EDURISK e sapere tecnico | 2002 -2011

Summary of the seismic risk education activities carried out within the projects edurisk 2002 to 2011, addressed to students of vocational schools, their families and to an adult audience. The information, mostly of a technical nature, introduces concepts of vulnerability and esposition as factors on which act to reduce the level of ris

Hedgehog pathway mutations drive oncogenic transformation in high-risk T-cell acute lymphoblastic leukemia.

The role of Hedgehog signaling in normal and malignant T-cell development is controversial. Recently, Hedgehog pathway mutations have been described in T-ALL, but whether mutational activation of Hedgehog signaling drives T-cell transformation is unknown, hindering the rationale for therapeutic intervention. Here, we show that Hedgehog pathway mutations predict chemotherapy resistance in human T-ALL, and drive oncogenic transformation in a zebrafish model of the disease. We found Hedgehog pathway mutations in 16% of 109 childhood T-ALL cases, most commonly affecting its negative regulator PTCH1. Hedgehog mutations were associated with resistance to induction chemotherapy (P = 0.009). Transduction of wild-type PTCH1 into PTCH1-mutant T-ALL cells induced apoptosis (P = 0.005), a phenotype that was reversed by downstream Hedgehog pathway activation (P = 0.007). Transduction of most mutant PTCH1, SUFU, and GLI alleles into mammalian cells induced aberrant regulation of Hedgehog signaling, indicating that these mutations are pathogenic. Using a CRISPR/Cas9 system for lineage-restricted gene disruption in transgenic zebrafish, we found that ptch1 mutations accelerated the onset of notch1-induced T-ALL (P = 0.0001), and pharmacologic Hedgehog pathway inhibition had therapeutic activity. Thus, Hedgehog-activating mutations are driver oncogenic alterations in high-risk T-ALL, providing a molecular rationale for targeted therapy in this disease

Reciprocity as a foundation of financial economics

This paper argues that the subsistence of the fundamental theorem of contemporary financial mathematics is the ethical concept ‘reciprocity’. The argument is based on identifying an equivalence between the contemporary, and ostensibly ‘value neutral’, Fundamental Theory of Asset Pricing with theories of mathematical probability that emerged in the seventeenth century in the context of the ethical assessment of commercial contracts in a framework of Aristotelian ethics. This observation, the main claim of the paper, is justified on the basis of results from the Ultimatum Game and is analysed within a framework of Pragmatic philosophy. The analysis leads to the explanatory hypothesis that markets are centres of communicative action with reciprocity as a rule of discourse. The purpose of the paper is to reorientate financial economics to emphasise the objectives of cooperation and social cohesion and to this end, we offer specific policy advice

Body size estimation in women with anorexia nervosa and healthy controls using 3D avatars

A core feature of anorexia nervosa is an over-estimation of body size. However, quantifying this over-estimation has been problematic as existing methodologies introduce a series of artefacts and inaccuracies in the stimuli used for judgements of body size. To overcome these problems, we have: (i) taken 3D scans of 15 women who have symptoms of anorexia (referred to henceforth as anorexia spectrum disorders, ANSD) and 15 healthy control women, (ii) used a 3D modelling package to build avatars from the scans, (iii) manipulated the body shapes of these avatars to reflect biometrically accurate, continuous changes in body mass index (BMI), (iv) used these personalized avatars as stimuli to allow the women to estimate their body size. The results show that women who are currently receiving treatment for ANSD show an over-estimation of body size which rapidly increases as their own BMI increases. By contrast, the women acting as healthy controls can accurately estimate their body size irrespective of their own BMI. This study demonstrates the viability of combining 3D scanning and CGI techniques to create personalised realistic avatars of individual patients to directly assess their body image perception

Tegumentary leishmaniasis and coinfections other than HIV

<div><p>Background</p><p>Tegumentary leishmaniasis (TL) is a disease of skin and/or mucosal tissues caused by <i>Leishmania</i> parasites. TL patients may concurrently carry other pathogens, which may influence the clinical outcome of TL.</p><p>Methodology and principal findings</p><p>This review focuses on the frequency of TL coinfections in human populations, interactions between <i>Leishmania</i> and other pathogens in animal models and human subjects, and implications of TL coinfections for clinical practice. For the purpose of this review, TL is defined as all forms of cutaneous (localised, disseminated, or diffuse) and mucocutaneous leishmaniasis. Human immunodeficiency virus (HIV) coinfection, superinfection with skin bacteria, and skin manifestations of visceral leishmaniasis are not included. We searched MEDLINE and other databases and included 73 records: 21 experimental studies in animals and 52 studies about human subjects (mainly cross-sectional and case studies). Several reports describe the frequency of <i>Trypanosoma cruzi</i> coinfection in TL patients in Argentina (about 41%) and the frequency of helminthiasis in TL patients in Brazil (15% to 88%). Different hypotheses have been explored about mechanisms of interaction between different microorganisms, but no clear answers emerge. Such interactions may involve innate immunity coupled with regulatory networks that affect quality and quantity of acquired immune responses. Diagnostic problems may occur when concurrent infections cause similar lesions (e.g., TL and leprosy), when different pathogens are present in the same lesions (e.g., <i>Leishmania</i> and <i>Sporothrix schenckii</i>), or when similarities between phylogenetically close pathogens affect accuracy of diagnostic tests (e.g., serology for leishmaniasis and Chagas disease). Some coinfections (e.g., helminthiasis) appear to reduce the effectiveness of antileishmanial treatment, and drug combinations may cause cumulative adverse effects.</p><p>Conclusions and significance</p><p>In patients with TL, coinfection is frequent, it can lead to diagnostic errors and delays, and it can influence the effectiveness and safety of treatment. More research is needed to unravel how coinfections interfere with the pathogenesis of TL.</p></div

Phase II randomised discontinuation trial of brivanib in patients with advanced solid tumours

Background: Brivanib is a selective inhibitor of vascular endothelial growth factor and fibroblast growth factor (FGF) signalling. We performed a phase II randomised discontinuation trial of brivanib in 7 tumour types (soft-tissue sarcomas [STS], ovarian cancer, breast cancer, pancreatic cancer, non-small-cell lung cancer [NSCLC], gastric/esophageal cancer and transitional cell carcinoma [TCC]). Patients and methods: During a 12-week open-label lead-in period, patients received brivanib 800 mg daily and were evaluated for FGF2 status by immunohistochemistry. Patients with stable disease at week 12 were randomised to brivanib or placebo. A study steering committee evaluated week 12 response to determine if enrolment in a tumour type would continue. The primary objective was progression-free survival (PFS) for brivanib versus placebo in patients with FGF2-positive tumours. Results: A total of 595 patients were treated, and stable disease was observed at the week 12 randomisation point in all tumour types. Closure decisions were made for breast cancer, pancreatic cancer, NSCLC, gastric cancer and TCC. Criteria for expansion were met for STS and ovarian cancer. In 53 randomised patients with STS and FGF2-positive tumours, the median PFS was 2.8 months for brivanib and 1.4 months for placebo (hazard ratio [HR]: 0.58, p Z 0.08). For all randomised patients with sarcomas, the median PFS was 2.8 months (95% confidence interval [CI]: 1.4e4.0) for those treated with brivanib compared with 1.4 months (95% CI: 1.3e1.6) for placebo (HR Z 0.64, 95% CI: 0.38e1.07; p Z 0.09). In the 36 randomised patients with ovarian cancer and FGF2-positive tumours, the median PFS was 4.0 (95% CI: 2.6e4.2) months for brivanib and 2.0 months (95% CI: 1.2e2.7) for placebo (HR: 0.56, 95% CI: 0.26e1.22). For all randomised patients with ovarian cancer, the median PFS in those randomised to brivanib was 4.0 months (95% CI: 2.6e4.2) and was 2.0 months (95% CI: 1.2e2.7) in those randomised to placebo (HR Z 0.54, 95% CI: 0.25e1.17; p Z 0.11). Conclusion: Brivanib demonstrated activity in STS and ovarian cancer with an acceptable safety profile. FGF2 expression, as defined in the protocol, is not a predictive biomarker of the efficacy of brivanib

Adaptive servoventilation improves cardiac function and respiratory stability

Cheyne–Stokes respiration (CSR) in patients with chronic heart failure (CHF) is of major prognostic impact and expresses respiratory instability. Other parameters are daytime pCO2, VE/VCO2-slope during exercise, exertional oscillatory ventilation (EOV), and increased sensitivity of central CO2 receptors. Adaptive servoventilation (ASV) was introduced to specifically treat CSR in CHF. Aim of this study was to investigate ASV effects on CSR, cardiac function, and respiratory stability. A total of 105 patients with CHF (NYHA ≥ II, left ventricular ejection fraction (EF) ≤ 40%) and CSR (apnoea–hypopnoea index ≥ 15/h) met inclusion criteria. According to adherence to ASV treatment (follow-up of 6.7 ± 3.2 months) this group was divided into controls (rejection of ASV treatment or usage <50% of nights possible and/or <4 h/night; n = 59) and ASV (n = 56) adhered patients. In the ASV group, ventilator therapy was able to effectively treat CSR. In contrast to controls, NYHA class, EF, oxygen uptake, 6-min walking distance, and NT-proBNP improved significantly. Moreover, exclusively in these patients pCO2, VE/VCO2-slope during exercise, EOV, and central CO2 receptor sensitivity improved. In CHF patients with CSR, ASV might be able to improve parameters of SDB, cardiac function, and respiratory stability

Risk Factors, Molecular Epidemiology and Outcomes of Ertapenem-Resistant, Carbapenem-Susceptible Enterobacteriaceae: A Case-Case-Control Study

Background: Increasing prevalence of ertapenem-resistant, carbapenem-susceptible Enterobacteriaceae (ERE) in Singapore presents a major therapeutic problem. Our objective was to determine risk factors associated with the acquisition of ERE in hospitalized patients; to assess associated patient outcomes; and to describe the molecular characteristics of ERE. Methods: A retrospective case-case-control study was conducted in 2009 at a tertiary care hospital. Hospitalized patients with ERE and those with ertapenem-sensitive Enterobacteriaceae (ESE) were compared with a common control group consisting of patients with no prior gram-negative infections. Risk factors analyzed included demographics; co-morbidities; instrumentation and antibiotic exposures. Two parallel multivariate logistic regression models were performed to identify independent variables associated with ERE and ESE acquisition respectively. Clinical outcomes were compared between ERE and ESE patients. Results: Twenty-nine ERE cases, 29 ESE cases and 87 controls were analyzed. Multivariate logistic regression showed that previous hospitalization (Odds ratio [OR], 10.40; 95 % confidence interval [CI], 2.19–49.20) and duration of fluoroquinolones exposure (OR, 1.18 per day increase; 95 % CI, 1.05–1.34) were unique independent predictors for acquiring ERE. Duration of 4 th-generation cephalosporin exposure was found to predict for ESE acquisition (OR, 1.63 per day increase; 95 % CI, 1.05– 2.54). In-hospital mortality rates and clinical response rates were significantly different between ERE and ESE groups