A randomised,investigator-initiated,clinical trial of the effects of fentanyl on P2Y12-receptor inhibition in patients with ST-elevation myocardial infarction who are pre-treated with crushed ticagrelor: rationale and design of the Opioids aNd crushed Ticagrelor In Myocardial infarction Evaluation (ON-TIME 3) trial

Background

Fast and accurate platelet inhibition is an important therapeutic goal in the acute treatment of patients with ST-elevation myocardial infarction (STEMI). Platelet inhibitory effects induced by oral P2Y12-receptor antagonists are delayed in STEMI patients undergoing primary percutaneous coronary intervention (PCI) due to haemodynamic changes and delayed gastro-intestinal absorption. Concomitant use of opioids, although recommended in the American College of Cardiology/American Heart Association and European Society of Cardiology STEMI guidelines, further delays gastro-intestinal absorption. To date, trials investigating alternative analgesics in STEMI patients have been scarce. This trial aims to assess the feasibility of a novel drug strategy for treatment of STEMI patients with crushed ticagrelor in combination with paracetamol (acetaminophen) instead of opioids.

Hypothesis

STEMI patients who are pre-treated with crushed ticagrelor and paracetamol have a higher level of platelet inhibition after primary PCI than patients pre-treated with crushed ticagrelor and fentanyl.

Study design

The Opioids aNd crushed Ticagrelor In Myocardial infarction Evaluation (ON-TIME 3) trial is a randomised controlled trial designed to examine whether administration of paracetamol instead of fentanyl can optimise platelet inhibition in STEMI patients who are pre-treated with crushed ticagrelor in the ambulance. One hundred and ninety patients with STEMI will be randomised (1:1 fashion) to intravenous (IV) fentanyl or IV paracetamol. The primary endpoint is the level of platelet reactivity units measured immediately after primary PCI.

Summary

The ON-TIME 3 trial (NCT03400267) aims to achieve optimal platelet inhibition and pain relief in STEMI patients receiving crushed ticagrelor in the ambulance by investigating IV fentanyl and IV paracetamol as analgesics.

     

Subordinates explore but dominants profit: resource competition in high Arctic barnacle goose flocks

Social dominance plays an important role in assessing and obtaining access to patchy or scarce food sources in group-foraging herbivores. We investigated the foraging strategies of individuals with respect to their social position in the group in a flock of nonbreeding, moulting barnacle geese, Branta leucopsis, on high Arctic Spitsbergen. We first determined the dominance rank of individually marked birds. The dominance of an individual was best described by its age and its sex-specific body mass. Mating status explained the large variation in dominance among younger birds, as unpaired yearlings ranked lowest. In an artificially created, competitive situation, subordinate individuals occupied explorative front positions in the flock and were the first to find sites with experimentally enriched vegetation. Nevertheless, they were displaced quickly from these favourable sites by more dominant geese which were able to monopolize them. The enhanced sites were subsequently visited preferentially by individuals that succeeded in feeding there when the exclosures were first opened. Data on walking speed of foraging individuals and nearest-neighbour distances in the group suggest that subordinates try to compensate for a lower energy intake by exploring and by lengthening the foraging bout. Observations of our focal birds during the following breeding season revealed that females that returned to the study area were significantly more dominant in the previous year than those not seen in the area again. Copyright 2001 The Association for the Study of Animal Behaviour.     

Transformation of NIH/3T3 to Anchorage Independence by H-Ras Is Accompanied by Loss of Suppressor Activity

Despite their familiar sensitivity to transformation by dominant-acting ras oncogenes, NIH/3T3 cells carry a ras suppressor. When tested by cell fusion they were able to suppress the anchorage-independent phenotype of both mouse and human cells transformed by activated H-ras or N-ras. This suppression occurred without a decrease in expression of the activated ras oncogene. Ras-transformed NIH/3T3 clones cured of their oncogene by benzamide treatment reverted to a non-transformed phenotype, but had lost the ability to suppress other ras transformants, indicating that their initial transformation was accompanied by suppressor loss. In hamster cells an active ras oncogene increased the rate of chromosome segregation by >100-fold. These results suggest that in vitro transformation of NIH/3T3 cells by ras may be more similar to multistep in vivo tumor development than previously suspected, involving not only expression of an active oncogene but also loss of a suppressor activity, perhaps induced by the clastogenic oncogene.     

A Second Las17 Monomeric Actin‐Binding Motif Functions in Arp2/3‐Dependent Actin Polymerization During Endocytosis

During clathrin‐mediated endocytosis (CME), actin assembly provides force to drive vesicle internalization. Members of the Wiskott–Aldrich syndrome protein (WASP) family play a fundamental role stimulating actin assembly. WASP family proteins contain a WH2 motif that binds globular actin (G‐actin) and a central‐acidic motif that binds the Arp2/3 complex, thus promoting the formation of branched actin filaments. Yeast WASP (Las17) is the strongest of five factors promoting Arp2/3‐dependent actin polymerization during CME. It was suggested that this strong activity may be caused by a putative second G‐actin‐binding motif in Las17. Here, we describe the in vitro and in vivo characterization of such Las17 G‐actin‐binding motif (LGM) and its dependence on a group of conserved arginine residues. Using the yeast two‐hybrid system, GST‐pulldown, fluorescence polarization and pyrene‐actin polymerization assays, we show that LGM binds G‐actin and is necessary for normal Arp2/3‐mediated actin polymerization in vitro. Live‐cell fluorescence microscopy experiments demonstrate that LGM is required for normal dynamics of actin polymerization during CME. Further, LGM is necessary for normal dynamics of endocytic machinery components that are recruited at early, intermediate and late stages of endocytosis, as well as for optimal endocytosis of native CME cargo. Both in vitro and in vivo experiments show that LGM has relatively lower potency compared to the previously known Las17 G‐actin‐binding motif, WH2. These results establish a second G‐actin‐binding motif in Las17 and advance our knowledge on the mechanism of actin assembly during CME.      

The Sla1 adaptor‐clathrin interaction regulates coat formation and progression of endocytosis

Clathrin‐mediated endocytosis is a fundamental transport pathway that depends on numerous protein‐protein interactions. Testing the importance of the adaptor protein‐clathrin interaction for coat formation and progression of endocytosis in vivo has been difficult due to experimental constrains. Here, we addressed this question using the yeast clathrin adaptor Sla1, which is unique in showing a cargo endocytosis defect upon substitution of 3 amino acids in its clathrin‐binding motif (sla1^AAA) that disrupt clathrin binding. Live‐cell imaging showed an impaired Sla1‐clathrin interaction causes reduced clathrin levels but increased Sla1 levels at endocytic sites. Moreover, the rate of Sla1 recruitment was reduced indicating proper dynamics of both clathrin and Sla1 depend on their interaction. sla1^AAA cells showed a delay in progression through the various stages of endocytosis. The Arp2/3‐dependent actin polymerization machinery was present for significantly longer time before actin polymerization ensued, revealing a link between coat formation and activation of actin polymerization. Ultimately, in sla1^AAA cells a larger than normal actin network was formed, dramatically higher levels of various machinery proteins other than clathrin were recruited, and the membrane profile of endocytic invaginations was longer. Thus, the Sla1‐clathrin interaction is important for coat formation, regulation of endocytic progression and membrane bending.      

Personal Health Promotion

Mortality data on the leading causes of death conceal the relationship to underlying risk factors; if we classified deaths according to risk factors, annually there might be an estimated 350,000 smoking-related deaths, 200,000 alcohol-related deaths and 135,000 nutrition-related cancer deaths. Similarly, five causes of death—heart disease, lung cancer, cirrhosis of the liver, suicide and motor vehicle accidents—contribute most to the risk of dying in the next ten years for a 40-year-old white man. Review of protective factors shows that adopting and maintaining a healthful life-style can contribute to reducing risk. Practicing physicians can assume both direct and indirect roles in promoting personal health maintenance.     

Lifecycle of the bruchid beetle Bruchidius uberatus and its predation of Acacia nilotica seeds in a tree savanna in Botswana

The life cycle of the bruchid beetle Bruchidius uberatus in seeds of Acacia nilotica has been investigated under field and laboratory condition. In contrast to the multivoltine populations in the Sudan, in Botswana most beetles of B. uberatus are univoltine. They emerge from the seed and pod in early spring (October to November). Only a small part of the population, which emerge in late summer (February to March) is multivoltine, as confirmed by rearing experiments. The reproductive activity of females is not stimulated by pollen, as found in feeding experiments. Minimum life-span of adult beetles varies between 4 and 40 days, but it did not differ between univoltine and multivoltine beetles. Other data on life-history are 22 days for hatching of the fist-instar larva at a temperature regime of 20/15 °C (day/night) and 15 days at a temperature regime of 32/15 °C and 3 to 11 months for development from larvae to beetle.During dry storage of seeds B. uberatus can destroy the total amount of stored seeds within a few years. In stored seed pool, host-specificity of larva is low.The life cycles of the Botswana population have been discussed in relation to that of the species in the Sudan.

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Zusammenfassung Der Lebenszyklus des Samenkäfers Bruchidius uberatus in Samen von Acacia nilotica wurde unter Feld- und Laborbedingungen untersucht. Im Gegensatz zu multivoltinen Populationen im Sudan (Peake, 1982) sind die Populationen von B. uberatus in Botswana vor allem univoltin. Adulte Käfer verlassen die Samen von A. nilotica während des Süd-Frühlings (Oktober/November). Im Spätsommer (Februar/März) geschlüpfte Käfer entstammen multivoltinen Genotypen, wie Züchtungsexperimente gezeigt haben. Die reproduktive Aktivität der Weibchen wird nicht durch die Zufuhr von Pollen oder Zucker stimuliert.Die Entwicklungsdauer vom Ei bis zum 1. Larvenstadium beträgt 15 Tage bis 52 und 3 bis 11 Monate bis zum adulten Käfer, deren Lebenserwartung unter Laboratoriumbedingungen 4 bis 40 Tage beträgt. Hierbei besteht kein Unterschied zwischen uni- und multivoltinen Käfern. Der lange Lebenszyklus in Botswana steht im Gegensatz zu dem 40-tägigen Lebenszyklus von B. uberatus im Sudan, der offensichtlich durch die Jahrhunderte andauernde Sammlung von Früchten verursacht ist.Samenvorräte, die zu Forstzwecken längere Zeit aufbewahrt werden, können innerhalb von 5 bis 8 Jahren völlig zerstört werden. Dabei ist die Wirtsspezifität gering. Die Infektion betrifft auch andere Acacia-Arten, z.B. A. burkei, A. erioloba, A. hebeclada, A. mellifera, A. robusta und A. tortilis. Durch die rasche Zerstörung der Embryoachse haben die Käfer keinen positiven Einfluss auf die Keimung dieser hartschaligen Acacia-Samen.

     

Eliciting and integrating expert knowledge to assess the viability of the critically endangered golden sun‐moth Synemon plana

The critically endangered golden sun‐moth Synemon plana occurs in urban fringe areas of southeastern Australia that are currently experiencing rapid and extensive development. The urban fringe is a complex and uncertain environment in which to manage threatened species with the intersection of fragmented natural habitats, built environments and human populations generating novel, poorly understood interactions. In this context, management frameworks must incorporate ecological processes as well as social considerations. Here, we explore how biodiversity sensitive urban design might improve the fate of the golden sun‐moth, and threatened species generally, in urban fringe environments. We: (i) developed an expert‐informed Bayesian Belief Network model that synthesizes the current understanding of key determinants of golden sun‐moth population viability at sites experiencing urbanizing pressure; (ii) quantified the nature and strength of cause‐effect relationships between these factors using expert knowledge; and (iii) used the model to assess expectations of moth population viability in response to different combinations of management actions. We predict that adult survival, bare ground cover and cover of resource plants are the most important variables affecting the viability of golden sun‐moth populations. We also demonstrate the potential for biodiversity sensitive urban design as a complementary measure to conventional management for this species. Our findings highlight how expert knowledge may be a valuable component of conservation management, especially in addressing uncertainty around conservation decisions when empirical data are lacking, and how structured expert judgements become critical in supporting decisions that may help ameliorate extinction risks faced by threatened species in urban environments.