Showing papers by "University of Perugia published in 1999"

The p66shc adaptor protein controls oxidative stress response and life span in mammals

Abstract: Gene mutations in invertebrates have been identified that extend life span and enhance resistance to environmental stresses such as ultraviolet light or reactive oxygen species. In mammals, the mechanisms that regulate stress response are poorly understood and no genes are known to increase individual life span. Here we report that targeted mutation of the mouse p66shc gene induces stress resistance and prolongs life span. p66shc is a splice variant of p52shc/p46shc (ref. 2), a cytoplasmic signal transducer involved in the transmission of mitogenic signals from activated receptors to Ras. We show that: (1) p66shc is serine phosphorylated upon treatment with hydrogen peroxide (H2O2) or irradiation with ultraviolet light; (2) ablation of p66shc enhances cellular resistance to apoptosis induced by H2O2 or ultraviolet light; (3) a serine-phosphorylation defective mutant of p66shc cannot restore the normal stress response in p66shc-/- cells; (4) the p53 and p21 stress response is impaired in p66shc-/- cells; (5) p66shc-/- mice have increased resistance to paraquat and a 30% increase in life span. We propose that p66shc is part of a signal transduction pathway that regulates stress apoptotic responses and life span in mammals.

Negative regulation of erythropoiesis by caspase-mediated cleavage of GATA-1

Abstract: The production of red blood cells follows the sequential formation of proerythroblasts and basophilic, polychromatophilic and orthochromatic erythroblasts, and is promoted by the hormone erythropoietin (Epo) in response to tissue hypoxia. However, little is known about the negative regulation of this process. Death receptors are a family of surface molecules that trigger caspase activation and apoptosis in a variety of cell types. Here we show that immature erythroid cells express several death receptors whose ligands are produced by mature erythroblasts. Exposure of erythroid progenitors to mature erythroblasts or death-receptor ligands resulted in caspase-mediated degradation of the transcription factor GATA-1, which is associated with impaired erythroblast development. Expression of a caspase-resistant GATA-1 mutant, but not of the wild-type gene, completely restored erythroid expansion and differentiation following the triggering of death receptors, indicating that there is regulatory feedback between mature and immature erythroblasts through caspase-mediated cleavage of GATA-1. Similarly, erythropoiesis blockade following Epo deprivation was largely prevented by the expression of caspase-inhibitory proteins or caspase-resistant GATA-1 in erythroid progenitors. Caspase-mediated cleavage of GATA-1 may therefore represent an important negative control mechanism in erythropoiesis.

Food intake patterns and 25-year mortality from coronary heart disease: Cross-cultural correlations in the Seven Countries Study

Abstract: In the Seven Countries Study, associations between the intake of food-groups and 25-year mortality from coronary heart disease (CHD, defined as sudden coronary death or fatal myocardial infarction) were investigated. Baseline surveys were carried out between 1958 and 1964. A number of individual characteristics were measured in 12,763 middle-aged men belonging to 16 cohorts in seven countries (USA, Finland, The Netherlands, Italy, former Yugoslavia, Greece and Japan). Dietary information was collected in sub-samples using the weighed record method. Vital status of all participants was verified at regular intervals during 25 years of follow-up and the underlying cause of death was adjudicated. Eighteen different food-groups and combinations were considered for comparison among cohorts. Large differences in food-group consumption were seen, with high consumption of dairy products in Northern Europe, meat in the USA, vegetables, legumes, fish, and wine in Southern Europe, and cereals, soy products, and fish in Japan. Population death rates from CHD showed large differences, ranging from 268 per 1000 in East Finland to 25 per 1000 in Crete, Greece. Animal food-groups were directly correlated, and vegetable food-groups (except potatoes) as well as fish and alcohol were inversely correlated with CHD mortality. Univariate analysis showed significant positive correlation coefficients for butter (R = 0.887), meat (R = 0.645), pastries (R = 0.752), and milk (R = 0.600) consumption, and significant negative correlation coefficients for legumes (R = -0.822), oils (R = -0.571), and alcohol (R = -0.609) consumption. Combined vegetable foods (excluding alcohol) were inversely correlated (R = -0.519), whereas combined animal foods (excluding fish) were directly correlated (R = 0.798) with CHD death rates. Multivariate stepwise analysis selected butter, lard + margarine and meat as significant predictors and produced an R2 of 0.922. These findings were confirmed by factor analysis. These cross-cultural analyses are consistent with the hypothesis that dietary patterns are important determinants of differences in population CHD death rates, and confirm the opposite effects on apparent risk of animal and vegetable foods.

Global nonexistence theorems for a class of evolution equations with dissipation

Abstract: .We study abstract evolution equations with nonlinear damping terms and source terms, including as a particular case a nonlinear wave equation of the type \( \ba{cl} u_{tt}-\Delta u+ b|u_t|^{m-2}u_t=c|u|^{p-2}u, & (t,x)\in [0,T)\times\Omega,\\[6pt] u(t,x)=0, & (t,x)\in [0,T)\times\partial \Omega,\\[6pt] u(0,\cdot)=u_0\in H_0^1(\Omega), \quad u_t(0,\cdot)=v_0\in L^2(\Omega),\es& \ea \) where \( 0$, $p>2$, $m>1\). We prove a global nonexistence theorem for positive initial value of the energy when \( 1 1\).

Itraconazole Oral Solution as Prophylaxis for Fungal Infections in Neutropenic Patients with Hematologic Malignancies: A Randomized, Placebo-Controlled, Double-Blind, Multicenter Trial

Abstract: To evaluate the efficacy and safety of itraconazole oral solution for preventing fungal infections, a randomized, placebo-controlled, double-blind, multicenter trial was conducted: 405 neutropenic patients with hematologic malignancies were randomly assigned to receive either itraconazole, 2.5 mg/kg every 12 hours (201 patients), or placebo (204 patients). Proven and suspected deep fungal infection occurred in 24% of itraconazole recipients and in 33% of placebo recipients, a difference of 9 percentage points (95% confidence interval [CI], 0.6% to 22.5%; P = .035). Fungemia due to Candida species was documented in 0.5% of itraconazole recipients and in 4% of placebo recipients, a difference of 3.5 percentage points (95% CI, 0.5% to 6%; P = .01). Deaths due to candidemia occurred in none of the itraconazole recipients compared with 4 placebo recipients, a difference of 2 percentage points (95% CI, 0.05% to 4%; P = .06). Aspergillus infection was documented in four itraconazole recipients (one death) and one placebo recipient (one death). Side effects causing drug interruption occurred in 18% of itraconazole recipients and 13% of placebo recipients. Itraconazole oral solution was well-tolerated and effectively prevented proven and suspected deep fungal infection as well as systemic infection and death due to Candida species.

Comparison of clinical and genetic variables of cardiac events associated with loud noise versus swimming among subjects with the long QT syndrome.

Abstract: Acute auditory stimuli and swimming activities are frequently associated with syncope, aborted cardiac arrest, and death in the long QT syndrome (LQTS) We investigated the clinical and genetic findings associated with cardiac events precipitated by these arousal factors The study population involved 195 patients with an index cardiac event associated with a loud noise (n = 77) or swimming activity (n = 118) Patients with events associated with loud auditory stimuli were older at their index event and were more likely to be women than patients who experienced events during swimming-related activities Patients with an index event associated with loud noise were likely to have subsequent events related to auditory stimuli; patients with an index event associated with swimming were likely to have recurrent events related to swimming or physical activities Family patterning of auditory and swimming and/or physical activity-related events was evident Genotype analyses in 25 patients revealed a significant difference in the distribution of index cardiac events by genotype (p <0001), with all 19 patients with swimming-related episodes associated with LQT1 genotype and 5 of 6 patients with auditory-related events associated with LQT2 genotype The clinical profile and genotype findings of patients with LQTS who experience cardiac events related to acute auditory stimuli are quite different from those who experience events accompanying swimming activities

Phenolic compounds of olive fruit: one- and two-dimensional nuclear magnetic resonance characterization of Nüzhenide and its distribution in the constitutive parts of fruit.

Abstract: The phenolic composition of peel, pulp, and seed of the olive fruit was studied for several Italian cultivars used for oil extraction. The seed contained a compound never previously detected in peel and in pulp. The spectroscopic characterization of this compound proved, for the first time, the presence of nuzhenide in the olive seed. Study of the phenolic composition showed that oleuropein, demethyloleuropein, and verbascoside were present in all of the constitutive parts of the fruit; by contrast, nuzhenide was exclusively present in the seeds of all the cultivars at all ripening stages studied.

Multiple mantle metasomatism in central-southern Italy: Geochemical effects, timing and geodynamic implications

Abstract: The regional petrological and geochemical variations observed in the Recent magmatism along the Italian peninsula are interpreted to testify to the coexistence of distinct sectors of upper mantle. These are suggested to result from at least three compositionally and temporally distinct metasomatic events that affected petrologically different premetasomatic mantle sources. Geological and geochemical evidence suggests that metasomatism in the northern sector occurred during the Alpine subduction by introduction of a composition similar to the deeply subducted Dora Maira metagranites into a residual lithospheric mantle of upper crustal material. Metasomatic events beneath the Roman and Neapolitan areas are younger. These are related to the addition of melts and fluids into a fertile asthenospheric mantle during the latest stage of the west-directed Apennine subduction of the Adria plate and during the current northwest subduction of the Ionian sea floor.

Interleukin-4 Causes Susceptibility to Invasive Pulmonary Aspergillosis through Suppression of Protective Type I Responses

Abstract: Aspergillus fumigatus, an opportunistic fungal pathogen, causes multiple allergic and nonallergic airway diseases. Invasive pulmonary aspergillosis (IPA) is a nonallergic, life-threatening disease of immunocompromised patients. In a murine model of IPA, interleukin (IL)-4-deficient (IL-4-/-) BALB/c mice were used to examine the role of IL-4 in lung pathology and immune responses. IL-4-/- mice were more resistant than wild-type mice to infection caused by multiple intranasal injections of viable A. fumigatus conidia. Resistance was associated with decreased lung inflammatory pathology, impaired T helper (Th)-2 responses (including lung eosinophilia), and an IL-12-dependent Th1 response. In contrast, development of host-detrimental antifungal Th2 cells occurred in IL-12-/- and interferon-gamma-/- mice and in IL-4-/- mice when subjected to IL-12 neutralization. These results demonstrate that IL-4 renders mice susceptible to infection with A. fumigatus by inhibition of protective Th1 responses. IL-4 appears to have a distinct role in the pathogenesis of allergic and nonallergic lung diseases caused by the fungus.

High‐performance liquid chromatography evaluation of phenols in olive fruit, virgin olive oil, vegetation waters, and pomace and 1D‐ and 2D‐nuclear magnetic resonance characterization

Abstract: Phenolic compounds are the most important antioxidants of virgin olive oil. This paper reports on the application of solid phase extraction (SPE) in the separation of phenolic compounds from olive fruit, olive oil, and by-products of the mechanical extraction of the oil and the complete spectroscopic characterization by nuclear magnetic resonance of demethyloleuropein and verbascoside extracted from olive fruit. SPE led to a higher recovery of phenolic compounds from olives than did liquid/liquid extraction. SPE also was used to separate phenolic compounds from pomaces and vegetation waters. Phenylacid and phenyl-alcohol concentrations in extracts obtained from SPE and liquid/liquid extraction were not significantly different (P<0.05). The recovery of the dialdehydic form of elenolic acid linked to 3,4-(dihydroxyphenyl)ethanol and an isomer of oleuropein aglycon, however, was low.

Long-term intensive treatment of type 1 diabetes with the short-acting insulin analog lispro in variable combination with NPH insulin at mealtime.

Abstract: OBJECTIVE: To establish whether the short-acting insulin analog lispro can be successfully implemented in long-term intensive insulin therapy in type 1 diabetes, and if so, what its effects are on glycemic control and frequency and awareness of hypoglycemia. RESEARCH DESIGN AND METHODS: We randomized 56 type 1 diabetic patients to treatment with either lispro (n = 28) or human regular insulin (Hum-R; n = 28) as mealtime insulin for 1 year (open design, parallel groups). Lispro was injected at mealtime and Hum-R was given 10-40 min before meals (bedtime NPH was continued on both occasions). With lispro, NPH was added at breakfast (approximately 70/30), lunch (approximately 60/40), and supper (approximately 80/20) (mixing percentage of lispro/NPH) to optimize premeal and bedtime blood glucose. RESULTS: Total daily insulin units were no different in the two treatment groups, but with lispro approximately 30% less short-acting insulin at meals and approximately 30% more NPH was needed versus Hum-R (P

Olive oil hydroxytyrosol protects human erythrocytes against oxidative damages

Abstract: Hydroxytyrosol, the major representative phenolic compound of virgin olive oil, is a dietary component. Its possible protective effect on hydrogen peroxide (H(2)O(2))-induced oxidative alterations was investigated in human erythrocytes. Cells were pretreated with micromolar hydroxytyrosol concentrations and then exposed to H(2)O(2) over different time intervals. Subsequently, erythrocytes were analyzed for oxidative hemolysis and lipid peroxidation. Our data demonstrate that hydroxytyrosol prevents both oxidative alterations, therefore, providing protection against peroxide-induced cytotoxicity in erythrocytes. The effect of oxidative stress on erythrocyte membrane transport systems, as well as the protective role of hydroxytyrosol, also were investigated in conditions of nonhemolytic mild H(2)O(2) treatment. Under these experimental conditions, a marked decrease in the energy-dependent methionine and leucine transport is observable; this alteration is quantitatively prevented by hydroxytyrosol pretreatment. On the other hand, the energy-independent glucose transport is not affected by the oxidative treatment. The reported data give new experimental support to the hypothesis of a protective role played by nonvitamin antioxidant components of virgin olive oil on oxidative stress in human systems.

Molecular Beam Scattering of Aligned Oxygen Molecules. The Nature of the Bond in the O2−O2 Dimer

Abstract: Molecular beam experiments are reported for collisions between oxygen molecules. Total integral cross sections have been measured as a function of the collision energy with the control of molecular alignment. The low collision energy (in the thermal and subthermal range) and the high angular resolution permit observation of the “glory” effect, manifestation of quantum-mechanical interference, which allows an accurate probe of intermolecular interactions. This first complete experimental characterization of the interaction yields a ground (singlet) state bond energy of 17.0 ± 0.8 meV for the most stable dimer geometry (the two oxygen molecules lying parallel at a distance of 3.56 ± 0.07 A). Also the splittings among the singlet, the triplet, and the quintet surfaces are obtained, and a full representation of their angular dependence is reported via a novel harmonic expansion functional form for diatom−diatom interactions. These results indicate that most of the bonding in the dimer comes from van der Waals...

Absolute quantification of brain metabolites by proton magnetic resonance spectroscopy in normal-appearing white matter of multiple sclerosis patients

Abstract: The aim of this research was to obtain an absolute quantification of the N-acetyl-aspartate, choline, creatine and phosphocreatine levels in normal-appearing white matter by means of 1H magnetic resonance spectroscopy in a group of multiple sclerosis patients (27 with the relapsing-remitting form and 13 with the secondary progressive form). These values were compared with those of a group of 12 age-matched healthy control subjects. A significant decrease in the N-acetyl-aspartate concentration was found in normal-appearing white matter of frontal and parietal brain areas in multiple sclerosis patients compared with the same areas in control subjects. This reduction was more evident in progressive patients. The decrease in the N-acetyl-aspartate concentration in normal-appearing white matter significantly correlated with the Expanded Disability Status and the lesional load. No significant change was found in the concentration of creatine or choline. This finding concurs with previous evidence of heterogeneity in the multiple sclerosis pathological process which is not confined to the lesions and involves not only myelin, but also axons, even in white matter which appears normal on MRI.

A review of artificial neural networks applications in microwave computer‐aided design (invited article)

Abstract: Neural networks found significant applications in microwave CAD. In this paper, after providing a brief description of neural networks employed so far in this context, we illustrate some of their most significant applications and typical issues arising in practical implementation. We also summarize current research tendencies and introduce use of self-organizing maps enhancing model accuracy and applicability. We conclude considering some future developments and exciting perspectives opened from use of neural networks in microwave CAD. ©1999 John Wiley & Sons, Inc. Int J RF and Microwave CAE 9: 158–174, 1999.

Inference for Lorenz curve orderings

Abstract: In this paper we consider the issue of performing statistical inference for Lorenz curve orderings. This involves testing for an ordered relationship in a multivariate context and making comparisons among more than two population distributions. Our approach is to frame the hypotheses of interest as sets of linear inequality constraints on the vector of Lorenz curve ordinates, and apply order-restricted statistical inference to derive test statistics and their sampling distributions. We go on to relate our results to others which have appeared in recent literature, and use Monte Carlo analysis to highlight their respective properties and comparative performances. Finally, we discuss in general terms the issue and problems of framing hypotheses, and testing them, in the context of the study of income inequality, and suggest ways in which the distributional analyst could best proceed, illustrating with empiricalexamples.