Role of protein kinase C-delta in the regulation of collagen gene expression in scleroderma fibroblasts

Working with cultured dermal fibroblasts derived from control individuals and patients with systemic sclerosis (SSc), we have examined the effects of protein kinase C-delta (PKC-delta) on type I collagen biosynthesis and steady-state levels of COL1A1 and COL3A1 mRNAs. Rottlerin, a specific inhibitor of PKC-delta, exerted a powerful, dose-dependent inhibition of type I and type III collagen gene expression in normal and SSc cells. Optimal rottlerin concentrations caused a 70-90% inhibition of type I collagen production, a \u3e80% reduction in COL1A1 mRNA, and a \u3e70% reduction in COL3A1 mRNA in both cell types. In vitro nuclear transcription assays and transient transfections with COL1A1 promoter deletion constructs demonstrated that rottlerin profoundly reduced COL1A1 transcription and that this effect required a 129-bp promoter region encompassing nucleotides -804 to -675. This COL1A1 segment imparted rottlerin sensitivity to a heterologous promoter. Cotransfections of COL1A1 promoter constructs with a dominant-negative PKC-delta expression plasmid showed that suppression of this kinase silenced COL1A1 promoter activity. The results indicate that PKC-delta participates in the upregulation of collagen gene transcription in SSc and suggest that treatment with PKC-delta inhibitors could suppress fibrosis in this disease

Mobility patterns of the elderly tourist in Algarve

The present work is part of the Project for Scientific Research and Techno-logical Development "Accessibility for All in Tourism" focuses on modal in-terfaces designed according to the concepts of "Universal Design" and "Age Sensitive Design". In this project 851 surveys were carried out for elderly tourists, who arrived in Algarve (Portugal) through the international Airport of Faro, in the summer of 2018, with a view to understanding their prefer-ences and needs in terms of mobility. It presents the characterization of the senior tourist in Algarve, according to: gender, age, academic qualification, situation in the relation to the profession, nationality, disability and/or disa-bilities that affects mobility and the need to use technical aids to move. It analyses and compares, from the point of view of sustainable mobility, the mobility of the elderly tourist, by gender and age group, in the country where they reside and in the Algarve region. This information is useful for local au-thorities and for transport operators in order to make the mobility of elderly tourists, in Algarve, more sustainable from a social, economic and environ-mental standpoint.The Research Project ACCES4ALL - Accessibility for All in Tourisminfo:eu-repo/semantics/publishedVersio

Three dimensional rotational angiography imaging of double aortic arch vascular ring

Three dimensional (3D) rotational angiography is a technique used increasingly for imaging in congenital heart disease. Here the use of this technique for imaging of double aortic arch vascular ring is described and the advantages of this modality. are discussed. 3D rotational angiography is an excellent tool for imaging of various vascular anomalies. It provides high quality accurate images through a quick and safe procedure.peer-reviewe

Cognitive architectures as Lakatosian research programmes: two case studies

Cognitive architectures - task-general theories of the structure and function of the complete cognitive system - are sometimes argued to be more akin to frameworks or belief systems than scientific theories. The argument stems from the apparent non-falsifiability of existing cognitive architectures. Newell was aware of this criticism and argued that architectures should be viewed not as theories subject to Popperian falsification, but rather as Lakatosian research programs based on cumulative growth. Newell's argument is undermined because he failed to demonstrate that the development of Soar, his own candidate architecture, adhered to Lakatosian principles. This paper presents detailed case studies of the development of two cognitive architectures, Soar and ACT-R, from a Lakatosian perspective. It is demonstrated that both are broadly Lakatosian, but that in both cases there have been theoretical progressions that, according to Lakatosian criteria, are pseudo-scientific. Thus, Newell's defense of Soar as a scientific rather than pseudo-scientific theory is not supported in practice. The ACT series of architectures has fewer pseudo-scientific progressions than Soar, but it too is vulnerable to accusations of pseudo-science. From this analysis, it is argued that successive versions of theories of the human cognitive architecture must explicitly address five questions to maintain scientific credibility

Real-Time Predictions of Reservoir Size and Rebound Time during Antiretroviral Therapy Interruption Trials for HIV

Monitoring the efficacy of novel reservoir-reducing treatments for HIV is challenging. The limited ability to sample and quantify latent infection means that supervised antiretroviral therapy (ART) interruption studies are generally required. Here we introduce a set of mathematical and statistical modeling tools to aid in the design and interpretation of ART-interruption trials. We show how the likely size of the remaining reservoir can be updated in real-time as patients continue off treatment, by combining the output of laboratory assays with insights from models of reservoir dynamics and rebound. We design an optimal schedule for viral load sampling during interruption, whereby the frequency of follow-up can be decreased as patients continue off ART without rebound. While this scheme can minimize costs when the chance of rebound between visits is low, we find that the reservoir will be almost completely reseeded before rebound is detected unless sampling occurs at least every two weeks and the most sensitive viral load assays are used. We use simulated data to predict the clinical trial size needed to estimate treatment effects in the face of highly variable patient outcomes and imperfect reservoir assays. Our findings suggest that large numbers of patients—between 40 and 150—will be necessary to reliably estimate the reservoir-reducing potential of a new therapy and to compare this across interventions. As an example, we apply these methods to the two “Boston patients”, recipients of allogeneic hematopoietic stem cell transplants who experienced large reductions in latent infection and underwent ART-interruption. We argue that the timing of viral rebound was not particularly surprising given the information available before treatment cessation. Additionally, we show how other clinical data can be used to estimate the relative contribution that remaining HIV+ cells in the recipient versus newly infected cells from the donor made to the residual reservoir that eventually caused rebound. Together, these tools will aid HIV researchers in the evaluating new potentially-curative strategies that target the latent reservoir

Chronic pain, psychopathology, and DSM-5 somatic symptom disorder

Unlike acute pain that warns us of injury or disease, chronic or persistent pain serves no adaptive purpose. Though there is no agreed on definition of chronic pain, it is commonly referred to as pain that is without biological value, lasting longer than the typical healing time, not responsive to treatments based on specific remedies, and of a duration greater than 6 months. Chronic pain that is severe and intractable has detrimental consequences, including psychological distress, job loss, social isolation, and, not surprisingly, it is highly comorbid with depression and anxiety. Historically, pain without an apparent anatomical or neurophysiological origin was labelled as psychopathological. This approach is damaging to the patient and provider alike. It pollutes the therapeutic relationship by introducing an element of mutual distrust as well as implicit, if not explicit, blame. It is demoralizing to the patient who feels at fault, disbelieved, and alone. Moreover, many medically unexplained pains are now understood to involve an interplay between peripheral and central neurophysiological mechanisms that have gone awry. The new Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, somatic symptom disorder overpsychologizes people with chronic pain; it has low sensitivity and specificity, and it contributes to misdiagnosis, as well as unnecessary stigma. Adjustment disorder remains the most appropriate, accurate, and acceptable diagnosis for people who are overly concerned about their pain.Preparation of this manuscript was facilitated by support from a Canadian Institutes of Health Research (CIHR) Canada Research Chair in Health Psychology awarded to Dr Katz and a CIHR Canada Graduate Master’s Award to Samantha Fashler