Targeting myocardial remodelling to develop novel therapies for heart failure: a position paper from the Working Group on Myocardial Function of the European Society of Cardiology

The failing heart is characterized by complex tissue remodelling involving increased cardiomyocyte death, and impairment of sarcomere function, metabolic activity, endothelial and vascular function, together with increased inflammation and interstitial fibrosis. For years, therapeutic approaches for heart failure (HF) relied on vasodilators and diuretics which relieve cardiac workload and HF symptoms. The introduction in the clinic of drugs interfering with beta-adrenergic and angiotensin signalling have ameliorated survival by interfering with the intimate mechanism of cardiac compensation. Current therapy, though, still has a limited capacity to restore muscle function fully, and the development of novel therapeutic targets is still an important medical need. Recent progress in understanding the molecular basis of myocardial dysfunction in HF is paving the way for development of new treatments capable of restoring muscle function and targeting specific pathological subsets of LV dysfunction. These include potentiating cardiomyocyte contractility, increasing cardiomyocyte survival and adaptive hypertrophy, increasing oxygen and nutrition supply by sustaining vessel formation, and reducing ventricular stiffness by favourable extracellular matrix remodelling. Here, we consider drugs such as omecamtiv mecarbil, nitroxyl donors, cyclosporin A, SERCA2a (sarcoplasmic/endoplasmic Ca(2 +) ATPase 2a), neuregulin, and bromocriptine, all of which are currently in clinical trials as potential HF therapies, and discuss novel molecular targets with potential therapeutic impact that are in the pre-clinical phases of investigation. Finally, we consider conceptual changes in basic science approaches to improve their translation into successful clinical applications.

Dickens, Hogarth and artistic perception: the case of Nicholas Nickleby

This essay considers the interest shared by William Hogarth and Charles Dickens on the idea of instrumentality in the art of realism. Taking his cue from eighteenth-century epistemological philosophy, Hogarth developed an idea of beauty and realism as insisting upon the need for human subjectivity or perspective. Naïve realism was a style that troubled both Hogarth and Dickens and both men developed forms in which caricature, melodrama and exaggeration is crucial to the development of verisimilitude. Considering the progress pieces and the writings of Hogarth as a preface to the style of Dickens, I argue that Nicholas Nickleby developed an extraordinary self-reflexivity. Both Nicholas and his uncle Ralph form part of a narrative study of the implications of filtering perception through the distorting lens of the individual.

Evaluation of simulated sea-ice concentrations from sea-ice/ocean models using satellite data and polynya classification methods

Sea-ice concentrations in the Laptev Sea simulated by the coupled North Atlantic-Arctic Ocean-Sea-Ice Model and Finite Element Sea-Ice Ocean Model are evaluated using sea-ice concentrations from Advanced Microwave Scanning Radiometer-Earth Observing System satellite data and a polynya classification method for winter 2007/08. While developed to simulate largescale sea-ice conditions, both models are analysed here in terms of polynya simulation. The main modification of both models in this study is the implementation of a landfast-ice mask. Simulated sea-ice fields from different model runs are compared with emphasis placed on the impact of this prescribed landfast-ice mask. We demonstrate that sea-ice models are not able to simulate flaw polynyas realistically when used without fast-ice description. Our investigations indicate that without landfast ice and with coarse horizontal resolution the models overestimate the fraction of open water in the polynya. This is not because a realistic polynya appears but due to a larger-scale reduction of ice concentrations and smoothed ice-concentration fields. After implementation of a landfast-ice mask, the polynya location is realistically simulated but the total open-water area is still overestimated in most cases. The study shows that the fast-ice parameterization is essential for model improvements. However, further improvements are necessary in order to progress from the simulation of large-scale features in the Arctic towards a more detailed simulation of smaller-scaled features (here polynyas) in an Arctic shelf sea.

Wear of Ball Attachments After 1 to 8 Years of Clinical Use: A Qualitative Analysis

The purpose of this study was to analyze and compare scanning electron microscopy (SEM) observations of ball attachments that had been worn by patients during three periods of clinical use. One hundred forty-four specimens of ball anchor attachments (gold alloy matrix and titanium patrix) were studied by SEM after periods of approximately 1, 3.5, and 8 years of clinical use. Twenty new attachment components were examined as controls. SEM images revealed signs of mechanical wear for the ball attachments studied. The surfaces of the titanium patrix were associated primarily with roughening after short-term use, whereas surfaces of the gold alloy matrix showed wear, roughening, and loss of microscopic material in the form of flakes. Severe mechanical wear on both surfaces was noted after longer periods of use. The mechanical changes were not correlated with patient-mediated observations regarding the time-dependent retentive efficacy of the attachments. One year of clinical wear appeared to have limited effect on the ball attachment tested. Conversely, longer periods of use led to marked modifications in shape of the matrix and patrix components. Int J Prosthodont 2011;24:270-272.

Circadian Pattern of Wheel-Running Activity of a South American Subterranean Rodent (Ctenomys cf knightii)

Circadian rhythms are regarded as essentially ubiquitous features of animal behavior and are thought to confer important adaptive advantages. However, although circadian systems of rodents have been among the most extensively studied, most comparative biology is restricted to a few related species. In this study, the circadian organization of locomotor activity was studied in the subterranean, solitary north Argentinean rodent, Ctenomys knightii. The genus, Ctenomys, commonly known as Tuco-tucos, comprises more than 50 known species over a range that extends from 12S latitude into Patagonia, and includes at least one social species. The genus, therefore, is ideal for comparative and ecological studies of circadian rhythms. Ctenomys knightii is the first of these to be studied for its circadian behavior. All animals were wild caught but adapted quickly to laboratory conditions, with clear and precise activity-rest rhythms in a light-dark (LD) cycle and strongly nocturnal wheel running behavior. In constant dark (DD), the rhythm expression persisted with free-running periods always longer than 24h. Upon reinstatement of the LD cycle, rhythms resynchronized rapidly with large phase advances in 7/8 animals. In constant light (LL), six animals had free-running periods shorter than in DD, and 4/8 showed evidence of splitting. We conclude that under laboratory conditions, in wheel-running cages, this species shows a clear nocturnal rhythmic organization controlled by an endogenous circadian oscillator that is entrained to 24h LD cycles, predominantly by light-induced advances, and shows the same interindividual variable responses to constant light as reported in other non-subterranean species. These data are the first step toward understanding the chronobiology of the largest genus of subterranean rodents.

Recurrent Deletion of ZNF630 at Xp11.23 Is Not Associated With Mental Retardation

ZNF630 is a member of the primate-specific Xp11 zinc finger gene cluster that consists of six closely related genes, of which ZNF41, ZNF81, and ZNF674 have been shown to be involved in mental retardation. This suggests that mutations of ZNF630 might influence cognitive function. Here, we detected 12 ZNF630 deletions in a total of 1,562 male patients with mental retardation from Brazil, USA, Australia, and Europe. The breakpoints were analyzed in 10 families, and in all cases they were located within two segmental duplications that share more than 99% sequence identity, indicating that the deletions resulted from non-allelic homologous recombination. In 2,121 healthy male controls, 10 ZNF630 deletions were identified. In total, there was a 1.6-fold higher frequency of this deletion in males with mental retardation as compared to controls, but this increase was not statistically significant (P-value = 0.174). Conversely, a 1.9-fold lower frequency of ZNF630 duplications was observed in patients, which was not significant either (P-value = 0.163). These data do not show that ZNF630 deletions or duplications are associated with mental retardation. (C) 2010 Wiley-Liss, Inc.

Neonatal mitochondrial encephaloneuromyopathy due to a defect of mitochondrial protein synthesis

Mitochondrial diseases are clinically and genetically heterogeneous disorders due to primary mutations in mitochondrial DNA (mtDNA) or nuclear DNA (nDNA). We studied a male infant with severe congenital encephalopathy, peripheral neuropathy, and myopathy. The patient`s lactic acidosis and biochemical defects of respiratory chain complexes I, III, and IV in muscle indicated that he had a mitochondrial disorder while parental consanguinity suggested autosomal recessive inheritance. Cultured fibroblasts from the patient showed a generalized defect of mitochondrial protein synthesis. Fusion of cells from the patient with 143B206 rho(0) cells devoid of mtDNA restored cytochrome c oxidase activity confirming the nDNA origin of the disease. Our studies indicate that the patient has a novel autosomal recessive defect of mitochondrial protein synthesis. (C) 2008 Elsevier B.V. All rights reserved.

Comparative genomics of the neglected human malaria parasite Plasmodium vivax

The human malaria parasite Plasmodium vivax is responsible for 25 - 40% of the similar to 515 million annual cases of malaria worldwide. Although seldom fatal, the parasite elicits severe and incapacitating clinical symptoms and often causes relapses months after a primary infection has cleared. Despite its importance as a major human pathogen, P. vivax is little studied because it cannot be propagated continuously in the laboratory except in non- human primates. We sequenced the genome of P. vivax to shed light on its distinctive biological features, and as a means to drive development of new drugs and vaccines. Here we describe the synteny and isochore structure of P. vivax chromosomes, and show that the parasite resembles other malaria parasites in gene content and metabolic potential, but possesses novel gene families and potential alternative invasion pathways not recognized previously. Completion of the P. vivax genome provides the scientific community with a valuable resource that can be used to advance investigation into this neglected species.

Carpentry Students at Work

Carpentry students from the New York Trade School at work during a class. Black and white photograph.

Vi och vår arbetsplats : - beskrivning och utvärdering av en utbildning, samt dess påverkan på arbetsmiljöarbetet ur ett regionalt samverkans perspektiv

Utbildningen Vi och vår arbetsplats utgör ett exempel på regional samverkan kring arbetsmiljöarbete. Den ansågs intressant att beskriva och utvärdera med tanke på att förutsättningar för samverkan fanns mellan arbetsplatser, mellan regionala arbetsmiljöaktörer (utbildningsanordnare) samt mellan arbetsplatser och regionala arbetsmiljöaktörer.Syftet är att beskriva och utvärdera arbetsmiljöutbildningen Vi och vår arbetsplats. Frågor som avses att besvara är hur deltagare och kursledning ser på utbildningen, samt hur den kan förbättras, likväl som vilket arbetsmiljöarbete samt vilka kontakter inom arbetsmiljöområdet som kommit till stånd till följd av utbildningen.Vi och vår arbetsplats är en tvådagarsutbildning uppdelad på två kurstillfällen à en dag med en mellanliggande arbetsuppgift. Utbildningen vänder sig till olika arbetsplatser inom en region och förutsätter att en arbetsmiljöansvarig och en personalrepresentant deltar från varje arbetsplats. Ambitionen är att deltagarnas önskemål ska styra innehållet varför kursledningen förutsätts ha en bred kompetens inom arbetsmiljöområdet.Arbetsmiljöansvariga och skyddsombud från åtta arbetsplatser inom Borlänge kommun representerande vård, skola och administration deltog i den studerade utbildningen. Utvärderingen gjordes genom deltagande, enkäter, intervjuer och fokusgrupp.Sammantaget var kursdeltagarna mycket positiva till utbildningen. Framförallt uppskattades att både chef och skyddsombud deltog, att lära sig att arbetsmiljöarbetet är en process, utbytet av erfarenheter samt det psykosociala innehållet. De områden som kunde förbättras var främst lokalerna, samt bättre presentationer och dokumentation till varandra av deltagarnas projektarbeten. Även kursledningen såg utifrån sitt perspektiv områden som kunde utvecklas, t ex samordningen inom kursledningen.Samtliga arbetsplatser hade fortsatt med sina projektarbeten efter utbildningen och därtill bedrivit annat arbetsmiljöarbete. Utbildningen bidrog till att väcka och/eller bibehålla ett engagemang för arbetsmiljöarbete bland kursdeltagarna.Kursdeltagarna började snabbt kommunicera med varandra och utbyta erfarenheter. Även medarbetare till kursdeltagarna blev involverade i arbetsmiljöarbetet och exempel fanns på att effekterna spred sig till närliggande avdelningar.Den övergripande slutsatsen är att utbildningskonceptet Vi och vår arbetsplats är framgångsrikt. Starkt bidragande är att både chefer och skyddsombud från samma arbetsplats deltar. Andra slutsatser är att utbildningen bidrar till att väcka och/eller bibehålla ett engagemang för arbetsmiljöarbete bland kursdeltagarna samt att kommunikation och erfarenhetsutbyte mellan personer på olika arbetsplatser inom arbetsmiljöområdet gynnas av utbildningen.Några förbättringsförslag kan ges för utbildningen Vi och vår arbetsplats sett ur ett regionalt samverkansperspektiv för att stödja arbetsmiljöarbetet. Ett är att i än högre grad applicera innehållet till deltagarnas verksamheter. Ett annat är att inrikta utbildningens innehåll på praktiskt tillämpbar kunskap och den grundläggande arbetsmiljökunskap som då erfodras. Ett tredje är att öka samstämmigheten inom kursledningen avseende mål, pedagogik och roller. Därtill kan kommunikation och erfarenhetsutbyte mellan kursdeltagarna underlättas genom tidig spridning av kontaktuppgifter (e-post), samt dokumentation av arbetsuppgifterna. Slutligen bör den ursprungliga utbildningsplanen kompletteras med en uppföljning efter 3-6 månader och fortsatta möten stödjas.

Vem blir långtidsarbetslös?

I ett antal länder har man på senare tid utvecklat statistiska modeller som ett stöd för förmedlarna att förutsäga vilka arbetslösa som riskerar att bli långtidsarbetslösa, s k profiling. I den här rapporten redovisar vi resultaten av att skatta hasardmodeller för att förutsäga vem som riskerar att bli långtidsarbetslös bland dem som registrerar sig som arbetslösa arbetssökande vid arbetsförmedlingen. Av resultaten framgår det att den skattade modellen lyckas relativt väl med att förutsäga vem som riskerar att bli arbetslös i minst sex månader – träffsäkerheten i prognoser som görs utanför modellens skattningsperiod är nästan 70 %.

Multimodal Literacy as a form of Communication : What is the state of the students at Dalarna University multimodal literacy?

Literacy is an invaluable asset to have, and has allowed for communication, documentation and the spreading of ideas since the beginning of the written language. With technological advancements, and new possibilities to communicate, it is important to question the degree to which people’s abilities to utilise these new methods have developed in relation to these emerging technologies. The purpose of this bachelor’s thesis is to analyse the state of students’ at Dalarna University mulitimodal literacy, as well as their experience of multimodality in their education. This has led to the two main research questions: What is the state of the students at Dalarna University multimodal literacy? And: How have the students at Dalarna University experienced multimodality in education? The paper is based on a mixed-method study that incorporates both a quantitative and qualitative aspect to it. The main thrust of the research paper is, however, based on a quantitative study that was conducted online and emailed to students via their program coordinators. The scope of the research is in audio-visual modes, i.e. audio, video and images, while textual literacy is presumed and serves as an inspiration to the study. The purpose of the study is to analyse the state of the students’ multimodal literacy and their experience of multimodality in education. The study revealed that the students at Dalarna University have most skill in image editing, while not being very literate in audio or video editing. The students seem to have had mediocre experience creating meaning through multimodality both in private use and in their respective educational institutions. The study also reveals that students prefer learning by means of video (rather than text or audio), yet are not able to create meaning (communicate) through it.

Group photo at New York Trade School Commencement Ceremony, 1959

A group of administrators from the New York Trade School pose at the 1959 commencement ceremony held May 19, 1959. Original caption: "Front: (left to right) Wm. F. Vanderbeek - Kenneth Schweiger - Bernard Rosenstadt - Ralph D. Cole - George E. McLaughlin - Herbert Brod - Edward Hansen. Back: (left to right) James Wright - Lawrence Levenstein - Ronald B. Smith - Roy Wall."