topical calcipotriol and betamethasone dipropionate (Cal/BD) foam. METHODS: TRM markers (CD4, CD8, CD103, CD69, CD49, CXCR6) and tissue expression of cytokines (IL-17A, IL-22) in the lesional psoriatic skin from 10 patients compared to 10 healthy skin samples were estimated by immunohistochemistry. Biopsy samples from the area of the same psoriatic plaque were collected three times: before the initiation of therapy, 4 and 12 weeks after its initiation. RESULTS: The presence of TRM markers in the epidermis and dermis of psoriatic lesions was significantly higher when compared to the skin of control group patients. A reduction in the expression of the characteristic TRM markers (CD8, CD4, CD103, CD69, CXCR6, IL-17A and IL-22) was observed in the epidermis on week 12 of therapy, while a depletion in the expression of TRM in the dermis was demonstrated only in CD4 and IL-22. CONCLUSIONS: Topical treatment with Cal/BD foam significantly decreased the expression of TRM markers mainly in the epidermis, and to a lesser extent in the dermis, during the 12-week observation period. It probably results from a worse penetration of the drug into the dermis and the effect of the preparation mainly on the epidermis. The persistence of a high expression of TRM markers in the dermis may result in the rapid recurrence of lesions after discontinuation of topical treatment.

Changes in Tumor Necrosis Factor α (TNFα) and Peptidyl Arginine Deiminase 4 (PAD-4) Levels in Serum of General Treated Psoriatic Patients.

Psoriasis is an autoimmune disease in which the disturbed dependencies between lymphocytes, dendritic cells, keratinocytes and neutrophils play the most important role. One of them is the overproduction of neutrophil extracellular traps (NETs). The release of NETs can be induced by pathogens, as well as antibodies and immune complexes, cytokines and chemokines, including TNFα. The first step of the NET creation is the activation of peptidyl arginine deiminase 4 (PAD-4). PAD-4 seems to be responsible for citrullination of histones and chromatin decondensation, but the data on PAD-4 in NETs is inconclusive. Thus, the current study aimed to determine PAD-4 and TNFα levels in the serum of psoriatic patients by ELISA and observe the response of these factors to systemic (anti-17a, anti-TNFα and methotrexate) therapies. Increased levels of both PAD-4 and its main stimulus factor TNFα in pre-treatment patients have been reported along with the concentrations of proteins correlated with disease severity (PASI, BSA). Before treatment, the irregularities in the case of anti-nuclear antibodies level (ANA) were also observed. All of the applied therapies led to a decrease in PAD-4 and TNFα levels after 12 weeks. The most significant changes, both in protein concentrations as well as in scale scores, were noted with anti-TNFα therapy (adalimumab and infliximab). This phenomenon may be associated with the inhibition of TNFα production at different stages of psoriasis development, including NET creation. The obtained data suggest the participation of PAD-4 in the activation of neutrophils to produce NETs in psoriasis, which may create opportunities for modern therapies with PAD inhibitors. However, further exploration of gene and protein expression in psoriatic skin is needed.

Excretion of mephedrone and its phase I metabolites in urine after a controlled intranasal administration to healthy human volunteers.

Mephedrone is a stimulant drug structurally related to cathinone. At present, there are no data available on the excretion profile of mephedrone and its metabolites in urine after controlled intranasal administration to human volunteers. In this study, six healthy male volunteers nasally insufflated 100 mg of pure mephedrone hydrochloride (Day 1). Urine was collected at different timepoints on Day 1 and then on Days 2, 3 and 30. Samples were analysed for the presence of mephedrone and its metabolites, namely, dihydro-mephedrone, nor-mephedrone (NOR), hydroxytolyl-mephedrone, 4-carboxy-mephedrone (4-carboxy) and dihydro-nor-mephedrone (DHNM), by a validated liquid chromatography-tandem mass spectrometry method. All analytes were detected in urine, where 4-carboxy (Cmax = 29.8 µg/ml) was the most abundant metabolite followed by NOR (Cmax = 377 ng/ml). DHNM was found at the lowest concentrations (Cmax = 93.1 ng/ml). Analytes exhibited a wide range of detection windows, but only 4-carboxy and DHNM were detectable in all samples on Day 3, extending the detection time of mephedrone use. Moreover, mephedrone had a mean renal clearance of 108 ± 140 ml/min, and 1.3 ± 1.7% of unchanged parent drug was recovered in urine in the first 6 h post administration. It is hoped that this novel information will be useful in future studies involving mephedrone and other stimulant drugs.

Chronic Plaque Psoriasis in Poland: Disease Severity, Prevalence of Comorbidities, and Quality of Life.

The epidemiology of psoriasis has not been widely assessed in Polish population so far. This study aimed to investigate psoriasis epidemiological situation by evaluating disease course and severity, management, comorbidities, environmental factors, and knowledge about this disorder among psoriatic patients in Poland. A cross-sectional cohort population-based study enrolled 1080 psoriatic patients and 1200 controls. The mean age of psoriasis onset was 27.6 years; 78.24% had type I psoriasis. Positive family history of psoriasis was reported in 44.81% of patients, whereas itch was reported in vast majority of patients (83.33%). Based on PASI score moderate psoriasis was the most common in studied group (mean 12.63 ± 9.33, range 0−67.2). The DLQI score (12.01 ± 7.41, range 0−30.0) indicated a very large effect of psoriasis on the quality of life. Hypertension was the most prevalent comorbidity (33.80%), followed by obesity (16.85%) and dyslipidemia (11.85%). Stress was the foremost cause of disease exacerbation (66.20%); however, infections (44.07%) and seasonal changes (45.09%) had also an impact on the course of psoriasis. Psoriatic patients were more often smokers (37.59%) vs. general population (27.50%; p < 0.0001). In conclusion, epidemiological studies help clinicians in better disease and patient understanding, which may translate into better management and patient compliance.

Assessment of the Tissue Resident Memory Cells in Lesional Skin of Patients with Psoriasis and in Healthy Skin of Healthy Volunteers.

BACKGROUND: In the course of plaque psoriasis, tissue resident memory cells (TRM) are responsible for the phenomenon of "immune memory" of lesions, i.e., the appearance of recurrences of lesions in the same location, as well as Koebner phenomenon. We present results determining the location and amount of TRM in psoriatic lesions in patients suffering from plaque psoriasis, as well as an analysis of the relationship between TRM markers expression and the duration and severity of the disease. METHODS: TRM markers (CD4, CD8, CD103, CD69, CD49, CXCR6) and tissue expression of cytokines (IL-17, IL-22) in the lesional psoriatic skin of 32 patients compared with 10 healthy skin samples were evaluated by immunohistochemistry. RESULTS: The presence of TRM markers in both the epidermis and skin with psoriatic eruptions was demonstrated in much higher amounts compared with the skin of healthy volunteers. A significant positive relationship was demonstrated between the expression of TRM markers in patients with plaque psoriasis and the duration of skin lesions. There was no relationship between the amount of TRM and the severity of plaque psoriasis. CONCLUSIONS: A thorough understanding of the mechanisms responsible for the development and relapse of plaque psoriasis may contribute to the implementation of more effective therapies.

Pharmacokinetics of Mephedrone and Its Metabolites in Whole Blood and Plasma after Controlled Intranasal Administration to Healthy Human Volunteers.

Mephedrone is a popular synthetic cathinone, known for its psychostimulant effects. At present, there is no data available on the pharmacokinetics of mephedrone and its metabolites in concurrently collected whole blood and plasma samples after a controlled intranasal administration to healthy volunteers. In this study, six healthy male volunteers nasally insufflated 100 mg of pure mephedrone hydrochloride (Day 1). Whole blood and plasma samples were collected at different time points after the administration and were analyzed for the presence of mephedrone and its metabolites, dihydro-mephedrone (DHM), nor-mephedrone (NOR), hydroxytolyl-mephedrone (HYDROXY), 4-carboxy-mephedrone (4-CARBOXY) and dihydro-nor-mephedrone (DHNM), by validated liquid chromatography-tandem mass spectrometry methods. All analytes were detected in whole blood and plasma for 6 h post administration, with mephedrone and NOR also being detectable on Day 2 in some participants. 4-CARBOXY, followed by NOR, was the most abundant metabolite in both matrices. Compared to other psychostimulants, mephedrone showed rapid absorption (mean Tmax of 52.5 ± 20.7 min in plasma and 55.0 ± 18.2 min in whole blood) and elimination (mean t1/2 of 1.98 ± 0.30 h in plasma and 2.12 ± 0.33 h in whole blood). In addition, statistical analysis showed that median whole blood to plasma distribution ratios, reported here for the first time, were statistically different from 1 (unity) for mephedrone (median: 1.11), DHM (median: 1.30) and NOR (median: 0.765). It is hoped that the study will aid forensic and clinical toxicologists in detection, identification and interpretation of cases associated with mephedrone use.

Pharmacokinetics of Mephedrone Enantiomers in Whole Blood after a Controlled Intranasal Administration to Healthy Human Volunteers.

Mephedrone, which is one of the most popular synthetic cathinones, has one chiral centre and thus exists as two enantiomers: R-(+)-mephedrone and S-(-)-mephedrone. There are some preliminary data suggesting that the enantiomers of mephedrone may display enantioselective pharmacokinetics and exhibit different neurological effects. In this study, enantiomers of mephedrone were resolved via chromatographic chiral recognition and the absolute configuration was unambiguously determined by a combination of elution order and chiroptical analysis (i.e., circular dichroism). A chiral liquid chromatography tandem mass spectrometry method was fully validated and was applied to the analysis of whole blood samples collected from a controlled intranasal administration of racemic mephedrone hydrochloride to healthy male volunteers. Both enantiomers showed similar kinetics, however, R-(+)-mephedrone had a greater mean Cmax of 48.5 ± 11.9 ng/mL and a longer mean half-life of 1.92 ± 0.27 h compared with 44.6 ± 11.8 ng/mL and 1.63 ± 0.23 h for S-(-)-mephedrone, respectively. Moreover, R-(+)-mephedrone had a lower mean clearance and roughly 1.3 times greater mean area under the curve than S-(-)-mephedrone. Significant changes in the enantiomeric ratio over time were observed, which suggest that the analytes exhibit enantioselective pharmacokinetics. Even though the clinical significance of this finding is not yet fully understood, the study confirms that the chiral nature, and consequently the enantiomeric purity of mephedrone, can be a crucial consideration when interpreting toxicological results.