Dupilumab for bullous pemphigoid with intractable pruritus

Bullous pemphigoid (BP) is an autoimmune blistering disorder that predominantly affects the elderly. Treatment regimens typically include topical and systemic immunosuppressive medications. Although effective, systemic corticosteroids are sometimes poorly tolerated in the elderly patient, contributing to the overall morbidity and mortality of BP. Dupilumab is a monoclonal antibody targeting interleukin 4 receptor alpha (IL4R?), approved for the treatment of atopic dermatitis, as well as moderate to severe asthma and chronic rhinosinusitis with nasal polyposis. In recent reports, dupilumab has been successfully used off-label to treat a variety of pruritic disorders, including chronic spontaneous urticaria [1], anal and genital itch [2], allergic contact dermatitis [3], and prurigo nodularis [4, 5]. We report here a case of an elderly patient with refractory BP whose symptoms of pruritus and blistering became well-controlled with the addition of dupilumab to the treatment regimen

Reasons for the Disappearing Jury Trial: Perspectives from Attorneys and Judges

The article discusses the results of a national survey of U.S. attorneys and judges on the possible reasons behind the disappearing jury trials in the country and the potential system effects on the decline of jury trials

Arsenite binds to the RING finger domains of RNF20-RNF40 histone E3 ubiquitin ligase and inhibits DNA double-strand break repair.

Arsenic is a widespread environmental contaminant. However, the exact molecular mechanisms underlying the carcinogenic effects of arsenic remain incompletely understood. Core histones can be ubiquitinated by RING finger E3 ubiquitin ligases, among which the RNF20-RNF40 heterodimer catalyzes the ubiquitination of histone H2B at lysine 120. This ubiquitination event is important for the formation of open and biochemically accessible chromatin fiber that is conducive for DNA repair. Herein, we found that arsenite could bind directly to the RING finger domains of RNF20 and RNF40 in vitro and in cells, and treatment with arsenite resulted in substantially impaired H2B ubiquitination in multiple cell lines. Exposure to arsenite also diminished the recruitment of BRCA1 and RAD51 to laser-induced DNA double-strand break (DSB) sites, compromised DNA DSB repair in human cells, and rendered cells sensitive toward a radiomimetic agent, neocarzinostatin. Together, the results from the present study revealed, for the first time, that arsenite may exert its carcinogenic effect by targeting cysteine residues in the RING finger domains of histone E3 ubiquitin ligase, thereby altering histone epigenetic mark and compromising DNA DSB repair. Our results also suggest arsenite as a general inhibitor for RING finger E3 ubiquitin ligases

Stop Thinking and Start Doing: Three-Year Accelerator-to-Practice Program as a Market-Based Solution for Legal Education

Law school applications are the lowest they‘ve been in thirty years. Law school enrollment is down significantly from last year, and analysts see the trend continuing for the 2014–2015 academic year. The lack of current job opportunities and the potential for massive student loan payments has scared away prospective students from entering the legal profession. Commentators continue to suggest that obtaining a legal education might no longer be worth the investment. This Essay disagrees. Too many people suffer unnecessary harms due to a lack of affordable legal services. Continued progress in achieving necessary access to legal assistance relies on a constant influx of new, talented, and energetic lawyers. Providing the best training possible to each new generation of lawyers is essential for the continued development of individual liberties and the equitable treatment of all in our society. Many thinkers throughout legal academia are responding to these concerns by carefully considering what steps will actually help students, institutions, and the overall system of justice. Too many respond to current concerns about legal education with what we believe is the primary fallacy of legal educators today: namely, that the mission of law schools is to prepare students to think like lawyers. This Essay argues that the central function of law school is to prepare students to be lawyers, and to do what lawyers do. Although these two aims might seem similar, they are actually representative of the wide gulf between two distinct concepts: that of law school as a liberal arts education in law and that of law school as a professional education for lawyers. These goals are not mutually exclusive, but the former concept has dominated legal study development. Decisions regarding curriculum, faculty appointments, standards for promotion and tenure, and pay incentives have solidified legal academia‘s preference for the theoretical over the experiential approach to learning

A requirements engineering and management training course for software development professionals

Devising a course for software professionals working in industry depends on several factors. In order to create a course that fulfils professionals’ expectations, it is important to take account of the skills of the participants, the time available, and the specific topics to be covered. This paper presents the curriculum of a course in requirements engineering and management intended for software developers with a first-level academic degree in computing and experience in developing real software solutions. This context requires the course to concentrate on topics that were not taught in the participants’ previous education and that can have a positive impact on their daily practices

The Swiss Board Directors Network in 2009

We study the networks formed by the directors of the most important Swiss boards and the boards themselves for the year 2009. The networks are obtained by projection from the original bipartite graph. We highlight a number of important statistical features of those networks such as degree distribution, weight distribution, and several centrality measures as well as their interrelationships. While similar statistics were already known for other board systems, and are comparable here, we have extended the study with a careful investigation of director and board centrality, a k-core analysis, and a simulation of the speed of information propagation and its relationships with the topological aspects of the network such as clustering and link weight and betweenness. The overall picture that emerges is one in which the topological structure of the Swiss board and director networks has evolved in such a way that special actors and links between actors play a fundamental role in the flow of information among distant parts of the network. This is shown in particular by the centrality measures and by the simulation of a simple epidemic process on the directors network.Comment: Submitted to The European Physical Journal

Piecewise smooth systems near a co-dimension 2 discontinuity manifold: can one say what should happen?

We consider a piecewise smooth system in the neighborhood of a co-dimension 2 discontinuity manifold $\Sigma$. Within the class of Filippov solutions, if $\Sigma$ is attractive, one should expect solution trajectories to slide on $\Sigma$. It is well known, however, that the classical Filippov convexification methodology is ambiguous on $\Sigma$. The situation is further complicated by the possibility that, regardless of how sliding on $\Sigma$ is taking place, during sliding motion a trajectory encounters so-called generic first order exit points, where $\Sigma$ ceases to be attractive. In this work, we attempt to understand what behavior one should expect of a solution trajectory near $\Sigma$ when $\Sigma$ is attractive, what to expect when $\Sigma$ ceases to be attractive (at least, at generic exit points), and finally we also contrast and compare the behavior of some regularizations proposed in the literature. Through analysis and experiments we will confirm some known facts, and provide some important insight: (i) when $\Sigma$ is attractive, a solution trajectory indeed does remain near $\Sigma$, viz. sliding on $\Sigma$ is an appropriate idealization (of course, in general, one cannot predict which sliding vector field should be selected); (ii) when $\Sigma$ loses attractivity (at first order exit conditions), a typical solution trajectory leaves a neighborhood of $\Sigma$; (iii) there is no obvious way to regularize the system so that the regularized trajectory will remain near $\Sigma$ as long as $\Sigma$ is attractive, and so that it will be leaving (a neighborhood of) $\Sigma$ when $\Sigma$ looses attractivity. We reach the above conclusions by considering exclusively the given piecewise smooth system, without superimposing any assumption on what kind of dynamics near $\Sigma$ (or sliding motion on $\Sigma$) should have been taking place.Comment: 19 figure