Mild hypothermia prevents cerebral edema and CSF lactate accumulation in acute liver failure

Evidence from both clinical and experimental studies demonstrates that mild hypothermia prevents encephalopathy and brain edema in acute liver failure (ALF). As part of a series of studies to elucidate the mechanism(s) involved in this protective effect, groups of rats with ALF resulting from hepatic devascularization were maintained at either 37°C (normothermic) or 35°C (hypothermic), and neurological status was monitored in relation to cerebrospinal fluid (CSF) concentrations of ammonia and lactate. CSF was removed via implanted cisterna magna catheters. Mild hypothermia resulted in a delay in onset of encephalopathy and prevention of brain edema; CSF concentrations of ammonia and lactate were concomitantly decreased. Blood ammonia concentrations, on the other hand, were not affected by hypothermia in ALF rats. These findings suggest that brain edema and encephalopathy in ALF are the consequence of ammonia-induced impairment of brain energy metabolism and open the way for magnetic resonance spectroscopic monitoring of cerebral function in ALF. Mild hypothermia could be beneficial in the prevention of severe encephalopathy and brain edema in patients with ALF awaiting liver transplantation.CIH

L-ornithine-L-aspartate in experimental portal-systemic encephalopathy: therapeutic efficacy and mechanism of action

Strategies aimed at the lowering of blood ammonia remain the treatment of choice in portal-systemic encephalopathy (PSE). L-ornithine-L-aspartate (OA) has recently been shown to be effective in the prevention of ammonia-precipitated coma in humans with PSE. These findings prompted the study of mechanisms of the protective effect of OA in portacaval-shunted rats in which reversible coma was precipitated by ammonium acetate administration (3.85 mmol/kg i.p.). OA infusions (300 mg/kg/h, i.v) offered complete protection in 12/12 animals compared to 0/12 saline-infused controls. This protective effect was accompanied by significant reductions of blood ammonia, concomitant increases of urea production and significant increases in blood and cerebrospinal fluid (CSF) glutamate and glutamine. Increased CSF concentrations of leucine and alanine also accompanied the protective effect of OA. These findings demonstrate the therapeutic efficacy of OA in the prevention of ammonia-precipitated coma in portacaval-shunted rats and suggest that this protective effect is both peripherally-mediated (increased urea and glutamine synthesis) and centrally-mediated (increased glutamine synthesis)

Density‑dependent winter survival of immatures in an irruptive raptor with pulsed breeding

Highly mobile predators can show strong numerical responses to pulsed resources, sometimes resulting in irruptions where large numbers of young invade landscapes at a continental scale. High production of young in irruption years may have a strong influence on the population dynamics unless immature survival is reduced compared to non-irruption years. This could occur if subordinate individuals (mainly immatures) are forced into suboptimal habitats due to density-dependent effects in irruption years. To test whether irruptive individuals had lower survival than non-irruptive ones, we combined necropsy results (N = 365) with telemetry (N = 185) from more than 20 years to record timing and causes of mortality in snowy owls (Bubo scandiacus), which irrupt into eastern North America during winter following high breeding output caused by lemming peaks in the Arctic. Mortality was more than four times higher in irruption years than non-irruption years, but only for immatures, and occurred disproportionately in early winter for immatures, but not adults. Mortality was also higher in eastern North America, where owl abundance fluctuates considerably between years, compared to core winter regions of the Arctic and Prairies where populations are more stable. Most mortality was not due to starvation, but rather associated with human activity, especially vehicle collisions. We conclude that immature snowy owls that irrupt into eastern North America are limited by density-dependent factors, such as increased competition forcing individuals to occupy risky human-altered habitats. For highly mobile, irruptive animals, resource pulses may have a limited impact on population dynamics due to low subsequent survival of breeding output during the nonbreeding season.publishedVersio

Le FORUM, Vol. 37 No. 4

https://digitalcommons.library.umaine.edu/francoamericain_forum/1039/thumbnail.jp

Negative feedback regulation of the ERK1/2 MAPK pathway

The extracellular signal-regulated kinase 1/2 (ERK1/2) mitogen-activated protein kinase (MAPK) signalling pathway regulates many cellular functions, including proliferation, differentiation, and transformation. To reliably convert external stimuli into specific cellular responses and to adapt to environmental circumstances, the pathway must be integrated into the overall signalling activity of the cell. Multiple mechanisms have evolved to perform this role. In this review, we will focus on negative feedback mechanisms and examine how they shape ERK1/2 MAPK signalling. We will first discuss the extensive number of negative feedback loops targeting the different components of the ERK1/2 MAPK cascade, specifically the direct posttranslational modification of pathway components by downstream protein kinases and the induction of de novo gene synthesis of specific pathway inhibitors. We will then evaluate how negative feedback modulates the spatiotemporal signalling dynamics of the ERK1/2 pathway regarding signalling amplitude and duration as well as subcellular localisation. Aberrant ERK1/2 activation results in deregulated proliferation and malignant transformation in model systems and is commonly observed in human tumours. Inhibition of the ERK1/2 pathway thus represents an attractive target for the treatment of malignant tumours with increased ERK1/2 activity. We will, therefore, discuss the effect of ERK1/2 MAPK feedback regulation on cancer treatment and how it contributes to reduced clinical efficacy of therapeutic agents and the development of drug resistance

La nuit inuit (vécu et représentations de la nuit chez les Inuit du nord de la Terre de Baffin (Nunavut, Arctique canadien))

Décrire la nuit quotidienne des Inuit de l Arctique canadien vivant au nord de la Terre de Baffin, donner à lire et à comprendre leurs points de vue sur l espace-temps nocturne, tenter de cerner et d analyser les singularités de cette nuit tant au niveau du vécu que des représentations, sans négliger les éléments comparatifs provenant d autres aires culturelles, voilà les principaux objectifs assignés à cette recherche. L attention à la parole inuit traverse l ensemble de la recherche. Voie privilégiée sous divers aspects, elle l inscrit dans une démarche de type ethnolinguistique. Organise e en trois parties, la thèse présente dans un premier temps le cadre nocturne : nuit arctique, nuit au quotidien, cosmogonies, notions d obscurité et de lumière. Puis, le vécu de la nuit est analysé à l état de veille : influences et propriétés attribuées à la nuit sur la naissance, la maladie et la mort, sur les déplacements et la chasse, sur les rituels, les cérémoniels et les fêtes, ainsi que sur la peur. Enfin, le vécu de la nuit est envisagé dans son versant endormi : ethnographie du sommeil, expériences oniriques et esquisse d une théorie du sommeil. Ces analyses, menées dans une perspective diachronique, mettent en évidence l existence, chez les Inuit, de complémentarités et de continuums qui marquent les couples nuit/jour et obscurité/ lumière, lesquels sont éloignés des schèmes binaires ou dualistes qui sont les nôtres, mais que la pensée inuit tend à rejeter. Au-delà de la spécificité inuit, le présent travail se veut une contribution à une réflexion comparative et pluridisciplinaire, amorcée il y a plusieurs années à l Université Paris Ouest Nanterre La Défense, sur ce que pourrait être une anthropologie de la nuit.The objectives of this work are to describe the daily night of the Inuit living in Northern Baffin Island (Nunavut, Arctic Canada), to allow a reading and understanding of the Inuit own points of view on nocturnal space-time, and hence to try to grasp and analyse the singularities of this night at the level of both experiences and representations. As often as possible, comparative data emanating from other cultural areas has been included. An emphasis is put on language and the spoken word, which permeates through all of the research, fitting it into an ethnolinguistic approach. Structured in three parts, the work presents first the nocturnal framework: Arctic night, day-to-day night, cosmogonies, notions of darkness and light. Then the night experience is analysed while in the state of wakefulness: influences and properties attributed to the night relating to birth, disease and death, to travelling and hunting, to rituals, ceremonies and festivals, and to fear. Finally the night experience is considered in the state of sleep: ethnography of sleep, dream experiences, sketching of a theory of sleep. These analyses, carried out diachronically, highlight the complementarities and continuums which characterize the night/day and darkness/light pairings, which do not match the binary or dualistic schemes that are our own and that Inuit thought tends to reject. Beyond its specificity to the Inuit, this work is also a contribution to a comparative and multidisciplinary reflection, started several years ago at the University Paris Ouest Nanterre La Défense, on what could be an anthropology of the night.NANTERRE-BU PARIS10 (920502102) / SudocSudocFranceF

Deletion of C9ORF72 Results in Motor Neuron Degeneration and Stress Sensitivity in <i>C. elegans</i>

<div><p>An expansion of the hexanucleotide GGGGCC repeat in the first intron of <i>C9ORF72</i> gene was recently linked to amyotrophic lateral sclerosis. It is not known if the mutation results in a gain of function, a loss of function or if, perhaps both mechanisms are linked to pathogenesis. We generated a genetic model of ALS to explore the biological consequences of a null mutation of the <i>Caenorhabditis elegans C9ORF72</i> orthologue, <i>F18A1.6</i>, also called <i>alfa-1</i>. <i>alfa-1</i> mutants displayed age-dependent motility defects leading to paralysis and the specific degeneration of GABAergic motor neurons. <i>alfa-1</i> mutants showed differential susceptibility to environmental stress where osmotic stress provoked neurodegeneration. Finally, we observed that the motor defects caused by loss of <i>alfa-1</i> were additive with the toxicity caused by mutant TDP-43 proteins, but not by the mutant FUS proteins. These data suggest that a loss of <i>alfa-1/C9ORF72</i> expression may contribute to motor neuron degeneration in a pathway associated with other known ALS genes.</p> </div

Genetic interactions between <i>alfa-1(ok3062)</i>, <i>TDP-43</i>, and FUS.

<div><p>(A) <i>TDP-43</i>^<i>A315T</i>; <i>alfa-1(ok3062)</i> worms had a higher rate of paralysis that either <i>TDP-43</i>^<i>A315T</i> or <i>alfa-1(ok3062)</i> worms alone (P<0.005).</p> <p>(B) <i>FUS</i>^S57∆ worms, <i>alfa-1(ok3062)</i> worms, and <i>FUS</i>^S57∆; <i>alfa-1(ok3062)</i> worms showed similar rates of paralysis.</p></div

ALFA-1 is the orthologue of C9ORF72 in <i>C. elegans</i>.

<div><p>(A) Protein sequence alignment using Clustal W and BoxShade of C9ORF72 isoform 1 and ALFA-1 isoform 1. Overall, these sequences share 26% identify and 59 % similarity. </p> <p>(B) ALFA-1 has two predicted transcripts and the <i>ok3062</i> deletion mutation spans exons 3 and 4 for both transcripts.</p> <p>(B) RT-PCR confirming the complete loss of expression of the <i>alfa-1</i> transcripts. <i>act-3</i> was used as a control.</p></div