Effects of sildenafil on maximum walking time in patients with arterial claudication: The ARTERIOFIL study

BACKGROUND: Patients with lower extremity peripheral artery disease (PAD) frequently experience claudication, a clinical symptom indicative of reduced walking capacity. Recommended care consists of exercise rehabilitation combined with optimal medical treatment and surgery. The effects of a single oral dose of sildenafil, a phosphodiesterase type-5 inhibitor, on patients with claudication are discussed. The aim of this study was to test the efficacy of a single 100 mg dose of sildenafil compared to placebo in terms of maximal walking time (MWT) in patients with claudication. METHODS: The ARTERIOFIL study is a crossover, double-blind, prospective, randomized, single-center study conducted at Angers University Hospital in France. MWT (primary endpoint) was assessed using a treadmill test (10% incline; 3.2 km/h). Secondary endpoints (pain-free walking time (PFWT), transcutaneous oximetry during exercise and redox cycle parameters and safety) were also studied. RESULTS: Fourteen patients were included of whom two were ultimately excluded. In the 12 remaining patients, the MWT was significantly improved during the sildenafil period compared with the placebo period (300 s [95% CI 172 s-428 s] vs 402 s [95% CI 274 s-529 s] p < 0.01). Sildenafil had no significant effect on pain-free walking time or skin tissue oxygenation during exercise. According to redox cycle parameters, sildenafil significantly reduced blood glucose and pyruvate levels and the 3-hydroxybutyrate/acetoacetate ratio, while there was no significant effect on lactate, 3-hydroxybutyrate, acetoacetate and free fatty acid levels. Symptomatic transient hypotension was observed in two women. CONCLUSIONS: The ARTERIOFIL study has shown that a single 100 mg oral dose of sildenafil had a significant effect on increase in MWT but had no significant effects on PFWT and oxygenation parameters in patients with claudication. A double-blind, prospective, randomized, multicenter study (VIRTUOSE©) is ongoing to evaluate the chronic effect of six month-long sildenafil treatment on MWT in PAD patients with claudication. CLINICAL TRIAL REGISTRATION: This clinical trial was registered at clinicaltrials.gov, registration. number: NCT02832570, (https://clinicaltrials.gov/ct2/show/NCT02832570)

The H19 gene: regulation and function of a non-coding RNA

The H19 gene encodes a 2.3-kb non-coding mRNA which is strongly expressed during embryogenesis. This gene belongs to an imprinted cluster, conserved on mouse chromosome 7 and human chromosome 11p15. H19 is maternally expressed and the neighbouring Igf2 gene is transcribed from the paternal allele. These two genes are co-expressed in endoderm- and mesoderm-derived tissues during embryonic development, which suggests a common mechanism of regulation. The regulatory elements (imprinted control region, CTCF insulation, different enhancer sequences, promoters of the two genes, matrix attachment regions) confer a differential chromatin architecture to the two parental alleles leading to reciprocal expression. The role of the H19 gene is unclear but different aspects have been proposed. H19 influences growth by way of a cis control on Igf2 expression. Although H19(-/-) mice are viable, a role for this gene during development has been suggested by viable H19(-/-) parthenogenetic mice. Finally it has been described as a putative tumour suppressor gene. H19 has been studied by numerous laboratories over the last fifteen years, nevertheless the function of this non-coding RNA remains to be elucidated

Conserved Domains of the Nullo Protein Required for Cell-Surface Localization and Formation of Adherens Junctions

During cellularization, the Drosophila melanogaster embryo undergoes a transition from syncytial to cellular blastoderm with the de novo generation of a polarized epithelial sheet in the cortex of the embryo. This process couples cytokinesis with the establishment of apical, basal, and lateral membrane domains that are separated by two spatially distinct adherens-type junctions. In nullo mutant embryos, basal junctions fail to form at the onset of cellularization, leading to the failure of cleavage furrow invagination and the generation of multinucleate cells. Nullo is a novel protein that appears to stabilize the initial accumulation of cadherins and catenins as they form a mature basal junction. In this article we characterize a nullo homologue from D. virilis and identify conserved domains of Nullo that are required for basal junction formation. We also demonstrate that Nullo is a myristoylprotein and that the myristate group acts in conjunction with a cluster of basic amino acids to target Nullo to the plasma membrane. The membrane association of Nullo is required in vivo for its role in basal junction formation and for its ability to block apical junction formation when ectopically expressed during late cellularization

The Hot Serial Cereal Experiment for modeling wheat response to temperature: Field experiments and AgMIP-Wheat multi-model simulations.

The data set reported here includes the part of a Hot Serial Cereal Experiment (HSC) experiment recently used in the AgMIP-Wheat project to analyze the uncertainty of 30 wheat models and quantify their response to temperature. The HSC experiment was conducted in an open-field in a semiarid environment in the southwest USA. The data reported herewith include one hard red spring wheat cultivar (Yecora Rojo) sown approximately every six weeks from December to August for a two-year period for a total of 11 planting dates out of the 15 of the entire HSC experiment. The treatments were chosen to avoid any effect of frost on grain yields. On late fall, winter and early spring plantings temperature free-air controlled enhancement (T-FACE) apparatus utilizing infrared heaters with supplemental irrigation were used to increase air temperature by 1.3°C/2.7°C (day/night) with conditions equivalent to raising air temperature at constant relative humidity (i.e. as expected with global warming) during the whole crop growth cycle. Experimental data include local daily weather data, soil characteristics and initial conditions, detailed crop measurements taken at three growth stages during the growth cycle, and cultivar information. Simulations include both daily in-season and end-of-season results from 30 wheat models

Complement factor H: using atomic resolution structure to illuminate disease mechanisms.

Complement Factor H has recently come to the fore with variant forms implicated in a range of serious disease states. This review aims to bring together recent data concerning the structure and biological activity of this molecule to highlight the way in which a molecular understanding of function may open novel therapeutic possibilities. In particular we examine the evidence for and against the hypothesis that sequence variations in factor H may predispose to disease if they perturb its ability to recognise and respond appropriately to polyanionic carbohydrates on host surfaces that require protection from complement-mediated damage

Statistical analysis of large simulated yield datasets for studying climate effects.

Many simulation studies have been carried out to predict the effect of climate change on crop yield. Typically, in such study, one or several crop models are used to simulate series of crop yield values for different climate scenarios corresponding to different hypotheses of temperature, CO2 concentration, and rainfall changes. These studies usually generate large datasets including thousands of simulated yield data. The structure of these datasets is complex because they include series of yield values obtained with different mechanistic crop models for different climate scenarios defined from several climatic variables (temperature, CO2 etc.). Statistical methods can play a big part for analyzing large simulated crop yield datasets, especially when yields are simulated using an ensemble of crop models. A formal statistical analysis is then needed in order to estimate the effects of different climatic variables on yield, and to describe the variability of these effects across crop models. Statistical methods are also useful to develop meta-models i.e., statistical models summarizing complex mechanistic models. The objective of this paper is to present a random-coefficient statistical model (mixed-effects model) for analyzing large simulated crop yield datasets produced by the international project AgMip for several major crops. The proposed statistical model shows several interesting features; i) it can be used to estimate the effects of several climate variables on yield using crop model simulations, ii) it quantities the variability of the estimated climate change effects across crop models, ii) it quantifies the between-year yield variability, iv) it can be used as a meta-model in order to estimate effects of new climate change scenarios without running again the mechanistic crop models. The statistical model is first presented in details, and its value is then illustrated in a case study where the effects of climate change scenarios on different crops are compared. See more from this Division: Special Sessions See more from this Session: Symposium--Perspectives on Climate Effects on Agriculture: The International Efforts of AgMI

Soil nitrogen mineralisation simulated by crop models across different environments and the consequences for model improvment

Soil nitrogen mineralisation simulated by crop models across different environments and the consequences for model improvment. iCROPM2016 International Crop Modelling Symposiu