4,141 research outputs found
Drugs Affecting 5-HT Systems
No full textSeminar transcriptIt was in the very early hours of a February morning in 1977 that I first looked down the microscope and saw yellow fluorescence, characteristic of 5-hydroxytryptamine (5-HT) in frozen sections of Octopus brain. After struggling for two years with the capricious fluorescence histochemical technique to locate catecholamines and 5-HT, I finally had a successful result, and the PhD that had seemed a remote possibility for many months finally began to look feasible. Given the enormously important topic of this volume – the discovery and development of drugs affecting 5-HT systems – this small excursion into Octopus neurochemistry might seem irrelevant. However, cephalopod molluscs have played important roles in the history of 5-HT. More than 30000 pairs of posterior salivary glands of Octopus vulgaris were used by Vittorio Erspamer, for the first extraction and identification of enteramine, which was later shown to be identical to serotonin discovered by John Gaddum, and chemically characterized as 5-hydroxytryptamine. Other molluscs have provided some of the most sensitive bioassays for 5-HT, as Gaddum and Paasonen described in 1955, and several participants in this Witness Seminar recollected either using such bioassays or investigating invertebrate pharmacology at the beginning of their careers. Many reflected, however, that invertebrate receptors seemed to be very different from those found in mammals; they had, as David Wallis put it, ‘a parallel pharmacology’. One Witness, Merton Sandler, remembered attending a lecture by Vittorio Erspamer in London in the early 1950s, and being intrigued enough to start work on the degradative enzyme monoamine oxidase, a field which became highly significant for the development of a whole class of therapeutic drugs: the monoamine oxidase inhibitor
The Effects of Serotonin Receptor Antagonists on Contraction and Relaxation Responses Induced by Electrical Stimulation in the Rat Small Intestine
No full textBackground: The main source of 5-HT in body is in enterchromafin cells of intestine, different studies mentioned different roles for endogenous 5-HT and receptors involved and it is not clearified the mechanism of action of endogenous 5-HT.
Objectives: To study the role of endogenous 5-HT on modulation of contraction and relaxation responses induced by electrical field stimulation (EFS) in different regions of the rat intestine.
Materials and Methods: Segments taken from the rat duodenum, jejunum, mid and terminal ileum were vertically mounted, connected to a transducer and exposed to EFS with different frequencies in the absence and presence of various inhibitors of enteric mediators i. e. specific 5-HT receptor antagonists.
Results: EFS-induced responses were sensitive to TTX and partly to atropine, indicating a major neuronal involvement and a cholinergic system. Pre-treatment with WAY100635 (a 5-HT1A receptor antagonist) and granisetron up to 10.0 µM, GR113808 (a 5-HT4 receptor antagonist), methysergide and ritanserin up to 1.0 µM, failed to modify responses to EFS inall examined tissues. In the presence of SB258585 1.0 µM (a 5-HT6 receptor antagonist) there was a trend to enhance contraction in the proximal part of the intestine and reduce contraction in the distal part. Pre-treatment with SB269970A 1.0 µM (5-HT7 receptor antagonist) induced a greater contractile response to EFS at 0.4 Hz only in the duodenum.
Conclusions: The application of 5-HT1A, 5-HT2, 5-HT3, 5-HT4, 5-HT6 and 5-HT7 receptor antagonists, applied at concentrations lower than 1.0 µM did not modify the EFS-induced contraction and relaxation responses, whichsuggests the unlikely involvement of endogenous 5-HT in mediating responses to EFS in the described test conditions.
Keywords: Electric Stimulation Therapy; Serotonin 5-HT1 Receptor Antagonists; Intestine, Smal
Thripomorpha blantoni Cook 1955
No full textblantoni (Cook), 1955 b: 363, pl. IV i–k (M segment 7, M term., wing) (Rhegmoclema). Type locality: Panama, Bocas del Toro Prov., Almirante. HT M (NMNH). N. comb. Distr.: Panama, Colombia (Valle del Cauca(Rio Raposo)).Published as part of Amorim, Dalton De Souza, 2016, FAMILY SCATOPSIDAE, pp. 239-245 in Zootaxa 4122 (1) on page 242, DOI: 10.11646/zootaxa.4122.1.21, http://zenodo.org/record/26443
Risk analysis of High-Temperature Aquifer Thermal Energy Storage (HT-ATES)
No full textThe storage of heat in aquifers, also referred to as Aquifer Thermal Energy Storage (ATES), bears a high potential to bridge the seasonal gap between periods of highest thermal energy demand and supply. With storage temperatures higher than 50 °C, High-Temperature (HT) ATES is capable to facilitate the integration of (non-)renewable heat sources into complex energy systems. While the complexity of ATES technology is positively correlated to the required storage temperature, HT-ATES faces multidisciplinary challenges and risks impeding a rapid market uptake worldwide. Therefore, the aim of this study is to provide an overview and analysis of these risks of HT-ATES to facilitate global technology adoption. Risk are identified considering experiences of past HT-ATES projects and analyzed by ATES and geothermal energy experts. An online survey among 38 international experts revealed that technical risks are expected to be less critical than legal, social and organizational risks. This is confirmed by the lessons learned from past HT-ATES projects, where high heat recovery values were achieved, and technical feasibility was demonstrated. Although HT-ATES is less flexible than competing technologies such as pits or buffer tanks, the main problems encountered are attributed to a loss of the heat source and fluctuating or decreasing heating demands. Considering that a HT-ATES system has a lifetime of more than 30 years, it is crucial to develop energy concepts which take into account the conditions both for heat sources and heat sinks. Finally, a site-specific risk analysis for HT-ATES in the city of Hamburg revealed that some risks strongly depend on local boundary conditions. A project-specific risk management is therefore indispensable and should be addressed in future research and project developments.Accepted Author ManuscriptWater Resource
Improving identification of HT-ATES performance drivers and -barriers
No full textHigh temperature aquifer thermal energy storage (HT-ATES) can potentially solve the mismatch between heat supply and demand. It can provide a large scale seasonal heat storage solution. Thereby it enables an increase in full load hours of the base heat source, which can benefit project performance on both costs and emissions. However, the limited number of successful pilot projects indicates the technology has not escaped its state of infancy. There is a gap from concept to implementation, which is signified by the disagreement of experts on performance drivers and barriers of HT-ATES. This research aims to narrow the described knowledge gap, by improving identification of HT-ATES performance drivers and barriers. Thereby it strives to improve decision making of HT-ATES implementation, and further enhance future HT-ATES application in heating projects. The broad scope of research demands both a diagnostic and design-orientated approach, and fits seamlessly with a multi-criteria decision analysis. The analysis entails the stages of creating, evaluating, comparing and ranking of case-specific scenarios. Parametric variation changes the conditions for HT-ATES implementation across the scenarios. A simulation model is developed and connected to a groundwater model to apply the parametric variation, to create the different scenarios, and consequently to produce the quantitative information for further evaluation. During the stages of creating, evaluating, comparing and ranking, the methodology systematically produces new results on the opportunities and risks introduced by HT-ATES, and additionally on the HT-ATES performance drivers and barriers. The results show that HT-ATES enables the opportunity of improving project performance with respect to the internal rate of return and emissions. Groundwater impact remains the greatest risk, but it can be minimised with smart decision making. To support the decision maker and to overcome the risk of groundwater impact, the research proposes several performance-enhancing, non-explicit guidelines. The guidelines focus on realising an HT-ATES implementation, where project performance with respect to internal rate of return, emissions and groundwater impact are balanced. Thereby they explain the major HT-ATES performance drivers and barriers. The guidelines are summarised below. The decision maker is recommended to .. 1. .. minimise the uncertainty, through thorough subsurface characterization before implementation. Secondly, to focus on aquifers with a minimum depth of 200 [m] and a minimum hydraulic conductivity of 5 [m/d] 2. .. assure network return temperatures during peak demand are below expected storage temperatures 3. .. not consider project life-times exceeding 20 years 4. .. assure yearly maximum base source heat production is always lower than yearly consumer heat demand 5. .. to strive for a flat demand curve and apply peak-shaving, by means of, for example, variable heat prices Currently, the guidelines have the purpose of giving direction to the decision maker, but they will become more explicit once the methodology is improved, and the uncertainty and number of assumptions in the model is decreased.Electrical Engineering | Sustainable Energy Technolog
Transforming Ates To Ht-Ates, Insights From Dutch Pilot Project
No full textAquifer Thermal Energy Storage (ATES) systems combined with a heat pump save energy for space heating and cooling of buildings. In most countries the temperature of the stored heat is allowed up to 25-30°C. However, when heat is available at higher temperatures (e.g. waste heat, solar heat), it is more efficient to store higher temperatures because that improves heat pump performance or makes it unnecessary. Therefore, interest in HT-ATES development is growing. Next to developing new HT-ATES projects, there is also a large potential for additional energy savings by transforming ‘regular’ low-temperature LT-ATES systems to a HT-ATES. Such a transformation is tested for a greenhouse system in the Netherlands. This greenhouse has a LT-ATES system operational since 2012, and from 2015 onwards heat is stored in the warm well at temperatures up to 45°C. In this HT-ATES transformation pilot, water quality parameters are closely monitored as well as temperature distribution in the subsurface (using DTS). Together with the operators, the results from the ATES monitoring are used to continuously improve system performance. Numerical groundwater and heat flow simulations of actual and expected well pumping data are used to evaluate how well operation can be optimized. In this paper, the optimization using monitoring results and simulations is discussed as well as general and site specific lessons/conclusions for such transformations.Water Resource
The development of atypical hemolytic uremic syndrome depends on complement C5.
No full textGene variants in the alternative pathway of the complement system strongly associate with atypical hemolytic uremic syndrome (aHUS), presumably by predisposing to increased complement activation within the kidney. Complement factor H (CFH) is the major regulator of complement activation through the alternative pathway. Factor H-deficient mice transgenically expressing a mutant CFH protein (Cfh(-/-).FHΔ16-20) that functionally mimics the CFH mutations reported in aHUS patients spontaneously develop thrombotic microangiopathy. To investigate the role of complement C5 activation in this aHUS model, we generated C5-deficient Cfh(-/-).FHΔ16-20 mice. Both C5-sufficient and C5-deficient Cfh(-/-).FHΔ16-20 mice had abnormal C3 deposition within the kidney, but spontaneous aHUS did not develop in any of the C5-deficient mice. Furthermore, although Cfh(-/-).FHΔ16-20 animals demonstrated marked hypersensitivity to experimentally triggered renal injury, animals with concomitant C5 deficiency did not. These data demonstrate a critical role for C5 activation in both spontaneous aHUS and experimentally triggered renal injury in animals with defective complement factor H function. This study provides a rationale to investigate therapeutic inhibition of C5 in human aHUS
Characterization of the 5-HT(7) receptor as a new therapeutic target for the treatment of pain
No full text[eng] The work showed in this Thesis has been part of the “5-HT7 and neuropathic pain” project in the pharmaceutical company Esteve. Thus, the aim of this Thesis was in line with the goal of the 5-HT7 project at Esteve, focused on drug discovery of 5-HT7 receptor ligands for the treatment of neuropathic pain.
Taking the advantage of a genetic approach (5-HT7 receptor knockout mice) and pharmacological tools (5-HT7 receptor ligands) we investigated at the preclinical level the role of 5-HT7 receptors in nociception and the therapeutic interest of 5-HT7 receptor ligands on pain treatment. The 5-HT7 receptor ligands used were SB-258719 and SB-269970 as 5- HT7 receptor antagonists, and AS-19, MSD-5a, E-55888 and E-57431 as 5-HT7 receptor agonists. E-55888 and E-57431 developed by Esteve were described for the first time and their binding profile and functionality (cAMP formation) were examined. In vivo behavioural studies were performed in mice and rats subjected to nociceptive, inflammatory, neurogenic or neuropathic pain conditions.
Our results showed that 5-HT7 receptors per se were not involved in the nociceptive response to a normally noxius stimulus, although when co-activated together with opioid receptors potentiated the opioidergic analgesic response in nociceptive pain conditions. Indeed, 5-HT7 receptor knockout and wild-type mice showed similar sensitivity to a noxious heat stimulus, and systemic administration of the 5-HT7 receptor agonist E-55888 or the 5-HT7 receptor antagonist SB-258719 showed no effects on acute nociceptive pain using the tail flick test in mice. However, the 5-HT7 receptor agonist E-55888 enhanced the morphine-induced analgesia in this test and this potentiation was significantly reversed by the 5-HT7 receptor antagonist SB-258719.
On the other hand, we studied the role of 5-HT7 receptors in pain conditions involving central sensitization. We showed that the 5-HT7 receptor agonists AS-19, E-55888 and E-57431 inhibited capsaicin-induced mechanical hypersensitivity, nerve injury-induced mechanical and thermal hypersensitivity and reduced the phase II formalin-induced nociception. In contrast, a promotion of mechanical hypersensitivity after administration of the 5-HT7 receptor antagonists SB-258719 and SB-269970 was observed. This reduction of hypersensitivity by agonists and promotion of hypersensitivity by antagonists was reversed by antagonists and agonists, respectively. It is important to note that effectiveness of the treatment with 5-HT7 receptor agonists was not masked by non-specific motor effects, as no motor incoordination was found in the rota-rod test at the doses used and no tolerance to the effect was evidenced following repeated systemic administrations.
The antinociceptive effects exerted by systemic 5-HT7 receptor agonists seemed to be mediated by 5-HT7 receptors localized in the spinal cord. We found that intrathecal administration of the 5-HT7 receptor agonist E-57431 inhibited mechanical hypersensitivity secondary to capsaicin injection and nerve injury-induced mechanical hypersensitivity. In contrast, a pronociceptive effect was observed after local intraplantar injection of the selective 5-HT7 receptor agonist E-57431 in the capsaicin model. Thus, the antinociceptive role mediated by central 5-HT7 receptors seems to predominate over their pronociceptive role at the periphery, resulting in an overall analgesic effect when 5-HT7 receptor agonists are administered by a systemic route. In line with these spinal antinociceptive effects, we found an increased immunoreactivity of 5-HT7 receptors in the ipsilateral dorsal horn of the spinal cord in sciatic nerve-injured mice. This increased 5-HT7 receptor expression in the dorsal horn induced by nerve injury could represent a physiological, compensatory, protective spinal mechanism relevant to the control of nociception in neuropathic pain conditions.
We observed that 5-HT7 receptors co-localized with GABAergic neurons in the ipsilateral dorsal horn of the spinal cord. Therefore, we suggested that an indirect action through activation of 5-HT7 receptors localized on inhibitory interneurons may be responsible of the antinociceptive effects observed after administration of 5-HT7 receptor agonists.
Finally, using 5-HT7 receptor knockout mice, we demonstrated that the 5-HT7 receptor agonists AS-19, E-55888 and E-57431 exerted in vivo target specific effects on pain control. We observed that systemic administration of these 5-HT7 receptor agonists reduced phase II formalin-induced nociception in wild-type but not in 5-HT7 receptor knockout mice. Taken together, these data add a piece of knowledge to the role played by 5-HT7 receptors in the control of pain and point to a new potential use of 5-HT7 receptor agonists as promising drugs for the treatment of neuropathic pain.[cat] El treball mostrat en aquesta Tesi ha format part del projecte “5-HT7 i dolor neuropàtic” de l’empresa farmacèutica Esteve. Per tant, els objectius d’aquesta Tesi estan en línea amb l’objectiu del projecte 5-HT7 d’Esteve focalitzat en el descobriment de compostos amb afinitat pel receptor 5-HT7 pel tractament del dolor neuropàtic.
A partir de l’aproximació genètica amb l’ús de ratolins genoanul•lats pel receptor 5-HT7 i d’eines farmacològiques com compostos amb afinitat pel receptor 5-HT7, vàrem investigar a nivell preclínic el paper dels receptors 5-HT7 en el dolor i l’interès terapèutic dels lligands del receptor 5-HT7 en dolor. Entre els compostos utilitzats hi trobem el SB-258719 i el SB- 269970 com antagonistes pel receptor 5-HT7, i el AS-19, MSD-5a, E-55888 i el E-57431 com agonistes pel receptor 5-HT7. E-55888 i E-57431 van ser descrits per primera vegada i es va estudiar el seu perfil d’afinitat, selectivitat i funcionalitat. Es van realitzar estudis de comportament in vivo en ratolí i rata sotmesos a unes condicions de dolor nociceptiu, inflamatori, neurogènic i neuropàtic.
Els nostres resultats van mostrar que els receptors 5-HT7 per si mateixos no estaven implicats en la resposta a un estímul nociu, mentre que sí interaccionen amb el sistema opiodèrgic en condicions de dolor nociceptiu. Ratolins genoanul•lats pel receptor 5-HT7 van mostrar la mateixa sensibilitat enfront un estímul tèrmic nociu. L’administració sistèmica de l’agonista del receptor 5-HT7 E-55888 o l’antagonista del receptor 5-HT7 SB-258719 no van mostrar efecte en el dolor agut nociceptiu. En canvi, vàrem observar que els efectes antinociceptius de la morfina per via oral obtinguts en resposta a l’estímul tèrmic nociu del tail-flick, eren potenciats amb l’administració sistèmica conjunta de l’agonista del receptor 5-HT7 E-55888. Aquesta potenciació va ser revertida al mateix temps amb la coadministració de l’antagonista del receptor 5-HT7 SB-258719.
També vàrem estudiar el paper dels receptors 5-HT7 en condicions de dolor i sensibilització central. L’administració sistèmica d’agonistes selectius pel receptor 5-HT7 inhibia la hipersensibilitat mecànica induïda per capsaicina, la hipersensibilitat mecànica i tèrmica induïda per la lesió del nervi ciàtic, i el dolor induït per la fase II del model de la formalina. Això suggeria la implicació dels receptors 5-HT7 en condicions de sensibilització central. En canvi, es va observar una promoció de la hipersensibilitat mecànica amb els antagonistes del receptor 5-HT7. Tant els efectes dels agonistes i antagonistes del receptor 5-HT7 es van revertir amb la coadministració d’antagonistes i agonistes del receptor 5-HT7, respectivament. És important senyalar que les dosis amb eficàcia analgèsica dels agonistes del receptor 5-HT7 eren inferior a les dosis que produïen efectes adversos amb el test del rota-rod. A més, no es va observar tolerància de l’efecte analgèsic amb l’administració de dosis repetides de l’agonista del receptor 5-HT7 E-57431.
L’efecte analgèsic obtingut amb l’administració sistèmica dels agonistes pel receptor 5-HT7 semblava ser degut a l’activació de receptors 5-HT7 localitzats a nivell espinal. Vàrem trobar que l’administració intratecal de l’agonista del receptor 5-HT7 E-57431 inhibia la hipersensibilitat mecànica secundària a la injecció de capsaicina i la induïda per la lesió del nervi ciàtic. En canvi, es va observar un increment de la hipersensibilitat mecànica induïda per capsaicina amb la injecció local intraplantar de l’agonista del receptor 5-HT7 E-57431. En resum, l’efecte antinociceptiu obtingut a través de l’activació dels receptors 5-HT7 a nivell espinal sembla predominar respecte l’efecte pronociceptiu de la perifèria quan s’administra sistèmicament un agonista pel receptor 5-HT7. En línea amb l’efecte antinociceptiu observat a nivell espinal, vàrem trobar un increment de la immunoreactivitat dels receptors 5-HT7 de l’asta dorsal de la medul•la espinal en ratolins amb lesió del nervi ciàtic. Aquest increment en l’expressió del receptor 5-HT7 en l’asta dorsal induït per la lesió del nervi podria representar un mecanisme espinal fisiològic, compensatori i protector rellevant pel control de dolor en condicions de dolor neuropàtic.
Vàrem observar una col•localització dels receptors 5-HT7 en cèl•lules GABAèrgiques. En aquest sentit, l’activació dels receptors 5-HT7 col•localitzats en interneurones inhibitòries de l’asta dorsal de la medul•la espinal podria ser el mecanisme d’acció implicat en els efectes antinociceptius observats amb els agonistes del receptor 5-HT7.
Finalment, utilitzant ratolins genoanul•lats pel receptor 5-HT7, vàrem demostrar que els agonistes pel receptor 5-HT7 AS-19, E-55888 i E-57431 exercien efectes diana específics em el control de dolor. L’administració subcutània d’aquests agonistes pel receptor 5-HT7 reduïren la nocicepció induïda per formalina de la fase II en ratolins salvatges però no en ratolins genoanul•lats, suggerint una especificitat dels efectes obtinguts in vivo a través del receptor 5-HT7.
Aquest treball aporta un millor coneixement del paper del receptor 5-HT7 en el control del dolor i suggereix un nou potencial ús terapèutic dels agonistes pel receptor 5-HT7 com a fàrmacs prometedors pel tractament del dolor neuropàtic
"Put your own house in order first": local perceptions of EU influence on Romani integration policies in the Czech Republic
No full textThis article examines the influence of the European Union (EU) on the development and implementation of Romani integration policy in the Czech Republic from the perspective of those responsible for policy delivery. Based on analysis of key policy documents and research conducted in the Czech Republic, this article first examines how Romani integration became a more important issue during membership negotiations and then discusses how the criticism of the European Commission's Regular Reports was received by those responsible for implementing pro-Romani policies. Finally, the paper assesses how the status of full EU membership has impacted on integration policy. The article concludes that while funding for Romani integration projects has benefitted some groups, the overall impression of the EU is of a remote institution, quick to criticise and unwilling to practise what it preaches
Arachidonoyl serotonin (AA-5-HT) modulates general fear-like behavior and inhibits mesolimbic dopamine release
No full textCannabinergic and vanilloidergic signaling are potential mechanisms for the treatment of anxiety symptoms because of the anxiolytic properties of cannabinoid type 1 receptor (CB1R) activation and transient potential vanilloid type 1 channel (TRPV1) inhibition. Arachidonoyl serotonin (AA-5-HT), a fatty acid amide hydrolase and TRPV1 inhibitor provides a means of modulating these systems. We examined the effects of AA-5-HT on anxiety- and fear-like behaviors in male low (C57BL/6 J; [B6]) and high (BALB/cJ; [BCJ]) anxiety mice in light/dark box (LDB), open-field (OF), and fear extinction (FE) paradigms. AA-5-HT (1 mg/kg) did not affect anxiety-related behaviors in the LDB or OF in B6 mice. However, AA-5-HT attenuated generalized fear compared to vehicle treated B6s. AA-5-HT increased rearing and locomotion in the LDB in BCJ mice but did not affect fear-related behaviors. in vivo amperometry was used to determine the effects of AA-5-HT on dopamine release in the basolateral amygdala (BLA) and nucleus accumbens (NAc). AA-5-HT inhibited dopamine release in the BLA of BCJs and the NAc of B6s. Our results indicate that context interacts with basal anxiety levels to modulate the effects of AA-5-HT on some anxiety- and fear-related behaviors. We also provide evidence of cannabinergic and dopaminergic interactions in the BLA which could affect anxiety and fear. We suggest that this dose of AA-5-HT exhibits limited utility as a treatment for anxiety symptoms because it affects only some aspects of anxiety- and fear-related behavior in a manner dependent on baseline anxiety and environmental context
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