Saccharomyces boulardii CNCM I-745 changes lipidemic profile and gut microbiota in a hamster hypercholesterolemic model.

Hypercholesterolemia is a main risk factor of cardiovascular disease. Probiotics are a safe approach to reduce elevated cholesterol without any deleterious effect to human health. Saccharomyces boulardii CNCM I-745 probiotic properties are well documented in a context of intestinal dysbiosis. Recent in vitro and preclinical studies have suggested its potential effects on dyslipidemia. This is the first controlled study investigating the effects of S. boulardii CNCM I-745 on lipidemic profile and gut microbiota in a hamster hypercholesterolemic model. Daily administration (3 g/kg) of S. boulardii for 21 or 39 days in hamsters fed a 0.3% cholesterol-diet significantly reduced total plasma cholesterol (P<0.001) and increased faecal total cholesterol (P<0.05) compared to vehicle-treated animals. S. boulardii significantly modified the gut microbiota composition of the hamster fed a 0.3% cholesterol-diet. These microbial abundancy modifications of the microbiota were correlated to variations of lipidemic values or liver genes expressions. In particularly we found that abundance of g_Allobaculum, the most modified taxon after S. boulardii treatment (+236%; P<0.05), was correlated to variations in plasmatic lipoproteins level and ABCG5 hepatic gene expression. We also observed a not previously described correlation between the levels of g_Oxalobacter in the gut microbiota and total cholesterol plasma concentration. In conclusion, we confirmed the cholesterol-lowering effects of S. boulardii intake and we demonstrated for the first time the S. boulardii effect on gut microbiota in the context of hypercholesterolemia in hamsters. Our results provide new insights for a beneficial and safe approach of hypercholesterolemia treatment and could be considered for clinical development, alone or in addition to conventional treatment.

Emergence and multiple reassortments of French 2015-2016 highly pathogenic H5 avian influenza viruses.

From November 2015 to August 2016, 81 outbreaks of highly pathogenic (HP) H5 avian influenza virus were detected in poultry farms from South-Western France. These viruses were mainly detected in farms raising waterfowl, but also in chicken or guinea fowl flocks, and did not induce severe signs in waterfowl although they did meet the HP criteria. Three different types of neuraminidases (N1, N2 and N9) were associated with the HP H5 gene. Full genomes sequences of 24 H5HP and 6 LP viruses that circulated in the same period were obtained by next generation sequencing, from direct field samples or after virus isolation in SPF embryonated eggs. Phylogenetic analyses of the eight viral segments confirmed that they were all related to the avian Eurasian lineage. In addition, analyses of the "Time of the Most Recent Common Ancestor" showed that the common ancestor of the H5HP sequences from South-Western France could date back to early 2014 (±1 year). This pre-dated the first detection of H5 HP in poultry farms and was consistent with a silent circulation of these viruses for several months. Finally, the phylogenetic study of the different segments showed that several phylogenetic groups could be established. Twelve genotypes of H5HP were detected implying that at least eleven reassortment events did occur after the H5HP cleavage site emerged. This indicates that a large number of co-infections with both highly pathogenic H5 and other avian influenza viruses must have occurred, a finding that lends further support to prolonged silent circulation.

First complete genome sequence of European turkey coronavirus suggests complex recombination history related with US turkey and guinea fowl coronaviruses.

A full-length genome sequence of 27,739  nt was determined for the only known European turkey coronavirus (TCoV) isolate. In general, the order, number and size of ORFs were consistent with other gammacoronaviruses. Three points of recombination were predicted, one towards the end of 1a, a second in 1b just upstream of S and a third in 3b. Phylogenetic analysis of the four regions defined by these three points supported the previous notion that European and American viruses do indeed have different evolutionary pathways. Very close relationships were revealed between the European TCoV and the European guinea fowl coronavirus in all regions except one, and both were shown to be closely related to the European infectious bronchitis virus (IBV) Italy 2005. None of these regions of sequence grouped European and American TCoVs. The region of sequence containing the S gene was unique in grouping all turkey and guinea fowl coronaviruses together, separating them from IBVs. Interestingly the French guinea fowl virus was more closely related to the North American viruses. These data demonstrate that European turkey and guinea fowl coronaviruses share a common genetic backbone (most likely an ancestor of IBV Italy 2005) and suggest that this recombined in two separate events with different, yet related, unknown avian coronaviruses, acquiring their S-3a genes. The data also showed that the North American viruses do not share a common backbone with European turkey and guinea fowl viruses; however, they do share similar S-3a genes with guinea fowl virus.

Sitagliptin promotes macrophage-to-faeces reverse cholesterol transport through reduced intestinal cholesterol absorption in obese insulin resistant CETP-apoB100 transgenic mice.

Dipeptidyl peptidase-4 inhibitors (DPP-4i) improve glycaemic control in type 2 diabetes, but their benefits on reverse cholesterol transport (RCT) remain unknown. We evaluated the effects of DPP-4i sitagliptin 500 mg/kg/day on RCT in obese insulin-resistant CETP-apoB100 transgenic mice. Metformin 300 mg/kg/day orally was used as a reference compound. Both metformin and sitagliptin showed the expected effects on glucose parameters. Although no significant effect was observed on total cholesterol and high-density lipoprotein (HDL) cholesterol levels, sitagliptin, but not metformin, increased faecal cholesterol mass excretion by 132% (p < 0.001 vs. vehicle), suggesting a potent effect on cholesterol metabolism. Mice were then injected i.p. with (3) H-cholesterol labelled macrophages to measure RCT over 48 h. Compared with vehicle, sitagliptin significantly increased macrophage-derived (3) H-cholesterol faecal excretion by 39%. Administration of (14) C-cholesterol labelled olive oil orally showed a significant reduction of (14) C-tracer plasma appearance over time with sitagliptin, indicating that this drug promotes RCT through reduced intestinal cholesterol absorption.

Use of recombinant factor VIIa (NovoSeven(®)) in 8 patients with ongoing life-threatening bleeding treated with fondaparinux.

BACKGROUND: Fondaparinux has a favourable efficacy-safety profile but if major bleeding occurs, reversal of antithrombotic treatment is challenging. We present clinical and biological observations from patients treated with rFVIIa for bleeding under fondaparinux. METHODS: Fondaparinux-treated patients with bleeding (>10% haematocrit decrease) and cardiovascular collapse were eligible. Patients received a single 90 µg/kg bolus rFVIIa. Clinical success was defined as clinical bleeding control without thrombotic complication. A biological criterion of successful antagonization was defined as a >100% increase in peak thrombin generation (C(max)). RESULTS: 8 patients were treated (5 ACS, 3 VTE). Patients received aspirin and clopidogrel (n = 5), eptifibatide (n = 2), fluindione (n = 5). In addition to standard haemostatic methods, all patients received rFVIIa and transfusion. Clinical progression was favourable in 4, with bleeding clinically controlled in <6 h. 1 patient died. Biological success was observed in 4 patients with lowest baseline anti-Xa (0.67-0.92 U/L); ¾ had clinical success. In patients with baseline anti-Xa >1.0 U/L (1.14-1.62 U/L), increase in C(max) was low; ¾ had no clinical bleeding control. CONCLUSION: This series is the largest describing rFVIIa use to control bleeding in patients under fondaparinux. rVFIIa was considered efficient in 50%, suggesting inefficacy in the context of elevated anti-Xa.

First full-length sequences of the S gene of European isolates reveal further diversity among turkey coronaviruses.

An increasing incidence of enteric disorders clinically suggestive of the poult enteritis complex has been observed in turkeys in France since 2003. Using a newly designed real-time reverse transcriptase-polymerase chain reaction assay specific for the nucleocapsid (N) gene of infectious bronchitis virus (IBV) and turkey coronaviruses (TCoV), coronaviruses were identified in 37% of the intestinal samples collected from diseased turkey flocks. The full-length spike (S) gene of these viruses was amplified, cloned and sequenced from three samples. The French S sequences shared 98% identity at both the nucleotide and amino acid levels, whereas they were at most 65% and 60% identical with North American (NA) TCoV and at most 50% and 37% identical with IBV at the nucleotide and amino acid levels, respectively. Higher divergence with NA TCoV was observed in the S1-encoding domain. Phylogenetic analysis based on the S gene revealed that the newly detected viruses form a sublineage genetically related with, but significantly different from, NA TCoV. Additionally, the RNA-dependent RNA polymerase gene and the N gene, located on the 5' and 3' sides of the S gene in the coronavirus genome, were partially sequenced. Phylogenetic analysis revealed that both the NA TCoV and French TCoV (Fr TCoV) lineages included some IBV relatives, which were however different in the two lineages. This suggested that different recombination events could have played a role in the evolution of the NA and Fr TCoV. The present results provide the first S sequence for a European TCoV. They reveal extensive genetic variation in TCoV and suggest different evolutionary pathways in North America and Europe.

Phylogeny and genotyping of recent avian low-pathogenic H5 subtype influenza viruses from French ducks.

H5 low-pathogenic avian influenza virus (LPAIV) has the potential to become highly pathogenic and to cause serious problems in animal and public health. AIV surveillance and characterization in both wild and domestic species is therefore necessary. In order to acquire molecular information and to identify possible reassortments in French viruses, we analysed the entire genome of five H5N3, three H5N2 and two H5N1 LPAIV, isolated in France between 2002 and 2008 mostly from captive ducks (free-range commercial poultry or decoy ducks). Some of the genome sequences showed atypical characteristics, such as an insertion of 1 aa in the PB1 protein of one H5N3, a highly truncated PB1-F2 protein (11 aa in length instead of 90 aa) in one H5N2, and an insertion of 8 aa in the NS1 protein of H5N1. These two last molecular characteristics have not been described previously. Phylogenetic analysis demonstrated that all genes of French LPAIV, except the closely related matrix protein genes, clustered within the Eurasian avian influenzavirus lineage and fell into at least two phylogenetic subgroups. In addition, the French H5 LPAIV were segregated into eight genotypes, suggesting that many reassortment events have occurred in H5 LPAIV in Europe. However, it is not known whether the reassortment events have occurred in wild waterfowl and/or in captive birds in direct or indirect contact with wild birds.

Metabolism of high density lipoprotein apolipoprotein A-I and cholesteryl ester in insulin resistant dog: a stable isotope study.

AIMS: In reverse cholesterol transport (RCT), hepatic Scavenger Receptor class B type I (SR-BI) plays an important role by mediating the selective uptake of high-density lipoprotein cholesteryl ester (HDL-CE). However, little is known about this antiatherogenic mechanism in insulin resistance. HDL-CE selective uptake represents the main process for HDL-CE turnover in dog, a species lacking cholesteryl ester transfer protein activity. We therefore investigate the effects of diet induced insulin resistance on RCT. METHODS: Five beagle dogs, in healthy and insulin resistant states, underwent a primed constant infusion of [1,2(13)C(2)]acetate and [5,5,5-(2)H(3)]leucine, as labelled precursors of CE and apolipoprotein (apo) A-I, respectively. Data were analysed using modelling methods. RESULTS: HDL-apo A-I concentration did not change in insulin resistant state but apo A-I absolute production rate (APR) and fractional catabolic rate (FCR) were both higher (2.2- and 2.4-fold, respectively, p < 0.05). HDL-CE levels were lower (1.2-fold, p < 0.05). HDL-CE APR and FCR were both lower (2.3- and 2-fold, respectively, p < 0.05), as well as selective uptake (2.6-fold, p < 0.05). CONCLUSIONS: Lower HDL-CE selective uptake suggests that RCT is impaired in obese insulin resistant dog.

Effects of atorvastatin on high-density lipoprotein apolipoprotein A-I metabolism in dogs.

BACKGROUND: The mechanisms involved in the decline of high-density lipoprotein (HDL) levels at a higher dose of atorvastatin have not yet been elucidated. We investigated the effects of atorvastatin on HDL-apolipoprotein (apo) A-I metabolism in dogs, a species lacking cholesteryl ester transfer protein activity. MATERIALS AND METHODS: Seven ovariectomized normolipidaemic female Beagle dogs underwent a primed constant infusion of [5,5,5-(2)H(3)] leucine to determine HDL-apo A-I kinetics before and after atorvastatin treatment (5 mg kg(-1) d(-1) for 6 weeks). Plasma lipoprotein profiles, activity of HDL-modifying enzymes involved in reverse cholesterol transport and hepatic scavenger receptor class B type I (SR-BI) expression were also studied. RESULTS: Atorvastatin treatment decreased HDL-cholesterol levels (3.56 +/- 0.24 vs. 2.64 +/- 0.15 mmol L(-1), P < 0.05). HDL-triglycerides were not affected. HDL-phospholipids levels were decreased (4.28 +/- 0.13 vs. 3.29 +/- 0.13 mmol L(-1), P < 0.05), as well as phospholipids transfer protein (PLTP) activity (0.83 +/- 0.05 vs. 0.60 +/- 0.05 pmol microL(-1) min(-1), P < 0.05). Activity of lecithin: cholesterol acyl transferase (LCAT), hepatic lipase (HL) and SR-BI expression did not change. HDL-apo A-I absolute production rate (APR) was higher after treatment (twofold, P < 0.05) as well as fractional catabolic rate (FCR) (threefold, P < 0.05). This resulted in lower HDL-apo A-I levels (2.36 +/- 0.03 vs. 1.55 +/- 0.04 g l(-1), P < 0.05). Plasma lipoprotein profiles showed a decrease in large HDL(1) levels, with lower apo A-I and higher apo E levels in this subfraction. CONCLUSIONS: Although a high dose of atorvastatin up-regulated HDL-apo A-I production, this drug also increased HDL-apo A-I FCR in dogs. This effect could be explained by a higher uptake of apo E-enriched HDL(1) by hepatic lipoprotein receptors.

Metabolism of cholesterol ester of apolipoprotein B100-containing lipoproteins in dogs: evidence for disregarding cholesterol ester transfer.

BACKGROUND: It has been shown that dogs exhibit no cholesterol ester transfer protein (CETP) activity in vitro, in contrast to humans. The aim of our study was to determine modalities of in vivo plasma cholesterol ester turnover in this species, using a kinetic approach with stable isotopes. MATERIALS AND METHODS: Kinetics of very low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) were studied in seven adult male Beagle dogs using a dual isotope approach through endogenous labelling of both their cholesterol moiety and their protein moiety. A primed constant infusion of both [1,2(13)C]acetate and [5,5,5-2H3]leucine enabled us to obtain measurable deuterium enrichments by gas chromatography-mass spectrometry for plasma leucine and apoB100, as well as measurable 13C enrichment by gas chromatography-combustion-isotopic ratio mass spectrometry for unesterified cholesterol and cholesterol ester in the VLDL and LDL. Two identical multicompartmental models (SAAM II) were used together for the analysis of tracer kinetics' data of proteins and cholesterol. RESULTS: Characterization of the apoB100-containing lipoprotein cholesterol ester model allowed determination of kinetic parameters of VLDL and LDL cholesterol ester metabolism. We succeeded in modelling VLDL and LDL cholesterol ester metabolism and apoB100 metabolism simultaneously. Fractional catabolic rate (FCR) of apoB100 and CE had the same values. Introducing cholesterol ester transfer between lipoproteins in the model did not significantly improve the fit. Total VLDL FCR was 2.97 +/- 01.47 h(-1). Approximately one-quarter corresponded to the direct removal of VLDL (0.81 +/- 00.34 h(-1)) and the remaining three-quarters corresponded to the fraction of VLDL converted to LDL, which represented a conversion of VLDL into LDL of 2.16 +/- 01.16 h(-1). Low-density lipoproteins were produced exclusively from VLDL conversion and were then removed (0.031 +/- 0.004 h(-1)) from plasma. CONCLUSION: These kinetic data showed that VLDL cholesterol ester and LDL cholesterol ester metabolism followed VLDL and LDL apoB100 metabolism, and that consequently there is no in vivo transfer of cholesterol ester in dogs.

[Syncope, conduction disorders. Controversial indications for cardiac stimulation]. / Syncopes, troubles conductifs. Indications discutées de la stimulation cardiaque.

The objective of permanent pacemaker implantation is to provide against an increased risk of death or to improve quality of life by abolishing symptoms. In both cases, certain indications for pacing have clearly demonstrated to be strongly beneficial in well selected patients, but other are still controversial, due to the lack of convincing and converging published data, or to the absence of general consensus among specialists, or because selection criteria for pacing have been poorly defined. We try to clarify when to pace or not to pace in such conditions as first degree AV block, type I second degree AV block, intracardiac conduction defects, including those occurring at the acute stage of myocardial infarct or after cardiac surgery, sick sinus syndrome in cardiac transplant recipients, carotid sinus syndrome, vasovagal syncope, and unexplained syncopes.

[Left intra-atrial membrane without pulmonary vein obstruction: benign condition of progressive evolution? Apropos of 7 cases]. / Membrane intra-auriculaire gauche sans obstruction veineuse pulmonaire: pathologie bénigne ou évolutive? A propos de 7 observations.

Left triatrial heart is defined as division of the left atrium into two chambers, proximal and distal, by a variably perforated membrane. The data of appearance of symptoms, often in early childhood, is related to the degree of obstruction and the presence or not of an inter-atrial shunt. Widescale usage of echocardiography, the investigation of choice for this diagnosis, has led to the detection of this abnormality in older patients, sometimes asymptomatic, without pulmonary hypertension. Three adults were referred for transthoracic and transoesophageal echocardiography to investigate systemic embolic disease (2 cerebral, 1 mesenteric). Two other adults underwent the same investigations for diagnosis of the aetiology of atrial fibrillation with mitral regurgitation. Two cases were asymptomatic children, one with a clinically benign murmur and the other with ventricular extrasystoles with no malignant features. In these seven cases, transthoracic (n = 5) and/or transoesophageal (n = 7) echocardiography demonstrated a left atrial membrane corresponding to the classical description of cor triatrium. The Doppler study showed no obstruction in 6 cases and minimal obstruction in 1 case. In our series, as in similar cases reported in the literature, the diagnosis of a left atrial membrane did not lead to surgery. Although we do not know the long-term outcome of this abnormality in asymptomatic children, the observations of complications in the adult suggest a potential of evolution which poses the question of optimal management.

Environmental correlates of food chain length.

In 113 community food webs from natural communities, the average and maximal lengths of food chains are independent of primary productivity, contrary to the hypothesis that longer food chains should arise when more energy is available at their base. Environmental variability alone also does not appear to constrain average or maximal chain length. Environments that are three dimensional or solid, however, such as a forest canopy or the water column of the open ocean, have distinctly longer food chains than environments that are two dimensional or flat, such as a grassland or lake bottom.

Trophic links of community food webs.

This report describes and explains regularities in the numbers and kinds of trophic links in community food webs. To a first approximation, the mean number of trophic links in a community food web is proportional to the total number of trophic species. The mean number of trophic links between any two categories of trophic species (basal, intermediate, and top) is proportional to the geometric mean number of species in the categories joined. These linear relationships, and scale-invariance in the proportions of basal, intermediate, and top species, make it possible to predict with remarkable precision the proportions of each kind of trophic link among all community food webs. The differences between food webs in constant and in fluctuating environments reflect apparently greater constraints on the trophic organization of food webs in fluctuating environments.