Development of novel cellular model for affinity studies of histamine H(4) receptor ligands

The G protein-coupled histamine H4 receptor (H4R) is the last member of histamine receptors family discovered so far. Its expression pattern, together with postulated involvement in a wide variety of immunological and inflammatory processes make histamine H4 receptor an interesting target for drug development. Potential H4R ligands may provide an innovative therapies for different immuno-based diseases, including allergy, asthma, pruritus associated with allergy or autoimmune skin conditions, rheumatoid arthritis and pain. However, none of successfully developed selective and potent histamine H4 receptor ligands have been introduced to the market up to date. For that reason there is still a strong demand for pharmacological models to be used in studies on potent H4R ligands. In current work we present the development of novel mammalian cell line, stably expressing human histamine H4 receptor, with use of retroviral transduction approach. Obtained cell line was pharmacologically characterized in radioligand binding studies and its utility for affinity testing of potent receptor ligands was confirmed in comparative studies with the use of relevant insect cells expression model. Obtained results allow for statement that developed cellular model may be successfully employed in search for new compounds active at histamine H4 receptor

Unmethyl-esterified homogalacturonan and extensins seal Arabidopsis graft union

Background: Grafting is a technique widely used in horticulture. The processes involved in grafting are diverse, and the technique is commonly employed in studies focusing on the mechanisms that regulate cell differentiation or response of plants to abiotic stress. Information on the changes in the composition of the cell wall that occur during the grafting process is scarce. Therefore, this study was carried out for analyzing the composition of the cell wall using Arabidopsis hypocotyls as an example. During the study, the formation of a layer that covers the surface of the graft union was observed. So, this study also aimed to describe the histological and cellular changes that accompany autografting of Arabidopsis hypocotyls and to perform preliminary chemical and structural analyses of extracellular material that seals the graft union. Results: During grafting, polyphenolic and lipid compounds were detected, along with extracellular deposition of carbohydrate/protein material. The spatiotemporal changes observed in the structure of the extracellular material included the formation of a fibrillar network, polymerization of the fibrillar network into a membranous layer, and the presence of bead-like structures on the surface of cells in established graft union. These bead-like structures appeared either “closed” or “open”. Only three cell wall epitopes, namely: LM19 (un/low-methyl-esterified homogalacturonan), JIM11, and JIM20 (extensins), were detected abundantly on the cut surfaces that made the adhesion plane, as well as in the structure that covered the graft union and in the bead-like structures, during the subsequent stages of regeneration. Conclusions: To the best of our knowledge, this is the first report on the composition and structure of the extracellular material that gets deposited on the surface of graft union during Arabidopsis grafting. The results showed that unmethyl-esterified homogalacturonan and extensins are together involved in the adhesion of scion and stock, as well as taking part in sealing the graft union. The extracellular material is of importance not only due to the potential pectin–extensin interaction but also due to its origin. The findings presented here implicate a need for studies with biochemical approach for a detailed analysis of the composition and structure of the extracellular material

Factors influencing sustainable employment of persons with acquired brain injury (ABI) or spinal cord injury (SCI): A qualitative study evaluating the perspective of health and work professionals

BackgroundThe number of persons with acquired brain injury (ABI) or spinal cord injury (SCI) who leave the labor market early despite successfully return to work post-injury, demonstrates the challenge for them to remain employed. Evidence on how enabling and hindering factors influence daily work across the lifespan and how they affect employment-related services is scarce. Professionals directly involved in work integration can add to this evidence through their experiential knowledge.PurposeTo identify and explore the factors that enable or hinder sustainable employment for persons with ABI or SCI from the perspective of health and work professionals.MethodsWe conducted 23 semi-structured interviews with professionals in Switzerland, directly involved in work reintegration and retention of persons with ABI or SCI. Interviews were transcribed verbatim and thematically analyzed.ResultsParticipants identified three main themes related to the concept of “sustainable employment”. First, the value and impact of initial work integration; an early, multidisciplinary, person-centered work integration, with the early involvement of employers is ideal. A good match between the worker and the workplace is sought. Second, critical factors for long-term sustainable work: the main risks for persons with ABI are changing supervisors, workplace restructuring and the introduction of new technologies, while deteriorating health and the occurrence of secondary health problems are the greatest risk for persons with SCI. Third, the relevance of knowledge, experience and attitudes of professionals; Knowledge of the consequences of an ABI or SCI, the legal basis and the social security process, and the attitude of professionals towards the injured worker were considered important.ConclusionsFrom the professional's perspective, enabling and hindering factors for sustainable employment in the long-term are fundamentally very similar for persons with ABI and SCI. But different physical, mental and neuropsychological effects call for individually adapted measures. While persons with SCI primarily require ongoing medical care, conscious management of changes in the workplace is critical for persons with ABI. For both groups, an easily accessible counseling and support service should be established for work-threatening problems in the long-term. Furthermore, diagnosis-specific training programs for professionals of employment-related services and disability management should be developed

Facilitators and Barriers to Sustainable Employment After Spinal Cord Injury or Acquired Brain Injury: The Person's Perspective

BackgroundSustaining employment after initial return to work represents a major challenge for people with a disability. While individuals with spinal cord injury (SCI) and acquired brain injury (ABI) make a prime example for this challenge, their view on factors supporting and hindering sustainable employment have rarely been investigated in depth so far.PurposeTo examine facilitators and barriers to sustainable employment, as perceived by persons with SCI or ABI.MethodsFourteen focus groups and four individual interviews were conducted and thematically analyzed.ResultsPerceived facilitators and barriers to sustainable employment reflected the three biopsychosocial areas of personal, impairment-related and environmental factors. For both condition groups, key facilitators included environmental factors (i.e., aspects of the work organization, the workplace, supportive private and work environment) and personal factors (i.e., the ability to self-advocate, to communicate and to learn how to live with one's own disability). Major barriers comprised injury-related impairments, including decreased mobility and pain for people with SCI and fatigue and limited cognitive resources for persons with ABI, as well as environmental factors related to insurance procedures and the social security system for both conditions.ConclusionsThe biopsychosocial factors identified in our study as well as their interplay should receive particular attention to optimally support sustainable employment in vocational integration and work retention practice. Interventions should particularly focus on the empowerment of those affected as well as on the creation of supportive work environments that match their abilities and needs

Structural Features of 1,3,4-Thiadiazole-Derived Ligands and Their Zn(II) and Cu(II) Complexes Which Demonstrate Synergistic Antibacterial Effects with Kanamycin

Classical synthetic protocols were applied for the isolation of three novel 1,3,4-thiadiazole derivatives which were then complexed with the biologically important Cu(II) and Zn(II) ions. All free ligands and their corresponding complexes were characterized using a number of spectroscopic techniques including Ultraviolet-visible (UV–vis), Fluorescence, Infrared (FT-IR), tandem liquid chromatography-mass (LC-MS), X-ray diffraction (XRD), and Nuclear Magnetic Resonance (NMR) spectroscopy (1H, 13C, HSQC, HMBC). The results obtained are consistent with the formation of dihydrate complexes, in which the chelation of the metal ion occurs via one of the thiadiazole nitrogen atoms and the deprotonated hydroxyl group of the neighboring resorcynyl moiety. The Zn(II) complexes utilize a 1:1 ligand–metal ratio, while in the Cu(II) complexes the ligand–metal ratio is 2:1. Although the antibacterial testing identified moderate activity of the compounds against the tested bacterial strains and additionally modest antioxidant activity, a strong synergistic antibacterial effect against Staphylococcus aureus, using concomitant treatment of thiadiazole derivatives with the commercial antibiotic kanamycin, was observed. The most active thiadiazole derivative demonstrated a minimal inhibitory concentration (MIC) of 500 μg/mL while it was 125 μg/mL in the presence of kanamycin. Moreover, in the presence of few thiadiazole derivatives the MIC value of kanamycin decreased from 0.39 μg/mL to 0.5 μg/mL. The antioxidant activity (IC50) of the most active thiadiazole derivative was determined as 0.13 mM which was nearly three-fold lower compared to that of TROLOX (0.5 mM)

Regiony w prawie i praktyce. Polska – Ukraina

Monografię stanowią opracowania powstałe na bazie referatów wygłoszonych podczas samorządowo-prawnej sesji tematycznej Regiony w prawie i praktyce, zorganizowanej przez Wydział Prawa i Administracji Uniwersytetu Łódzkiego w ramach międzynarodowej konferencji naukowej Europa Wschodnia w XXI wieku. Polska – Ukraina: partnerstwo regionów (Łódź, 21–22 października 2014 r.). Autorzy dokonali analizy i oceny reform prawa samorządu terytorialnego i kształtowania się pozycji ustrojowej regionów oraz praktyki ich funkcjonowania w Polsce i na Ukrainie, w tym w kontekście doświadczeń innych państw europejskich. W publikacji podjęto różnorodną tematykę w szeroko rozumianym aspekcie regionalnym w prawie konstytucyjnym i administracyjnym. Doniosłe pod względem prawnym, teoretycznym i praktycznym problemy, nieraz budzące kontrowersje, wymagały od Autorów nie tylko przedstawienia własnego – często krytycznego – stanowiska, lecz także wskazania pożądanych kierunków zmian legislacyjnych. Praca dotyczy trudnej i złożonej, a jednocześnie bardzo ważnej i stale aktualnej problematyki. Zakres rozważań podjętych w pracy jest przy tym bardzo szeroki. Publikacja w sposób twórczy analizuje wspomniane problemy […]. Należy ją uznać za opracowanie o wysokich walorach naukowych, zarówno porządkujące złożoną i trudną problematykę, jak również inspirujące i zachęcające do głębszej refleksji i dyskusji. Moim zdaniem jego czytelnikami powinni być nie tylko przedstawiciele nauki, lecz także szerokie grono praktyków, tj. urzędników pracujących w instytucjach administracji publicznej.Wydanie publikacji zostało dofinansowane przez Wydział Prawa i Administracji Uniwersytetu Łódzkiego, Katedrę Prawa Konstytucyjnego UŁ, Katedrę Prawa Administracyjnego i Nauki, Administracji UŁ oraz Centrum Studiów Wyborczych UŁ

Non-imidazole-based histamine H3 receptor antagonists with anticonvulsant activity in different seizure models in male adult rats

A series of twelve novel non-imidazole-based ligands (3-14) was developed and evaluated for its in vitro binding properties at the human histamine H3 receptor (hH3R). The novel ligands were investigated for their in vivo protective effects in different seizure models in male adult rats. Among the H3R ligands (3-14) tested, ligand 14 showed significant and dose-dependent reduction in the duration of tonic hind limb extension in maximal electroshock (MES)-induced seizure model subsequent to acute systemic administration (5, 10, and 20 mg/kg, intraperitoneally), whereas ligands 4, 6, and 7 without appreciable protection in MES model were most promising in pentylenetetrazole (PTZ) model. Moreover, the protective effect observed for ligand 14 in MES model was lower than that observed for the reference drug phenytoin and was entirely abrogated when rats were co-administered with the brain-penetrant H1R antagonist pyrilamine (PYR) but not the brain-penetrant H2R antagonist zolantidine (ZOL), demonstrating that histaminergic neurotransmission by activation of postsynaptically located H1Rs seems to be involved in the protective action. On the contrary, PYR and ZOL failed to abrogate the full protection provided by 4 in PTZ model and the moderate protective effect by 14 in strychnine (STR) model. Moreover, the experimental and in silico estimation of properties such as metabolism was performed for five selected test compounds. Also, lipophilicity using planar reversed-phase thin-layer chromatography method was included for better understanding of the molecular properties of the tested compounds. Additionally, the absorption, distribution, metabolism, and elimination and toxicity parameters were evaluated for the most promising compounds 2, 4, 6, 7, and 14 utilizing in vitro methods. These interesting results highlight the potential of H3R ligands as new antiepileptic drugs or as adjuvants to available epilepsy medications

Modification of internal hernia classification system after laparoscopic Roux-en-Y bariatric surgery

INTRODUCTION: The occurrence of internal hernia is not an uncommon late complication following the laparoscopic bariatric Roux-en-Y gastric bypass procedure. In some instances, it can be life threatening if not treated in a timely manner. Although there are numerous publications in the literature addressing internal hernia, they are mostly retrospective, and focus mainly on describing the different reconstructive orientation as far as the bowel is concerned. AIM: Our study aim is to address the relationship between the three basic elements of internal hernia, namely: intestinal mesentery defect, the involved intestine and herniated loop direction. Although a developed and widely accepted classification system of internal hernia has not been established yet, we hope this study can help the system to be established. MATERIAL AND METHODS: We studied all patients who underwent revision bariatric operations in the Freiburg and Lübeck University Hospitals (2007–2013). A single surgeon performed and documented all revision procedures for internal hernia. The post-operative follow-up period is up to 6 years. All patients with internal hernias were included whether their primary surgery was performed in our center or performed in other institutions, being referred to our center for further management. The presence of hernia defect, the type of herniated intestinal loop and the direction by which the herniated intestinal loop migrated were analyzed. RESULTS: Twenty-five patients with internal hernia were identified; in 2 patients more than one hernia type coexisted. The most frequent constellation of internal hernias was BP limb herniation into the Brolin space and migrating from left to right direction (28%). The highest incidence of internal hernia was found to be following Roux-en-Y gastric bypass (68%); the biliopancreatic limb (BP) limb was the most commonly involved intestine (51.9%). The incidence of Petersen hernia was the highest (59.3%), and left-right direction was more common. The most common hernia direction of the biliopancreatic limb was from left to right (92.6%), but alimentary limb (AL; 57.1%) and common channel (CC; 66.7%) often favor the other course. CONCLUSIONS: There are existing different types of internal hernias after bariatric operations including separate mesenterial spaces, various intestine parts and herniation direction. Our SDL classification system may offer a useful pathway that facilitates the understanding, and systematic approach to internal hernia, which can be used by bariatric quality registers

ESIPT-related origin of dual fluorescence in the selected model 1,3,4-thiadiazole derivatives

In our previous work, we discussed the emergence of the dual fluorescence phenomenon in selected compounds from the group of 1,3,4-thiadiazoles. The results obtained in a number of experimental studies, supported by [TD]DFT calculations, clearly indicated that the phenomenon of dual fluorescence stemmed from an overlap of several factors, including the correct conformation of the analyzed molecule and, very significantly in this context, aggregation effects. Where those two conditions were met, we could observe the phenomenon of intermolecular charge transfer (CT) and the emergence of electronic states responsible for long wave emissions. However, in light of the new studies presented in this paper, we were able, for the first time, to provide a specific theory for the effect of dual fluorescence observed in the analyzed group of 1,3,4-thiadiazoles. We present the results of spectroscopic measurements conducted for two selected analogues from the 1,3,4-thiadiazole group, both in polar and non-polar solvents, which clearly evidence (as we have already suspected in the past, albeit have not shown in publications to date) the possibility of processes related to emission from the tautomer formed in the process of excited state intramolecular proton transfer, which is responsible for the long-wavelength emissions observed in the selected analogues. The presented results obtained with the use of UV-Vis, fluorescence (stationary and time-resolved), FTIR, and Raman spectroscopy, as well as from calculations of dipole moment changes between the ground and excited state with the use of two derivatives with different structures of the resorcylic system, corroborated our standing hypothesis. At the same time, they excluded the presence of ground state keto forms of the analyzed analogues unless necessitated by the structure of the molecule itself. In this case, aggregation factors enhance the observed effects related to the dual fluorescence of the analyzed compounds (by way of AIE—aggregated induced emissions)

Synthesis, biological activity and molecular modelling studies of tricyclic alkylimidazo-, pyrimido- and diazepinopurinediones

Syntheses and biological activities of imidazo-, pyrimido- and diazepino[2,1-f]purinediones containing N-alkyl substituents (with straight, branched or unsaturated chains) are described. Tricyclic derivatives were synthesized by the cyclization of 8-bromo-substituted 7-(2-bromoethyl)-, 7-(3-chloropropyl)- or 7-(4-bromobutyl)-theophylline with primary amines under various conditions. Compound 22 with an ethenyl substituent was synthesized by dehydrohalogenation of 9-(2-bromoethyl)-1,3-dimethyltetrahydropyrimido[2,1-f]purinedione. The obtained derivatives (5-35) were initially evaluated for their affinity at rat A1 and A2A adenosine receptors (AR), showing moderate affinity for both adenosine receptor subtypes. The best ligands were diazepinopurinedione 28 (K i = 0.28 μM) with fivefold A2A selectivity and the non-selective A1/A2A AR ligand pyrimidopurinedione 35 (K i A1 = 0.28 μM and K i A2A = 0.30 μM). The compounds were also evaluated for their affinity at human A1, A2A, A2B and A3 ARs. All of the obtained compounds were docked to the A2A AR X-ray structure in complex with the xanthine-based, potent adenosine receptor antagonist-XAC. The likely interactions of imidazo-, pyrimido- and diazepino[2,1-f]purinediones with the residues forming the A2A binding pocket were discussed. Furthermore, the new compounds were tested in vivo as anticonvulsants in maximal electroshock, subcutaneous pentylenetetrazole (ScMet) and TOX tests in mice (i.p.). Pyrimidopurinediones showed anticonvulsant activity mainly in the ScMet test. The best derivative was compound 11, showing 100 % protection at a dose of 100 mg/kg without symptoms of neurotoxicity. Compounds 6, 7, 8 and 14 with short substituents showed neurotoxicity and caused death. In rat tests (p.o.), 9 was characterized by a high protection index (>13.3). AR affinity did not apparently correlate with the antiepileptic potency of the compounds