Frequent and Persistent PLCG1 Mutations in Sezary Cells Directly Enhance PLC gamma 1 Activity and Stimulate NF kappa B, AP-1, and NFAT Signaling

Phospholipase C Gamma 1 (PLCG1) is frequently mutated in primary cutaneous T-cell lymphoma (CTCL). This study functionally interrogated nine PLCG1 mutations (p.R48W, p.S312L, p.D342N, p.S345F, p.S520F, p.R1158H, p.E1163K, p.D1165H, and the in-frame indel p.VYEEDM1161V) identified in Sézary Syndrome, the leukemic variant of CTCL. The mutations were demonstrated in diagnostic samples and persisted in multiple tumor compartments over time, except in patients who achieved a complete clinical remission. In basal conditions, the majority of the mutations confer PLCγ1 gain-of-function activity through increased inositol phosphate production and the downstream activation of NFκB, AP-1, and NFAT transcriptional activity. Phosphorylation of the p.Y783 residue is essential for the proximal activity of wild-type PLCγ1, but we provide evidence that activating mutations do not require p.Y783 phosphorylation to stimulate downstream NFκB, NFAT, and AP-1 transcriptional activity. Finally, the gain-of-function effects associated with the p.VYEEDM1161V indel suggest that the C2 domain may have a role in regulating PLCγ1 activity. These data provide compelling evidence to support the development of therapeutic strategies targeting mutant PLCγ1

Emergency vaccination of rabies under limited resources – combating or containing?

BACKGROUND: Rabies is the most important viral zoonosis from a global perspective. Worldwide efforts to combat the disease by oral vaccination of reservoirs have managed to eradicate wildlife rabies in large areas of central Europe and North-America. Thus, repeated vaccination has been discontinued recently on a geographical scale. However, as rabies has not yet been eradicated globally, a serious risk of re-introduction remains. What is the best spatial design for an emergency vaccination program – particularly if resources are limited? Either, we treat a circular area around the detected case and run the risk of infected hosts leaving the limited control area, because a sufficient immunisation level has not yet been built up. Or, initially concentrate the SAME resources in order to establish a protective ring which is more distant from the infected local area, and which then holds out against the challenge of the approaching epidemic. METHODS: We developed a simulation model to contrast the two strategies for emergency vaccination. The spatial-explicit model is based on fox group home-ranges, which facilitates the simulation of rabies spread to larger areas relevant to management. We used individual-based fox groups to follow up the effects of vaccination in a detailed manner. Thus, regionally – bait distribution orientates itself to standard schemes of oral immunisation programs and locally – baits are assigned to individual foxes. RESULTS: Surprisingly, putting the controlled area ring-like around the outbreak does not outperform the circular area of the same size centred on the outbreak. Only during the very first baitings, does the ring area result in fewer breakouts. But then as rabies is eliminated within the circle area, the respective ring area fails, due to the non-controlled inner part. We attempt to take advantage of the initially fewer breakouts beyond the ring when applying a mixed strategy. Therefore, after a certain number of baitings, the area under control was increased for both strategies towards the same larger circular area. The circle-circle strategy still outperforms the ring-circle strategy and analysis of the spatial-temporal disease spread reveals why: improving control efficacy by means of a mixed strategy is impossible in the field, due to the build-up time of population immunity. CONCLUSION: For practical emergency management of a new outbreak of rabies, the ring-like application of oral vaccination is not a favourable strategy at all. Even if initial resources are substantially low and there is a serious risk of rabies cases outside the limited control area, our results suggest circular application instead of ring vaccination

Living Well with Diabetes: a randomized controlled trial of a telephone-delivered intervention for maintenance of weight loss, physical activity and glycaemic control in adults with type 2 diabetes

Background By 2025, it is estimated that approximately 1.8 million Australian adults (approximately 8.4% of the adult population) will have diabetes, with the majority having type 2 diabetes. Weight management via improved physical activity and diet is the cornerstone of type 2 diabetes management. However, the majority of weight loss trials in diabetes have evaluated short-term, intensive clinic-based interventions that, while producing short-term outcomes, have failed to address issues of maintenance and broad population reach. Telephone-delivered interventions have the potential to address these gaps. Methods/Design Using a two-arm randomised controlled design, this study will evaluate an 18-month, telephone-delivered, behavioural weight loss intervention focussing on physical activity, diet and behavioural therapy, versus usual care, with follow-up at 24 months. Three-hundred adult participants, aged 20-75 years, with type 2 diabetes, will be recruited from 10 general practices via electronic medical records search. The Social-Cognitive Theory driven intervention involves a six-month intensive phase (4 weekly calls and 11 fortnightly calls) and a 12-month maintenance phase (one call per month). Primary outcomes, assessed at 6, 18 and 24 months, are: weight loss, physical activity, and glycaemic control (HbA1c), with weight loss and physical activity also measured at 12 months. Incremental cost-effectiveness will also be examined. Study recruitment began in February 2009, with final data collection expected by February 2013. Discussion This is the first study to evaluate the telephone as the primary method of delivering a behavioural weight loss intervention in type 2 diabetes. The evaluation of maintenance outcomes (6 months following the end of intervention), the use of accelerometers to objectively measure physical activity, and the inclusion of a cost-effectiveness analysis will advance the science of broad reach approaches to weight control and health behaviour change, and will build the evidence base needed to advocate for the translation of this work into population health practice

Malignant inflammation in cutaneous T-cell lymphoma: a hostile takeover

Cutaneous T-cell lymphomas (CTCL) are characterized by the presence of chronically inflamed skin lesions containing malignant T cells. Early disease presents as limited skin patches or plaques and exhibits an indolent behavior. For many patients, the disease never progresses beyond this stage, but in approximately one third of patients, the disease becomes progressive, and the skin lesions start to expand and evolve. Eventually, overt tumors develop and the malignant T cells may disseminate to the blood, lymph nodes, bone marrow, and visceral organs, often with a fatal outcome. The transition from early indolent to progressive and advanced disease is accompanied by a significant shift in the nature of the tumor-associated inflammation. This shift does not appear to be an epiphenomenon but rather a critical step in disease progression. Emerging evidence supports that the malignant T cells take control of the inflammatory environment, suppressing cellular immunity and anti-tumor responses while promoting a chronic inflammatory milieu that fuels their own expansion. Here, we review the inflammatory changes associated with disease progression in CTCL and point to their wider relevance in other cancer contexts. We further define the term "malignant inflammation" as a pro-tumorigenic inflammatory environment orchestrated by the tumor cells and discuss some of the mechanisms driving the development of malignant inflammation in CTCL

Using Web Authoring to Increase Learner Engagement

Trainee teachers use GeoData's WebQuiz (1998) application to create interactive web pages that they then use in their teaching practice schools. The software enables them to create and refine quizzes of questions (multiple choice, text entry and true/false) on the Internet. The quizzes are then freely accessible to pupils through the worldwide web. The activity promotes a deeper knowledge and understanding by the trainee teacher of the topic of the quiz and the issues of assessment. The quiz is seen to be one element of e-learning which includes other activities that facilitate collaboration, publishing and sharing resources such as: chat rooms, interactive web pages, on-line games and simulations, email and on-line portfolios. There are implications drawn from constructivists’ approaches to teaching, situated learning and the current e-learning developments. The theoretical basis for the design of assessment materials is an important element of computer assisted assessment (CAA) and trainee teachers’ understanding of the principles. The conclusions are that the quiz authoring increases engagement in the object of the learning and so learning is enhanced

Anatomy and morphometric aspects of the trachea of Saimiri sciureus Linnaeus, 1758: knowledge for emergency procedures

The aim of this work is to study the morphological characteristics of the trachea of Saimiri sciureus through quantification and measurement of the cartilaginous rings, providing information to facilitate the election of more appropriate endotracheal tube, laryngeal mask or tracheostomy tube for anesthetic and emergency procedures, as it is a species of Neotropical primates most commonly used as biological models, and little is known about their morphology. Nine animals were investigated, being 4 adults and 5 young acquired from the Centro Nacional de Primatas (National Primate Center - CENP) - Ananindeua - PA, which died from natural causes and then fixed in aqueous buffered formalin 10%. Saimiri sciureus trachea comprises an average of 32.8 incomplete rings and an average length of 3.74 cm in young animals, while in adults it demonstrated an average of 30.25 rings and average length of 3.67 cm. The shape of the light and its proportion varied along the trachea. Endotracheal tube with a diameter the 2.0 - 2.5mm, laryngeal mask number 1.0 or tracheostomy tube neonatal Shiley number 3.0, can be placed in animals weighing 600g - 1.2 Kg. Given the great importance of the species studied, which is widely used as a biological model, the detailing on the morphology and morphometry of tracheal animal studies provides new approaches needed in respiratory emergency, as well as, facilitates the development of future anesthetic protocols.<br>Estudou-se as características morfológicas da traqueia do Saimiri sciureus através da quantificação e mensuração dos anéis cartilaginosos, a fim de fornecer informações que facilitem a eleição mais adequada de sonda endotraqueal, máscara laríngea ou cânula de trasqueostomia para procedimentos anestésicos e de emergência, visto que é uma das espécies de primatas neotropicais mais comumente utilizadas como modelos biológicos e pouco se sabe sobre sua morfologia. Foram utilizados nove animais, sendo quatro adultos e cinco jovens, oriundos do Centro Nacional de Primatas (CENP) - Ananindeua - PA, os quais vieram a óbito por causas naturais e, posteriormente, foram fixados em solução aquosa de formol tamponado a 10%. A traqueia do Saimiri sciureus é composta por uma média de 32, 8 anéis incompletos nos animais jovens e comprimento médio de 3, 74cm, já os adultos apresentam uma média de 30, 25 anéis e comprimento médio de 3, 67cm. A forma da luz e suas proporções variaram ao longo da traqueia. Sonda endotraqueal com diâmetro de 2, 0 - 2, 5mm, máscara laríngea número 1, 0 ou cânula de traqueostomia neonatal Shiley número 3, 0, podem ser colocados em animais pesando 600g - 1, 2 K. Dada a grande importância da espécie estudada, que é amplamente utilizada como modelo biológico, o detalhamento sobre o estudo da morfologia e morfometria traqueal animal, fornece novas abordagens necessárias em emergência respiratória, bem como facilita o desenvolvimento de futuros protocolos anestésicos