The Victorian and the Historical in Post-Victorian Fiction

Zadanie pt. „Digitalizacja i udostępnienie w Cyfrowym Repozytorium Uniwersytetu Łódzkiego kolekcji czasopism naukowych wydawanych przez Uniwersytet Łódzki” nr 885/P-DUN/2014 dofinansowane zostało ze środków MNiSW w ramach działalności upowszechniającej nauk

Animal models of social communication of emotions and empathy

Pomimo, że stan emocjonalny wydaje się być unikatową własnością przypisaną do osobnika, który go doświadcza, nie bez znaczenia jest jego wpływ na inne osobniki. W przypadku zwierząt, komunikowanie emocji, zwłaszcza tych negatywnych, takich jak stres czy doświadczenie bólu, ma kluczowe znaczenie dla przeżycia w naturalnym środowisku. Zwierzęta, podobnie jak ludzie, posiadają swoiste wyspecjalizowane mechanizmy służące przekazywaniu i odbieraniu informacji o stanie emocjonalnym innych osobników, znajdujących się w danym środowisku. Obecność drugiego osobnika powoduje wyciszenie reakcji lękowej u warunkowanych lękowo zwierząt, a także może powodować wzrost lęku u osobników niewarunkowanych. Zjawisko to nazywane jest social buffering, czyli społeczny przekaz emocji. Zostało ono dokładnie zbadane pod względem zarówno behawioralnym, jak i neurobiologicznym, dając podstawy do twierdzenia, że neurobiologia stresu oraz społecznych zachowań są ze sobą mocno powiązane.Despite of the fact, that emotional state seems to be an unique property of the individual experiencing it, not without significance is its influence over conspecifics. In case of animals, communication of emotions, especially negative, like stress or pain experience is crucial for surviving in natural environment. Animals, similarly to people, possess specialized mechanisms for passing and receiving information about the emotional state of others. Presence of conspecific individuals causes alleviation of fear reaction in fear conditioned animals, as well as could exaggerate fear in non-fearful individuals. This phenomenon is called social buffering, that is the social transfer of emotions. It was precisely examined in various studies, which gave ground for claiming, that neurobiology of stress and neurobiology of social behavior are strongly related

Analgesic effects of pyrazolyl-pyridine based scaffolds, peripherial CB2 receptors modulators, in treatment of osteoarthritis-related pain

Osteoartroza (OA) jest jedną z najczęstszych chorób układu ruchu wśród osób powyżej 60 roku życia. Chorzy cierpią na sztywność stawu, utrudnienie poruszania się oraz przewlekły, trudny do uśmierzenia ból. Osteoartrozie, poza degradacją chrząstki stawowej towarzyszy przewlekły, lokalny stan zapalny o niskim natężeniu. Niestety, dotychczasowe możliwości leczenia są bardzo ograniczone i koncentrują się jedynie na redukcji bólu oraz utrzymaniu funkcjonalności stawu.Nowe podejście do leczenia przewlekłego bólu w OA stanowi układ endokanabinoidowy. Analgetyczny efekt kanabinoidów w leczeniu bólu różnego pochodzenia jest dobrze udokumentowany. Wyróżnia się dwa główne typy receptorów kanabinoidowych: CB1 i CB2. Receptory CB1 znajdują się głównie w ośrodkowym układzie nerwowym. Dzięki tej lokalizacji, ich aktywacja przez kannabinoidy jest ściśle związana z wywieranymi przez nie działaniami niepożądanymi. Receptory CB2 występują głównie na obwodzie oraz na komórkach układu immunologicznego. Selektywna modulacja receptorów CB2, z uwagi na ich obwodową lokalizację, nie wywołuje tak wielu efektów niepożądanych (takich jak nadmierne pobudzenie, zawroty głowy, senność, zaburzenia poznawcze), jak aktywacja receptorów CB1. Co więcej, z uwagi na umiejscowienie receptorów CB2 na komórkach odpornościowych, ich modulacja przyczynia się do obniżenia stanu zapalnego towarzyszącego przebiegowi choroby. Dlatego też ten typ receptorów wydaje się być obiecującym celem terapeutycznym w leczeniu osteoartrozy.W niniejszej pracy sprawdzono analgetyczny efekt nowych związków, pochodnych pirazolilopirydyny, będących ligandami receptorów CB2, w zwierzęcym i komórkowym modelu OA. Przetestowano trzy związki: pełnego agonistę CB2 (COR1114) oraz dwóch odwrotnych agonistów CB2 (COR1119 i COR1073). Wyniki pokazują znaczące podwyższenie progu bólowego u zwierząt z OA, którym podano zarówno agonistę, jak i odwrotnych agonistów CB2. Zaobserwowany analgetyczny efekt COR1114 spowodowany został poprzez ośrodkową aktywację receptorów CB2, natomiast efekt COR1119 oraz COR1073 można wytłumaczyć zahamowaniem zapalenia na obwodzie. Efekt ten zgodny jest z wynikami otrzymanymi w modelu in vitro: COR1119 w stężeniu 10 μM podwyższał ekspresję genu inhibitora makrofagów (MIF), natomiast po wcześniejszej prozapalnej stymulacji TNFα (50 ng/ml), poziom mRNA dla IL1β został znacząco obniżony w przypadku traktowania komórek COR1073.Testowane związki wykazują efekt analgetyczny w zwierzęcym modelu OA, oraz działanie przeciwzapalne w modelu in vitro. Stanowią obiecującą perspektywę do dalszego badania modulatorów układu endokanabinoidowego w leczeniu bólu przewlekłego.Osteoarthritis (OA) is one of the most common diseases of the locomotor system among people over 60. Patients suffer from joint stiffness, difficulties in limb motion and chronic, hard to mitigate pain. Osteoarthritis, beyond cartilage degradation, accompany local, chronic, but low-grade inflammation. Unfortunately, current therapeutic possibilities are limited and concentrate only on reducing pain and maintaining joint functionality.A novel approach for OA-related chronic pain treatment is endocannabinoid system. Analgesic effects of cannabinoids in treatment of pain of various origin is well documented. We can distinguish two types of cannabinoid receptors: CB1 and CB2. CB1 receptors are mainly located in central nervous system. Because of such location, their activation is closely related to undesirable effects they exert. CB2 receptors are mainly located at the periphery and on the immune cells. Selective activation of CB2 receptors, due to its peripheral localization, do not trigger so many undesirable side effects (such as excessive arousal, dizziness, drowsiness, cognitive impairment), as CB1 receptors activation. What is more, due to occurrence of CB2 receptors on the immune cells, their modulation contributes to reduction of the inflammation accompanying the disease. That is why this type of receptors seems to be a promising therapeutic goal in osteoarthritis treatment.In current work, the therapeutic effects of novel pyrazolyl-pyridine basedligands of CB2 receptors, were studied in both in vivo and in vitro models of OA. Three compounds were tested: full CB2 agonist (COR1114) and two CB2 inverse agonists (COR1119 and COR1073). Results show a significant increase of pain threshold in animals suffering from OA, treated with either full or inverse agonists. The observed analgesic effect of COR1114 was induced through the central activation of CB2 receptors, whilst the effect of COR1119 and COR1073 can be explained by inhibition of the inflammation at the periphery. This effect is consistent with the results obtained in the in vitro model of OA elicted by proinflammatory stimulus. COR1119 in 10 μM concentration increased the expression of macrophage inhibitor factor (MIF) gene, following pro-inflammatory TNFα (50 ng/ml) stimulation, whereas elevated levels of IL1β mRNA were significantly diminished after COR1073 treatment.In conclusion, tested compounds exhibit analgesic effect in the animal model of OA and anti-inflammatory effect in the in vitro model. They are a promising compounds forfurther investigation in research upon therapeutic modulators of the endocannabinoid system in chronic pain treatment

Alterations in Anandamide Synthesis and Degradation during Osteoarthritis Progression in an Animal Model

Osteoarthritis (OA) is a degenerative joint disease manifested by movement limitations and chronic pain. Endocannabinoid system (ECS) may modulate nociception via cannabinoid and TRPV1 receptors. The purpose of our study was to examine alterations in the spinal and joint endocannabinoid system during pain development in an animal model of OA. Wistar rats received intra-articular injection of 3mg of sodium monoiodoacetate (MIA) into the knee joint. Animals were sacrificed on day 2, 7, 14, 21, 28 after injection and lumbar spinal cord, cartilage and synovium were collected. Changes in the transcription levels of the ECS elements were measured. At the spinal level, gene expression levels of the cannabinoid and TRPV1 receptors as well as enzymes involved in anandamide synthesis and degradation were elevated in the advanced OA phase. In the joint, an important role of the synovium was demonstrated, since cartilage degeneration resulted in attenuation of the changes in the gene expression. Enzymes responsible for anandamide synthesis and degradation were upregulated particularly in the early stages of OA, presumably in response to early local joint inflammation. The presented study provides missing information about the MIA-induced OA model and encourages the development of a therapy focused on the molecular role of ECS

CB2 agonism controls pain and subchondral bone degeneration induced by mono-iodoacetate: Implications GPCR functional bias and tolerance development

Background and purpose: The endocannabinoid system became a promising target for osteoarthritis (OA) treatment. Functional selectivity of cannabinoids may increase their beneficial properties while reducing side effects. The aim of the present study was to evaluate the analgesic potential of two functionally biased CB2 agonists in different treatment regimens to propose the best pharmacological approach for OA management. Experimental approach: Two functionally selective CB2 agonists were administered i.p. – JWH133 (cAMP biased) and GW833972A (β-arrestin biased), in a chemically induced model of OA in rats. The drugs were tested in acute and chronic treatment regimens. Analgesic effects were assessed by pressure application measurement and kinetic weight bearing. X-ray microtomography was used for the morphometric analysis of the femur’s subchondral bone tissue. Underlying biochemical changes were analysed via RT-qPCR. Key results: Dose-response studies established the effective dose for both JWH133 and GW833972A. In chronic treatment paradigms, JWH133 was able to elicit analgesia throughout the course of the experiment, whereas GW833972A lost its efficacy after 2 days of treatment. Later studies revealed improvement in subchondral bone architecture and decrement of matrix metalloproteinases and proinflammatory factors expression following JWH133 chronic treatment. Conclusion and implications: Data presents analgesic and disease-modifying potential of CB2 agonists in OA treatment. Moreover, the study revealed more pronounced tolerance development for analgesic effects of the β-arrestin biased CB2 agonist GW833972A. These results provide a better understanding of the molecular underpinnings of the anti-nociceptive potential of CB2 agonists and may improve drug development processes for any cannabinoid-based chronic pain therapy

Krakowskie Studia Międzynarodowe nr 2, 2010 (Miscellanea Americana)

The present volume of Krakowskie Studia Międzynarodowe [Krakow International Studies] is as diverse as America is. Many of the problems discussed here seem from the European perspective – or at least the Western European one – exotic, even parochial, but this is a misunderstanding of what the United States is. In Ame­rica they are real since America is a baroque, extremely pluralistic country, with the citizens devoid of an apologizing attitude towards the democratic process and debating fiercely in public. The first essay, by Marta Dębska, “A Brief History of Americanization”, is a general, concise historical-comparative study which explains the meaning of this term, crucial for America. Andrzej Bryk takes up an issue which Dębska touches on in the conclusion of her essay. Marta du Vall analyzes the very interesting phenomenon of American com­passionate conservatism as a new version of the welfare state, an issue which has been in the air for a long time. Maciej Brachowicz discusses the topic of abortion, which in the American context is especially contested. The subject of Tocqueville and slavery has always fascinated students of America, and Wojciech Kaczor is no exception. He analyzes the problem from the point of view of a French aristocrat. In turn Piotr Musie­wicz analyzes the question of the 19th-century movement reforming the doctrine of the Anglican Church and the repercussions of this reform for the American Episco­pal Church. Rafał Marek takes up another topic connected with this religious side of American life, the issue of the Orthodox Church in the United States in the context of American church-state relations. Marta Majorek takes up the work of one of the best-known scholars and thinkers of anarchism, Robert Paul Wolff, living proof of the robust presence of the anarchist streak in the American psyche full of mistrust of state power. Beata Szyjka addresses the topic of the visa lottery in the United States, pla­cing it within the historical, legal and social context of American immigration law. The last article in the volume is an exception to the entirely Polish group of mainly young students of America publishing in this volume. It is written by one of the most distinguished American scholars of political philosophy, Catherine H. Zuckert of the University of Notre Dame. It is devoted to the work of Ralph Elli­son. As usual the American volume of Krakowskie Studia Międzynarodowe con­tains its Archive section. This time we publish an excerpt from a work by Richard John Neuhaus

Design, Synthesis, and Physicochemical and Pharmacological Profiling of 7‐Hydroxy-5-oxopyrazolo[4,3‐b]pyridine-6-carboxamide Derivatives with Antiosteoarthritic Activity In Vivo

The hallmark of joint diseases, such as osteoarthritis (OA), is pain, originating from both inflammatory and neuropathic components, and compounds able to modulate the signal trans- duction pathways of the cannabinoid type-2 receptor (CB2R) can represent a helpful option in the treatment of OA. In this perspective, a set of 18 cannabinoid type-2 receptor (CB2R) ligands was developed based on an unprecedented structure. With the aim of improving the physicochemical properties of previously reported 4-hydroxy-2-quinolone-3-carboxamides, a structural opti- mization program led to the discovery of isosteric 7-hydroxy-5- oxopyrazolo[4,3-b]pyridine-6-carboxamide derivatives. These new compounds are endowed with high affinity for the CB2R and moderate to good selectivity over the cannabinoid type-1 receptor (CB1R), associated with good physicochemical characteristics. As to the functional activity at the CB2R, compounds able to act either as agonists or as inverse agonists/antagonists were discovered. Among them, compound 51 emerged as a potent CB2R agonist able to reduce pain in rats carrying OA induced by injection of monoiodoacetic acid (MIA)