Review of presentations at the 6th European Lupus Meeting 3-5 March 2005.

The 6th European Lupus Meeting was held at the Royal College of Physicians of London and was attended by 450 delegates. The conference brought together leading speakers from Europe and North America who reviewed current knowledge and exciting new developments in both clinical and basic science aspects of systemic lupus erythematosus. This review summarizes the major points covered in each session

Development of Pharmacological Strategies for Mitochondrial Disorders.

Mitochondrial diseases are an unusually genetically and phenotypically heterogeneous group of disorders, which are extremely challenging to treat. Currently, apart from supportive therapy, there are no effective treatments for the vast majority of mitochondrial diseases. Huge scientific effort however, is continuously put into understanding the mechanisms underlying mitochondrial disease pathology and developing potential treatments. To date a variety of treatments have been evaluated by randomised clinical trials, but unfortunately none of these has delivered breakthrough results. Increased understanding of mitochondrial pathways and the development of many animal models, some of which are accurate phenocopies of human diseases, are facilitating the discovery and evaluation of novel prospective treatments. Targeting reactive oxygen species has been a treatment of interest for many years, however only in recent years has it been possible to direct antioxidant delivery specifically into the mitochondria. Increasing mitochondrial biogenesis, whether by pharmacological approaches, dietary manipulation or exercise therapy is also currently an active area of research. Modulating mitochondrial dynamics and mitophagy and the mitochondrial membrane lipid milieu have also emerged as possible treatment strategies. Recent technological advances in gene therapy, including allotopic and transkingdom gene expression and mitochondrially-targeted transcription activator-like nucleases, have led to promising results in cell and animal models of mitochondrial diseases, but most of these techniques are still far from clinical applicability

The AMR problem: demanding economies, biological margins, and co-producing alternative strategies

 This is the final version. Available from Palgrave Macmillan via the DOI in this record.Widespread antimicrobial resistance (AMR) poses a threat to public and animal health, and has consequences for the structure and sustainability of food production. The problem is often framed as one of inappropriate antimicrobial use, which drives emergence and selection of resistant microbes. The answer to this framing of the problem is to lower disease incidence and transmission rates, regulate antimicrobial uses and to educate prescribers and users of medicines. In this paper we argue that this seemingly straightforward programme of action is beset by at least two difficulties. First, in many parts of the world, disease dynamics and antimicrobial uses are embedded within biosocially demanding settings. Second, antibiotic use is one among many possible drivers of resistance. We focus on the aquatic environment and aquacultural food production where resistance drivers may relate to a variety of processes. Using interviews, survey data, and participatory modelling exercises with competency groups in Bangladesh’s shrimp and prawn aquaculture sector, we demonstrate the need to understand economic and biological drivers of disease, farmer adaptations to disease risks and the potential paradox of pursuing pathogen-free food production as a means to reduce AMR risks. We argue that the AMR problem needs to be framed as an adaptive rather than technical challenge, and involves ownership, change and experimentation across a range of relevant sites.Economic and Social Research Council (ESRC

Mapping the complete glycoproteome of virion-derived HIV-1 gp120 provides insights into broadly neutralizing antibody binding

The surface envelope glycoprotein (SU) of Human immunodeficiency virus type 1 (HIV-1), gp120SU plays an essential role in virus binding to target CD4+ T-cells and is a major vaccine target. Gp120 has remarkably high levels of N-linked glycosylation and there is considerable evidence that this “glycan shield” can help protect the virus from antibody-mediated neutralization. In recent years, however, it has become clear that gp120 glycosylation can also be included in the targets of recognition by some of the most potent broadly neutralizing antibodies. Knowing the site-specific glycosylation of gp120 can facilitate the rational design of glycopeptide antigens for HIV vaccine development. While most prior studies have focused on glycan analysis of recombinant forms of gp120, here we report the first systematic glycosylation site analysis of gp120 derived from virions produced by infected T lymphoid cells and show that a single site is exclusively substituted with complex glycans. These results should help guide the design of vaccine immunogens

Home Parenteral Nutrition in Patients with Advanced Cancer: A Systematic Review and Meta-Analysis

The use of home parenteral nutrition (HPN) in patients with incurable cancer remains controversial with significant variation worldwide. We aimed to systematically evaluate the literature from 1960 to 2018 examining the use of HPN in advanced cancer patients for all intestinal failure indications and assess the potential benefits/burdens of HPN in this cohort of patients. The primary end point was survival and secondary end points were quality of life and nutritional/performance status. Meta-analysis was performed with a random effects model, where suitable. Of 493 studies retrieved, 22 met the quality inclusion criteria. Studies were mainly conducted in Western countries (Italy, USA, Canada, Germany), including a total of 3564 patients (mean age 57.8 years). Mean duration for HPN was 5.0 mo. Mean overall survival was 7.3 mo. Patients with improved performance status survived for longer on HPN. Quality of life was sparsely reported though there was no observed negative impact of PN. HPN-related complications were reported in eight studies only and were mainly catheter-related blood stream infections. In conclusion, HPN is used for several indications in advanced cancer, though there is significant heterogeneity of results. Disparities in geographical distribution of the studies may reflect variation in accessing HPN

The pleiotropic effects of decanoic acid treatment on mitochondrial function in fibroblasts from patients with complex I deficient Leigh syndrome

There is growing interest in the use of the ketogenic diet (KD) to treat inherited metabolic diseases including mitochondrial disorders. However, neither the mechanism whereby the diet may be working, nor if it could benefit all patients with mitochondrial disease, is known. This study focusses on decanoic acid (C10), a component of the medium chain triglyceride KD, and a ligand for the nuclear receptor PPAR-γ known to be involved in mitochondrial biogenesis. The effects of C10 were investigated in primary fibroblasts from a cohort of patients with Leigh syndrome (LS) caused by nuclear-encoded defects of respiratory chain complex I, using mitochondrial respiratory chain enzyme assays, gene expression microarray, qPCR and flow cytometry. Treatment with C10 increased citrate synthase activity, a marker of cellular mitochondrial content, in 50 % of fibroblasts obtained from individuals diagnosed with LS in a PPAR-γ-mediated manner. Gene expression analysis and qPCR studies suggested that treating cells with C10 supports fatty acid metabolism, through increasing ACADVL and CPT1 expression, whilst downregulating genes involved in glucose metabolism (PDK3, PDK4). PCK2, involved in blocking glucose metabolism, was upregulated, as was CAT, encoding catalase. Moreover, treatment with C10 also decreased oxidative stress in complex I deficient (rotenone treated) cells. However, since not all cells from subjects with LS appeared to respond to C10, prior cellular testing in vitro could be employed as a means for selecting individuals for subsequent clinical studies involving C10 preparations

PERTANGGUNGJAWABAN PIDANA BAGI YANG MENYEDIAKAN TEMPAT PENYALAHGUNAAN NARKOTIKA DILIHAT DARI PERSPEKTIF HUKUM PIDANA DAN HUKUM PIDANA ISLAM

Mudahnya mengakses narkotika ditandai dari peredaran yang sulit dicegah, banyaknya oknum yang terlibat, teknik distribusi yang semakin bervariasi hingga banyaknya tempat- tempat hiburan yang memudahkan untuk mengakses benda-benda terlarang tersebut. Tujuan dari penelitian ini adalah ingin mengetahui pertanggungjawaban pidana bagi penyedia tempat penyalahgunaan narkotika dilihat dari perspektif Hukum Pidana dan Hukum Pidana Islam. Pendekatan dalam penelitian ini adalah pendekatan kualitatif untuk memahami fenomena apa saja yang dialami oleh subjek penelitian dengan jenis penelitian book survey dan content analysis. Sedangkan teknik dalam pengumpulan data dalam penelitian ini menggunakan library research. Berdasarkna penelitian yang dilakukan diperoleh hasil dari penelitian sebagai berikut, pertama yaitu pertanggungjawaban pidana bagi penyedia tempat penyalahgunaan narkotika dapat dilihat berdasarkan pasal 55 KUHP dan Undang-Undang Nomor 35 tahun 2009 pasal 131. Kedua; di dalam Al-Qur‟an dan Sunnah tidak menjelaskan tentang sanksi hukum bagi produsen, pengedar narkoba ataupun penyedia tempat penyalahgunaan narkotika, oleh karena itu hukum bagi mereka adalah takzi

Convexity-Increasing Morphs of Planar Graphs

We study the problem of convexifying drawings of planar graphs. Given any planar straight-line drawing of an internally 3-connected graph, we show how to morph the drawing to one with strictly convex faces while maintaining planarity at all times. Our morph is convexity-increasing, meaning that once an angle is convex, it remains convex. We give an efficient algorithm that constructs such a morph as a composition of a linear number of steps where each step either moves vertices along horizontal lines or moves vertices along vertical lines. Moreover, we show that a linear number of steps is worst-case optimal. To obtain our result, we use a well-known technique by Hong and Nagamochi for finding redrawings with convex faces while preserving y-coordinates. Using a variant of Tutte's graph drawing algorithm, we obtain a new proof of Hong and Nagamochi's result which comes with a better running time. This is of independent interest, as Hong and Nagamochi's technique serves as a building block in existing morphing algorithms.Comment: Preliminary version in Proc. WG 201