Induction of tolerance to insulin is achievable in animal models of Type I (insulin-dependent) Diabetes mellitus by oral treatment with this hormone, which can lead to prevention of the disease. In ...the Diabetes Prevention Trial of Type I diabetes (DPT-1), oral insulin is given with the aim of preventing disease insurgence. We investigated whether if given at diagnosis of Type I diabetes in humans, oral insulin can still act as a tolerogen and therefore preserve residual beta-cell function, which is known to be substantial at diagnosis.
A double-blind trial was carried out in patients (mean age +/- SD: 14 +/- 8 years) with recent-onset Type I diabetes to whom oral insulin (5 mg daily) or placebo was given for 12 months in addition to intensive subcutaneous insulin therapy. A total of 82 patients with clinical Type I diabetes ( < 4 weeks duration) were studied. Basal C peptide and glycated haemoglobin were measured and the insulin requirement monitored every 3 months up to 1 year. Insulin antibodies were also measured in 27 patients treated with oral insulin and in 18 patients receiving placebo at the beginning of the trial and after 3, 6 and 12 months of treatment.
The trial was completed by 80 patients. Overall and without distinction between age at diagnosis, at 3, 6, 9 and 12 months baseline mean C-peptide secretion in patients treated with oral insulin did not differ from that of those patients treated with placebo. In patients younger than 15 years a tendency for lower C-peptide values at 9 and 12 months was observed in the oral insulin group. Insulin requirement at 1 year was similar between the two groups as well as the percentage of glycated haemoglobin. Finally, IgG insulin antibodies were similar in the two groups at each time point.
The results of this study indicate that the addition of 5 mg of oral insulin does not modify the course of the disease in the first year after diagnosis and probably does not statistically affect the humoral immune response against insulin.
We study the correlation between the gamma-ray flux F_g, averaged over the first 11 months of Fermi survey and integrated above 100 MeV, and the radio flux density (F_r at 20 GHz) of Fermi sources ...associated with a radio counterpart in the AT20G survey. Considering the blazars detected in both bands, the correlation is highly significant and it is F_g~F_r^0.85+-0.04, similar for BL Lac and FSRQ sources. However, only a small fraction (~1/15) of the AT20G radio sources with flat radio spectrum, are detected by Fermi. To understand if this correlation is real, we examine the selection effects introduced by the flux limits of the radio and gamma-ray surveys, and the importance of variability of the gamma-ray flux. We find that the radio/gamma-ray flux correlation is real, but its slope is steeper than the observed one, i.e. F_g~F_r^delta with delta in the range 1.25-1.5. The observed F_g-F_r correlation and the fraction of radio sources detected by Fermi is reproduced assuming a long term gamma-ray flux variability following a log-normal probability distribution with standard deviation sigma>0.5 (corresponding to F_g varying by at least a factor 3). Such a variability is compatible with what observed when comparing, for the sources in common, the EGRET and the Fermi gamma-ray fluxes (even if the Fermi fluxes are averaged over ~1 year). Another indication of variability is the non detection of 12 out of 66 EGRET blazars by Fermi, despite its higher sensitivity.We also study the strong linear correlation between the gamma-ray and the radio luminosity of the 144 AT20G-Fermi associations with known redshift and show that it is statistically robust. Two possible implications of these correlations are discussed: the contribution of blazars to the extragalactic gamma-ray background and the prediction of blazars that might undergo extremely high states of gamma-ray emission in the next years.
THESEUS is a space mission concept aimed at exploiting Gamma-Ray Bursts for investigating the early Universe and at providing a substantial advancement of multi-messenger and time-domain ...astrophysics. These goals will be achieved through a unique combination of instruments allowing GRB and X-ray transient detection over a broad field of view (more than 1sr) with 0.5-1 arcmin localization, an energy band extending from several MeV down to 0.3 keV and high sensitivity to transient sources in the soft X-ray domain, as well as on-board prompt (few minutes) follow-up with a 0.7 m class IR telescope with both imaging and spectroscopic capabilities. THESEUS will be perfectly suited for addressing the main open issues in cosmology such as, e.g., star formation rate and metallicity evolution of the inter-stellar and intra-galactic medium up to redshift \(\sim\)10, signatures of Pop III stars, sources and physics of re-ionization, and the faint end of the galaxy luminosity function. In addition, it will provide unprecedented capability to monitor the X-ray variable sky, thus detecting, localizing, and identifying the electromagnetic counterparts to sources of gravitational radiation, which may be routinely detected in the late '20s / early '30s by next generation facilities like aLIGO/ aVirgo, eLISA, KAGRA, and Einstein Telescope. THESEUS will also provide powerful synergies with the next generation of multi-wavelength observatories (e.g., LSST, ELT, SKA, CTA, ATHENA).
We present the results of the spectral analysis of the public data of 438 Gamma Ray Bursts (GRBs) detected by the Fermi Gamma ray Burst Monitor (GBM) up to March 2010. For 432 bursts we could fit the ...time integrated spectrum. In 318 cases we can reliably constrain the peak energy Epeak of their \nu F_\nu spectrum by analyzing their time integrated spectrum between 8 keV and 35 MeV. 80% of these spectra are fitted by a power law with an exponential cutoff, and the remaining with the Band function. Among these 318 GRBs, 274 and 44 belong to the long and short GRB class, respectively. Long GRBs have a typical peak energy Epeak=160 keV and low energy spectral index alpha=-0.92. Short GRBs have harder peak energy (Epeak=490 keV) and harder low energy spectral index (alpha=-0.50) than long bursts. For each Fermi GRB we analyzed also the spectrum corresponding to the peak flux of the burst. On average, the peak spectrum has harder low energy spectral index but similar Epeak than the corresponding time-integrated spectrum for the same burst. The spectral parameters derived in our analysis of Fermi/GBM bursts are globally consistent with those reported in the GRB Cicular Network (GCN) archive after December 2008, while we found systematic differences, concerning the low energy power law index, for earlier bursts.
We derive the luminosity function and redshift distribution of short Gamma Ray Bursts (SGRBs) using (i) all the available observer-frame constraints (i.e. peak flux, fluence, peak energy and duration ...distributions) of the large population of Fermi SGRBs and (ii) the rest-frame properties of a complete sample of Swift SGRBs. We show that a steep \(\phi(L)\propto L^{-a}\) with a>2.0 is excluded if the full set of constraints is considered. We implement a Monte Carlo Markov Chain method to derive the \(\phi(L)\) and \(\psi(z)\) functions assuming intrinsic Ep-Liso and Ep-Eiso correlations or independent distributions of intrinsic peak energy, luminosity and duration. To make our results independent from assumptions on the progenitor (NS-NS binary mergers or other channels) and from uncertainties on the star formation history, we assume a parametric form for the redshift distribution of SGRBs. We find that a relatively flat luminosity function with slope ~0.5 below a characteristic break luminosity ~3\(\times10^{52}\) erg/s and a redshift distribution of SGRBs peaking at z~1.5-2 satisfy all our constraints. These results hold also if no Ep-Liso and Ep-Eiso correlations are assumed. We estimate that, within ~200 Mpc (i.e. the design aLIGO range for the detection of GW produced by NS-NS merger events), 0.007-0.03 SGRBs yr\(^{-1}\) should be detectable as gamma-ray events. Assuming current estimates of NS-NS merger rates and that all NS-NS mergers lead to a SGRB event, we derive a conservative estimate of the average opening angle of SGRBs: \(\theta_{jet}\)~3-6 deg. Our luminosity function implies an average luminosity L~1.5\(\times 10^{52}\) erg/s, nearly two orders of magnitude higher than previous findings, which greatly enhances the chance of observing SGRB "orphan" afterglows. Efforts should go in the direction of finding and identifying such orphan afterglows as counterparts of GW events.
To investigate the origin of insulin in amniotic fluid amniocenteses were carried out in pregnancies with live, dead and anencephalic fetuses. Amniotic fluid insulin of pregnant women bearing live ...fetuses was 9.0 +/- 2.1 microU/ml; in six women with dead foetuses amniotic fluid insulin was not detected. A significant positive correlation was observed between gestational age and the amniotic fluid concentration of insulin. In the amniotic fluid of the four women bearing anencephalic fetuses, the amount of hormone was within normal limits (10.0 +/- 1.4 microU/ml). Intravenous glucose administration (0.33 g/kg body weight) to the mother doses not influence levels of insulin in amniotic fluid, but brought about changes in amniotic fluid glucose concentration. These findings support the conclusion that human amniotic fluid insulin is of fetal rather than maternal origin.
We cross-matched the 6-year Swift/Burst Alert Telescope (BAT) survey of active galactic nuclei (AGN) with the AT20G radio survey of the southern sky, which is one of the largest high-frequency radio ...surveys available. With these data we investigated the possible correlation between the radio and the X-ray emission at the highest radio and X-ray frequencies. We found 37 AGN with a high probability of association (>80 per cent), among which 19 are local Seyfert galaxies (with median redshift z = 0.03) and 18 blazars. We found that \approx 20 per cent of the AGN detected in hard X-rays are also bright radio sources at 20 GHz, but the apparent correlation between the radio and hard X-ray luminosity is completely driven by the different median redshifts of the two subgroups of AGN. When we consider only the local Seyfert sample we find no evidence of a correlation between their 20 GHz and 15-55 keV power. Therefore it appears that at high frequencies the radio-X connection, which had been previously observed at lower frequencies, disappears. The disappearance of the radio-X correlation at high radio and X-ray frequencies could be tested through Very Long Baseline Interferometry and the use of the Nuclear Spectroscopic Telescope Array (NuSTAR) satellite.
Cell mediated immune response in vitro to a number of antigens has been reported in patients with Type 1 diabetes. The aim of the present study was to develop an in vivo intradermal (delayed type ...hypersensitivity) skin test using antigens known to be recognized by lymphocytes of patients with Type 1 diabetes and to compare, where possible, the in vivo response to the in vitro T cell proliferation to the same antigens.
The skin test was performed in the following group of patients: 55 with recent onset Type 1 diabetes; 16 patients with Type 1 diabetes of longer duration; 10 patients with autoimmune thyroid disease and 20 patients with Latent Autoimmune Diabetes in Adults (LADA). Type 1 diabetes specific antigens for the skin test included glutamic acid decarboxilase (GAD65), insulin and beta casein, whereas diabetes non specific antigens included tetanus toxoid, diphteria, proteus, tubercolin, streptococcus, and glycerol as control. A multitest device consisting of heads delivering intradermally 10 µl of solution containing the antigens was applied to the forearms; the specific antigens were injected in one forearm whereas the non specific antigens were injected in the other forearm. Reading of the reaction, which was considered positive in the presence of a nodule of 2 mm diameter was performed 48 h after the multitest application. The in vitro T cell response to diabetes specific antigens used in the multitest was studied using conventional proliferation assays in patients with recent onset Type 1 diabetes and in age matched normal subjects.
Only recent onset Type 1 diabetes patients showed an in vivo positive response to GAD65, such response being detectable in 10 patients (18%). Two patients reacted also to beta casein and insulin, all other patient groups resulted negative but 2 patients with longer duration of Type 1 diabetes. There was no apparent link between the in vivo skin test and in vitro T cell proliferation to GAD65.
We conclude that in vivo cell mediated immune reaction to GAD65, insulin and beta casein can be visualized in a minority of patients with recent onset Type 1 diabetes. Further studies are required to determine specificity and whether altering the dose can improve the sensitivity of the test.
Pregnancy is believed to exacerbate diabetes complications, although the degree to which this occurs, and the advice that should be given to women contemplating pregnancy is unclear. We examined 776 ...nulliparous and 582 parous women with Type 1 diabetes from a cross-sectional study performed in 31 European centres. Glycaemic control was better in parous women. Age and duration adjusted prevalence of microalbuminuria was similar in parous and nulliparous women, but macroalbuminuria was lower in parous women (6% versus 10%, p < 0.0001). Prevalence of all retinopathy was lower in parous women (34% in women who had two or more pregnancies, 45% in women who had one), compared with 48% in nulliparous women (chi 2 for trend = 47.1, p < 0.0001). Proliferative retinopathy was lower in parous (8% and 7%, respectively) compared with nulliparous women (16%, chi 2 for trend = 52.2, p < 0.0001). These differences persisted when adjusted for glycaemic control. Excluding referrals for pregnancy, parous women were more likely to have been referred to the diabetes clinic with complications than nulliparous women (p = 0.001). It is unlikely that our findings can be explained by women with complications being advised against pregnancy, or by the better glycaemic control in parous women. Equivalent levels of microalbuminuria and background retinopathy in parous and nulliparous women suggests that pregnancy may not exacerbate these early complications.
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