Showing papers by "University of Milan published in 2002"

Finite-time Analysis of the Multiarmed Bandit Problem

Abstract: Reinforcement learning policies face the exploration versus exploitation dilemma, i.e. the search for a balance between exploring the environment to find profitable actions while taking the empirically best action as often as possible. A popular measure of a policy's success in addressing this dilemma is the regret, that is the loss due to the fact that the globally optimal policy is not followed all the times. One of the simplest examples of the exploration/exploitation dilemma is the multi-armed bandit problem. Lai and Robbins were the first ones to show that the regret for this problem has to grow at least logarithmically in the number of plays. Since then, policies which asymptotically achieve this regret have been devised by Lai and Robbins and many others. In this work we show that the optimal logarithmic regret is also achievable uniformly over time, with simple and efficient policies, and for all reward distributions with bounded support.

Twenty-Year Follow-up of a Randomized Study Comparing Breast-Conserving Surgery with Radical Mastectomy for Early Breast Cancer

Abstract: Background We conducted 20 years of follow-up of women enrolled in a randomized trial to compare the efficacy of radical (Halsted) mastectomy with that of breast-conserving surgery. Methods From 1973 to 1980, 701 women with breast cancers measuring no more than 2 cm in diameter were randomly assigned to undergo radical mastectomy (349 patients) or breast-conserving surgery (quadrantectomy) followed by radiotherapy to the ipsilateral mammary tissue (352 patients). After 1976, patients in both groups who had positive axillary nodes also received adjuvant chemotherapy with cyclophosphamide, methotrexate, and fluorouracil. Results Thirty women in the group that underwent breast-conserving therapy had a recurrence of tumor in the same breast, whereas eight women in the radical-mastectomy group had local recurrences (P<0.001). The crude cumulative incidence of these events was 8.8 percent and 2.3 percent, respectively, after 20 years. In contrast, there was no significant difference between the two groups in th...

Antiphospholipid syndrome: Clinical and immunologic manifestations and patterns of disease expression in a cohort of 1,000 patients

Abstract: Objective. To analyze the clinical and immunologic manifestations of antiphospholipid syndrome (APS) in a large cohort of patients and to define patterns of disease expression. Methods. The clinical and serologic features of APS (Sapporo preliminary criteria) in 1,000 patients from 13 European countries were analyzed using a computerized database. Results. The cohort consisted of 820 female patients (82.0%) and 180 male patients (18.0%) with a mean +/- SD age of 42 +/- 14 years at study entry. "Primary" APS was present in 53.1% of the patients; APS was associated with systemic lupus erythematosus (SLE) in 36.2%, with lupus-like syndrome in 5.0%, and with other diseases in 5.9%. A variety of thrombotic manifestations affecting the majority of organs were recorded. A catastrophic APS occurred in 0.8% of the patients. Patients with APS associated with SLE had more episodes of arthritis and livedo reticularis, and more frequently exhibited thrombocytopenia and leukopenia. Female patients had a higher frequency of arthritis, livedo reticularis, and migraine. Male patients had a higher frequency of myocardial infarction, epilepsy, and arterial thrombosis in the lower legs and feet. In 28 patients (2.8%), disease onset occurred before age 15; these patients had more episodes of chorea and jugular vein thrombosis than the remaining patients. In 127 patients (12.7%), disease onset occurred after age 50; most of these patients were men. These patients had a higher frequency of stroke and angina pectoris, but a lower frequency of livedo reticularis, than the remaining patients. Conclusion. APS may affect any organ of the body and display a broad spectrum of manifestations. An association with SLE, the patient's sex, and the patient's age at disease onset can modify the disease expression and define specific subsets of APS.

Analysis of the mouse transcriptome based on functional annotation of 60,770 full-length cDNAs

Abstract: Only a small proportion of the mouse genome is transcribed into mature messenger RNA transcripts There is an international collaborative effort to identify all full-length mRNA transcripts from the mouse, and to ensure that each is represented in a physical collection of clones Here we report the manual annotation of 60,770 full-length mouse complementary DNA sequences These are clustered into 33,409 'transcriptional units', contributing 901% of a newly established mouse transcriptome database Of these transcriptional units, 4,258 are new protein-coding and 11,665 are new non-coding messages, indicating that non-coding RNA is a major component of the transcriptome 41% of all transcriptional units showed evidence of alternative splicing In protein-coding transcripts, 79% of splice variations altered the protein product Whole-transcriptome analyses resulted in the identification of 2,431 sense-antisense pairs The present work, completely supported by physical clones, provides the most comprehensive survey of a mammalian transcriptome so far, and is a valuable resource for functional genomics

Updated Definitions of Healthy Ranges for Serum Alanine Aminotransferase Levels

Abstract: Serum alanine aminotransferase (ALT) activity, the variable most commonly measured to assess hepatic disease, fails to identify many patients with hepatic injury. Current standards for “normal” ALT...

Untranslated regions of mRNAs

Abstract: Gene expression is finely regulated at the post-transcriptional level. Features of the untranslated regions of mRNAs that control their translation, degradation and localization include stem-loop structures, upstream initiation codons and open reading frames, internal ribosome entry sites and various cis-acting elements that are bound by RNA-binding proteins.

Human SIR2 deacetylates p53 and antagonizes PML/p53-induced cellular senescence

Abstract: The yeast Sir2 protein mediates chromatin silencing through an intrinsic NAD-dependent histone deacetylase activity. Sir2 is a conserved protein and was recently shown to regulate lifespan extension both in budding yeast and worms. Here, we show that SIRT1, the human Sir2 homolog, is recruited to the promyelocytic leukemia protein (PML) nuclear bodies of mammalian cells upon overexpression of either PML or oncogenic Ras (Ha-rasV12). SIRT1 binds and deacetylates p53, a component of PML nuclear bodies, and it can repress p53-mediated transactivation. Moreover, we show that SIRT1 and p53 co-localize in nuclear bodies upon PML upregulation. When overexpressed in primary mouse embryo fibroblasts (MEFs), SIRT1 antagonizes PML-induced acetylation of p53 and rescues PML-mediated premature cellular senescence. Taken together, our data establish the SIRT1 deacetylase as a novel negative regulator of p53 function capable of modulating cellular senescence.

Italian cross-sectional growth charts for height, weight and BMI (6-20 y).

Abstract: Objective To trace growth charts for height, weight and body mass index (BMI) that apply to the whole Italian population. Different charts were drawn for central-north and south Italy since children in central-north regions are known to be taller and leaner. Design: Cross-sectional study. Setting: A sample of schoolchildren covering 16 of the 20 Italian regions, with data collected between 1994 and 2000. Subjects: A total of 27 421 girls and 27 374 boys, aged 6–20 y. Methods: Height and weight were measured using portable Harpenden stadiometers and properly calibrated scales, respectively. SIEDP references are presented both as centiles and as LMS curves for the calculation of standard deviation scores. According to International Obesity Task Force, SIEDP charts for BMI include the limits for overweight and obesity, ie the centiles having, at 18 y of age, the value of 25 and 30 kg/m2, respectively. Results: The comparison between SIEDP and Tanner et al's charts for height, still in use among most Italian paediatricians, shows that before puberty Italian children are 2–4 cm taller than their English peers. Because of these differences, Tanner's charts fail to detect, when applied to Italian children, 50–90% of short children aged 6–11 y, ie with stature below the 3rd centile of their reference population. Rolland-Cachera et al's centiles for BMI are lower than those of SIEDP standards, mainly during adolescence (up to 6.6 kg/m2 for the 97th centile), and apply poorly to Italian children. The prevalence of overweight is 27 (boys) and 19% (girls) in south Italy vs 17 (boys) and 10% (girls) in central-north Italy. Conclusions: These references intend to supply Italian paediatricians with a tool that avoids the use of outdated or inadequate charts, and thus should be suitable for monitoring their patients' growth. Sponsorship: Italian Society for Pediatric Endocrinology and Diabetes (SIEDP).

Fork Reversal and ssDNA Accumulation at Stalled Replication Forks Owing to Checkpoint Defects

Abstract: Checkpoint-mediated control of replicating chromosomes is essential for preventing cancer. In yeast, Rad53 kinase protects stalled replication forks from pathological rearrangements. To characterize the mechanisms controlling fork integrity, we analyzed replication intermediates formed in response to replication blocks using electron microscopy. At the forks, wild-type cells accumulate short single-stranded regions, which likely causes checkpoint activation, whereas rad53 mutants exhibit extensive single-stranded gaps and hemi-replicated intermediates, consistent with a lagging-strand synthesis defect. Further, rad53 cells accumulate Holliday junctions through fork reversal. We speculate that, in checkpoint mutants, abnormal replication intermediates begin to form because of uncoordinated replication and are further processed by unscheduled recombination pathways, causing genome instability.

The BABAR detector

Abstract: BABAR, the detector for the SLAC PEP-II asymmetric e+e- B Factory operating at the upsilon 4S resonance, was designed to allow comprehensive studies of CP-violation in B-meson decays. Charged particle tracks are measured in a multi-layer silicon vertex tracker surrounded by a cylindrical wire drift chamber. Electromagentic showers from electrons and photons are detected in an array of CsI crystals located just inside the solenoidal coil of a superconducting magnet. Muons and neutral hadrons are identified by arrays of resistive plate chambers inserted into gaps in the steel flux return of the magnet. Charged hadrons are identified by dE/dx measurements in the tracking detectors and in a ring-imaging Cherenkov detector surrounding the drift chamber. The trigger, data acquisition and data-monitoring systems, VME- and network-based, are controlled by custom-designed online software. Details of the layout and performance of the detector components and their associated electronics and software are presented.

Putting order in risk measures

Abstract: This paper introduces a set of axioms that define convex risk measures. Duality theory provides the representation theorem for these measures and the link with pricing rules.

Antioxidant and other biological activities of phenols from olives and olive oil

Abstract: Olive oil is the principal source of fats in the Mediterranean diet, which has been associated with a lower incidence of coronary heart disease and certain cancers. Phenolic compounds, e.g., hydroxytyrosol and oleuropein, in extra-virgin olive oil are responsible for its peculiar pungent taste and for its high stability. Recent findings demonstrate that olive oil phenolics are powerful antioxidants, both in vitro and in vivo, and possess other potent biological activities that could partially account for the observed healthful effects of the Mediterranean diet.

A reputation-based approach for choosing reliable resources in peer-to-peer networks

Abstract: Peer-to-peer (P2P) applications have seen an enormous success, and recently introduced P2P services have reached tens of millions of users. A feature that significantly contributes to the success of many P2P applications is user anonymity. However, anonymity opens the door to possible misuses and abuses, exploiting the P2P network as a way to spread tampered with resources, including Trojan Horses, viruses, and spam. To address this problem we propose a self-regulating system where the P2P network is used to implement a robust reputation mechanism. Reputation sharing is realized through a distributed polling algorithm by which resource requestors can assess the reliability of a resource offered by a participant before initiating the download. This way, spreading of malicious contents will be reduced and eventually blocked. Our approach can be straightforwardly piggybacked on existing P2P protocols and requires modest modifications to current implementations.

A single motif responsible for ubiquitin recognition and monoubiquitination in endocytic proteins

Abstract: Ubiquitination is a post-translation modification in which ubiquitin chains or single ubiquitin molecules are appended to target proteins, giving rise to poly- or monoubiquitination, respectively1,2,3,4. Polyubiquitination targets proteins for destruction by the proteasome. The role of monoubiquitination is less understood, although a function in membrane trafficking is emerging, at least in yeast1,3,5. Here we report that a short amino-acid stretch at the carboxy-termini of the monoubiquitinated endocytic proteins Eps15 and eps15R is indispensable for their monoubiquitination. A similar sequence, also required for this modification, is found in other cytosolic endocytic proteins, such as epsins and Hrs. These sequences comprise a protein motif, UIM (ref. 6), which has been proposed to bind to ubiquitin. We confirm this for the UIMs of eps15, eps15R, epsins and Hrs. Thus, the same motif in several endocytic proteins is responsible for ubiquitin recognition and monoubiquitination. Our results predict the existence of a UIM:ubiquitin-based intracellular network. Eps15/eps15R, epsins and Hrs may function as adaptors between ubiquitinated membrane cargo and either the clathrin coat or other endocytic scaffolds. In addition, through their own ubiquitination, they may further contribute to the amplification of this network in the endocytic pathway.

Non-redundant role of the long pentraxin PTX3 in anti-fungal innate immune response

Abstract: Pentraxins are a superfamily of conserved proteins that are characterized by a cyclic multimeric structure1. The classical short pentraxins, C-reactive protein (CRP) and serum amyloid P component (SAP), are acute-phase proteins produced in the liver in response to inflammatory mediators2,3,4. Short pentraxins regulate innate resistance to microbes and the scavenging of cellular debris and extracellular matrix components2,3,4,5. In contrast, long pentraxins have an unrelated, long amino-terminal domain coupled to the carboxy-terminal pentraxin domain, and differ, with respect to short pentraxins, in their gene organization, chromosomal localization, cellular source, and in their stimuli-inducing and ligand-recognition ability6. To investigate the in vivo function of the long pentraxin PTX3, we generated mice deficient in Ptx3 by homologous recombination. Ptx3-null mice were susceptible to invasive pulmonary aspergillosis. Ptx3 binds selected microbial agents, including conidia of Aspergillus fumigatus, and we found that susceptibility of Ptx3-null mice was associated with defective recognition of conidia by alveolar macrophages and dendritic cells, as well as inappropriate induction of an adaptive type 2 response. Thus, the long pentraxin Ptx3 is a secreted pattern-recognition receptor that has a non-redundant role in resistance to selected microbial agents, in particular to the opportunistic fungal pathogen Aspergillus fumigatus.

Alcohol and Hepatocellular Carcinoma: The Effect of Lifetime Intake and Hepatitis Virus Infections in Men and Women

Abstract: The authors investigated the dose-effect relation between alcohol drinking and hepatocellular carcinoma (HCC) in men and women separately, also considering hepatitis B and hepatitis C virus infections. They enrolled 464 subjects (380 men) with a first diagnosis of HCC as cases and 824 subjects (686 men) unaffected by hepatic diseases as controls; all were hospitalized in Brescia, northern Italy, in 1995-2000. Spline regression models showed a steady linear increase in the odds ratio of HCC for increasing alcohol intake, for values of >60 g of ethanol per day, with no substantial differences between men and women. Duration of drinking and age at start had no effect on the odds ratio when alcohol intake was considered. Former drinkers who had stopped 1-10 years previously had a higher risk of HCC than current drinkers did. The effect of alcohol drinking was evident even in the absence of hepatitis B or hepatitis C virus infection. In addition, a synergism between alcohol drinking and either infection was found, with approximately a twofold increase in the odds ratio for each hepatitis virus infection for drinkers of >60 g per day.

A fine-grained access control system for XML documents

Abstract: Web-based applications greatly increase information availability and ease of access, which is optimal for public information. The distribution and sharing of information via the Web that must be accessed in a selective way, such as electronic commerce transactions, require the definition and enforcement of security controls, ensuring that information will be accessible only to authorized entities. Different approaches have been proposed that address the problem of protecting information in a Web system. However, these approaches typically operate at the file-system level, independently of the data that have to be protected from unauthorized accesses. Part of this problem is due to the limitations of HTML, historically used to design Web documents. The extensible markup language (XML), a markup language promoted by the World Wide Web Consortium (W3C), is de facto the standard language for the exchange of information on the Internet and represents an important opportunity to provide fine-grained access control. We present an access control model to protect information distributed on the Web that, by exploiting XML's own capabilities, allows the definition and enforcement of access restrictions directly on the structure and content of the documents. We present a language for the specification of access restrictions, which uses standard notations and concepts, together with a description of a system architecture for access control enforcement based on existing technology. The result is a flexible and powerful security system offering a simple integration with current solutions.

Identification by redox proteomics of glutathionylated proteins in oxidatively stressed human T lymphocytes.

Abstract: Formation of mixed disulfides between glutathione and the cysteines of some proteins (glutathionylation) has been suggested as a mechanism through which protein functions can be regulated by the redox status. The aim of this study was to identify the proteins of T cell blasts that undergo glutathionylation under oxidative stress. To this purpose, we radiolabeled cellular glutathione with 35S, exposed T cells to oxidants (diamide or hydrogen peroxide), and performed nonreducing, two-dimensional electrophoresis followed by detection of labeled proteins by phosphorimaging and their identification by mass spectrometry techniques. We detected several proteins previously not recognized to be glutathionylated, including cytoskeletal proteins (vimentin, myosin, tropomyosin, cofilin, profilin, and the already known actin), enzymes (enolase, aldolase, 6-phosphogluconolactonase, adenylate kinase, ubiquitin-conjugating enzyme, phosphoglycerate kinase, triosephosphate isomerase, and pyrophosphatase), redox enzymes (peroxiredoxin 1, protein disulfide isomerase, and cytochrome c oxidase), cyclophilin, stress proteins (HSP70 and HSP60), nucleophosmin, transgelin, galectin, and fatty acid binding protein. Based on the presence of several protein isoforms in control cells, we suggest that enolase and cyclophilin are heavily glutathionylated under basal conditions. We studied the effect of glutathionylation on some of the enzymes identified in the present study and found that some of them (enolase and 6-phosphogluconolactonase) are inhibited by glutathionylation, whereas the enzymatic activity of cyclophilin (peptidylprolyl isomerase) is not. These findings suggest that protein glutathionylation might be a common mechanism for the global regulation of protein functions.

Effective wave equations for the dynamics of cigar-shaped and disk-shaped Bose condensates

Abstract: Starting from the three-dimensional (3D) Gross-Pitaevskii equation and using a variational approach, we derive an effective 1D wave equation that describes the axial dynamics of a Bose condensate confined in an external potential with cylindrical symmetry. The trapping potential is harmonic in the transverse direction and generic in the axial one. Our equation, that is a time-dependent nonpolynomial nonlinear Schr\"odinger equation (1D NPSE), can be used to model cigar-shaped condensates, whose dynamics is essentially 1D. We show that 1D NPSE gives much more accurate results than all other effective equations recently proposed. By using 1D NPSE we find analytical solutions for bright and dark solitons, which generalize the ones known in the literature. We deduce also an effective 2D nonpolynomial Schr\"odinger equation (2D NPSE) that models disk-shaped Bose condensates confined in an external trap that is harmonic along the axial direction and generic in the transverse direction. In the limiting cases of weak and strong interaction, our approach gives rise to Schr\"odinger-like equations with different polynomial nonlinearities.

Laparoscopic Versus Open Colorectal Surgery: A Randomized Trial on Short-Term Outcome

Abstract: Objective The primary endpoint was to compare the impact of laparoscopic and open colorectal surgery on 30-day postoperative morbidity. Lymphocyte proliferation to mitogens and gut oxygen tension were surrogate endpoints. Background Data Evidence-based proof of the effect of laparoscopic colorectal surgery on immunometabolic response and clinically relevant outcome variables is scanty. Further randomized trials are desirable before proposing laparoscopy as a superior technique. Methods Two hundred sixty-nine patients with colorectal disease were randomly assigned to laparoscopic (n = 136) or open (n = 133) colorectal resection. Four trained members of the surgical staff who were not involved in the study registered postoperative complications. Lymphocyte proliferation to Candida albicans and phytohemagglutinin was evaluated before and 3 and 15 days after surgery. Operative gut oxygen tension was monitored continuously by a polarographic microprobe. Results In the laparoscopic group the conversion rate was 5.1%. The overall morbidity rate was 20.6% in the laparoscopic group and 38.3% in the open group. Postoperative infections occurred in 15 of the 136 patients in the laparoscopic group and 31 of the 133 patients in the open group. The mean length of hospital stay was 10.4 ± 2.9 days in the laparoscopic group and 12.5 ± 4.1 days in the open group. On postoperative day 3, lymphocyte proliferation was impaired in both groups. Fifteen days after surgery, the proliferation index returned to baseline values only in the laparoscopic group. Intraoperative gut oxygen tension was higher in the laparoscopic than in the open group. Conclusions Laparoscopic colorectal surgery resulted in a significant reduction of 30-day postoperative morbidity. Lymphocyte proliferation and gut oxygen tension were better preserved in the laparoscopic group than in the open group.

Functional and clinical characterization of KCNJ2 mutations associated with LQT7 (Andersen syndrome)

Abstract: Andersen syndrome (AS) is a rare, inherited disorder characterized by periodic paralysis, long QT (LQT) with ventricular arrhythmias, and skeletal developmental abnormalities. We recently established that AS is caused by mutations in KCNJ2, which encodes the inward rectifier K(+) channel Kir2.1. In this report, we characterized the functional consequences of three novel and seven previously described KCNJ2 mutations using a two-microelectrode voltage-clamp technique and correlated the findings with the clinical phenotype. All mutations resulted in loss of function and dominant-negative suppression of Kir2.1 channel function. In mutation carriers, the frequency of periodic paralysis was 64% and dysmorphic features 78%. LQT was the primary cardiac manifestation, present in 71% of KCNJ2 mutation carriers, with ventricular arrhythmias present in 64%. While arrhythmias were common, none of our subjects suffered sudden cardiac death. To gain insight into the mechanism of arrhythmia susceptibility, we simulated the effect of reduced Kir2.1 using a ventricular myocyte model. A reduction in Kir2.1 prolonged the terminal phase of the cardiac action potential, and in the setting of reduced extracellular K(+), induced Na(+)/Ca(2+) exchanger-dependent delayed afterdepolarizations and spontaneous arrhythmias. These findings suggest that the substrate for arrhythmia susceptibility in AS is distinct from the other forms of inherited LQT syndrome.

Entangling macroscopic oscillators exploiting radiation pressure

Abstract: It is shown that radiation pressure can be profitably used to entangle macroscopic oscillators like movable mirrors, using present technology. We prove a new sufficient criterion for entanglement and show that the achievable entanglement is robust against thermal noise. Its signature can be revealed using common optomechanical readout apparatus.

Correlates and predictors of adherence to highly active antiretroviral therapy: overview of published literature.

Abstract: Knowledge of factors associated with medication adherence could help HIV clinicians to target persons in need of intervention, design these interventions, and help researchers to plan studies of adherence. This review summarizes the results of 20 studies investigating the issue of barriers to optimal highly active antiretroviral therapy (HAART) adherence. Only a few determinants were consistently associated with nonadherence. Symptoms and adverse drug effects, psychologic distress, lack of social or family support, complexity of the HAART regimen, low patient self-efficacy, and inconvenience of treatment were the factors most consistently associated with nonadherence. There were inconsistent findings regarding the relationship of adherence and the following variables: sociodemographic characteristics, substance abuse, depressive symptoms, quality of life, CD4+ cell count, knowledge and beliefs about treatment, patients' satisfaction with health care, and patient-provider relationship. A synthesis of findings relating various factors to adherence to HAART is difficult to reach because of several limitations of the existing body of research. These limitations concern the measurement of adherence, the assessment of correlates and predictors of adherence, the study population, and the study design.