Search

Epilepsy is a neurological disorder involving a number of disease syndromes with a complex etiology. A properly matched antiseizure drug (ASD) gives remission in up to 70% of patients. Nevertheless, there is still a group of about 30% of patients suffering from drug-resistant epilepsy. Consequently, the development of new more effective and/or safer ASDs is still an unmet clinical need. Thus, our current studies were focused on the structural optimization/modifications of one of the leading compounds, KA-11, aiming at the improvement of its antiseizure activity. As a result, we designed and synthesized two close analogs with highly pronounced drug-like physicochemical properties according to in silico predictions, namely KA-228 and KA-232, which were subsequently tested in a panel of animal seizure models, i.e., MES, 6 Hz (32 mA), scPTZ and ivPTZ. Among these compounds, KA-232, which was designed as a water-soluble salt, was distinctly more effective than KA-228 and assured similar antiseizure protection as its chemical prototype KA-11. With the aim of a more detailed characterization of both new molecules, in vitro binding tests were performed to evaluate the potential mechanisms of action. Furthermore, KA-232 was also evaluated in several ADME-Tox studies, and the results obtained strongly supported its drug-like potential. The proposed chemical modification of KA-11 enabled the identification of new pharmacologically active chemotypes, particularly water-soluble KA-232, which, despite the lack of better efficacy than the leading compound, may be used as a chemical prototype for the development of new ASDs, as well as substances potentially active in other neurological or neurodegenerative conditions.

Umbelliferone (7-hydroxycoumarin; UMB) is a coumarin with many biological properties, including antiepileptic activity. This study evaluated the effect of UMB on the ability of classical and novel antiepileptic drugs (e.g., lacosamide (LCM), levetiracetam (LEV), phenobarbital (PB) and valproate (VPA)) to prevent seizures evoked by the 6-Hz corneal-stimulation-induced seizure model. The study also evaluated the influence of this coumarin on the neuroprotective properties of these drugs in two in vitro models of neurodegeneration, including trophic stress and excitotoxicity. The results indicate that UMB (100 mg/kg, i.p.) significantly enhanced the anticonvulsant action of PB (p < 0.01) and VPA (p < 0.05), but not that of LCM orLEV, in the 6-Hz test. Whether alone or in combination with other anticonvulsant drugs (at their ED50 values from the 6-Hz test), UMB (100 mg/kg) did not affect motor coordination; skeletal muscular strength and long-term memory, as determined in the chimney; grip strength; or passive avoidance tests, respectively. Pharmacokinetic characterization revealed that UMB had no impact on total brain concentrations of PB or VPA in mice. The in vitro study indicated that UMB has neuroprotective properties. Administration of UMB (1 µg/mL), together with antiepileptic drugs, mitigated their negative impact on neuronal viability. Under trophic stress (serum deprivation) conditions, UMB enhanced the neurotrophic abilities of all the drugs used. Moreover, this coumarin statistically enhanced the neuroprotective effects of PB (p < 0.05) and VPA (p < 0.001) in the excitotoxicity model of neurodegeneration. The obtained results clearly indicate a positive effect of UMB on the anticonvulsant and neuroprotective properties of the selected drugs.

In our recent studies, we identified compound N-benzyl-2-(2,5-dioxopyrrolidin-1-yl)propanamide (AS-1) as a broad-spectrum hybrid anticonvulsant which showed potent protection across the most important animal acute seizure models such as the maximal electroshock (MES) test, the subcutaneous pentylenetetrazole (s.c. PTZ) test, and the 6-Hz (32 mA) test in mice. Therefore, AS-1 may be recognized as a candidate for new anticonvulsant effective in different types of human epilepsy with a favorable safety margin profile determined in the rotarod test in mice. In the aim of further pharmacological evaluation of AS-1, in the current study, we examined its activity in the 6-Hz (44 mA) test, which is known as the model of drug-resistant epilepsy. Furthermore, we determined also the antiseizure activity in the kindling model of epilepsy induced by repeated injection of pentylenetetrazole (PTZ) in mice. As a result, AS-1 revealed relatively potent protection in the 6-Hz (44 mA) test, as well as delayed the progression of kindling induced by repeated injection of PTZ in mice at doses of 15 mg/kg, 30 mg/kg, and 60 mg/kg. Importantly, the isobolographic analysis showed that a combination of AS-1 and valproic acid (VPA) at the fixed ratio of 1:1 displayed a supra-additive (synergistic) interaction against PTZ-induced seizures in mice. Thus, AS-1 may be potentially used in an add-on therapy with VPA. Moreover, incubation of zebrafish larvae with AS-1 substantially decreased the number, cumulative but not the mean duration of epileptiform-like events in electroencephalographic assay. Finally, the in vitro ADME-Tox studies revealed that AS-1 is characterized by a very good permeability in the parallel artificial membrane permeability assay test, excellent metabolic stability on human liver microsomes (HLMs), no significant influence on CYP3A4/CYP2D6 activity, and moderate inhibition of CYP2C9 in a concentration of 10 μM, as well as no hepatotoxic properties in HepG2 cells (concentration of 10 μM). Electronic supplementary material The online version of this article (10.1007/s13311-019-00773-w) contains supplementary material, which is available to authorized users.

Jerusalem artichoke ( Helianthus tuberosus Linne ) is a tuberous perennial plant of the Asteraceae family, which originates from North America, and is also known as wild sunflower or topinambur (TPB). It is characterized by good tolerance to frost, drought and poor soil, strong resistance to pests and plant diseases. For ages it was cultivated due to being both an edible tuber and having healing properties. In folk medicine, TPB leaves are used for the treatment of bone fractures and pain. TPB tubers are rich in sugar and have therefore been used for the production of functional food ingredients, such as inulin. Moreover, TPB is one of the potential crops for bioenergy production, such as bioethanol, biobuthanol and biodiesel, and chemicals (lactic acid, butyric acid). A number of bioactive compounds from the above ground parts of this plant have been isolated which have demonstrating antifungal, antioxidant and anticancer activities. In recent years, a number of animal experiments have been carried out to assess the health properties of TPB. Obtained results show that TPB possess a wide spectrum of medical applications, e.g. reduction in the levels of plasma glucose, total cholesterol and triglyceride. Interestingly, TPB has been shown to be a valuable alternative source of prebiotic compounds. This review article presents recent scientific reports on the chemical and biological properties of TPB and its potential use as a prebiotic diet supplement.

The aim of the study was to evaluate the impact of second generation antiepileptic drug levetiracetam (LEV) with arachidonyl-2′-chloroethylamide (ACEA) on proliferating neural precursor cells in mouse brain. Additionally, we established the relationship between treatment with ACEA in combination with LEV and hippocampal neurogenesis in mouse brain. All experiments were performed on male CB57/BL mice injected i.p. with LEV (10 mg/kg), ACEA (10 mg/kg) and PMSF (30 mg/kg) for 10 days. Experiments were provided in two stages: stage 1- an acute response of proliferating neural precursor cells to ACEA and LEV administration (Ki-67 staining), stage 2 – a long term response to ACEA and LEV administration (BrDU, NeuN, GFAP staining). Results indicate that ACEA + PMSF and ACEA + PMSF + LEV significantly increased the total number of Ki-67 positive cells comparing to the control group. PMSF and LEV administered alone and in combination had no significant impact on cell proliferation compared to the control group. Results from neurogenesis study indicated that ACEA + PMSF administered alone and in combination with LEV increased the total number of BrDU cells compared to the control group, although LEV on its own decreased the number of BrDU cells. Moreover, the combination of ACEA + PMSF + LEV significantly increased the total number of newborn neurons compared to the control group. In turn, LEV significantly decreased the process of neurogenesis. Astrocytes were considerably reduced in all treated groups as compare to the control mice. These data provide substantial evidence that LEV administered chronically decreases the proliferation and differentiation of newly born cells while combination of LEV + ACEA significantly increases the level of newborn neurons in the dentate subgranular zone.

Epilepsy, one of the most common neurological disorders, is a chronic disease of the brain manifested by seizures due to sudden, spontaneous bioelectrical discharges in nerve cells. An estimated 50 million people worldwide suffer from epilepsy. Antiepileptic drugs are the mainstream treatment for epilepsy; however, the drug resistance occurring in 20-30% of patients and side effects of available medications have resulted in a search for natural remedies that can support disease therapy. Coumarins may be a promising option. They are a group of natural plant-derived substances of great interest due to their broad spectrum of biological activities, including potent pharmacological properties. Recent data from experimental models demonstrates the possibility for coumarin use as a supporting t reatment of epileptic seizures. This article focuses on the most recent research reports available in the literature relating to the use of several selected coumarins in different experimental models of epilepsy.

Xanthotoxin (8-methoxypsoralen; XANT) is a furanocoumarin which has many biological properties, including antiepileptic activity. This study evaluated the effect of XANT on the ability of classical and novel antiepileptic drugs to prevent seizures evoked by the 6-Hz corneal stimulation-induced seizure model, which is thought to be an experimental model of psychomotor (limbic) seizures in humans. XANT (50 mg/kg, administered i.p.) significantly potentiated the anticonvulsant activity of levetiracetam and valproate, decreasing their median effective dose (ED50 ) values from 19.37 to 2.83 mg/kg (P < 0.01) for levetiracetam and from 92.89 to 44.44 mg/kg (P < 0.05) for valproate. Neither XANT (50 mg/kg) alone nor its combination with the anticonvulsant drugs (at their ED50 values from the 6-Hz test) affected motor coordination; skeletal muscular strength and long-term memory, as determined in the chimney; and grip strength and passive avoidance tests, respectively. Measurement of total brain antiepileptic drug concentrations revealed that XANT (50 mg/kg) had no impact on levetiracetam total brain concentrations, indicating the pharmacodynamic nature of interaction between these antiepileptic drugs in the mouse 6 Hz model. However, XANT (50 mg/kg, i.p.) significantly increased total brain concentrations of valproate (P < 0.01), indicating the pharmacokinetic nature of interactions between drugs. XANT in combination with levetiracetam exerts beneficial anticonvulsant pharmacodynamic interactions in the 6 Hz mouse psychomotor seizure model.

Status epilepticus (SE) is a frequent medical emergency that can lead to a variety of neurological disorders, including cognitive impairment and abnormal neurogenesis. The aim of the presented study was the in vitro evaluation of potential neuroprotective properties of a new pyrrolidine-2,5-dione derivatives compound C11, as well as the in vivo assessment of the impact on the neurogenesis and cognitive functions of C11 and levetiracetam (LEV) after pilocarpine (PILO)-induced SE in mice. The in vitro results indicated a protective effect of C11 (500, 1000, and 2500 ng/mL) on astrocytes under trophic stress conditions in the MTT (3-[4,5-dimethylthiazole-2-yl]-2,5-diphenyltetrazolium bromide) test. The results obtained from the in vivo studies, where mice 72 h after PILO SE were treated with C11 (20 mg/kg) and LEV (10 mg/kg), indicated markedly beneficial effects of C11 on the improvement of the neurogenesis compared to the PILO control and PILO LEV mice. Moreover, this beneficial effect was reflected in the Morris Water Maze test evaluating the cognitive functions in mice. The in vitro confirmed protective effect of C11 on astrocytes, as well as the in vivo demonstrated beneficial impact on neurogenesis and cognitive functions, strongly indicate the need for further advanced molecular research on this compound to determine the exact neuroprotective mechanism of action of C11.

Stirling engine is a device that produces mechanical energy using heat from any source of energy, without the need of combustion of any fuel inside the device. Renewable energy sources, which are mostly low-temperature energy sources, can be used to produce mechanical and electrical energy in Stirling engines. The paper presents an overview of the existing prototype Stirling engines designed for using of low-temperature energy sources, including renewable energy sources. Commercial devices for electric power generation offered for use in home, usually do not exceed 1 kW. Using the Schmidt model, the analyze of influence of temperature working fluid in the expansion space (heater) on the efficiency and the electric power generated in the Stirling engine of alpha type has been presented in the paper.

Możliwość opracowania studium krajobrazu kulturowego, opiniowanego przez wojewódzkiego konserwatora zabytków, jako materiał wyjściowy do sporządzania studium uwarunkowań i kierunków zagospodarowania przestrzennego gminy, podobnie jak ma to miejsce w przypadku opracowania ekofizjograficznego (wykonywanego obowiązkowo zgodnie z Ustawą o planowaniu i zagospodarowaniu przestrzennym z 2003), jest zjawiskiem spotykanym sporadycznie. Świadome planowanie rozwoju krajobrazów kulturowych wymaga szerokiej wiedzy konserwatorskiej i licznych studiów historycznych, których pełne wyniki nie zawsze mogą zostać zawarte w zwięzłych zaleceniach służb konserwatorskich. Przedstawiony przykład założenia parkowo-dworskiego w Czarnolesie, którego ostatnia dokumentacja planistyczna sięga roku 1989 (brak aktualnej), pokazuje skomplikowany proces analitycznego dochodzenia do sformułowania stref ochrony konserwatorskiej w przekształconym środowisku kulturowym. W opracowaniu wykonano analizy walorów przyrodniczych, historycznych, przemian układu kompozycyjnego oraz bezpośredniego otoczenia założenia, a także analizy dotyczące obecnego programu użytkowego, uwarunkowań prawno-własnościowych, dzięki którym możliwe było określenie wartości zabytkowej obiektu, ocena obecnego stanu zachowania substancji zabytkowej ogrodu krajobrazowego oraz wyznaczenie funkcji i istniejącego programu użytkowego. Na podstawie analiz określono zakres działań rewaloryzacyjnych, mających na celu odnowienie walorów XIX-wiecznego ogrodu krajobrazowego. Opracowane studium krajobrazu kulturowego zawiera wytyczne konserwatorskie przedstawiające kierunki oraz wskazania do zagospodarowania terenu założenia parkowo-dworskiego w zakresie jego przeznaczenia, spełnianych funkcji, form ochrony konserwatorskiej i przyrodniczych, układu kompozycyjnego oraz kompozycji układów roślinnych i nasadzeń. Po uwzględnieniu określonych stref ochrony konserwatorskiej możliwe było wytypowanie celów projektowych, na jakie składają się dwa podstawowe działania w odniesieniu do projektowanego fragmentu czarnoleskiego założenia, tj. rewaloryzacja historycznej kompozycji parku poprzez wydobycie struktur zachowanych i wymagane uzupełnienie elementów niezachowanych oraz adaptacja wytypowanej przestrzeni o niskich walorach historycznych poprzez nadanie jej nowego przeznaczenia w zakresie spełnianej funkcji muzealnej z poszanowaniem istniejącej substancji zabytkowej.

Despite extensive knowledge about quality of life of people suffering from dermatological diseases, data on patients with morphea are scarce. The aim of our study was to compare the quality of life of healthy controls and morphea patients, as well as to determine the correlation of this variable with the level of dispositional optimism. The study included 47 patients with morphea and 47 healthy controls, matched for gender and age. Cantril’s Ladder and Life Orientation Test-Revised were used to assess the levels of life satisfaction and dispositional optimism, respectively. LoSSI was used for the objective assessment. The anticipated level of life quality and the level of dispositional optimism were statistically significantly lower in morphea patients (p = 0.032 and p = 0.014, respectively) when compared to controls. There were no differences in the assessment of current (p = 0.168) and past (p = 0.318) levels of life quality. Also, we proved that type of morphea did not differentiate the current (p = 0.175), past (p = 0.620) and future (p = 0.356) assessment of the quality of life. In the group of morphea patients there was a statistically significant correlation between the level of dispositional optimism and current (p = 0.002, r = 0.43), as well as anticipated (p

2013 | Volume19 | Issue 4 | 11 This publication concerns psychological characterization of workload and coping with stress among commercial aircraft crews. Analysis was conducted on two study groups: experimental group – pilots (n=19) and commercial aircraft cabin crew (n=22), and control group – shopping mall employees (n=28). Occupational task load was assessed using Polish version of NASA-TLX tool. Styles of coping with stress were evaluated using Polish version of Coping Inventory for Stressful Situations (CISS) by N.S. Endler and D.A. Parker. We validated diff erences between pilots and aircraft cabin crew and control group both with regard to the style of coping with stress as well as specifi cs of occupational burden. It was noted that assessment of both subjective workload and styles of coping with stress among pilots and aircraft personnel in comparison to control group also characterizes work specifi cs for both of those vocational groups. Methods of studying subjective workload and styles of coping with stress may be used for diff erential diagnosis of task-related aspects of various vocations. pilots, aircraft personnel, workload, coping with stress DIFFERENTIAL DIAGNOSIS OF SUBJECTIVE WORKLOAD AND STYLES OF COPING WITH STRESS AMONG AIRCRAFT CREWMEMBERS

Two groups were subjected to analysis: experimental group – pilots (n=19) and board crew of commercial aircrafts (n=22) and control group – merchants (n=28). Styles of coping with stress were studied using Polish version of Coping Inventory for Stressful Situations (CISS) by N.S. Endler and D.A. Parker. Personality assessment was performed with the help of NEO-FFI questionnaire by P.T. Costa and R.R. McCrae based on Five Factor Theory of Personality.

Introduction: Morphea (localized scleroderma) is a rare cutaneous disease characterized by skin fibrosis of unknown pathogenesis. Transforming growth factor-β (TGF-β) is a potent profibrotic factor. The role of TGF-β in morphea remains unclear. Aim: The goal of this study was to estimate the expression level of TGF-β1 in skin and peripheral blood mononuclear cells as well as the plasma levels of TGF-β1 in plaque morphea (MEP). Material and methods: The study involved 20 MEP patients. Three control groups were involved: 1 - plasma: 36 healthy volunteers; 2 - PBMC: 47 healthy volunteers; 3 - skin biopsies: 13 samples collected during mastectomy (breast cancer was not skin involved). The analysis of TGF-β1 plasma levels was performed with the use an adequate ELISA kit, while real-time polymerase chain reaction was employed for the expression of TGF-β1 in peripheral blood mononuclear cells (PBMC) and skin. Results: In our study we have not detected differences in TGF-β 1 expression in PBMC, skin, nor in plasma levels of TGF-β1 between MEP patients and healthy controls, regardless of disease activity and its duration. Conclusions: The results of our study contradict the claim of the substantial role of TGF-β1 in the most common morphea subtype - MEP.

Introduction: Morphea is a disease included in the group of scleroderma type autoimmune diseases. Interleukin (IL)-17A may play a role at every stage of its pathogenesis. The study aimed at evaluation of IL-17A and IL-23 (as the main cytokine which is supposed to stimulate and maintain synthesis of IL-17) in pathogenesis of morphea. Material and methods: The studies were performed on 41 blood samples from patients with morphea. Skin was sampled from 29 patients. The evaluation included: (1) expression of IL-17A and IL-23 genes in peripheral blood mononu clear cells (PBMC) using real-time polymerase chain reaction (PCR), (2) plasma concentrations of IL-17A and IL-23 using ELISA, (3) expression of IL-17A and IL- 23 genes in skin using real-time PCR. Results: The results of gene expression are expressed as median number of copies per million copies of GAPDH. Higher expression of IL-17A has been demonstrated in PBMC of morphea vs. control group (2630 and 1906 respectively; p = 0.004), accompanied by absence of significant differences in its plasma concentration (10 pg/ml in both groups) and by lowered expression in affected skin (9119 and 19113 respectively; p = 0.036). The results failed to demonstrate elevated IL-23 plas ma concentration in morphea vs. control group (5 pg/ml and 6 pg/ml respective ly; p = 0.335) or its increased expression in the skin (292 vs. 427; p = 0.383), although we noted its increased expression in PBMC (4419 vs. 808; p < 0.001). Conclusions: Based on the observed correlations we suggest that: (1) IL-17A does not represent a factor which promotes tissue injury in morphea, (2) IL-23 may playa role in pathogenesis of morphea.

The clinical course of localized scleroderma may consist of bodily deformations, and bodily functions may also be affected. Additionally, the secondary lesions, such as discoloration, contractures, and atrophy, are unlikely to regress. The aforementioned symptoms and functional disturbances may decrease one's quality of life (QoL). Although much has been mentioned in the medical literature regarding QoL in persons suffering from dermatologic diseases, no data specifically describing patients with localized scleroderma exist. The aim of the study was to explore QoL in localized scleroderma patients and to examine their coping strategies in regard to optimism and QoL. The study included 41 patients with localized scleroderma. QoL was evaluated using the SKINDEX questionnaire, and levels of dispositional optimism were assessed using the Life Orientation Test-Revised. In addition, individual coping strategy was determined using the Mini-MAC scale and physical condition was assessed using the Localized Scleroderma Severity Index. The mean QoL score amounted to 51.10 points, with mean scores for individual components as follows: symptoms = 13.49 points, emotions = 21.29 points, and functioning = 16.32 points. A relationship was detected between QoL and the level of dispositional optimism as well as with coping strategies known as anxious preoccupation and helplessness-hopelessness. Higher levels of optimism predicted a higher general QoL. In turn, greater intensity of anxious preoccupied and helpless-hopeless behaviors predicted a lower QoL. Based on these results, it may be stated that localized scleroderma patients have a relatively high QoL, which is accompanied by optimism as well as a lower frequency of behaviors typical of emotion-focused coping strategies.

Lichen sclerosus is a chronic inflammatory skin disorder that belongs to a group of autoimmune connective tissue diseases, localized within the skin and mucous membrane of the anogenital area. In the latter location, the focal atrophy of the mucosa is the most visible sign. Lesions may be accompanied by symptoms such as itching, pain, burning. The disease occurs more often in females. The etiology is not fully understood. Genetic, infectious, hormonal factors and autoimmune mechanisms are taken into consideration. Early diagnosis and appropriate treatment is important to avoid further complications. This review aims to analyze available literature on the treatment of this disease entity