Conceptual and terminological confusion around Personalised Medicine: a coping strategy

The idea of personalised medicine (PM) has gathered momentum recently, attracting funding and generating hopes as well as scepticism. As PM gives rise to differing interpretations, there have been several attempts to clarify the concept. In an influential paper published in this journal, Schleidgen and colleagues have proposed a precise and narrow definition of PM on the basis of a systematic literature review. Given that their conclusion is at odds with those of other recent attempts to understand PM, we consider whether their systematic review gives them an edge over competing interpretations. We have found some methodological weaknesses and questionable assumptions in Schleidgen and colleagues’ attempt to provide a more specific definition of PM. Our perplexities concern the lack of criteria for assessing the epistemic strength of the definitions that they consider, as well as the logical principles used to extract a more precise definition, the narrowness of the pool from which they have drawn their empirical data, and finally their overlooking the fact that definitions depend on the context of use. We are also worried that their ethical assumption that only patients’ interests are legitimate is too simplistic and drives all other stakeholders’ interests—including those that are justifiable—underground, thus compromising any hope of a transparent and fair negotiation among a plurality of actors and interests. As an alternative to the shortcomings of attempting a semantic disciplining of the concept we propose a pragmatic approach. Rather than considering PM to be a scientific concept in need of precise demarcation, we look at it as an open and negotiable concept used in a variety of contexts including at the level of orienting research goals and policy objectives. We believe that since PM is still more an ideal than an achieved reality, a plurality of visions is to be expected and we need to pay attention to the people, reasons and interests behind these alternative conceptions. In other words, the logic and politics of PM cannot be disentangled and disagreements need to be tackled addressing the normative and strategic conflicts behind them

Jenter med bein i nesa : jenterollen i norsk barnelitteratur gjennom 50 år

I denne masteroppgaven undersøker jeg 150 spenningsbøker for barn, den totale utgivelsen av slike bøker fra periodene 1965-70, 1985-90 og 2005-10. Målet med undersøkelsen er å se på den historiske utviklingen av jenterollen i spenningslitteraturen over 50 år. Jeg undersøker om det finnes jentekarakterer innenfor denne sjangerlitteraturen som jentelesere har kunnet se opp til som forbilder gjennom disse tiårene. Oppgaven består av to deler. Den første er en kvantitativ redegjørelse for antallet jenter og gutter i bøkene og hva slags rolle disse har; om de er hovedpersoner eller hjelpere, om de er aktive eller passive aktører innenfor handlingen. Andre del er en kvalitativ analyse av fem utvalgte romaner. Jeg leter etter jentekarakterer som kan si noe om hvordan jenterollen var i spenningslitteraturen på den tiden. Undersøkelsen gir flere interessante funn: Grupper med både jenter og gutter er blitt vanlig; jentene tar og krever større plass både innenfor sjangeren og i den enkelte bok; utviklingen har vært stigende gjennom hele etterkrigstiden. Spenningssjangeren er med andre ord ikke lenger en guttesjanger.In this thesis I examine the entire Norwegian output of children’s mystery novels for the periods 1965-70, 1985-90 and 2005-10. My objective is to uncover the historical development of the female character in this genre over the past 50 years. In particular, I am looking for characters that might have been used as role models by girl readers. The thesis consists of two parts. Part one is a quantitative survey of the number of girls and boys present in some 150 novels, and a mapping of their respective roles, whether they are protagonists or helpers, whether they are active or passive in pursuing the action. The second part is a qualitative analysis of five selected novels. Concentrating on the historical status of girls in this genre, I read the selected novels looking for characters that might shed light on the periods in which the books were written. My study provides several interesting findings: Gender-mixed groups become ever more common; girls steadily demand more space, both within the genre at large and in the particular story; this trend has constantly been rising since the war. Suspense literature, therefore, is no longer boy’s literature.Master i bibliotek- og informasjonsvitenska

Autonomi, kompetanse og tilhørighet i kroppsøving på videregående skole. En kvalitativ studie på media og kommunikasjonsfag

Master i kroppsøvings- og idrettsvitenskap - Nord universitet 202

Intracellular Penetration and Accumulation of Radiographic Contrast Media in the Rat Kidney

Radiographic iodine-containing contrast media (meglumine calcium metrizoate, iohexol and meglumine sodium ioxaglate) were injected intravenously in rats. At various intervals after exposure, in situ cryofixation of kidneys was performed. Thin, freeze-dried cryosections were examined by electron microscopy and X-ray microanalysis. In endothelial cells, erythrocytes and tubular cells high dry weight concentrations of iodine were found. Twenty-four hours after iohexol was injected, no trace of iodine was found in the plasma, microvilli or the nuclei of the tubular cells. Small organelle-like compartments in the cytoplasm of the proximal tubular cells contained high concentrations of iodine, whereas no iodine was found in the surrounding cytoplasm. Since no metabolism of contrast medium has been demonstrated, the iodine signals must be emitted from contrast medium molecules. Other elements were also measured, with the concentrations being always within the ranges found in tubular cells of control animals. The detection of intracellular contrast thus does not seem to be an artifact due to cell injury, but rather represents a physiological event in healthy cells in the rat kidney. Our results are in contradiction to the prevailing opinion that contrast media do not enter healthy cells. However, previous conclusions have been based on the use of conventional preparation methods, and the highly water soluble contrast molecules may have been lost during the different steps of fixation and processing

Uptake of IgG in osteosarcoma correlates inversely with interstitial fluid pressure, but not with interstitial constituents

The uptake of therapeutic macromolecules in solid tumours is assumed to be hindered by the heterogeneous vascular network, the high interstitial fluid pressure, and the extracellular matrix. To study the impact of these factors, we measured the uptake of fluorochrome-labelled IgG using confocal laser scanning microscopy, interstitial fluid pressure by the ‘wick-in-needle’ technique, vascular structure by stereological analysis, and the content of the extracellular matrix constituents collagen, sulfated glycosaminoglycans and hyaluronan by colourimetric assays. The impact of the microenvironment on these factors was studied using osteosarcomas implanted either subcutaneously or orthotopically around the femur in athymic mice. The uptake of IgG was found to correlate inversely with the interstitial fluid pressure and the tumour volume in orthotopic, but not subcutaneous tumours. No correlation was found between IgG uptake and the level of any of the extracellular matrix constituents. The content of both collagen and glycosaminoglycans depended on the site of tumour growth. The orthotopic tumours had a higher vascular density than the subcutaneous tumours, as the vascular surface and length were 2–3-fold higher. The data indicate that the interstitial fluid pressure is a dominant factor in controlling the uptake of macromolecules in solid tumours; and the site of tumour growth is important for the uptake of macromolecules in small tumours, extracellular matrix content and vascularization.© 2001 Cancer Research Campaign http://www.bjcancer.co

Principal component analysis for the comparison of metabolic profiles from human rectal cancer biopsies and colorectal xenografts using high-resolution magic angle spinning 1H magnetic resonance spectroscopy

<p>Abstract</p> <p>Background</p> <p>This study was conducted in order to elucidate metabolic differences between human rectal cancer biopsies and colorectal HT29, HCT116 and SW620 xenografts by using high-resolution magnetic angle spinning (MAS) magnetic resonance spectroscopy (MRS) and for determination of the most appropriate human rectal xenograft model for preclinical MR spectroscopy studies. A further aim was to investigate metabolic changes following irradiation of HT29 xenografts.</p> <p>Methods</p> <p>HR MAS MRS of tissue samples from xenografts and rectal biopsies were obtained with a Bruker Avance DRX600 spectrometer and analyzed using principal component analysis (PCA) and partial least square (PLS) regression analysis.</p> <p>Results and conclusion</p> <p>HR MAS MRS enabled assignment of 27 metabolites. Score plots from PCA of spin-echo and single-pulse spectra revealed separate clusters of the different xenografts and rectal biopsies, reflecting underlying differences in metabolite composition. The loading profile indicated that clustering was mainly based on differences in relative amounts of lipids, lactate and choline-containing compounds, with HT29 exhibiting the metabolic profile most similar to human rectal cancers tissue. Due to high necrotic fractions in the HT29 xenografts, radiation-induced changes were not detected when comparing spectra from untreated and irradiated HT29 xenografts. However, PLS calibration relating spectral data to the necrotic fraction revealed a significant correlation, indicating that necrotic fraction can be assessed from the MR spectra.</p

Mimicking damaged DNA with a small molecule inhibitor of human UNG2

Human nuclear uracil DNA glycosylase (UNG2) is a cellular DNA repair enzyme that is essential for a number of diverse biological phenomena ranging from antibody diversification to B-cell lymphomas and type-1 human immunodeficiency virus infectivity. During each of these processes, UNG2 recognizes uracilated DNA and excises the uracil base by flipping it into the enzyme active site. We have taken advantage of the extrahelical uracil recognition mechanism to build large small-molecule libraries in which uracil is tethered via flexible alkane linkers to a collection of secondary binding elements. This high-throughput synthesis and screening approach produced two novel uracil-tethered inhibitors of UNG2, the best of which was crystallized with the enzyme. Remarkably, this inhibitor mimics the crucial hydrogen bonding and electrostatic interactions previously observed in UNG2 complexes with damaged uracilated DNA. Thus, the environment of the binding site selects for library ligands that share these DNA features. This is a general approach to rapid discovery of inhibitors of enzymes that recognize extrahelical damaged bases

The population genomic legacy of the second plague pandemic

SummaryHuman populations have been shaped by catastrophes that may have left long-lasting signatures in their genomes. One notable example is the second plague pandemic that entered Europe in ca. 1,347 CE and repeatedly returned for over 300 years, with typical village and town mortality estimated at 10%–40%.1 It is assumed that this high mortality affected the gene pools of these populations. First, local population crashes reduced genetic diversity. Second, a change in frequency is expected for sequence variants that may have affected survival or susceptibility to the etiologic agent (Yersinia pestis).2 Third, mass mortality might alter the local gene pools through its impact on subsequent migration patterns. We explored these factors using the Norwegian city of Trondheim as a model, by sequencing 54 genomes spanning three time periods: (1) prior to the plague striking Trondheim in 1,349 CE, (2) the 17th–19th century, and (3) the present. We find that the pandemic period shaped the gene pool by reducing long distance immigration, in particular from the British Isles, and inducing a bottleneck that reduced genetic diversity. Although we also observe an excess of large FST values at multiple loci in the genome, these are shaped by reference biases introduced by mapping our relatively low genome coverage degraded DNA to the reference genome. This implies that attempts to detect selection using ancient DNA (aDNA) datasets that vary by read length and depth of sequencing coverage may be particularly challenging until methods have been developed to account for the impact of differential reference bias on test statistics.Results and discussion STAR★Method