Pharmacological analysis of the increases in heart rate and diastolic blood pressure produced by (S)-isometheptene and (R)-isometheptene in pithed rats

Background: Isometheptene is a sympathomimetic drug effective in acute migraine treatment. It is composed of two enantiomers with diverse pharmacological properties. This study investigated in pithed rats the cardiovascular effects of (S)- isometheptene and (R)-isometheptene, and the pharmacological profile of the more potent enantiomer. Methods: The effects of i.v. bolus injections (0.03, 0.1, 0.3, 1 and 3 mg/kg) of isometheptene racemate, (S)-isometheptene or (R)-isometheptene on heart rate and blood pressure were analyzed in control experiments. The enantiomer producing more pronounced tachycardic and/or vasopressor responses was further analyzed in rats receiving i.v. injections of prazosin (0.1 mg/kg), rauwolscine (0.3 mg/kg), propranolol (1 mg/kg) or intraperitoneal reserpine (5 mg/kg, -24 h). Results: Compared to (R)-isometheptene, (S)-isometheptene produced greater vasopressor responses, whilst both compounds equipotently increased heart rate. The tachycardic responses to (S)-isometheptene were abolished after propranolol, but remained unaffected by the other antagonists. In contrast, the vasopressor responses to (S)-isometheptene were practically abolished after prazosin. Interestingly, after reserpine, the tachycardic responses to (S)-isometheptene were abolished, whereas its vasopressor responses were attenuated and subsequently abolished by prazosin. Conclusions: The different cardiovascular effects of the isometheptene enantiomers are probably due to differences in their mechanism of action, namely: (i) a mixed sympathomimetic action for (S)-isometheptene (a tyramine-like action and a direct stimulation of α1-adrenoceptors); and (ii) exclusively a tyramine like action for (R)-isometheptene. Thus, (R)-isometheptene may represent a superior therapeutic benefit as an antimigraine agent

Internode length is reduced during myelination and remyelination by neurofilament medium phosphorylation in motor axons

The distance between nodes of Ranvier, referred to as internode length, positively correlates with axon diameter, and is optimized during development to ensure maximal neuronal conduction velocity. Following myelin loss, internode length is reestablished through remyelination. However, remyelination results in short internode lengths and reduced conduction rates. We analyzed the potential role of neurofilament phosphorylation in regulating internode length during remyelination and myelination. Following ethidium bromide induced demyelination, levels of neurofilament medium (NF-M) and heavy (NF-H) phosphorylation were unaffected. Preventing NF-M lysine-serine-proline (KSP) repeat phosphorylation increased internode length by 30% after remyelination. To further analyze the role of NF-M phosphorylation in regulating internode length, gene replacement was used to produce mice in which all KSP serine residues were replaced with glutamate to mimic constitutive phosphorylation. Mimicking constitutive KSP phosphorylation reduced internode length by 16% during myelination and motor nerve conduction velocity by ~27% without altering sensory nerve structure or function. Our results suggest that NF-M KSP phosphorylation is part of a cooperative mechanism between axons and Schwann cells that together determine internode length, and suggest motor and sensory axons utilize different mechanisms to establish internode length

Explaining the onset of cohabitation under semi-presidentialism

Semi-presidentialism – where the constitution provides for both a directly elected fixed-term president and a prime minister and cabinet collectively responsible to the legislature – is an increasingly common form of government. For many observers cohabitation is the Achilles heel of semi-presidentialism. This article aims to identify the conditions that are associated with the onset of cohabitation.We specify a number of hypotheses that predict the conditions under which cohabitation should occur.We then test our hypotheses on the basis of a new data set that records every case of cohabitation in all semi-presidential electoral democracies from 1989 to 2008 inclusive.We confirm that cohabi- tation is more likely to occur in countries with a premier-presidential form of semi-presidentialism and show that it is more likely to follow an election that occurs midway through a parliamentary or presidential term, and that when cohabitation follows a presidential election, it is likely to do so in a country where there is only a very weak president. Overall, we find that the conditions under which cohabitation is most likely to occur are also the ones where it is most easily managed. Thus, our findings imply that cohabitation is not likely to be as problematic as the existing literature would suggest

Galaxies in the zone of avoidance: Misclassifications using machine learning tools

Automated methods for classifying extragalactic objects in large surveys offer significant advantages compared to manual approaches in terms of efficiency and consistency. However, the existence of the Galactic disk raises additional concerns. These regions are known for high levels of interstellar extinction, star crowding, and limited data sets and studies. In this study, we explore the identification and classification of galaxies in the zone of avoidance (ZoA). In particular, we compare our results in the near-infrared (NIR) with X-ray data. We analyzed the appearance of objects in the Galactic disk classified as galaxies using a published machine-learning (ML) algorithm and make a comparison with the visually confirmed galaxies from the VVV NIRGC catalog. Our analysis, which includes the visual inspection of all sources cataloged as galaxies throughout the Galactic disk using ML techniques reveals significant differences. Only four galaxies were found in both the NIR and X-ray data sets. Several specific regions of interest within the ZoA exhibit a high probability of being galaxies in X-ray data but closely resemble extended Galactic objects. Our results indicate the difficulty in using ML methods for galaxy classification in the ZoA, which is mainly due to the scarcity of information on galaxies behind the Galactic plane in the training set. They also highlight the importance of considering specific factors that are present to improve the reliability and accuracy of future studies in this challenging region.Comment: 10 pages, 11 figures, 2 tables. Accepted for publication in Astronomy & Astrophysic

Integral

Abstract In order to analyze the current process of operation of slaughterhouses and propose actions for an appropriate control, as well as implement the reduction of water used per slaughtered animal, this study of green production applied to the processes in a selected municipal slaughterhouse in Querétaro, Mexico was undertaken. Also, from treatability tests of wastewater, a mobile prototype of water treatment (1.5 m 3 /day) was conceptualized, designed and built. This prototype is operating at the slaughterhouse and demonstrates the efficiency of treatment of those waters. Along with the prototype, this project developed a technological folder with technical specifications, comparative analysis of production units and a business plan that brings together all the necessary information to evaluate the project and the general guidelines to implement it in other municipalities of Querétaro. The business plan is essential to seek funding, partners or investors, and serves as a guide for those leading the implementation of the results obtained in this project at other municipalities. Additionally, an environmental impact study was performed to identify and interpret the environmental impacts of a full scale project, with emphasis on environmental benefits

High school boys' and girls' writing conceptions and writing self-efficacy beliefs : what is their role in writing performance?

ABSTRACT: This study investigated the conceptions about writing and writing self-efficacy beliefs held by high school students in relation to the students’ gender as well as their associations with writing achievement. The results show that female students have more sophisticated writing conceptions than their male counterparts but no gender differences were found in writing self-efficacy beliefs. In addition, results reveal that writing self-efficacy beliefs and gender play an important role in predicting writing performance and that writing performance is moderated by students’ writing conceptions. Educational implications and further research are discussed

Clinical and molecular practice of European thoracic pathology laboratories during the COVID-19 pandemic. The past and the near future

BACKGROUND: This study evaluated the consequences in Europe of the COVID-19 outbreak on pathology laboratories orientated toward the diagnosis of thoracic diseases. MATERIALS AND METHODS: A survey was sent to 71 pathology laboratories from 21 European countries. The questionnaire requested information concerning the organization of biosafety, the clinical and molecular pathology, the biobanking, the workload, the associated research into COVID-19, and the organization of education and training during the COVID-19 crisis, from 15 March to 31 May 2020, compared with the same period in 2019. RESULTS: Questionnaires were returned from 53/71 (75%) laboratories from 18 European countries. The biosafety procedures were heterogeneous. The workload in clinical and molecular pathology decreased dramatically by 31% (range, 3%-55%) and 26% (range, 7%-62%), respectively. According to the professional category, between 28% and 41% of the staff members were not present in the laboratories but did teleworking. A total of 70% of the laboratories developed virtual meetings for the training of residents and junior pathologists. During the period of study, none of the staff members with confirmed COVID-19 became infected as a result of handling samples. CONCLUSIONS: The COVID-19 pandemic has had a strong impact on most of the European pathology laboratories included in this study. Urgent implementation of several changes to the organization of most of these laboratories, notably to better harmonize biosafety procedures, was noted at the onset of the pandemic and maintained in the event of a new wave of infection occurring in Europe

Pharmacological characterisation of capsaicin-induced relaxations in human and porcine isolated arteries

Capsaicin, a pungent constituent from red chilli peppers, activates sensory nerve fibres via transient receptor potential vanilloid receptors type 1 (TRPV1) to release neuropeptides like calcitonin gene-related peptide (CGRP) and substance P. Capsaicin-sensitive nerves are widely distributed in human and porcine vasculature. In this study, we examined the mechanism of capsaicin-induced relaxations, with special emphasis on the role of CGRP, using various pharmacological tools. Segments of human and porcine proximal and distal coronary arteries, as well as cranial arteries, were mounted in organ baths. Concentration response curves to capsaicin were constructed in the absence or presence of the CGRP receptor antagonist olcegepant (BIBN4096BS, 1 μM), the neurokinin NK1 receptor antagonist L-733060 (0.5 μM), the voltage-sensitive calcium channel blocker ruthenium red (100 μM), the TRPV1 receptor antagonist capsazepine (5 μM), the nitric oxide synthetase inhibitor Nω-nitro-l-arginine methyl ester HCl (l-NAME; 100 μM), the gap junction blocker 18α-glycyrrhetinic acid (10 μM), as well as the RhoA kinase inhibitor Y-27632 (1 μM). Further, we also used the K+ channel inhibitors 4-aminopyridine (1 mM), charybdotoxin (0.5 μM) + apamin (0.1 μM) and iberiotoxin (0.5 μM) + apamin (0.1 μM). The role of the endothelium was assessed by endothelial denudation in distal coronary artery segments. In distal coronary artery segments, we also measured levels of cyclic adenosine monophosphate (cAMP) after exposure to capsaicin, and in human segments, we also assessed the amount of CGRP released in the organ bath fluid after exposure to capsaicin. Capsaicin evoked concentration-dependent relaxant responses in precontracted arteries, but none of the above-mentioned inhibitors did affect these relaxations. There was no increase in the cAMP levels after exposure to capsaicin, unlike after (exogenously administered) α-CGRP. Interestingly, there were significant increases in CGRP levels after exposure to vehicle (ethanol) as well as capsaicin, although this did not induce relaxant responses. In conclusion, the capsaicin-induced relaxations of the human and porcine distal coronary arteries are not mediated by CGRP, NK1, NO, vanilloid receptors, voltage-sensitive calcium channels, K+ channels or cAMP-mediated mechanisms. Therefore, these relaxant responses to capsaicin are likely to be attributed to a non-specific, CGRP-independent mechanism