Mathematical modeling of transdermal delivery of topical drug formulations in a dynamic microfluidic diffusion chamber in health and disease.

Mathematical models of epidermal and dermal transport are essential for optimization and development of products for percutaneous delivery both for local and systemic indication and for evaluation of dermal exposure to chemicals for assessing their toxicity. These models often help directly by providing information on the rate of drug penetration through the skin and thus on the dermal or systemic concentration of drugs which is the base of their pharmacological effect. The simulations are also helpful in analyzing experimental data, reducing the number of experiments and translating the in vitro investigations to an in-vivo setting. In this study skin penetration of topically administered caffeine cream was investigated in a skin-on-a-chip microfluidic diffusion chamber at room temperature and at 32°C. Also the transdermal penetration of caffeine in healthy and diseased conditions was compared in mouse skins from intact, psoriatic and allergic animals. In the last experimental setup dexamethasone, indomethacin, piroxicam and diclofenac were examined as a cream formulation for absorption across the dermal barrier. All the measured data were used for making mathematical simulation in a three-compartmental model. The calculated and measured results showed a good match, which findings indicate that our mathematical model might be applied for prediction of drug delivery through the skin under different circumstances and for various drugs in the novel, miniaturized diffusion chamber.

PARP2 downregulation in T cells ameliorates lipopolysaccharide-induced inflammation of the large intestine.

Introduction: T cell-dependent inflammatory response with the upregulation of helper 17 T cells (Th17) and the downregulation of regulatory T cells (Treg) accompanied by the increased production of tumor necrosis alpha (TNFa) is characteristic of inflammatory bowel diseases (IBD). Modulation of T cell response may alleviate the inflammation thus reduce intestinal damage. Poly(ADP-ribose) polymerase-2 (PARP2) plays role in the development, differentiation and reactivity of T cell subpopulations. Our aim was to investigate the potential beneficial effect of T cell-specific PARP2 downregulation in the lipopolysaccharide (LPS) induced inflammatory response of the cecum and the colon. Methods: Low-dose LPS was injected intraperitoneally to induce local inflammatory response, characterized by increased TNFa production, in control (CD4Cre; PARP2+/+) and T cell-specific conditional PARP2 knockout (CD4Cre; PARP2f/f) mice. TNFa, IL-1b, IL-17 levels were measured by ELISA, oxidative-nitrative stress was estimated by immunohistochemistry, while PARP1 activity, p38 MAPK and ERK phosphorylation, and NF-kB expression in large intestine tissue samples were examined by Western-blot. Systemic & local T cell subpopulation; Th17 and Treg alterations were also investigated using flowcytometry and immunohistochemistry. Results: In control animals, LPS induced intestinal inflammation with increased TNFa production, while no significant elevation of TNFa production was observed in T cell-specific PARP2 knockout animals. The absence of LPS-induced elevation in TNFa levels was accompanied by the absence of IL-1b elevation and the suppression of IL-17 production, showing markedly reduced inflammatory response. The increase in oxidative-nitrative stress and PARP1-activation was also absent in these tissues together with altered ERK and NF-kB activation. An increase in the number of the anti-inflammatory Treg cells in the intestinal mucosa was observed in these animals, together with the reduction of Treg count in the peripheral circulation. Discussion: Our results confirmed that T cell-specific PARP2 downregulation ameliorated LPS-induced colitis. The dampened TNFa production, decreased IL-17 production and the increased intestinal regulatory T cell number after LPS treatment may be also beneficial during inflammatory processes seen in IBD. By reducing oxidative-nitrative stress and PARP1 activation, T cell-specific PARP2 downregulation may also alleviate intestinal tissue damage.

Lacking ARHGAP25 mitigates the symptoms of autoantibody-induced arthritis in mice.

Objective: Despite intensive research on rheumatoid arthritis, the pathomechanism of the disease is still not fully understood and the treatment has not been completely resolved. Previously we demonstrated that the GTPase-activating protein, ARHGAP25 has a crucial role in the regulation of basic phagocyte functions. Here we investigate the role of ARHGAP25 in the complex inflammatory process of autoantibody-induced arthritis. Methods: Wild-type and ARHGAP25 deficient (KO) mice on a C57BL/6 background, as well as bone marrow chimeric mice, were treated i.p. with the K/BxN arthritogenic or control serum, and the severity of inflammation and pain-related behavior was measured. Histology was prepared, leukocyte infiltration, cytokine production, myeloperoxidase activity, and superoxide production were determined, and comprehensive western blot analysis was conducted. Results: In the absence of ARHGAP25, the severity of inflammation, joint destruction, and mechanical hyperalgesia significantly decreased, similarly to phagocyte infiltration, IL-1ß, and MIP-2 levels in the tibiotarsal joint, whereas superoxide production or myeloperoxidase activity was unchanged. We observed a significantly mitigated phenotype in KO bone marrow chimeras as well. In addition, fibroblast-like synoviocytes showed comparable expression of ARHGAP25 to neutrophils. Significantly reduced ERK1/2, MAPK, and I-κB protein signals were detected in the arthritic KO mouse ankles. Conclusion: Our findings suggest that ARHGAP25 has a key role in the pathomechanism of autoantibody-induced arthritis in which it regulates inflammation via the I-κB/NF-κB/IL-1ß axis with the involvement of both immune cells and fibroblast-like synoviocytes.

A novel BRET-Based GAP assay reveals phosphorylation-dependent regulation of the RAC-specific GTPase activating protein ARHGAP25.

ARHGAP25, a RAC-specific GTPase activating protein (GAP), is an essential regulator of phagocyte effector functions such as phagocytosis, superoxide production, and transendothelial migration. Furthermore, its complex role in tumor behavior has recently been recognized. We previously demonstrated that phosphorylation of serine 363 in ARHGAP25 regulates hematopoietic stem cells and progenitor cells in mouse bone marrow. However, the significance of other potential phosphorylation sites of ARHGAP25 remained unknown. Now, we developed a novel, real-time bioluminescence resonance energy transfer (BRET) assay to monitor the GAP activity of ARHGAP25 in vitro. Using this approach, we revealed that phosphorylation of S363 and S488, but not that of S379-380, controls ARHGAP25's RACGAP activity. On the other hand, we found in granulocyte-differentiated human PLB-985 cells that superoxide production and actin depolymerization are regulated by residues S363 and S379-380. The present data demonstrate the value of our BRET-GAP assay and show that different phosphorylation patterns regulate ARHGAP25's GAP activity and its effect on superoxide production and phagocytosis.

Scientific career tracks and publication performance - relationships discovered in the Hungarian academic promotion system.

The paper aims to investigate the research patterns of Hungarian university full professors and career pathways in various disciplines. Hungary has a so-called 'multi-stage' formalized hierarchy that clearly defines the steps leading to achieve the appointment of full professor. Following the theoretical chapter in which different career scenarios - such as 'Top Researcher', 'Outstanding Lecturer' and 'Local Manager' are presented, an empirical analysis is carried out. The sample consists of a group of 327 professors. Our results point out that there are different research patterns and a significant gap can be observed between disciplines rather preferring international publication (scored by SJR) and the ones opting for publishing monographs. As far as career paths concerned, it was found that the number of years until reaching the PhD degree ranges between 6-13 years, 15.5-22 years are needed on average to achieve habilitation, while the time needed for getting the title of full professor ranges between 22-27 years. It is clearly perceivable that the gap in the number of years converges until reaching full professorship in each and every discipline.

Risk of eating disorders in university students: an international study in Hungary, Poland and Ukraine.

OBJECTIVE: In this international study, the prevalence of Eating disorders (EDs) was determined among university students and identified associated demographic and behavioral factors predicting disorders using data from three European countries. METHODS: The survey was conducted in Hungary, Poland, and Ukraine in 2018. Registered full-time students completed an online anonymous questionnaire. Students provided data about socioeconomic characteristics, body mass index (BMI), EDs, physical fitness and sport practice, psychological distress (stress, anxiety, depression), life orientation, alcohol, tobacco, and cannabis use. Data were analyzed using SPSS 24.0 software. RESULTS: From the 1965 returned questionnaires 1950 were analyzed, because of the missing data (67.3% female, mean age of the total participant's 21.40 ± 3.83 years old). EDs were observed in 26.3% of students. In logistic regression, EDs were predicted by female sex, higher BMI, single marital status, elevated psychological distress and limited access to health care. CONCLUSION: EDs are relatively common in university students especially in females. Students with higher distress and BMI, limited access to health care and living without partner are at risk for EDs. This result highlights the need for a public health approach. Universities are the last chance where students can be screened in an organized setting and offer interventions early when treatment is likely to be most effective.

Exercise addiction and its related factors in amateur runners.

BACKGROUND AND AIMS: This study examines exercise addiction (EA) in amateur runners from a multidimensional approach, including demographics (age, sex, educational attainment, and financial situation), training factors (duration of running activity, weekly time spent running, mean workout distance per session, other sports activities, and childhood physical activity), psychological features (perceived health, life satisfaction, loneliness, stress, anxiety, depression, body shape, and eating disorders), and anthropometrics (body mass index) that might predict EA. METHODS: The well-validated Exercise Dependence Scale (EDS) was applied to evaluate the prevalence of EA in amateur runners. A multinomial logistic regression was performed to find explanatory variables of risk of EA using the SPSS 24.0 statistical software. RESULTS: A total of 257 runners (48.9% females, Mage = 40.49, SD = 8.99 years) with at least 2 years running activity participated in an anonymous questionnaire survey. About 53.6% of respondents were characterized as non-dependent symptomatic and 37.8% as non-dependent asymptomatic. About 8.6% had prevalence of being at risk of EA. The logistic regression model displayed five variables that significantly predicted the risk of EA: (a) anxiety, (b) loneliness, (c) weekly time spent running, (d) childhood physical activity, and (e) education level. DISCUSSION AND CONCLUSIONS: Findings indicate that loneliness and anxiety may lead to withdrawal and uncontrolled behavior that in turn leads to increased amount of exercise in amateur runners. Lower level of education attainment is also a likely risk of EA development, and childhood sports activity is a predictor.

Health-related quality of life of adolescents with type 1 diabetes in the context of resilience.

BACKGROUND: Adolescents with type 1 diabetes (T1D) can be faced with deterioration in glycemic control (GC), reduced health-related quality of life (HRQoL), and other psychosocial problems. It is important to understand how the disease and its clinical conditions influence HRQoL and how adolescents are able to overcome the life adjustment difficulties. OBJECTIVE: To assess HRQoL of adolescents with T1D from demographic, clinical, personal, and behavioral point of view. SUBJECTS: A total of 229 adolescents with T1D (51.2% males) with a mean age of 15.35 (2.29) years old were recruited from three diabetes centers. The mean diabetes duration was 7.48 (3.87), the mean hemoglobin A1C (HbA1c) level was 10.3 (1.76) mmol/L. METHODS: A multicenter quantitative correlational design study was applied to investigate the influence of sex, age, diabetes duration, GC expressed by HbA1c, intensive insulin regimen, physical activity (PA), resilience (RS), and socioeconomic background on HRQoL. RESULTS: Presence of the diabetes symptoms and worry about the disease has negative impact on the patients' HRQoL. Stepwise multiple regression analyses indicated that insulin pump therapy, male sex, and higher level of RS were significantly related to an increase in HRQoL, whereas the higher level of PA, male sex, and better HRQoL was significantly related to positive change in RS. Patients treated with insulin pump therapy had significantly better HRQoL. CONCLUSIONS: Significant association can be observed between HRQoL and RS. Supposedly, higher level of PA promotes higher level of RS that in turn helps increase HRQoL in adolescents with T1D. Treatment with insulin pump therapy also promotes better HRQoL.

Physical activity and physical fitness as protective factors of adolescent health.

OBJECTIVE: This quantitative correlational design study aimed to examine the variation in adolescent health and lifestyle characteristics across self-reported physical activity (PA) and physical fitness (PF) levels. METHODS: Data were collected from 422 students (50.2% males) (16.33 SD = 1.66 y/o) attending a high school. An online questionnaire was used to gather data on the following characteristics: self-reported well-being, overall life satisfaction, depression (including self-harm and suicidal ideation), perceived health status, eating disorders, sleepiness, substance use (alcohol, tobacco and illicit drug use), body mass index, PA participation and PF levels. RESULTS: Of the participants, 42.4% reported at least 5 days of PA a week for 60 min per day. These high active individuals had significantly better well-being, health status, life satisfaction, PF and consumed fewer alcohol beverages. High PA and better PF inversely correlated with depression. CONCLUSIONS: It seems that high PA and better PF have a positive impact on adolescent perceived health, health-risk behaviors and mental health. Increased levels of PA can play a vital role in the primary care, prevention of health risks and in adolescent health promotion. Accordingly, educational institutions are an excellent setting to promote and provide sport facilities and encourage students to be more physically active.

Generic and disease-specific quality of life in adolescents with type 1 diabetes: comparison to age-matched healthy peers.

BACKGROUND: This study aimed to evaluate the health-related quality of life (HRQoL) of adolescents with type 1 diabetes (T1DM) on the basis of the pediatric quality of life inventory™ (PedsQL™) generic and diabetes-specific modules, and to compare it to that of healthy peers. METHODS: This retrospective case-control study involved 650 participants between ages of 13 and 19 years including 296 adolescents with T1DM from four diabetes centers and 354 healthy peers matched for age and gender from three different cities of the country. Participants completed the validated PedsQL™ for assessing the HRQoL. The analysis included an independent t-test to compare the means of the total and subscales of the PedsQL™ between boys and girls as well as between a healthy group and a group with T1DM. Gender differences in exercise, insulin therapy modalities were evaluated with the Pearson χ2-test. RESULTS: Adolescents with T1DM have similar HRQoL in all domains when compared to their healthy counterparts. Females report worse HRQoL regardless of the presence of the disease. Insulin pump therapy facilitates better glycemic control and HRQoL. Regular exercise positively correlates with the generic HRQoL in both groups; however, it has no relationship with glycemic control. CONCLUSIONS: Optimal metabolic control and improved HRQoL are the eventual goals of diabetes management. Despite the difficulties, adolescents with diabetes can manage their disease well and live normal lives, similar to their healthy peers. Although diabetes-related problems exist, it seems that regular exercise and staying physically active, as well as promoting insulin pump therapy where it is applicable are related to favorable HRQoL.