Abstract Background Guidelines for type 2 diabetes (T2D) recommend reducing HbA1c through lifestyle interventions and glucose-lowering drugs (metformin, then combination with dipeptidyl peptidase-4 ...inhibitors DPP-4Is among other glucose-lowering drugs). However, no double-blind randomized clinical trial (RCT) compared with placebo has so far demonstrated that DDP-4Is reduce micro- and macrovascular complications in T2D. Moreover, the safety of DPP-4Is (with increased heart failure and acute pancreatitis) remains controversial. Methods A systematic review of the literature (PubMed, Cochrane Library Central Register of Controlled Trials CENTRAL and https://clinicaltrials.gov ), including all RCTs vs placebo published up to May 2015 and the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS), published June 2015, was performed. Primary endpoints were all-cause mortality and death from cardiovascular causes; secondary endpoints were macrovascular and microvascular events. Safety endpoints were acute pancreatitis, pancreatic cancer, serious adverse events and severe hypoglycaemia. Results A total of 36 double-blind RCTs were included, allowing analyses of 54,664 patients. There were no significant differences in all-cause mortality (RR = 1.03, 95% confidence interval CI = 0.95–1.12), cardiovascular mortality (RR = 1.02, 95% CI = 0.92–1.12), myocardial infarction (RR = 0.98, 95% CI = 0.89–1.08), strokes (RR = 1.02, 95% CI = 0.88–1.17), renal failure (RR = 1.06, 95% CI = 0.88–1.27), severe hypoglycaemia (RR = 1.14, 95% CI = 0.95–1.36) and pancreatic cancer (RR = 0.54, 95% CI = 0.28–1.04) with the use of DPP-4Is. However, DDP-4Is were associated with an increased risk of heart failure (RR = 1.13, 95% CI = 1.01–1.26) and of acute pancreatitis (RR = 1.57, 95% CI = 1.03–2.39). Conclusion There is no significant evidence of short-term efficacy of DPP-4Is on either morbidity/mortality or macro-/microvascular complications in T2D. However, there are warning signs concerning heart failure and acute pancreatitis. This suggests a great need for additional relevant studies in future.
Context.
The amount of data collected by spectrometers from radio to ultraviolet (UV) wavelengths opens a new era where the statistical and chemical information contained in the observations can be ...used concomitantly to investigate the thermodynamical state and the evolution of the interstellar medium (ISM).
Aims.
In this paper, we study the statistical properties of the HI-to-H
2
transition observed in absorption in the local diffuse and multiphase ISM. Our goal is to identify the physical processes that control the probability of occurrence of any line of sight and the origins of the variations of the integrated molecular fraction from one line of sight to another.
Methods.
The turbulent diffuse ISM is modeled using the RAMSES code, which includes detailed treatments of the magnetohydrodynamics, the thermal evolution of the gas, and the chemistry of H
2
. The impacts of the UV radiation field, the mean density, the turbulent forcing, the integral scale, the magnetic field, and the gravity on the molecular content of the gas are explored through a parametric study that covers a wide range of physical conditions. The statistics of the HI-to-H
2
transition are interpreted through analytical prescriptions and compared with the observations using a modified and robust version of the Kolmogorov-Smirnov test.
Results.
The analysis of the observed background sources shows that the lengths of the lines of sight follow a flat distribution in logarithmic scale from ~100 pc to ~3 kpc. Without taking into account any variation of the parameters along a line of sight or from one line of sight to another, the results of one simulation, convolved with the distribution of distances of the observational sample, are able to simultaneously explain the position, the width, the dispersion, and most of the statistical properties of the HI-to-H
2
transition observed in the local ISM. The tightest agreement is obtained for a neutral diffuse gas modeled over ~200 pc, with a mean density
n̅
H̅
= 1−2 cm
−3
, illuminated by the standard interstellar UV radiation field, and stirred up by a large-scale compressive turbulent forcing. Within this configuration, the 2D probability histogram of the column densities of H and H
2
, poetically called the kingfisher diagram, is remarkably stable and is almost unaltered by gravity, the strength of the turbulent forcing, the resolution of the simulation, or the strength of the magnetic field
B
x
, as long as
B
x
< 4
μ
G. The weak effect of the resolution and our analytical prescription suggest that the column densities of HI are likely built up in large-scale warm neutral medium and cold neutral medium (CNM) structures correlated in density over ~20 pc and ~10 pc, respectively, while those of H
2
are built up in CNM structures between ~3 and ~10 pc.
Conclusions.
Combining the chemical and statistical information contained in the observations of HI and H
2
sheds new light on the study of the diffuse matter. Applying this new tool to several atomic and molecular species is a promising perspective to understanding the effects of turbulence, magnetic field, thermal instability, and gravity on the formation and evolution of molecular clouds.
Our previous work on rat hippocampus showed that a loss of docosahexaenoic acid (DHA) occurs in the fatty acid composition of phosphatidylethanolamine (PE), plasmenylethanolamine (PmE) and ...phosphatidylserine (PS) with increasing age. The present study investigated whether a DHA-enriched phospholipid dietary supplement could restore DHA levels and cholinergic activity. Male rats were fed a balanced diet containing both linoleic and α-linolenic acids until the age of 2, 18 and 21 months. From 18 to 21 months, one subgroup received a diet supplemented with DHA-enriched phospholipids from egg yolk (E-PL), and another a diet with DHA-enriched phospholipids from pig brain (B-PL). Compared to the control diet, the E-PL diet restored the proportion of polyunsaturated fatty acids (PUFAs: 22:6n-3 and 20:4n-6) in PE and PmE, while enhancing spontaneous and evoked-acetylcholine (Ach) release. The B-PL diet had no effect on PUFAs, but increased basal extracellular levels of Ach in 21-month-old rats as compared to the age-matched control. Our results show that supplementation with DHA-enriched egg PL can enhance Ach release and correct PUFA composition.
Neuronal death is a pathological hallmark of Alzheimer’s disease. We have shown previously that phosphorylated double-stranded RNA-dependent protein kinase is present in degenerating hippocampal ...neurons and in senile plaques of Alzheimer’s disease brains and that genetically down-regulating double-stranded RNA-dependent protein kinase activity protects against
in vitro β-amyloid peptide neurotoxicity. In this report, we showed that two double-stranded RNA-dependent protein kinase blockers attenuate, in human neuroblastoma cells, β-amyloid peptide toxicity evaluated by caspase 3 assessment. In addition, we have used the newly engineered APP
SL/presenilin 1 knock-in transgenic mice, which display a severe neuronal loss in hippocampal regions, to analyze the activation of double-stranded RNA-dependent protein kinase. Western blots revealed the increased levels of activated double-stranded RNA-dependent protein kinase and the inhibition of eukaryotic initiation factor 2 α activity in the brains of these double transgenic mice. Phosphorylated RNA-dependent protein kinase-like endoplasmic reticulum-resident kinase was also increased in the brains of these mice. The levels of activated double-stranded RNA-dependent protein kinase were also increased in the brains of patients with Alzheimer’s disease. At 3, 6 and 12 months, hippocampal neurons display double stranded RNA-dependent protein kinase labelings in both the nucleus and the cytoplasm. Confocal microscopy showed that almost constantly activated double-stranded RNA-dependent protein kinase co-localized with DNA strand breaks in apoptotic nuclei of CA1 hippocampal neurons. Taken together these results demonstrate that double-stranded RNA-dependent protein kinase is associated with neurodegeneration in APP
SL/presenilin 1 knock-in mice and could represent a new therapeutic target for neuroprotection.
In October 2009, in the context of an A(H1N1)v2009 influenza pandemic, a vaccination campaign was launched in France, in which one of the priority groups was pregnant women, on account of the high ...risk of developing complications following infection by this virus.
The aim of this multicentric, prospective, observational study was to assess safety and pregnancy outcomes in a cohort of pregnant women when receiving the A(H1N1)v2009 influenza pandemic vaccine.
This was a prospective study that followed up pregnant women recruited mainly in vaccination centres and maternity departments. Following the expected delivery date, follow-up data were collected concerning the delivery, the infant, and, if appropriate, the reasons why the pregnancy did not reach its term.
Between 1 November 2009 and 31 March 2010, 2,415 pregnant women were included at the time of vaccination; 97.6 % of women received a vaccine without adjuvant and 2.4 % received an adjuvanted vaccine. Ninety-two (3.9 %) women were vaccinated during the first trimester of pregnancy, 1,090 (46.5 %) during the second trimester, and 1,162 (49.6 %) during the third trimester. One hundred and thirty-three adverse events (5.5 % of women) were reported, of which 12 were unexpected or serious. There were 2,246 (93.0 %) known pregnancy outcomes with 12 spontaneous abortions (0.5 %), 6 stillbirths (0.3 %), and 4 therapeutic abortions (0.2 %). There were 65 neonates with congenital anomalies, among which 31 were major. But only one congenital malformation (1.4 %) was reported for the 92 women vaccinated in their first trimester. Of the women, 93.3 % were delivered full term and 6.7 % preterm. For 96 (4.2 %) neonates, a disorder was reported in the neonatal period and 130 (5.6 %) were transferred to the neonatology department.
This study suggests that exposure to the A(H1N1)v2009 pandemic influenza vaccine during pregnancy does not increase the risk of adverse pregnancy outcomes. However, because of the relatively small number of women exposed during the first trimester, other studies are needed to exclude an increased risk of malformation.
The aim of this study was to investigate the burden of disease associated with gastroenteric viruses (rotavirus, norovirus, sapovirus, astrovirus and enteric adenovirus) using structured surveillance ...of children aged <6 years in the community. Faecal samples were collected between 2000 and 2003 from 685 children with symptoms of gastroenteritis. The children comprised three groups; 223 in the structured surveillance cohort, 203 in a community cohort and 259 in a cohort of hospitalized children. All samples were tested for the presence of viral pathogens using molecular methods. Questionnaires were sent to the parents/carers of the children recruited to the structured surveillance cohort in order to collect data that would allow an estimation of the severity of illness by means of the Vesikari score, and of the cost associated with gastrointestinal disease in this age group. A viral aetiological agent was detected in 53·5% of samples tested. Rotavirus was the most common pathogen found in all three cohorts followed by norovirus and enteric adenoviruses. Multiple viruses were found in 8% of the samples, and commonly involved rotavirus and any other virus. G1P8 was the most commonly detected rotavirus strain and there was no significant difference in the distribution of rotavirus genotypes among the three cohorts. Analysis of the questionnaires indicated that rotavirus infections were likely to be more severe than any other virus infection, and children from whom a viral pathogen was identified were more likely to require rehydration therapy.
We present initial results from the Herschel GT key program: Herschel observations of EXtra-Ordinary Sources (HEXOS) and outline the promise and potential of spectral surveys with Herschel/HIFI. The ...HIFI instrument offers unprecedented sensitivity, as well as continuous spectral coverage across the gaps imposed by the atmosphere, opening up a largely unexplored wavelength regime to high-resolution spectroscopy. We show the spectrum of Orion KL between 480 and 560 GHz and from 1.06 to 1.115 THz. From these data, we confirm that HIFI separately measures the dust continuum and spectrally resolves emission lines in Orion KL. Based on this capability we demonstrate that the line contribution to the broad-band continuum in this molecule-rich source is ~20–40% below 1 THz and declines to a few percent at higher frequencies. We also tentatively identify multiple transitions of HD18O in the spectra. The first detection of this rare isotopologue in the interstellar medium suggests that HDO emission is optically thick in the Orion hot core with HDO/H2O ~ 0.02. We discuss the implications of this detection for the water D/H ratio in hot cores.
BACKGROUND Beta-2 agonists such as salbutamol are used, not only by asthmatic athletes to prevent exercise induced asthma, but also by non-asthmatic athletes as a potentially ergogenic agent. We have ...investigated whether inhaled salbutamol enhances endurance performance in non-asthmatic athletes. METHODS A prospective double blind, randomised, three way crossover design was used to study the effects of 200 μg and 800 μg inhaled salbutamol versus a placebo in 12 trained triathletes. The treatments were compared in three identical cycle ergometer sessions at 85% of the predetermined maximal oxygen uptake. Lung function, endurance time, metabolic parameters (glucose, potassium, lactate, free fatty acid, and glycerol), and psychomotor performance were evaluated. RESULTS Neither endurance time nor post-exercise bronchodilation were significantly different between the treatments. Metabolic parameters were affected by exercise but not by treatment. CONCLUSIONS Inhaled salbutamol, even in a high dose, did not have a significant effect on endurance performance in non-asthmatic athletes, although the bronchodilating effect of the drug at the beginning of exercise may have improved respiratory adaptation. Our results do not preclude an ergogenic effect of β2 agonists given by other routes or for a longer period.
The Cosmic Microwave Background (CMB) radiation offers a unique window into the early Universe, facilitating precise examinations of fundamental cosmological theories. However, the quest for ...detecting B -modes in the CMB, predicted by theoretical models of inflation, faces substantial challenges in terms of calibration and foreground modeling. The COSMOCal ( CO smic S urvey of M illimeter wavelengths O bjects for CMB experiments Calibration) project aims at enhancing the accuracy of the absolute calibration of the polarization angle ψ of current and future CMB experiments. The concept includes the build of a very well known artificial source emitting in the frequency range 20-350 GHz that would act as an absolute calibrator for several polarization facilities on Earth. A feasibility study to place the artificial source in geostationary orbit, in the far field for all the telescopes on Earth, is ongoing. In the meanwhile ongoing hardware work is dedicated to build a prototype to test the technology, the precision and the stability of the polarization recovering in the 1 mm band (220-300 GHz). High-resolution experiments as the NIKA2 camera at the IRAM 30m telescope will be deployed for such use. Once carefully calibrated (Δψ < 0.1◦) it will be used to observe astrophysical sources such as the Crab nebula, which is the best candidate in the sky for the absolute calibration of CMB experiments.
We present the results of the first extensive mid-infrared (IR) imaging survey of the rho Ophiuchi embedded cluster, performed with the ISOCAM camera on board the ISO satellite. The main molecular ...cloud L1688, as well as L1689N and L1689S, have been completely surveyed for point sources at 6.7 and 14.3 micron. A total of 425 sources are detected including 16 Class I, 123 Class II, and 77 Class III young stellar objects (YSOs). Essentially all of the mid-IR sources coincide with near-IR sources, but a large proportion of them are recognized for the first time as YSOs. Our dual-wavelength survey allows us to identify essentially all the YSOs with IR excess in the embedded cluster down to Fnu ~ 10 - 15 mJy. It more than doubles the known population of Class II YSOs and represents the most complete census to date of newly formed stars in the rho Ophiuchi central region. The stellar luminosity function of the complete sample of Class II YSOs is derived with a good accuracy down to L= 0.03 Lsun. A modeling of this lumino- sity function, using available pre-main sequence tracks and plausible star for- mation histories, allows us to derive the mass distribution of the Class II YSOs which arguably reflects the IMF of the embedded cluster. We estimate that the IMF in rho Ophiuchi is well described by a two-component power law with a low- mass index of -0.35+/-0.25, a high-mass index of -1.7 (to be compared with the Salpeter value of -1.35), and a break occurring at M = 0.55+/-0.25 Msun. This IMF is flat with no evidence for a low-mass cutoff down to at least 0.06 Msun.
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