Drug Discovery for Duchenne Muscular Dystrophy via Utrophin Promoter Activation Screening

Background: Duchenne muscular dystrophy (DMD) is a devastating muscle wasting disease caused by mutations in dystrophin, a muscle cytoskeletal protein. Utrophin is a homologue of dystrophin that can functionally compensate for its absence when expressed at increased levels in the myofibre, as shown by studies in dystrophin-deficient mice. Utrophin upregulation is therefore a promising therapeutic approach for DMD. The use of a small, drug-like molecule to achieve utrophin upregulation offers obvious advantages in terms of delivery and bioavailability. Furthermore, much of the time and expense involved in the development of a new drug can be eliminated by screening molecules that are already approved for clinical use. Methodology/Principal Findings: We developed and validated a cell-based, high-throughput screening assay for utrophin promoter activation, and used it to screen the Prestwick Chemical Library of marketed drugs and natural compounds. Initial screening produced 20 hit molecules, 14 of which exhibited dose-dependent activation of the utrophin promoter and were confirmed as hits. Independent validation demonstrated that one of these compounds, nabumetone, is able to upregulate endogenous utrophin mRNA and protein, in C2C12 muscle cells. Conclusions/Significance: We have developed a cell-based, high-throughput screening utrophin promoter assay. Using this assay, we identified and validated a utrophin promoter-activating drug, nabumetone, for which pharmacokinetics an

Psychological consequences in victims of maritime piracy: the Italian experience.

BACKGROUND AND AIM: Maritime piracy is a worrying phenomenon. Its recurrence in the last few years iscausing several problems to the safety of maritime routes. In spite of the number of seafarers kidnappedand maintained in captivity, psychological/mental disorders developed in victims of these criminal actshave not been investigated. This study has assessed psychological consequences of kidnapping in a groupof Italian seafarers held in captivity from 7 to 10 months. MATERIALS AND METHODS: Four Italian seafarers were examined at the 5th month after release. An initial, semi-structured interview was followed by 2 structured clinical evaluations for assessing the possible presence of psychopathological disorders. Instruments used were the Cognitive Behavioural Assessment (CBA 2.0) and the Clinician-Administered Post Traumatic Stress Disorder (PTSD) Scale (CAPS-DX). RESULTS: All victims showed high scores of state anxiety (56.00 ± 3.36) and social adjustment disorder (12.75 ± 2.21) to CBA 2.0. Moreover, 3 of them revealed traits of anxiety (58.75 ± 8.50) and emotionalinstability (8.25 ± 2.50). Two of them had somatic disorders (63.25 ± 15.94), depression (17.25 ± 4.78) and phobic problems (91.00 ± 7.02). In 3 of 4 victims examined, a PTSD diagnosis was made. Symptomsof recall resulted in higher CAPS-DX (13.00 ± 4.05) scores. CONCLUSIONS: Traumatic experiences such as being kept in captivity by pirates could entail relevant psychopathological disorders in victims and their families. Quality care interventions, aimed to develop paradigms for resilience training, represent a priority. An international partnerships and collaboration between institutions, clinicians and seafarer organisations can be useful to evaluate psychological conditions of these workers

Decomposition of cumulative chi-squared statistics, with some new tools for their interpretation

It is well known that the Pearson statistic χ2 can perform poorly in studying the association between ordinal categorical variables. Taguchi’s and Hirotsu’s statistics have been introduced in the literature as simple alternatives to Pearson’s chi-squared test for contingency tables with ordered categorical variables. The aim of this paper is to shed new light on these statistics, stressing their interpretations and characteristics, providing in this way new and different interpretations of these statistics. Moreover, a theoretical scheme is developed showing the links between the different proposals and classes of cumulative chi-squared statistical tests, starting from a unifying index of heterogeneity, unalikeability and variability measures. Users of statistics may find it attractive to understand well the different proposals. Some decompositions of both statistics are also highlighted. This paper presents a case study of optimizing the polysilicon deposition process in a very large-scale integrated circuit, to identify the optimal combination of factor levels. It is obtained by means of the information coming from a correspondence analysis based on Taguchi’s statistic and regression models for binary dependent variables. A new optimal combination of factor levels is obtained, different from many others proposed in the literature for this data