Development of universal antidotes to control aptamer activity.

With an ever increasing number of people taking numerous medications, the need to safely administer drugs and limit unintended side effects has never been greater. Antidote control remains the most direct means to counteract acute side effects of drugs, but, unfortunately, it has been challenging and cost prohibitive to generate antidotes for most therapeutic agents. Here we describe the development of a set of antidote molecules that are capable of counteracting the effects of an entire class of therapeutic agents based upon aptamers. These universal antidotes exploit the fact that, when systemically administered, aptamers are the only free extracellular oligonucleotides found in circulation. We show that protein- and polymer-based molecules that capture oligonucleotides can reverse the activity of several aptamers in vitro and counteract aptamer activity in vivo. The availability of universal antidotes to control the activity of any aptamer suggests that aptamers may be a particularly safe class of therapeutics.

La peste recogneue et combatue : ensemble la reformation des theriaques et antidotes opiatiques ... /

Mode of access: Internet.

Du libéralisme à l’anarcho-capitalisme : l’étatisme contemporain et ses antidotes

L'État est une organisation qui revendique et réussit généralement à faire respecter un monopole ultime de la force sur un territoire donné. Un tel monopole se traduit par l’imposition de sanctions à quiconque utilise la force sans une permission spécifique ou générale du monopoleur. Certes, il y a des conditions d'existence de l’État que cette définition ne saisit pas -une certaine reconnaissance de sa légitimité, par exemple-; elle ne réussit pas la tâche difficile de formuler des conditions suffisantes de l'existence de l’État. Mais elle se rapproche suffisamment de l’acception ordinaire du terme et elle nous servira assez bien pour que l'on s’en satisfasse. La revendication et l'exercice habituel d’un monopole ultime de la force constituent certainement, à tout le moins, des conditions nécessaires de l’existence de l'État. En plus de sa compatibilité avec ce que l'usage général perçoit comme le plus petit commun dénominateur, l'expérience historique ou la nature de l'État, cette définition offre l'avantage important de ne rien présumer de la question de l'État, de son fonctionnement de sa finalité, de son utilité et de sa moralité, bref de sa justification. C'est une pétition de principe trop courante que d'inclure dans la définition de l'État les fondements de sa justification. Tel qu’il est vécu, l’État, et surtout l'État démocratique moderne, ressemble fort à un rituel, un ensemble d'actions, de gestes et d'incantations que l’on répète sans effet et dont la véritable valeur réside dans leur répétition même. On chante l’hymne national; on vote tous les deux , quatre ou sept ans; les projets de loi présentés par la majorité parlementaire sont votés en première, deuxième et troisième lecture; on répète que l'État c'est nous. Ces rites ne sont pas nécessairement inoffensifs : les dieux ont toujours aimé les sacrifices. Mais l'une des fonctions sociales du rite, suggère Kenneth Boulding, est de contrer la frustration agressive que les problèmes insolubles engendrent chez les hommes, en leur fournissant un placebo pour solution. Ainsi agiraient les rituels sociaux , la magie, les cérémonies religieuses et les techniques comptables mêmes. Ajoutons le rituel étatique, qui répond au problème redoutable de légitimer une organisation qui prétend employer la force pour imposer l'harmonie. […]

Species differences in acrylonitrile metabolism and toxicity between experimental animals and humans based on observations in human accidental poisonings

The high acute toxicity of acrylonitrile may be a result of its intrinsic biological reactivity or of its metabolite cyanide. Intravenous N-acetylcysteine has been recommended for treatment of accidental intoxications in acrylonitrile workers, but such recommendations vary internationally. Acrylonitrile is metabolized in humans and experimental animals via two competing pathways; the glutathione-dependent pathway is considered to represent an avenue of detoxication whilst the oxidative pathway leads to a genotoxic epoxide, cyanoethylene oxide, and to elimination of cyanide. Cases of acute acrylonitrile overexposure or intoxication have occurred within persons having industrial contact with acrylonitrile; the route of exposure was by inhalation and/or by skin contact. The combined observations lead to the conclusion of a much higher impact of the oxidative metabolism of acrylonitrile in humans than in rodents. This is confirmed by differences in the clinical picture of acute life-threatening intoxications in both species, as well as by differential efficacies of antidotes. A combination of N-acetylcysteine with sodium thiosulfate seems an appropriate measure for antidote therapy of acute acrylonitrile intoxications. Clinical observations also highlight the practical importance of human individual susceptibility differences. Furthermore, differential adduct monitoring, assessing protein adducts with different rates of decay, enables the development of more elaborated biological monitoring strategies for the surveillance of workers with potential acrylonitrile contact.

The Threshold Learning Outcome on self-management for the Bachelor of Laws degree : a proposed focus for teaching strategies in the first year law curriculum

The Australian Learning and Teaching Council (ALTC) Discipline Scholars for Law, Professors Sally Kift and Mark Israel, articulated six Threshold Learning Outcomes (TLOs) for the Bachelor of Laws degree as part of the ALTC’s 2010 project on Learning and Teaching Academic Standards. One of these TLOs promotes the learning, teaching and assessment of self-management skills in Australian law schools. This paper explores the concept of self-management and how it can be relevantly applied in the first year of legal education. Recent literature from the United States (US) and Australia provides insights into the types of issues facing law students, as well as potential antidotes to these problems. Based on these findings, I argue that designing a pedagogical framework for the first year law curriculum that promotes students’ connection with their intrinsic interests, values, motivations and purposes will facilitate student success in terms of their personal well-being, ethical dispositions and academic engagement.

AA and the Redeployment of Temperance Literature

This essay is an examination that, primarily comparativist in its approach, links publication materials from the temperance and Prohibition periods with the Big Book to show how AA's narrative antidotes to the traumas of modernity (sited in alcohol abuse) were as much the product of premodernist and turn-of-the-century hysteria as they were an attempt to write a new chapter in America's relationship with alcohol based on contemporary medical and social research.

Faulty sausage production causing methaemoglobinaemia

A family outbreak of methaemoglobinaemia following ingestion of sausages made using 'saltpetre' is reported. Saltpetre is a generic term for several potassium and sodium based compounds. On this occasion imprecise ordering led to the use of sodium nitrite rather than the usual potassium nitrate, with extremely serious consequences.

Triacontyl p-coumarate: An inhibitor of snake venom metalloproteinases

Snake venom metalloproteinases (SVMPs) participate in a number of important biological, physiological and pathophysiological processes and are primarily responsible for the local tissue damage characteristic of viperid snake envenomations. The use of medicinal plant extracts as antidotes against animal venoms is an old practice, especially against snake envenomations. Such plants are sources of many pharmacologically active compounds and have been shown to antagonize the effects of some venoms and toxins. The present study explores the activity of triacontyl p-coumarate (PCT), an active compound isolated from root bark of Bombacopsis glabra vegetal extract (Bg), against harmful effects of Bothropoides pauloensis snake venom and isolated toxins (SVMPs or phospholipase A2). Before inhibition assays, Bg or PCT was incubated with venom or toxins at ratios of 1:1 and 1:5 (w/w; venom or isolated toxins/PCT) for 30 min at 37 °C. Treatment conditions were also assayed to simulate snakebite with PCT inoculated at either the same venom or toxin site. PCT neutralized fibrinogenolytic activity and plasmatic fibrinogen depletion induced by B. pauloensis venom or isolated toxin. PCT also efficiently inhibited the hemorrhagic (3MDH-minimum hemorrhagic dose injected i.d into mice) and myotoxic activities induced by Jararhagin, a metalloproteinase from B. jararaca at 1:5 ratio (toxin: inhibitor, w/w) when it was previously incubated with PCT and injected into mice or when PCT was administered after toxin injection. Docking simulations using data on a metalloproteinase (Neuwiedase) structure suggest that the binding between the protein and the inhibitor occurs mainly in the active site region causing blockade of the enzymatic reaction by displacement of catalytic water. Steric hindrance may also play a role in the mechanism since the PCT hydrophobic tail was found to interact with the loop associated with substrate anchorage. Thus, PCT may provide a alternative to complement ophidian envenomation treatments. © 2012 Elsevier Ltd. All rights reserved.

Il contratto a Tempo Determinato nel lavoro privato e pubblico. Assetti e linee di tendenza in un mercato del lavoro dinamico e globale

L’elaborato, dopo una ricostruzione della disciplina normativa presente in materia di contratto a tempo determinato in Italia e nei principali ordinamenti europei (Spagna, Francia ed Inghilterra), affronta i più rilevanti nodi problematici dell’istituto, in riferimento al settore privato e pubblico, mettendo in luce le principali querelle dottrinali e giurisprudenziali. Particolare attenzione è dedicata alle questioni insorte a seguito delle ultime modifiche normative di cui al c.d. Collegato lavoro (legge n. 183/2010), sino al decisivo intervento della Corte Costituzionale, con pronuncia n. 303 del 9 novembre 2011, che ha dichiarato legittima la disposizione introduttiva dell’indennità risarcitoria forfetizzata, aggiuntiva rispetto alla conversione del contratto. Tutte le problematiche trattate hanno evidenziato le difficoltà per le Corti Superiori, così come per i giudici comunitari e nazionali, di trovare una linea univoca e condivisa nella risoluzione delle controversie presenti in materia. L’elaborato si chiude con alcune riflessioni sui temi della flessibilità e precarietà nel mondo del lavoro, attraverso una valutazione quantitativa e qualitativa dell’istituto, nell’intento di fornire una risposta ad alcuni interrogativi: la flessibilità è necessariamente precarietà o può essere letta quale forma speciale di occupazione? Quali sono i possibili antidoti alla precarietà? In conclusione, è emerso come la flessibilità possa rappresentare un problema per le imprese e per i lavoratori soltanto nel lungo periodo. La soluzione è stata individuata nell’opportunità di investire sulla formazione. Si è così ipotizzata una nuova «flessibilità socialmente ed economicamente sostenibile», da realizzarsi tramite l’ausilio delle Regioni e, quindi, dei contributi del Fondo europeo di sviluppo regionale: al lavoratore, in tal modo, potrà essere garantita la continuità con il lavoro tramite percorsi formativi mirati e, d’altro canto, il datore di lavoro non dovrà farsi carico dei costi per la formazione dei dipendenti a tempo determinato.

Lesões de extravasamento de terapêutica intravenosa com propriedades vesicantes

Trabalho Final do Curso de Mestrado Integrado em Medicina, Faculdade de Medicina, Universidade de Lisboa, 2014

Getting muscles moving again after botulinum toxin: novel therapeutic challenges

The use of botulinum neurotoxins for the treatment of muscle hyperactivity and spasticity disorders has been remarkably successful, owing to the abilities of the toxins to elicit prolonged localized paralysis and the rarity of serious adverse effects. However, botulinum toxins are the most deadly protein toxins known, and existing antidotes possess limited effectiveness. Paradoxically, in situ, the intoxicated motoneuron does not die. It reacts by emanating a sprouting network known to implement new functional synapses, leading to resumption of neurotransmission. Recent studies have highlighted ways of accelerating this natural recovery process to overcome paralysis successfully. Developing new therapeutic strategies and treatments for botulism will require more research into the molecular understanding of this 'naturally occurring' recovery process.