Comparative study on the preventing effects of oral vanadyl sulfate and dietary restriction on the age-related glucose intolerance in rats.

BACKGROUND AND AIMS: Aging is associated with a progressive impairment of glucose tolerance. The aim of this study was to explore the protective effects of the chronic oral administration of the insulino-mimetic agent vanadyl sulfate (VOSO4) as compared with those exerted by a long-lasting dietary restriction. METHODS: Male Sprague-Dawley rats, either fed ad libitum (AL) or subjected to 40% dietary restriction (DR), were used. VOSO4 (0.5 mg/mL drinking water) was administered to a subgroup of AL rats for two months, starting at 16 months of age. Rats were subjected to an intravenous glucose tolerance test (IVGTT) at 16 and 18 months of age. Finally, the beta-cell responsiveness to glucose was evaluated in vitro by the isolated perfused pancreas preparation. RESULTS: The IVGTT performed in 16-month-old rats showed that DR prevented the development of the moderate glucose intolerance observed in AL rats. The IVGTT performed at 18 months of age confirmed the beneficial effect of DR and showed that VOSO4 was able to prevent the further age-related progression of glucose intolerance observed in AL rats. Pancreas perfusion studies showed that no increase in insulin secretion occurred in both VOSO4-treated and DR rats with respect to the age-matched AL controls, consistently with the in vivo observation of post-loading insulinaemic changes. CONCLUSIONS: On the basis of these results, we conclude that the beneficial effect of both treatments is mostly related to an improvement of tissue sensitivity to insulin rather than to an insulinotropic effect

Insufficient adaptive capability of pancreatic endocrine function in dexamethasone-treated ageing rats.

This study was aimed at exploring the capability of the pancreatic endocrine adaptive mechanisms of ageing Sprague-Dawley rats to counteract the metabolic challenge induced by the prolonged administration of dexamethasone (DEX) (0.13 mg/kg per day for 13 days). DEX treatment induced peripheral insulin resistance in 3-, 18- and 26-month-old rats, as indicated by the significant and persistent rise of plasma insulin levels in each age group (plasma insulin in 3-, 18- and 26-month-old rats from basal values of 4.3+/-0.8, 4.7+/-0.5 and 5.6+/-1.0 ng/ml (means+/-s.e.m.) respectively, rose to 11.9+/-1.7, 29.1+/-5.5 and 27.9+/-2.7 ng/ml respectively, after 9 days of administration). However, plasma glucose concentrations remained unchanged during the treatment in young rats, whereas they increased up to frankly diabetic levels in most 18-month-old and in all 26-month-old animals after a few days of DEX administration. Plasma free fatty acid concentrations increased 2-fold in 3- and 26-month-old rats and 4-fold in 18-month-old rats and could possibly be involved in the glucocorticoid-induced enhancement in insulin resistance, although they showed no significant correlation with glycaemic values. Incubation of pancreatic islets obtained from treated rats showed that DEX administration increased the insulin responsiveness of islets from not only younger but also older donors. However, in the islets of ageing rats, which already showed an age-dependent impairment of the sensitivity to glucose and other secretagogues, this enhancing effect was clearly attenuated with respect to the younger counterpart. Furthermore, DEX treatment depressed significantly the priming effect of glucose in islets isolated from all the three age groups. In conclusion, our results show that ageing rats are unable to counteract effectively a prolonged hyperglycaemic challenge as such induced by DEX administration. This homeostatic defect can be ascribed to the age-dependent failure of the endocrine pancreas to provide enough insulin to overcome the aggravation of an antecedent state of increased peripheral insulin resistance

Cell death and impairment of glucose-stimulated insulin secretion induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in the beta-cell line INS-1E.

The aim of this research was to characterize 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) toxicity on the insulin-secreting beta-cell line INS-1E. A sharp decline of cell survival (below 20%) was observed after 1 h exposure to TCDD concentrations between 12.5 and 25 nM. Ultrastructurally, beta-cell death was characterized by extensive degranulation, appearance of autophagic vacuoles, and peripheral nuclear condensation. Cytotoxic concentrations of TCDD rapidly induced a dose-dependent increase in intracellular calcium concentration. Blocking calcium entry by EGTA significantly decreased TCDD cytotoxicity. TCDD was also able to rapidly induce mitochondrial depolarization. Interestingly, 1 h exposition of INS-1E cells to very low TCDD concentrations (0.05-1 nM) dramatically impaired glucose-stimulated but not KCl-stimulated insulin secretion. In conclusion, our results clearly show that TCDD exerts a direct beta-cell cytotoxic effect at concentrations of 15-25 nM, but also markedly impairs glucose-stimulated insulin secretion at concentrations 20 times lower than these. On the basis of this latter observation we suggest that pancreatic beta-cells could be considered a specific and sensitive target for dioxin toxicity

Adiabatic compression and indirect detection of supersymmetric dark matter

Recent developments in the modelling of the dark matter distribution in our Galaxy point out the necessity to consider some physical processes to satisfy observational data. In particular, models with adiabatic compression, which include the effect of the baryonic gas in the halo, increase significantly the dark matter density in the central region of the Milky Way. On the other hand, the non-universality in scalar and gaugino sectors of supergravity models can also increase significantly the neutralino annihilation cross section. We show that the combination of both effects gives rise to a gamma-ray flux arising from the Galactic Center largely reachable by future experiments like GLAST. We also analyse in this framework the EGRET excess data above 1 GeV, as well as the recent data from CANGAROO and HESS. The analysis has been carried out imposing the most recent experimental constraints, such as the lower bound on the Higgs mass, the \bsg branching ratio, and the muon $g-2$. In addition, the recently improved upper bound on $B(B_s \to \mu^+ \mu^-)$ has also been taken into account. The astrophysical (WMAP) bounds on the dark matter density have also been imposed on the theoretical computation of the relic neutralino density through thermal production.Comment: 32 pages, 11 figures, final version to appear in JCA

Effects of SO(10) D-Term on Yukawa Unification and Unstable Minima of the Supersymmetric Scalar Potential

We study the effects of SO(10) D-terms on the allowed parameter space (APS) in models with $t - b - \tau$ and $b - \tau$ Yukawa unifiction. The former is allowed only for moderate values of the D-term, if very precise ($\le$ 5%) unification is required. Next we constrain the parameter space by looking for different dangerous directions where the scalar potential may be unbounded from below (UFB1 and UFB3). The common trilinear coupling $A_0$ plays a significant role in constraing the APS. For very precise $t - b - \tau$ Yukawa unification, $-m_{16} < or \approx A_0 < or \approx m_{16}$ can be probed at the LHC, where $m_{16}$ is the common soft breaking mass for the sfermions. Moreover, an interesting mass hierarchy with very heavy sfermions but light gauginos, which is strongly disfavoured in models without D-terms, becomes fairly common in the presence of the D-terms. The APS exhibits interesting characteristics if $m_{16}$ is not the same as the soft breaking mass $m_{10}$ for the Higgs sector. In $b - \tau$ unification models with D-terms, the APS consistent with Yukawa unification and radiative electroweak symmetry breaking, increases as the UFB1 constraint becomes weaker. However for $A_0 \leq 0$, a stronger UFB3 condition still puts, for a given $m_{16}$, a stringent upper bound on the common gaugino mass ($m_{1/2}$) and a lower bound on $m_{16}$ for a given $m_{1/2}$. The effects of sign of $\mu$ on Yukawa unification and UFB constraints are also discussed.Comment: Plain Latex, 22 pages, 11 figures. Small changes in the abstract, the pattern of discussion changed signifiantly, no change in the figures and results, a few new references added, version published in JP

b→sγb\to s\gamma Constraints on the Minimal Supergravity Model with Large tan⁡β\tan\beta

In the minimal supergravity model (mSUGRA), as the parameter $\tan\beta$ increases, the charged Higgs boson and light bottom squark masses decrease, which can potentially increase contributions from $tH^\pm$, \tg\tb_j and \tz_i\tb_j loops in the decay $b\to s\gamma$. We update a previous QCD improved $b\to s\gamma$ decay calculation to include in addition the effects of gluino and neutralino loops. We find that in the mSUGRA model, loops involving charginos also increase, and dominate over $tW$, $tH^\pm$, \tg\tq and \tz_i\tq contributions for \tan\beta\agt 5-10. We find for large values of $\tan\beta \sim 35$ that most of the parameter space of the mSUGRA model for $\mu <0$ is ruled out due to too large a value of branching ratio $B(b\to s\gamma)$. For $\mu >0$ and large $\tan\beta$, most of parameter space is allowed, although the regions with the least fine-tuning (low $m_0$ and $m_{1/2}$) are ruled out due to too low a value of $B(b\to s\gamma)$. We compare the constraints from $b\to s\gamma$ to constraints from the neutralino relic density, and to expectations for sparticle discovery at LEP2 and the Fermilab Tevatron $p\bar p$ colliders. Finally, we show that non-universal GUT scale soft breaking squark mass terms can enhance gluino loop contributions to $b\to s\gamma$ decay rate even if these are diagonal.Comment: 14 page REVTEX file plus 6 PS figure

Effective Interactions and Volume Energies in Charged Colloids: Linear Response Theory

Interparticle interactions in charge-stabilized colloidal suspensions, of arbitrary salt concentration, are described at the level of effective interactions in an equivalent one-component system. Integrating out from the partition function the degrees of freedom of all microions, and assuming linear response to the macroion charges, general expressions are obtained for both an effective electrostatic pair interaction and an associated microion volume energy. For macroions with hard-sphere cores, the effective interaction is of the DLVO screened-Coulomb form, but with a modified screening constant that incorporates excluded volume effects. The volume energy -- a natural consequence of the one-component reduction -- contributes to the total free energy and can significantly influence thermodynamic properties in the limit of low-salt concentration. As illustrations, the osmotic pressure and bulk modulus are computed and compared with recent experimental measurements for deionized suspensions. For macroions of sufficient charge and concentration, it is shown that the counterions can act to soften or destabilize colloidal crystals.Comment: 14 pages, including 3 figure

The Reach of the Fermilab Tevatron and CERN LHC for Gaugino Mediated SUSY Breaking Models

In supersymmetric models with gaugino mediated SUSY breaking (inoMSB), it is assumed that SUSY breaking on a hidden brane is communicated to the visible brane via gauge superfields which propagate in the bulk. This leads to GUT models where the common gaugino mass $m_{1/2}$ is the only soft SUSY breaking term to receive contributions at tree level. To obtain a viable phenomenology, it is assumed that the gaugino mass is induced at some scale $M_c$ beyond the GUT scale, and that additional renormalization group running takes place between $M_c$ and $M_{GUT}$ as in a SUSY GUT. We assume an SU(5) SUSY GUT above the GUT scale, and compute the SUSY particle spectrum expected in models with inoMSB. We use the Monte Carlo program ISAJET to simulate signals within the inoMSB model, and compute the SUSY reach including cuts and triggers approriate to Fermilab Tevatron and CERN LHC experiments. We find no reach for SUSY by the Tevatron collider in the trilepton channel. %either with or without %identified tau leptons. At the CERN LHC, values of $m_{1/2}=1000$ (1160) GeV can be probed with 10 (100) fb$^{-1}$ of integrated luminosity, corresponding to a reach in terms of $m_{\tg}$ of 2150 (2500) GeV. The inoMSB model and mSUGRA can likely only be differentiated at a linear $e^+e^-$ collider with sufficient energy to produce sleptons and charginos.Comment: 17 page revtex file with 9 PS figure

Tevatron-for-LHC Report: Preparations for Discoveries

This is the "TeV4LHC" report of the "Physics Landscapes" Working Group, focused on facilitating the start-up of physics explorations at the LHC by using the experience gained at the Tevatron. We present experimental and theoretical results that can be employed to probe various scenarios for physics beyond the Standard Model.Comment: 222 pp., additional contribution added, typos/layout correcte

Liver function following hepatitis C virus eradication by direct acting antivirals in patients with liver cirrhosis: data from the PITER cohort

Background: The development of direct-acting antivirals (DAA) for HCV has revolutionized the treatment of HCV, including its treatment in patients with HIV coinfection. The aim of this study was to compare the changes in liver function between coinfected and monoinfected patients with cirrhosis who achieved HCV eradication by DAA. Methods: Patients with pre-treatment diagnosis of HCV liver cirrhosis, consecutively enrolled in the multicenter PITER cohort, who achieved a sustained virological response 12 weeks after treatment cessation (SVR12) were analysed. Changes in Child-Pugh (C-P) class and the occurrence of a decompensating event was prospectively evaluated after the end of DAA treatment. Cox regression analysis was used to evaluate factors independently associated with changes in liver function following viral eradication. Results: We evaluated 1350 patients, of whom 1242 HCV monoinfected (median follow-up 24.7, range 6.8–47.5 months after viral eradication) and 108 (8%) HCV/HIV coinfected (median follow-up 27.1, range 6.0–44.6). After adjusting for age, sex, HCV-genotype, HBsAg positivity and alcohol use, HIV was independently associated with a more advanced liver disease before treatment (C-P class B/C vs A) (OR: 3.73, 95% CI:2.00–6.98). Following HCV eradication, C-P class improved in 17/20 (85%) coinfected patients (from B to A and from C to B) and in 53/82 (64.6%) monoinfected patients (from B to A) (p = 0.08). C-P class worsened in 3/56 coinfected (5.3%) (from A to B) and in 84/1024 (8.2%) monoinfected patients (p = 0.45) (from A to B or C and from B to C). Baseline factors independently associated with C-P class worsening were male sex (HR = 2.00; 95% CI = 1.18–3.36), platelet count &lt; 100,000/μl (HR = 1.75; 95% CI 1.08–2.85) and increased INR (HR = 2.41; 95% CI 1.51–3.84). Following viral eradication, in 7 of 15 coinfected (46.6%) and in 61 of 133 (45.8%) monoinfected patients with previous history of decompensation, a new decompensating event occurred. A first decompensating event was recorded in 4 of 93 (4.3%) coinfected and in 53 of 1109 (4.8%) monoinfected patients (p =&nbsp;0.83). Conclusions: Improvement of liver function was observed following HCV eradication in the majority of patients with cirrhosis; however viral eradication did not always mean cure of liver disease in both monoinfected and coinfected patients with advanced liver disease