Showing papers by "University of Cagliari published in 2003"

Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease

Abstract: Genes and mechanisms involved in common complex diseases, such as the autoimmune disorders that affect approximately 5% of the population, remain obscure. Here we identify polymorphisms of the cytotoxic T lymphocyte antigen 4 gene (CTLA4)—which encodes a vital negative regulatory molecule of the immune system—as candidates for primary determinants of risk of the common autoimmune disorders Graves' disease, autoimmune hypothyroidism and type 1 diabetes. In humans, disease susceptibility was mapped to a non-coding 6.1?kb 3′ region of CTLA4, the common allelic variation of which was correlated with lower messenger RNA levels of the soluble alternative splice form of CTLA4. In the mouse model of type 1 diabetes, susceptibility was also associated with variation in CTLA-4 gene splicing with reduced production of a splice form encoding a molecule lacking the CD80/CD86 ligand-binding domain. Genetic mapping of variants conferring a small disease risk can identify pathways in complex disorders, as exemplified by our discovery of inherited, quantitative alterations of CTLA4 contributing to autoimmune tissue destruction.

An increased estimate of the merger rate of double neutron stars from observations of a highly relativistic system

Abstract: The merger of close binary systems containing two neutron stars should produce a burst of gravitational waves, as predicted by the theory of general relativity. A reliable estimate of the double-neutron-star merger rate in the Galaxy is crucial in order to predict whether current gravity wave detectors will be successful in detecting such bursts. Present estimates of this rate are rather low, because we know of only a few double-neutron-star binaries with merger times less than the age of the Universe. Here we report the discovery of a 22-ms pulsar, PSR J0737-3039, which is a member of a highly relativistic double-neutron-star binary with an orbital period of 2.4 hours. This system will merge in about 85 Myr, a time much shorter than for any other known neutron-star binary. Together with the relatively low radio luminosity of PSR J0737-3039, this timescale implies an order-of-magnitude increase in the predicted merger rate for double-neutron-star systems in our Galaxy (and in the rest of the Universe).

A survey of applications of second-order sliding mode control to mechanical systems

Abstract: The effective application of sliding mode control to mechanical systems is not straightforward because of the sensitivity of these systems to chattering. Higher-order sliding modes can counteract this phenomenon by confining the switching control to the higher derivatives of the mechanical control variable, so that the latter results are continuous. Generally, this approach requires the availability of a number of time derivatives of the sliding variable, and, in the presence of noise, this requirement could be a practical limitation. A class of second-order sliding mode controllers, guaranteeing finite-time convergence for systems with relative degree two between the sliding variable and the switching control, could be helpful both in reducing the number of differentiator stages in the controller and in dealing with unmodelled actuator dynamics. In this paper different second-order sliding mode controllers, previously presented in the literature, are shown to belong to the above cited class, and some cha...

Suicidal behaviour in bipolar disorder: risk and prevention

Abstract: Bipolar (manic-depressive) disorder is a common and severe illness. It is also potentially fatal as a result of accidents and increased mortality associated with comorbid substance use and medical illnesses, but its highest lethality results from suicide. Suicide rates, averaging 0.4% per year in men and women diagnosed with bipolar disorder, are >20-fold higher than in the general population. Suicidal acts often occur early in the illness course and in association with severe depressive and dysphoric-agitated mixed phases of illness, especially following repeated, severe depressions. Systematic consideration of risk and protective factors enhances assessment of potentially suicidal patients. Short-term interventions employed empirically to manage acute suicidality include close clinical supervision, rapid hospitalisation and use of electroconvulsive treatment. Several plausible therapeutic interventions have limited evidence of long-term effectiveness against mortality risks associated with any psychiatric disorder, including antidepressant, antimanic, antipsychotic and electroconvulsive, as well as psychosocial, treatments. However, in bipolar disorder and other major affective disorders, lithium maintenance treatment is a notable exception, with strong and consistent evidence that it reduces suicidal risk. The growing range of drugs being introduced to treat acute and long-term phases of bipolar disorder, including antiepileptic drugs, atypical antipsychotics and relatively safe, modern antidepressants, require research assessment for their ability to limit premature mortality from suicide and other causes. For now, however, more can be done to improve treatment in major affective illnesses by application of current knowledge in a systematic fashion, with close and sustained clinical follow-up of patients at risk, hopefully with a resulting reduction of mortality rates.

Early effects of gliadin on enterocyte intracellular signalling involved in intestinal barrier function

Abstract: Background and aims: Despite the progress made in understanding the immunological aspects of the pathogenesis of coeliac disease (CD), the early steps that allow gliadin to cross the intestinal barrier are still largely unknown. The aim of this study was to establish whether gliadin activates a zonulin dependent enterocyte intracellular signalling pathway(s) leading to increased intestinal permeability. Methods: The effect of gliadin on the enterocyte actin cytoskeleton was studied on rat intestinal epithelial (IEC-6) cell cultures by fluorescence microscopy and spectrofluorimetry. Zonulin concentration was measured on cell culture supernatants by enzyme linked immunosorbent assay. Transepithelial intestinal resistance (Rt) was measured on ex vivo intestinal tissues mounted in Ussing chambers. Results: Incubation of cells with gliadin led to a reversible protein kinase C (PKC) mediated actin polymerisation temporarily coincident with zonulin release. A significant reduction in Rt was observed after gliadin addition on rabbit intestinal mucosa mounted in Ussing chambers. Pretreatment with the zonulin inhibitor FZI/0 abolished the gliadin induced actin polymerisation and Rt reduction but not zonulin release. Conclusions: Gliadin induces zonulin release in intestinal epithelial cells in vitro. Activation of the zonulin pathway by PKC mediated cytoskeleton reorganisation and tight junction opening leads to a rapid increase in intestinal permeability.

Spatial Spillovers and Innovation Activity in European Regions

Abstract: This paper explores the spatial distribution of innovative activity and the role of technological spillovers in the process of knowledge creation across 138 regions of 17 countries in Europe (the 15 members of the European Union plus Switzerland and Norway). The analysis is based on an original statistical databank set up by CRENoS on regional patenting at the European Patent Office spanning from 1978 to 1997 and classified by ISIC sectors (3 digit). In a first step, a deep exploratory spatial data analysis of the dissemination of innovative activity in Europe is performed. Some global and local indicators for spatial association are presented, summarising the presence of a dependence process in the distribution of innovative activity for different periods and sectors. Secondly, we attempt to model the behaviour of innovative activity at the regional level on the basis of a knowledge production function. Econometric results points to the relevance of internal factors (R&D expenditure, economic performance, agglomeration economies). Moreover, the production of knowledge by European regions seems to be also affected by spatial spillovers due to innovative activity performed in other regions.

Differential regulation of E2F1 apoptotic target genes in response to DNA damage

Abstract: E2F1, a member of the E2F family of transcription factors, in addition to its established proliferative effect, has also been implicated in the induction of apoptosis through p53-dependent and p53-independent pathways. Several genes involved in the activation or execution of the apoptotic programme have recently been shown to be upregulated at the transcriptional level by E2F1 overexpression, including the genes encoding INK4a/ARF, Apaf-1, caspase 7 and p73 (refs 3-5). E2F1 is stabilized in response to DNA damage but it has not been established how this translates into the activation of specific subsets of E2F target genes. Here, we applied a chromatin immunoprecipitation approach to show that, in response to DNA damage, E2F1 is directed from cell cycle progression to apoptotic E2F target genes. We identify p73 as an important E2F1 apoptotic target gene in DNA damage response and we show that acetylation is required for E2F1 recruitment on the P1p73 promoter and for its transcriptional activation.

The Parkes Multibeam Pulsar Survey - III. Young Pulsars and the Discovery and Timing of 200 Pulsars

Abstract: The Parkes Multibeam Pulsar Survey has unlocked vast areas of the Galactic plane, which were previously invisible to earlier low-frequency and less-sensitive surveys. The survey has discovered more than 600 new pulsars so far, including many that are young and exotic. In this paper we report the discovery of 200 pulsars for which we present positional and spin-down parameters, dispersion measures, flux densities and pulse profiles. A large number of these new pulsars are young and energetic, and we review possible associations of γ -ray sources with the sample of about 1300 pulsars for which timing solutions are known. Based on a statistical analysis, we estimate that about 19 ± 6 associations are genuine. The survey has also discovered 12 pulsars with spin properties similar to those of the Vela pulsar, nearly doubling the known population of such neutron stars. Studying the properties of all known ‘Vela-like’ pulsars, we find their radio luminosities to be similar to normal pulsars, implying that they are very inefficient radio sources. Finally, we review the use of the newly discovered pulsars as Galactic probes and discuss the implications of the new NE2001 Galactic electron density model for the determination of pulsar distances and luminosities.

Tumor vascularity and tryptase-positive mast cells correlate with a poor prognosis in melanoma.

Abstract: See commentary on page 361. Abstract Background The importance of angiogenesis in melanoma has been controversial and is not homogeneous. Mast cell density (MCD) is highly correlated with the extent of both normal and pathological angiogenesis, such as that in chronic inflammatory diseases and tumours. Methods We evaluated the prognostic significance of tumour microvascular density (MVD) and MCD in 25 advanced melanoma patients after resection and a 4–5-year follow up: 48% of the patients were alive and free of metastases (good prognostic subgroup); 16% had developed regional nodal metastases (intermediate prognostic subgroup); and 36% had died (poor prognostic subgroup). Tissues samples were investigated immunohistochemically to count microvessels and mast cells with an antifactor VIII and an antitryptase antibody, respectively. Results Immunohistological staining showed a higher number of microvessels and mast cells in melanoma lesions of poor prognosis as compared with intermediate prognosis and with good prognosis, respectively. Conclusions These data agree with those showing a close relationship between MCD and angiogenesis during tumour progression and demonstrate, for the first time, a prognostic significance of MCD in human melanoma.

How fast are tourism countries growing? The cross country evidence

Abstract: Specializing in tourism is an option available to a number of less developed countries and regions But is it a good option? To answer this question, we have compared the relative growth performance of 14 "tourism countries" within a sample of 143 countries, observed during the period 1980-95 Using standard OLS cross-country growth regressions, we have documented that the tourism countries grow significantly faster than all the other sub-groups considered in our analysis (OECD, Oil, LDC, Small) Moreover, we have shown that the reason why they are growing faster is neither that they are poorer than the average; nor that they have particularly high saving/investment propensities; nor that they are very open to trade In other words, the positive performance of the tourism countries is not significantly accounted for by the traditional growth factors of the Mankiw, Romer and Weil type of models Tourism specialization appears to be an independent determinant A corollary of our findings is that the role played by the tourism sector should not be ignored by the debate about whether smallness is harmful for growth (eg Easterly and Kraay (2000), who conclude that there is no growth disadvantage in smallness) Half of the thirty countries classified as microstates in this literature are heavily dependent on tourism Once this distinction is adopted, it is easy to see that the small tourism countries perform much better than the remaining small countries In our findings, smallness per se can be bad for growth, while the opposite is true when smallness goes together with a specialization in tourism

Baclofen antagonizes nicotine-, cocaine-, and morphine-induced dopamine release in the nucleus accumbens of rat.

Abstract: Evidence recently provided has suggested a specific involvement of the GABAergic system in modulating positive reinforcing properties of several drugs of abuse through an action on mesolimbic dopaminergic neurons. The GABA(B) receptor agonist baclofen has been proposed as a potential therapeutic agent for the clinical treatment of several forms of drug addiction. In the present study, using the in vivo microdialysis technique, we investigated the effect of baclofen on nicotine, cocaine, and morphine-induced increase in extracellular dopamine (DA) levels in the shell of the nucleus accumbens, a brain area supposedly involved in the modulation of the central effects of several drugs of abuse, of freely moving rats. As expected, nicotine (0.6 mg/kg s.c.), morphine (5 mg/kg s.c.), and cocaine (7.5 mg/kg i.p.) administration in rats induced a marked increase in extracellular DA concentrations in the nucleus accumbens, reaching a maximum value of +205 +/- 8.4%, +300 +/- 22.2%, and +370 +/- 30.7%, respectively. Pretreatment with baclofen (1.25 and 2.5 mg/kg i.p.) dose-dependently reduced the nicotine-, morphine-, and cocaine-evoked DA release in the shell of the nucleus accumbens. Furthermore, baclofen alone did not elicit changes in basal DA extracellular levels up to 180 min. Taken together, our data are in line with previous reports demonstrating the ability of baclofen to modulate the mesolimbic DAergic transmission and indicate baclofen as a putative candidate in the pharmacotherapy of polydrug abuse.

Chemical Composition of the Essential Oils of Juniperus from Ripe and Unripe Berries and Leaves and Their Antimicrobial Activity

Abstract: The composition of the essential oil from ripe and unripe berries and leaves of Juniperus oxycedrus L. ssp. oxycedrus, Juniperus phoenicea ssp. turbinata and Juniperus communis ssp. communis was analyzed by GC-MS, and microbiological assays were carried out. Samples were collected in different localities (Sardinia, Italy) and hydro distilled. The yields ranged between 2.54% +/- 0.21 (v\w dried weight) and 0.04% +/- 0.00. A total of 36 components were identified. The major compounds in the essential oils were alpha-pinene, beta-pinene, delta-3-carene, sabinene, myrcene, beta-phellandrene, limonene, and D-germacrene. Both qualitative and quantitative differences between species and between different parts of the plant were observed. The essential oils and their major compounds were tested against Candida albicans, Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa, and the minimum inhibitory concentration and minimum bactericidal concentration were determined. The results obtained led to a nonsignificant inhibitory effect, although all the essential oils from Juniperus phoenicea ssp. turbinata and the essential oil from leaves of Juniperus oxycedrus ssp. oxycedrus exhibited rather good or weak activity against Candida albicans and Staphylococcus aureus.

Novel natural ligands for Drosophila olfactory receptor neurones

Abstract: Due to its well-defined genome, the fruitfly Drosophila melanogaster has become a very important model organism in olfactory research. Despite all the research invested, few natural odour ligands have been identified. By using a combined gas chromatographic-single receptor neurone recording technique (GC-SC), we set out to identify active odour molecules in head space-collected volatiles from preferred food sources, i.e. different overripe or rotting fruit. In total, we performed 101 GC-SC experiments on 85 contacted sensilla. Using GC-mass spectrometry, we identified 24 active compounds. Synthetic samples of these compounds were used to establish dose-response curves for several of the receptor neurone types encountered. The response patterns of individual neurones were repeatable, and neurones were found to reside in stereotyped pairs. In total, we identified eight distinct sensillum types based on response profiles of 12 olfactory receptor neurone types. In most recordings, a single GC peak would produce a strong response, whereas a few other, often chemically related, compounds would produce weaker responses. The GC-SC recordings revealed that the olfactory receptor neurones investigated were often selective and could be divided into distinct functional types with discrete characteristics. Dose-response investigations revealed very low response thresholds to the tested compounds. Six of the novel ligands were also tested for their behavioural effect in a T-maze set up. Of these, five elicited attraction and one elicited repulsion.

Algorithm 829: Software for generation of classes of test functions with known local and global minima for global optimization

Abstract: A procedure for generating non-differentiable, continuously differentiable, and twice continuously differentiable classes of test functions for multiextremal multidimensional box-constrained global optimization is presented. Each test class consists of 100 functions. Test functions are generated by defining a convex quadratic function systematically distorted by polynomials in order to introduce local minima. To determine a class, the user defines the following parameters: (i) problem dimension, (ii) number of local minima, (iii) value of the global minimum, (iv) radius of the attraction region of the global minimizer, (v) distance from the global minimizer to the vertex of the quadratic function. Then, all other necessary parameters are generated randomly for all 100 functions of the class. Full information about each test function including locations and values of all local minima is supplied to the user. Partial derivatives are also generated where possible.

Prenatal exposure to a cannabinoid agonist produces memory deficits linked to dysfunction in hippocampal long-term potentiation and glutamate release.

Abstract: To investigate the possible long-term consequences of gestational exposure to cannabinoids on cognitive functions, pregnant rats were administered with the CB1 receptor agonist WIN 55,212-2 (WIN), at a dose (0.5 mg/kg) that causes neither malformations nor overt signs of toxicity. Prenatal WIN exposure induced a disruption of memory retention in 40- and 80-day-old offspring subjected to a passive avoidance task. A hyperactive behavior at the ages of 12 and 40 days was also found. The memory impairment caused by the gestational exposure to WIN was correlated with alterations of hippocampal long-term potentiation (LTP) and glutamate release. LTP induced in CA3–CA1 synapses decayed faster in brain slices of rats born from WIN-treated dams, whereas posttetanic and short-term potentiation were similar to the control group. In line with LTP shortening, in vivo microdialysis showed a significant decrease in basal and K+-evoked extracellular glutamate levels in the hippocampus of juvenile and adult rats born from WIN-treated dams. A similar reduction in glutamate outflow was also observed in primary cell cultures of hippocampus obtained from pups born from mothers exposed to WIN. The decrease in hippocampal glutamate outflow appears to be the cause of LTP disruption, which in turn might underlie, at least in part, the long-lasting impairment of cognitive functions caused by the gestational exposure to this cannabinoid agonist. These findings could provide an explanation of cognitive alterations observed in children born from women who use marijuana during pregnancy.

The Conjugated Linoleic Acid (CLA) Isomer, t10c12-CLA, Is Inversely Associated with Changes in Body Weight and Serum Leptin in Subjects with Type 2 Diabetes Mellitus

Abstract: Isomers of conjugated linoleic acid (CLA) are found in beef, lamb and dairy products. Diets containing CLA reduce adipose mass in various depots of experimental animals. In addition, CLA delays the onset of diabetes in the ZDF rat model for obesity-linked type 2 diabetes mellitus. We hypothesize that there would be an inverse association of CLA with body weight and serum leptin in subjects with type 2 diabetes mellitus. In this double-blind study, subjects with type 2 diabetes mellitus were randomized into one of two groups receiving either a supplement containing mixed CLA isomers (CLA-mix; 8.0 g daily, 76% pure CLA; n = 12) or a supplement containing safflower oil (placebo; 8.0 g daily safflower oil, n = 9) for 8 wk. The isomers of CLA in the CLA-mix supplement were primarily c9t11-CLA ( approximately 37%) and t10c12-CLA ( approximately 39%) in free fatty acid form. Plasma levels of CLA were inversely associated with body weight (P < 0.05) and serum leptin levels (P < 0.05). When levels of plasma t10c12-CLA isomer were correlated with changes in body weight or serum leptin, t10c12-CLA, but not c9t11-CLA, was inversely associated with body weights (P < 0.05) and serum leptin (P < 0.02). These findings strongly suggest that the t10c12-CLA isomer may be the bioactive isomer of CLA to influence the body weight changes observed in subjects with type 2 diabetes. Future studies are needed to determine a causal relationship, if any, of t10c12-CLA or c9t11-CLA to modulate body weight and composition in subjects with type 2 diabetes. Furthermore, determining the ability of CLA isomers to influence glucose and lipid metabolism as well as markers of insulin sensitivity is imperative to understanding the role of CLA to aid in the management of type 2 diabetes and other related conditions of insulin resistance.

Safety, Tolerability, and Pharmacokinetics of ICL670, a New Orally Active Iron-Chelating Agent in Patients with Transfusion-Dependent Iron Overload Due to β-Thalassemia

Abstract: ICL670 is an orally active representative of a new class of tridentate iron chelator developed for the treatment of blood transfusion-dependent iron overload in chronic anemias. In this randomized, double-blind study, patients with transfusion-dependent beta-thalassemia received single oral doses of ICL670 ranging from 2.5 to 80 mg/kg to investigate its safety, tolerability, and pharmacokinetics and to obtain preliminary information on pharmacodynamic effects. ICL670 was well tolerated, and no safety problems occurred up to 80 mg/kg. A plasma half-life of 11 to 19 hours was found for ICL670, supporting once-daily oral administration. AUC0-24 h and Cmax of ICL670 increased nearly proportionally with the dose. The urinary excretion of ICL670 and its iron complex was less than 0.1% of the dose, and this was in accordance with the expected predominant iron fecal excretion induced by ICL670 (based on preclinical experiments). Notwithstanding, a positive trend toward increased amounts of urinary excreted iron was observed when the AUC0-24 h of ICL670 and the iron complex exceeded specific threshold values at the 40- and 80-mg/kg dose levels.

The effect of protest votes on the estimates of WTP for use values of recreational sites

Abstract: Contingent valuation studies are often characterized by a considerable number of protest responses, which may cause selectivity bias on the final estimates for WTP. Sample selection models can detect and – if necessary – correct selectivity bias. In economic applications where the relevant dependent variable is continuous, sample selection models are generally estimated using Heckman's 2-step method rather than the FIML estimator. Either method has its own drawback: computational complexity for the FIML method, susceptibility to collinearity problems for the 2-step method. Using data on valuation of forest resources for recreational use, we analyse the performance of the two estimators. In this application, given the presence of some collinearity, the FIML is preferred to the 2-step method. A procedure is outlined to deal with selectivity problems in similar settings.

Chemical recycling of poly(ethylene terephthalate) (pet) by hydrolysis and glycolysis

Abstract: In this paper we review an interesting method of PET recycling, i.e. chemical recycling; it is based on the concept of depolymerizing the condensation polymer through solvolytic chain cleavage into low molecular products which can be purified and reused as raw materials for the production of high-quality chemical products. In this work our attention is confined to the hydrolysis (neutral, acid and alkaline) and glycolysis processes of PET chemical recycling; operating conditions and mechanism of each method are reported and described. The neutral hydrolysis has an auto accelerating character; two kinetic models have been proposed: an half-order and a second order kinetic model. The acid hydrolysis could be explained by a modified shrinking core model under chemical reaction control and the alkaline hydrolysis by a first-order model with respect to hydroxide ion concentration. To describe glycolysis, two different kinetic models have been proposed where EG can act or not as internal catalyst. Further experimental and theoretical investigations are required to shed light on the promising processes of PET chemical recycling reviewed in this work.

Novel Indolyl Aryl Sulfones Active against HIV-1 Carrying NNRTI Resistance Mutations: Synthesis and SAR Studies

Abstract: The potent anti-HIV-1 activities of L-737,126 (2) and PAS sulfones prompted us to design and test against HIV-1 in acutely infected MT-4 cells a number of novel 1- and 3-benzenesulfonylindoles. Indoles belonging to the 1-benzenesulfonyl series were found poorly or totally inactive. On the contrary, some of the 3-benzenesulfonyl derivatives turned out to be as potent as 2, being endowed with potencies in the low nanomolar concentration range. In particular, (2-methylphenyl)sulfonyl (72) and (3-methylphenyl)sulfonyl (73) derivatives showed EC(50) values of 1 nM. Introduction of two methyl groups at positions 3 and 5 of the phenyl ring of 2 furnished derivatives (80 and 83) which showed very potent and selective anti-HIV-1 activity not only against the wt strain, but also against mutants carrying NNRTI-resistant mutations at positions 103 and 181 of the reverse transcriptase gene.

Modelling zero values and protest responses in contingent valuation surveys

Abstract: In contingent valuation surveys the category of zero bidders refers to individuals that are not willing to pay anything for the programme under analysis. Specific questions can help to identify true zero values, coming from people that are indifferent to the programme, separately from protest responses: the latter are generally excluded from the analysis. This paper introduces a mixture-sample selection model that takes into account both zero values and protest responses in the estimates. The model is applied to the valuation of a traffic calming scheme aimed at reducing risks for residents in three villages in the north-east of England.