Fosfomycin versus meropenem in bacteraemic urinary tract infections caused by extended-spectrum β-lactamase-producing Escherichia coli (FOREST): study protocol for an investigator-driven randomised controlled trial.

INTRODUCTION Finding therapeutic alternatives to carbapenems in infections caused by extended-spectrum β-lactamase-producing Escherichia coli (ESBL-EC) is imperative. Although fosfomycin was discovered more than 40 years ago, it was not investigated in accordance with current standards and so is not used in clinical practice except in desperate situations. It is one of the so-called neglected antibiotics of high potential interest for the future. METHODS AND ANALYSIS The main objective of this project is to demonstrate the clinical non-inferiority of intravenous fosfomycin with regard to meropenem for treating bacteraemic urinary tract infections (UTI) caused by ESBL-EC. This is a 'real practice' multicentre, open-label, phase III randomised controlled trial, designed to compare the clinical and microbiological efficacy, and safety of intravenous fosfomycin (4 g/6 h) and meropenem (1 g/8 h) as targeted therapy for this infection; a change to oral therapy is permitted after 5 days in both arms, in accordance with predetermined options. The study design follows the latest recommendations for designing trials investigating new options for multidrug-resistant bacteria. Secondary objectives include the study of fosfomycin concentrations in plasma and the impact of both drugs on intestinal colonisation by multidrug-resistant Gram-negative bacilli. ETHICS AND DISSEMINATION Ethical approval was obtained from the Andalusian Coordinating Institutional Review Board (IRB) for Biomedical Research (Referral Ethics Committee), which obtained approval from the local ethics committees at all participating sites in Spain (22 sites). Data will be presented at international conferences and published in peer-reviewed journals. DISCUSSION This project is proposed as an initial step in the investigation of an orphan antimicrobial of low cost with high potential as a therapeutic alternative in common infections such as UTI in selected patients. These results may have a major impact on the use of antibiotics and the development of new projects with this drug, whether as monotherapy or combination therapy. TRIAL REGISTRATION NUMBER NCT02142751. EudraCT no: 2013-002922-21. Protocol V.1.1 dated 14 March 2014.

Physiologie du chasseur / par Deyeux ; vignettes d'Eugène Forest

Référence bibliographique : Lhéritier, 60

Hyperbolic reaction-diffusion equations for a forest fire model

Forest fire models have been widely studied from the context of self-organized criticality and from the ecological properties of the forest and combustion. On the other hand, reaction-diffusion equations have interesting applications in biology and physics. We propose here a model for fire propagation in a forest by using hyperbolic reaction-diffusion equations. The dynamical and thermodynamical aspects of the model are analyzed in detail

Critical role for the lactate transporter, monocarboxylate transporter 1 (mct1), in the regeneration of peripheral nerves

Axons, and particularly regenerating axons, have high metabolic needs in order to maintain critical functions such as axon transport and membrane depolarization. Though some of the required energy likely comes form extracellular glucose and ATP generated in the soma, we and others hypothesize that some of the energy may be supplied by lactate. Unlike glucose that requires glycolytic enzymes to produce pyruvate, lactate can be converted directly to pyruvate by lactate dehydrogenase and transported into mitochondria for oxidative metabolism. In order to be transported into or out of cells, lactate requires specific monocarboxylate transporters (MCTs), the most abundant of which is MCT1. If MCT1 and lactate are critical for nerve function and regeneration, we hypothesize that MCT1 heterozygote null mice, which appear phenotypically normal despite having approximately 40% MCT1 as compared to wildtype littermate mice, would have reduced capacity for repair following nerve injury. To investigate this, adult MCT1 heterozygote null mice or wild-type mice underwent unilateral sciatic nerve crush in the proximal thigh. We found that regeneration of the sciatic nerve, as measured by recovery of compound muscle action potentials (CMAP) in the lateral plantar muscles following proximal sciatic nerve stimulation, was delayed from a median of 21 days in wildtype mice to 38.5 days in MCT1 heterozygote mice. In fact, half of the MCT1 heterozygote null mice had no recovery of CMAP by the endpoint of the study at 42 days, while all of the wild-type mice had recovered. In addition, the maximal amplitude of CMAP recovery in MCT1 heterozygote mull mice was reduced from a mean of 3 mV to 0.5 mV. As would be expected, the denervated gastrocnemius muscle of MCT1 heterozygote null mice remained atrophic at 42 days compared to wild-type mice. Our experiments show that lactate supplied through MCT1 is necessary for nerve regeneration. Experiments are underway to determine whether loss of MCT1 prevents nerve regrowth directly due to reduced energy supply to axons or indirectly by dysfunctional Schwann cells normally dependent on lactate supply through MCT1.

Small and long non-coding RNAs in cardiac homeostasis and regeneration

Cardiovascular diseases and in particular heart failure are major causes of morbidity and mortality in the Western world. Recently, the notion of promoting cardiac regeneration as a means to replace lost cardiomyocytes in the damaged heart has engendered considerable research interest. These studies envisage the utilization of both endogenous and exogenous cellular populations, which undergo highly specialized cell fate transitions to promote cardiomyocyte replenishment. Such transitions are under the control of regenerative gene regulatory networks, which are enacted by the integrated execution of specific transcriptional programs. In this context, it is emerging that the non-coding portion of the genome is dynamically transcribed generating thousands of regulatory small and long non-coding RNAs, which are central orchestrators of these networks. In this review, we discuss more particularly the biological roles of two classes of regulatory non-coding RNAs, i.e. microRNAs and long non-coding RNAs, with a particular emphasis on their known and putative roles in cardiac homeostasis and regeneration. Indeed, manipulating non-coding RNA-mediated regulatory networks could provide keys to unlock the dormant potential of the mammalian heart to regenerate. This should ultimately improve the effectiveness of current regenerative strategies and discover new avenues for repair. This article is part of a Special Issue entitled: Cardiomyocyte Biology: Cardiac Pathways of Differentiation, Metabolism and Contraction.

Effect of controlled co-delivery of synergistic neurotrophic factors on early nerve regeneration in rats.

Present interventions to repair severed peripheral nerves provide slow and poor early axonal regeneration, which may cause unsatisfactory functional reinnervation. To improve early axonal regeneration in a 10 mm rat sciatic nerve gap model, we developed collagen nerve conduits loaded with the synergistically acting glial cell line-derived neurotrophic factor (GDNF) and nerve growth factor (NGF). For controlling the concomitant GDNF and NGF release, the collagen tubes were cross-linked by a dehydro-thermal treatment (110 degrees C; 20 mbar; 5 days) prior to impregnating the tubes with GDNF and NGF and by coating drug-loaded tubes with layers of poly(lactide-co-glycolide). The conduits made of cross-linked collagen released low initial amounts of GDNF and NGF (2% of both during first 3 days) and enhanced significantly the early (2 weeks) nerve regeneration in terms of axonal outgrowth and Schwann cell migration in a 10 mm rat sciatic nerve gap model, as compared to the conduits made of non-cross-linked collagen releasing higher initial amounts of GDNF and NGF (12-16% within 3 days), or those releasing GDNF alone. The enhancement of early axonal regeneration using controlled co-delivery of multiple synergistic neurotrophic factors is an important requisite for eventually establishing functional connections with the target organ.

Natural Regeneration of Oak in Iowa, December 1998

The oak and oak/hickory forests make up about 46% of Iowa's forestland. Approximately a third of these woodlands have adequate oak regeneration for the woodlands of the future. This report explains what is happening with Iowa's forestland.

Shifts in species and phylogenetic diversity between sapling and tree communities indicate negative density dependence in a lowland rain forest

1. As trees in a given cohort progress through ontogeny, many individuals die. This risk of mortality is unevenly distributed across species because of many processes such as habitat filtering, interspecific competition and negative density dependence. Here, we predict and test the patterns that such ecological processes should inscribe on both species and phylogenetic diversity as plants recruit from saplings to the canopy. 2. We compared species and phylogenetic diversity of sapling and tree communities at two sites in French Guiana. We surveyed 2084 adult trees in four 1-ha tree plots and 943 saplings in sixteen 16-m2 subplots nested within the tree plots. Species diversity was measured using Fisher's alpha (species richness) and Simpson's index (species evenness). Phylogenetic diversity was measured using Faith's phylogenetic diversity (phylogenetic richness) and Rao's quadratic entropy index (phylogenetic evenness). The phylogenetic diversity indices were inferred using four phylogenetic hypotheses: two based on rbcLa plastid DNA sequences obtained from the inventoried individuals with different branch lengths, a global phylogeny available from the Angiosperm Phylogeny Group, and a combination of both. 3. Taxonomic identification of the saplings was performed by combining morphological and DNA barcoding techniques using three plant DNA barcodes (psbA-trnH, rpoC1 and rbcLa). DNA barcoding enabled us to increase species assignment and to assign unidentified saplings to molecular operational taxonomic units. 4. Species richness was similar between saplings and trees, but in about half of our comparisons, species evenness was higher in trees than in saplings. This suggests that negative density dependence plays an important role during the sapling-to-tree transition. 5. Phylogenetic richness increased between saplings and trees in about half of the comparisons. Phylogenetic evenness increased significantly between saplings and trees in a few cases (4 out of 16) and only with the most resolved phylogeny. These results suggest that negative density dependence operates largely independently of the phylogenetic structure of communities. 6. Synthesis. By contrasting species richness and evenness across size classes, we suggest that negative density dependence drives shifts in composition during the sapling-to-tree transition. In addition, we found little evidence for a change in phylogenetic diversity across age classes, suggesting that the observed patterns are not phylogenetically constrained.

Earthquake impacts in old-growth Nothofagus forests in New Zealand

Six stands located on different land forms in mixed old-growth Nothofagus forests in the Matiri Valley (northwest of South Island. New Zealand) were sampled to examine the effects of two recent large earthquakes on tree establishment and tree-ring growth, and how these varied across land forms. 50 trees were cor ed in each stand to determine age structure and the cores were cross-dated to precisely date unusual periods of radial growth. The 1968 earthquake (M = 7.1, epicentre 35 km from the study area) had no discernible impact on the sampled stands. The impact of the 1929 earthquake (M = 7.7, epicentre 20 kin from the study area) varied between stands, depending on whether or not they had been damaged by soil or rock movement. In all stands, the age structures showed a pulse of N. fusca establishment following the 1929 earthquake, with this species dominating establishment in large gaps created by landslides. Smaller gaps, created by branch or tree death, were closed by both N. fusca and N. menziesii. The long period of releases (1929-1945) indicates that direct earthquake damage was not the only cause of tree death, and that many trees died subsequently most likely of pathogen attack or a drought in the early 1930s. The impacts of the 1929 earthquake are compared to a storm in 1905 and a drought in 1974-1978 which also affected forests in the region. Our results confirm that earthquakes are an important factor driving forest dynamics in this tectonically active region, and that the diversity of earthquake impacts is a major source of heterogeneity in forest structure and regeneration.

Thermal energetics of the New-Guinean moss-forest rat (Rattus niobe) in comparison with other tropical murid rodents.

The thermal energetics of rodents from cool, wet tropical highlands are poorly known. Metabolic rate, body temperature and thermal conductance were measured in the moss-forest rat, Rattus niobe (Rodentia), a small murid endemic to the highlands of New Guinea. These data were evaluated in the context of the variation observed in the genus Rattus and among tropical murids. In 7 adult R. niobe, basal metabolic rate (BMR) averaged 53.6±6.6mLO2h(-1), or 103% of the value predicted for a body mass of 42.3±5.8g. Compared to other species of Rattus, R. niobe combines a low body temperature (35.5±0.6°C) and a moderately low minimal wet thermal conductance cmin (5.88±0.7mLO2h(-1)°C(-1), 95% of predicted) with a small size, all of which lead to reduced energy expenditure in a constantly cool environment. The correlations of mean annual rainfall and temperature, altitude and body mass with BMR, body temperature and cmin were analyzed comparatively among tropical Muridae. Neither BMR, nor cmin or body temperature correlated with ambient temperature or altitude. Some of the factors which promote high BMR in higher latitude habitats, such as seasonal exposure to very low temperature and short reproductive season, are lacking in wet montane tropical forests. BMR increased with rainfall, confirming a pattern observed among other assemblages of mammals. This correlation was due to the low BMR of several desert adapted murids, while R. niobe and other species from wet habitats had a moderate BMR.

Wound repair and regeneration.

The repair of wounds is one of the most complex biological processes that occur during human life. After an injury, multiple biological pathways immediately become activated and are synchronized to respond. In human adults, the wound repair process commonly leads to a non-functioning mass of fibrotic tissue known as a scar. By contrast, early in gestation, injured fetal tissues can be completely recreated, without fibrosis, in a process resembling regeneration. Some organisms, however, retain the ability to regenerate tissue throughout adult life. Knowledge gained from studying such organisms might help to unlock latent regenerative pathways in humans, which would change medical practice as much as the introduction of antibiotics did in the twentieth century.

A new spot-thoraxed species of Drosophila from the Atlantic Forest of southeastern Brazil (Diptera, Drosophilidae)

Drosophila boraceia sp. nov. is described from a single male specimen collected at the Estação Biológica de Boracéia, Salesópolis, state of São Paulo, Brazil. At first inspection it looks like a species of Drosophila belonging to the fasciola subgroup of the repleta group, mainly because of the fasciola-like pattern of fused spots on the thorax. However, mostly due to the quite distinct structures of the male terminalia, it seems to be more similar to one ungrouped and also spot-thoraxed South American species, Drosophila atalaia Vilela & Sene, 1982. Illustrations of the terminalia are also provided.

Activities of tabanids (Diptera, Tabanidae) attacking domestic duck-Cairina moschata (Linnaeus) (Aves, Anatidae), introduced in a forest area in the Central Amazon, Manaus, Brazil

Presented here are the feeding habits, attack behavior, daily and annual activity of adult of Phorcotabanus cinereus (Wiedeman, 1821), Chrysops laetus (Fabricius, 1805) and Phaeotabanus cajennensis (Fabricius, 1787), while biting a domestic duck, Cairina moschata (Linnaeus, 1758). The last two species were recorded for the first time attacking birds. This study comprehended monthly observations of two consecutive days from April/97 to March/98 between 5:30 a.m. and 6:30 p.m. at the Army Instructional Base ((BI-2/CIGS) near Manaus. Annual occurrence of P. cinereus was from July to September, with a daily occurrence between 9:00 a.m. and 5:00 p.m. and highest activity at 12:00 a.m. and 2:00 p.m. C. laetus ocurred from June to October; with a daily occurrence between 8:00 a.m. and 3 p.m. and highest activity at 11:00 and 12:00 a.m. Occurrence of P. cajennensis with one specimen only, was in July between 10:00 and 11:00 a.m.

Thyroid hormone in biodegradable nerve guides stimulates sciatic nerve regeneration: a potential therapeutic approach for human peripheral nerve injuries.

It has been already demonstrated that thyroid hormone (T3) is one of the most important stimulating factors in peripheral nerve regeneration. We have recently shown that local administration of T3 in silicon tubes at the level of the transected rat sciatic nerve enhanced axonal regeneration and improved functional recovery. Silicon, however, cannot be used in humans because it causes a chronic inflammatory reaction. Therefore, in order to provide future clinical applications of thyroid hormone in human peripheral nerve lesions, we carried out comparative studies on the regeneration of transected rat sciatic nerve bridged either by biodegradable P(DLLA-(-CL) or by silicon nerve guides, both guides filled with either T3 or phosphate buffer. Our macroscopic observation revealed that 85% of the biodegradable guides allowed the expected regeneration of the transected sciatic nerve. The morphological, morphometric and electrophysiological analysis showed that T3 in biodegradable guides induces a significant increase in the number of myelinated regenerated axons (6862 +/- 1831 in control vs. 11799 +/- 1163 in T3-treated). Also, T3 skewed the diameter of myelinated axons toward larger values than in controls. Moreover, T3 increases the compound muscle action potential amplitude of the flexor and extensor muscles of the treated rats. This T3 stimulation in biodegradable guides was equally well to that obtained by using silicone guides. In conclusion, the administration of T3 in biodegradable guides significantly improves sciatic nerve regeneration, confirming the feasibility of our technique to provide a serious step towards future clinical application of T3 in human peripheral nerve injuries.