Individualized Angiotensin‐Converting Enzyme (ACE)‐Inhibitor Therapy in Stable Coronary Artery Disease Based on Clinical and Pharmacogenetic Determinants: The PERindopril GENEtic (PERGENE) Risk Model

Patients with stable coronary artery disease (CAD) constitute a heterogeneous group in which the treatment benefits by angiotensin-converting enzyme (ACE)-inhibitor therapy vary between individuals. Our objective was to integrate clinical and pharmacogenetic determinants in an ultimate combined risk prediction model.Clinical, genetic, and outcomes data were used from 8726 stable CAD patients participating in the EUROPA/PERGENE trial of perindopril versus placebo. Multivariable analysis of phenotype data resulted in a clinical risk score (range, 0-21 points). Three single-nucleotide polymorphisms (rs275651 and rs5182 in the angiotensin-II type I-receptor gene and rs12050217 in the bradykinin type I-receptor gene) were used to construct a pharmacogenetic risk score (PGXscore; range, 0-6 points). Seven hundred eighty-five patients (9.0%) experienced the primary endpoint of cardiovascular mortality, nonfatal myocardial infarction or resuscitated cardiac arrest, during 4.2 years of follow-up. Absolute risk reductions ranged from 1.2% to 7.5% in the 73.5% of patients with PGXscore of 0 to 2. As a consequence, estimated annual numbers needed to treat ranged from as low as 29 (clinical risk score ≥10 and PGXscore of 0) to 521 (clinical risk score ≤6 and PGXscore of 2). Furthermore, our data suggest that long-term perindopril prescription in patients with a PGXscore of 0 to 2 is cost-effective.Both baseline clinical phenotype, as well as genotype determine the efficacy of widely prescribed ACE inhibition in stable CAD. Integration of clinical and pharmacogenetic determinants in a combined risk prediction model demonstrated a very wide range of gradients of absolute treatment benefit

Miglioramento delle abilità linguistiche e dell'assertività nei disturbi del comportamento alimentare: studio randomizzato controllato di un'attività di laboratorio letterario [Improving linguistic skills and assertiveness in eating disorders: A randomized controlled trial on a literary workshop activity]

Objectives: To assess the effectiveness of a literary workshop activity for increasing linguistic skills and assertiveness in patients with eating disorders (ED). Methods: Twenty-four patients consequently admitted to the ED in-patient unit at the private clinic "Villa Maria Luigia" (Parma, Northern Italy) were enrolled in the study. Of these, 8 were randomly assigned to treatment and 16 to care as usual (the only difference between treatment and care as usual was the literary workshop activity). The literary workshop consisted in 15 weekly 60-minute group sessions. Linguistic and expressive skills were provided and tested during the sessions. The Rathus Assertiveness Schedule and the Verbal Fluency Test (phonemic and semantic) were administered to all patients at the beginning and end of hospitalization. Results: A significant improvement of semantic skills, phonetic skills and assertiveness (p < 0.01) was registered in the treatment group. A positive correlation was also found between variations of linguistic skills and assertiveness in the treatment group, but not in the control group. Conclusions: The results of this study suggest that a literary workshop activity within a rehabilitation program for patients suffering from ED can aid in improving communication and language skills that might have a positive and significant impact on levels of assertiveness

Rule reactivation and capture errors in goal directed behaviour

In everyday life people may act automatically, following "unwanted" lines of action which are triggered by contextual cues and may interfere with current goals. Such occurrences are known as "capture errors" in reference to errors that occur when a more salient behaviour takes place when a similar, but less salient, action was intended. Clinical neuropsychological studies suggest that reactivation of previous rules may play an important role in behavioural interference, but such reactivation has been little studied in normal subjects and simple experimental tasks. In the present study we develop this theme, presenting data on 4 subjects who spontaneously showed capture errors in verbal fluency tasks, and developing a new experimental paradigm specifically designed to elicit such interference in normal subjects. In the new paradigm, 101 normal subjects performed a simple series of working memory tasks, including occasional stimuli whose answer matched both the current and the previous rule. We found that normal controls indeed tend to commit more mistakes after the presentation of a stimulus whose answer is consistent with a current and preceding rule. In this case, however, the errors produced are not necessarily associated with a shift back to the old rule, suggesting that rule reactivation leads to a more general interference effect. We discuss the importance of our data from both theoretical and clinical perspectives

Neuroimaging Evidence of Major Morpho-Anatomical and Functional Abnormalities in the BTBR T+TF/J Mouse Model of Autism

BTBR T+tf/J (BTBR) mice display prominent behavioural deficits analogous to the defining symptoms of autism, a feature that has prompted a widespread use of the model in preclinical autism research. Because neuro-behavioural traits are described with respect to reference populations, multiple investigators have examined and described the behaviour of BTBR mice against that exhibited by C57BL/6J (B6), a mouse line characterised by high sociability and low self-grooming. In an attempt to probe the translational relevance of this comparison for autism research, we used Magnetic Resonance Imaging (MRI) to map in both strain multiple morpho-anatomical and functional neuroimaging readouts that have been extensively used in patient populations. Diffusion tensor tractography confirmed previous reports of callosal agenesis and lack of hippocampal commissure in BTBR mice, and revealed a concomitant rostro-caudal reorganisation of major cortical white matter bundles. Intact inter-hemispheric tracts were found in the anterior commissure, ventro-medial thalamus, and in a strain-specific white matter formation located above the third ventricle. BTBR also exhibited decreased fronto-cortical, occipital and thalamic gray matter volume and widespread reductions in cortical thickness with respect to control B6 mice. Foci of increased gray matter volume and thickness were observed in the medial prefrontal and insular cortex. Mapping of resting-state brain activity using cerebral blood volume weighted fMRI revealed reduced cortico-thalamic function together with foci of increased activity in the hypothalamus and dorsal hippocampus of BTBR mice. Collectively, our results show pronounced functional and structural abnormalities in the brain of BTBR mice with respect to control B6 mice. The large and widespread white and gray matter abnormalities observed do not appear to be representative of the neuroanatomical alterations typically observed in autistic patients. The presence of reduced fronto-cortical metabolism is of potential translational relevance, as this feature recapitulates previously-reported clinical observations

Effectiveness of early intervention programs for parents of preterm infants: a meta-review of systematic reviews

Background: Various intervention programs exist for parents of preterm babies and some systematic reviews (SRs) have synthesised the evidence of their effectiveness. These reviews are, however, limited to specific interventions, components, or outcomes, and a comprehensive evidence base is lacking. The aim of this meta-review was to appraise and meta-synthesise the evidence from existing SRs to provide a comprehensive evidence base on the effectiveness of interventions for parents of preterm infants on parental and infant outcomes. Methods: We conducted a comprehensive search of the following databases to identify relevant SRs: Cochrane library, Web of science, EMBASE, CINAHL, British Nursing Index, PsycINFO, Medline, ScienceDirect, Scopus, IBSS, DOAJ, ERIC, EPPI-Centre, PROSPERO, WHO Library. Additional searches were conducted using authors’ institutional libraries, Google Scholar, and the reference lists of identified reviews. Identified articles were screened in two stages against an inclusion criteria with titles and abstracts screened first followed by full-text screening. Selected SRs were appraised using the AMSTAR tool. Extracted data using a predesigned tool were synthesised narratively examining the direction of impact on outcomes. Results: We found 11 SRs eligible for inclusion that synthesised a total of 343 quantitative primary studies. The average quality of the SRs was ‘medium’. Thirty four interventions were reported across the SRs with considerable heterogeneity in the structural framework and the targeted outcomes that included maternal-infant dyadic, maternal/parental, and infant outcomes. Among all interventions, Kangaroo Care (KC) showed the most frequent positive impact across outcomes (n = 19) followed by Mother Infant Transaction Program (MITP) (n = 14). Other interventions with most consistent positive impact on infant outcomes were Modified-Mother Infant Transaction Program (M-MITP) (n = 6), Infant Health and Development Program (IHDP) (n = 5) and Creating Opportunities for Parent Empowerment (COPE) (n = 5). Overall, interventions with both home and facility based components showed the most frequent positive impact across outcomes. Conclusions: Neonatal care policy and planning for preterm babies should consider the implementation of interventions with most positive impact on outcomes. The heterogeneity in interventions and outcomes calls for the development and implementation of an integrated program for parents of preterm infants with a clearly defined global set of parental and infant outcomes

Robust optical delay lines via topological protection

Phenomena associated with topological properties of physical systems are naturally robust against perturbations. This robustness is exemplified by quantized conductance and edge state transport in the quantum Hall and quantum spin Hall effects. Here we show how exploiting topological properties of optical systems can be used to implement robust photonic devices. We demonstrate how quantum spin Hall Hamiltonians can be created with linear optical elements using a network of coupled resonator optical waveguides (CROW) in two dimensions. We find that key features of quantum Hall systems, including the characteristic Hofstadter butterfly and robust edge state transport, can be obtained in such systems. As a specific application, we show that the topological protection can be used to dramatically improve the performance of optical delay lines and to overcome limitations related to disorder in photonic technologies.Comment: 9 pages, 5 figures + 12 pages of supplementary informatio

Measurements of the Absolute Branching Ratios for the Dominant KL Decays, the KL Lifetime, and Vus with the KLOE Detector

From a sample of about 10^9 Phi mesons produced at DAFNE, we have selected KL mesons tagged by observing KS->pi+pi- decays. We present results on the major KL branching ratios, including those of the semileptonic decays needed for the determination of Vus. These branching ratio measurements are fully inclusive with respect to final-state radiation. The KL lifetime has also been measured.Comment: Submitted to Phys. Lett.

Discovery of extreme particle acceleration in the microquasar Cygnus X-3

The study of relativistic particle acceleration is a major topic of high-energy astrophysics. It is well known that massive black holes in active galaxies can release a substantial fraction of their accretion power into energetic particles, producing gamma-rays and relativistic jets. Galactic microquasars (hosting a compact star of 1-10 solar masses which accretes matter from a binary companion) also produce relativistic jets. However, no direct evidence of particle acceleration above GeV energies has ever been obtained in microquasar ejections, leaving open the issue of the occurrence and timing of extreme matter energization during jet formation. Here we report the detection of transient gamma-ray emission above 100 MeV from the microquasar Cygnus X-3, an exceptional X-ray binary which sporadically produces powerful radio jets. Four gamma-ray flares (each lasting 1-2 days) were detected by the AGILE satellite simultaneously with special spectral states of Cygnus X-3 during the period mid-2007/mid-2009. Our observations show that very efficient particle acceleration and gamma-ray propagation out of the inner disk of a microquasar usually occur a few days before major relativistic jet ejections. Flaring particle energies can be thousands of times larger than previously detected maximum values (with Lorentz factors of 105 and 102 for electrons and protons, respectively). We show that the transitional nature of gamma-ray flares and particle acceleration above GeV energies in Cygnus X-3 is clearly linked to special radio/X-ray states preceding strong radio flares. Thus gamma-rays provide unique insight into the nature of physical processes in microquasars.Comment: 29 pages (including Supplementary Information), 8 figures, 2 tables version submitted to Nature on August 7, 2009 (accepted version available at http://www.nature.com/nature/journal/vaop/ncurrent/pdf/nature08578.pdf