From piles to tiles: designing for overview and control in case handling systems

Poor overview and control of workload in electronic case handling systems is a potential health risk factor which affects the users. Case handling systems must therefore be designed to give the users a better overview and maximum control over their workload. In an earlier study, we developed a prototype interface for managing cases, based on the piles metaphor. This paper introduces a second prototype, which is designed to incorporate the findings of an evaluation of the piles metaphor prototype. In this second prototype cases are visualized as “tiles”, reflecting the number and complexity of the cases. This paper also describes some the results of the evaluation of the tiles prototype

Streptococcal M protein and human C4BP

Antigenic variation of surface proteins allows microorganisms to evade the immune system of the infected host. This phenomenon represents an apparent paradox, because the variable protein must retain an important function, while its antigenic properties vary extensively. The surface associated M protein of Streptococcus pyogenes, a common human pathogen, exhibits antigenic variation due to an N-terminal hypervariable region (HVR). The HVRs of many M proteins bind the human complement regulator C4b-binding protein (C4BP), which down-regulates deposition of complement on the bacterial surface and thereby protects the bacteria against complement-mediated phagocytosis. Different immunological, biochemical and structural aspects of this biologically important interaction is the focus of the four papers included in this thesis. C4BP-binding HVRs exhibit remarkable sequence divergence, yet bind the same ligand. In the first study, we found that such HVRs can be studied in isolated form, as synthetic peptides, thus allowing us to directly characterize the HVRs and their interaction with C4BP. Our data indicate that the peptides bind to the same region in C4BP and assume similar folds, although they are antigenically unrelated. In the second study, we show that such a synthetic peptide can be used to purify human C4BP by a simple one-step affinity-chromatography method. The third study was focused on the sequence divergence among C4BP-binding HVRs. Remarkably, analysis of seven HVRs demonstrated that they completely lack residue identities. However, use of site-specific mutagenesis to substitute relatively conserved residues in the M22 protein indicated that the predicted coiled-coil structure of the HVR is crucial for ability to bind C4BP. Interestingly, change of single residues that do not affect C4BP-binding induced major immunological changes. Together, the data in paper III indicate that HVRs of C4BP-binding M proteins have an extraordinary capacity for sequence change and antigenic variability, while retaining a specific ligand-binding function. In paper IV, we studied the three-dimensional structure of C4BP-binding HVRs, using peptides derived from the M4 and M22 proteins. No structure could be obtained, but the data clearly indicate that the central parts of the HVRs are folded as coiled-coils, both in solution and in complex with C4BP, while the termini are flexible. Remarkably, the peptides derived from M4 and M22 appear to adopt similar structures, in spite of a limited number of residue identities

Data-driven Algorithms for Dimension Reduction in Causal Inference

In observational studies, the causal effect of a treatment may be confounded with variables that are related to both the treatment and the outcome of interest. In order to identify a causal effect, such studies often rely on the unconfoundedness assumption, i.e., that all confounding variables are observed. The choice of covariates to control for, which is primarily based on subject matter knowledge, may result in a large covariate vector in the attempt to ensure that unconfoundedness holds. However, including redundant covariates can affect bias and efficiency of nonparametric causal effect estimators, e.g., due to the curse of dimensionality. Data-driven algorithms for the selection of sufficient covariate subsets are investigated. Under the assumption of unconfoundedness the algorithms search for minimal subsets of the covariate vector. Based, e.g., on the framework of sufficient dimension reduction or kernel smoothing, the algorithms perform a backward elimination procedure assessing the significance of each covariate. Their performance is evaluated in simulations and an application using data from the Swedish Childhood Diabetes Register is also presented.Comment: 27 pages, 2 figures, 11 table

Методологія педагогічних досліджень

(uk) З методологічних позицій розглядається загальна структура наукового дослідження з педагогіки.(ru) С методологических позиций рассматривается общая структура научного исследования по педагогике

Fat to dairy cows

Examensarbetet har genomförts i samarbete med Karlshamns AB, husdjursföreningarna i Blekinge-Kronoberg och Halland, samt Svenska Lantmännen i Skåne. Arbetet handlar om fettutfodring till mjölkkor. Fetterna som har använts är två olika sorters kalciumförsåpat fett som består av 85% fett och ca 15% kalcium samt ett härdat fett som består av 98 % fettsyror. De kalciumförsåpade fetterna innehåller en hög andel C18:1 och C16:0 och det som skiljer de två fetterna åt är i princip förhållandet mellan C18:1 och C16:0 fettsyrorna. Det härdade fettet består i stort sett enbart av C16:0 och C18:0 fettsyror, se tabell 2 och 12. Försök I är en sammanställning av resultat från ett försök med utfodring av kalciumförsåpat fett (Akofeed Kalkfett, tabell 2). Försöket pågick under en längre tid (15 månader) på två gårdar i Blekinge med normal avkastning och normala halter av fett och protein. Korna på gårdarna delades upp i två grupper efter laktationsnummer och kalvningsdatum. Den ena gruppen fick 0,6 kg Kalkfett (kalciumförsåpat fett) lagt ovanpå ordinarie kraftfodergivan medan den andra fungerade som kontrollgrupp. Syftet var att testa Kalkfettet så att det hade god smaklighet samt att se hur mjölkens sammansättning och avkastning påverkades av Kalkfettsutfodring. Man ville även se hur Kalkfettet påverkade mjölkens lukt och smak. Under hösten 2001 utfördes försök II med fettutfodring till mjölkkor. Två (vid starten tre) besättningar i Halland respektive Kronoberg deltog. Besättningarnas kor delades upp i två grupper efter laktationsnummer och kalvningsdatum. Den ena gruppen fick Kalkfett och den andra gruppen Torrfett (härdat fett) tillsatt i sina foderstater. Syftet med försök II var att studera hur mjölkens sammansättning och avkastning påverkas av utfodring av härdat respektive kalciumförsåpat fett i besättningar med låg fetthalt (10 000 kg ). I försök I fanns det inga signifikanta skillnader i mjölkavkastning och fetthalt i mjölken mellan gruppen som fick Kalkfett och kontrollgruppen. Proteinhalten i mjölken tenderade till att vara lägre hos de kor som fick Kalkfett. Trenden var att kor som fick extra fett i foderstaten fick ett senare laktationsmaximum, men också en mer utdragen laktation. I försök II fanns det inga signifikanta skillnader i mjölkavkastning, fett- och proteinhalt mellan gruppen som fick Kalkfett och gruppen som fick Torrfett. Fetthalten i foderstaterna i försök I var relativt hög redan innan försöket började vilket kan ha påverkat att det inte blev några signifikanta resultat på mjölkproduktionen då ännu mer fett tillsattes. Fettsyrasammansättningen på foderstaterna i försök II skilde en del mellan grupperna vilket även gav genomslag i mjölken. Gruppen som fick Torrfett hade lägre koncentration av oljesyra i mjölkfettet jämfört med gruppen som fick Kalkfett. Mjölken från kontrollgården med en normal fetthalt i mjölken innehöll en större andel kortkedjiga fettsyror än mjölken från besättningarna med låga fetthalter. Lukt och smak på mjölk från enskilda kor och från samlingsprov utfördes på mjölken från försök I. Det fanns ingen anmärkning på lukt och smak på mjölken varken hos de kor som utfodrades Kalkfett eller hos de kor som utgjorde kontrollgruppen. Under försök II fanns det ingen anmärkning på lukt och smak på gårdarnas tankmjölk. Smakligheten på Kalkfettet bedömdes vara godkänd. Korna åt Kalkfettet efter en kort periods tillvänjning. Torrfettets smaklighet var dock tveksam vid utfodring i lös form. På en gård i försök II vägrade korna att äta Torrfettet och den gården fick uteslutas från försöket.The aims of the investigations were to study milk composition in dairy cows fed extra fat. The fats that were used were of different kind a calcium-saponified fat and a saturated fat. The calcium-saponified fats (Akofeed Kalkfett) consisted of about 85% fatty acids and 15 % calcium. The calcium-saponified fat had a high level of C16:0 and C18:1 fatty acids. The saturated fat (Akofeed Torrfett) consisted of 98 % fatty acids. Most of the saturated fat consisted of C16:0 and C18:0 fatty acids. The first investigation (experiment I) was conducted during 15 months. Two dairy herds in Blekinge (south of Sweden) with normal milk yield (9,500 kg milk) and normal percentage of fat and protein (4.3 % and 3.4% respectively) participated in the experiment. The cows were divided in two groups. In total 38 cows were offered 0,6kg Akofeed Kalkfett on top of their ordinary ration of fodder. Also 34 cows were observed as a control group and did not receive any supplementary fat. The calcium-saponified fat was consumed and therefor concluded being palatable. The milk yield and the percentage of fat were the same between the two groups in experiment I. The results showed a tendency of lower percentage of protein in the milk from the group fed calcium-saponified fat. The cows fed fat reached the peak of lactation later and had a more extended lactation. Supplementary fat in the feed had no negative effects on milk flavour in organoleptic tests. The percentage of fat in the feed in experiment I was high already before the experiment started. This may have influenced the result because it is more difficult to get changes in milk production when the percentage of fat in the ration is >5%. In the autumn of 2001 another fat feeding investigation (experiment II) was conducted with feeding fat to dairy cows. Two (at the beginning three) herds in Halland and Kronoberg (south of Sweden) participated in the study. The herds in the experiment yielded above 10,500kg milk with low milk-fat percentage (below 3.8%). The aim of experiment II was to study effects on milk yield and milk composition when two different sorts of fat (calciumsaponified fat or saturated fatty acids) were fed. The cows were divided into two groups taken into account date of calving and the lactation number. One group of total 104 cows got calcium-saponified fat and one group of 102 cows got saturated fatty acids incorporated in the pelleted concentrate. The fatty acid composition of the feed differed in both groups. In addition, a control herd (of 50 cows) with a normal level of milk yield (9,600 kg milk) and milk-fat percentage (4.3%) was offered supplementary calcium-saponified fat or saturated fat on top of their ration as in experiment I. The cows in the control herd consumed the calciumsaponified fat after a short time of accustoming, but the palatability of the saturated fat was insufficient therefor the control herd was excluded from the experiment. There were no significant difference in milk yield, milk-fat percentage and milk-protein percentage between the groups in the high-yielding herds. The cows fed saturated fatty acids had less of C18:1 in the milk fat compared with the cows fed calcium-saponified fat. However, the milk fat from the control herd had more short chain fatty acids in the milk fat than the two high-yielding herds with low milk-fat percentage. There was no incidence of off-flavour of the tank milk of the two herds. There were no distinguished differences in milk yield and milk composition between the groups fed calcium-saponified fat or saturated fatty acids in experiment II. From an economical aspect the calcium-saponified fat was cheaper than saturated fatty acids and because of that calcium-saponified fat would be a preferable alternative

Cystatin C Is Downregulated in Prostate Cancer and Modulates Invasion of Prostate Cancer Cells via MAPK/Erk and Androgen Receptor Pathways

Cystatin C is believed to prevent tumor progression by inhibiting the activities of a family of lysosomal cysteine proteases. However, little is known about the precise mechanism of cystatin C function in prostate cancer. In the present study, we examined the expression of cystatin C and its association with matrix metalloproteinases 2 (MMP2) and androgen receptor (AR) in a tissue microarray comparing benign and malignant specimens from 448 patients who underwent radical prostatectomy for localized prostate cancer. Cystatin C expression was significantly lower in cancer specimens than in benign tissues (p<0.001) and there was a statistically significant inverse correlation between expression of cystatin C and MMP2 (rs2 = −0.056, p = 0.05). There was a clear trend that patients with decreased level of cystatin C had lower overall survival. Targeted inhibition of cystatin C using specific siRNA resulted in an increased invasiveness of PC3 cells, whereas induction of cystatin C overexpression greatly reduced invasion rate of PC3 in vitro. The effect of cystatin C on modulating the PC3 cell invasion was provoked by Erk2 inhibitor that specifically inhibited MAPK/Erk2 activity. This suggests that cystatin C may mediate tumor cell invasion by modulating the activity of MAPK/Erk cascades. Consistent with our immunohistochemical findings that patients with low expression of cystatin C and high expression of androgen receptor (AR) tend to have worse overall survival than patients with high expression of cystatin C and high AR expression, induced overexpression of AR in PC3 cells expressing cystatin C siRNA greatly enhanced the invasiveness of PC3 cells. This suggests that there may be a crosstalk between cystatin C and AR-mediated pathways. Our study uncovers a novel role for cystatin C and its associated cellular pathways in prostate cancer invasion and metastasis

Cytokine response to lipoprotein lipid loading in human monocyte-derived macrophages

BACKGROUND: Macrophage foam cell formation is a prominent feature of human atherosclerotic plaques, usually considered to be correlated to uptake of and inflammatory response to oxidized low density lipoproteins (OxLDL). However, there are alternative pathways for formation of macrophage foam cells and the effect of such lipid loading on macrophage function remains to be fully characterized. In the present study we investigated basal and inducible cytokine expression in primary human macrophages either loaded with triglycerides through incubation with very low density lipoproteins (VLDL) or with cholesterol through incubation with aggregated LDL (AgLDL). We then analyzed how foam cell lipid content affected secretion of three pro-inflammatory cytokines: interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), and of one chemokine: interleukin-8 (IL-8), all of which are considered pro-inflammatory, pro-atherosclerotic, and are expressed by cells in atherosclerotic tissue. RESULTS: Formation of triglyceride-loaded foam cells resulted in a four-fold increase in basal IL-1β secretion, whereas cholesterol loading lacked significant effect on IL-1β secretion. In contrast, secretion of TNF-α and IL-6 decreased significantly following both cholesterol and triglyceride loading, with a similar trend for secretion of IL-8. Lipid loading did not affect cell viability or expression of caspase-3, and did not significantly affect macrophage ability to respond to stimulation with exogenous TNF-α. CONCLUSION: Lipid loading of primary human macrophages resulted in altered cytokine secretion from cells, where effects were similar regardless of neutral lipid composition of cells. The exception was IL-1β, where triglyceride, but not cholesterol, lipid loading resulted in a stimulation of basal secretion of the cytokine. It is apparent that macrophage cytokine secretion is affected by lipid loading by lipoproteins other than OxLDL. As both VLDL and AgLDL have been found in the vessel wall, macrophage cytokine response to uptake of these lipoproteins may have a direct effect on atherosclerotic development in vivo. However, macrophage neutral lipid amount and composition did not affect cellular activation by exogenous TNF-α, making it likely that lipoprotein lipid loading can affect foam cell cytokine secretion during basal conditions but that the effects can be overruled by TNF-α during acute inflammation

Enzalutamide as a second generation antiandrogen for treatment of advanced prostate cancer

Prostate cancer (PCa) is the most common malignancy, and the third leading cancer-related cause of death among men of the Western world. Upon PCa progression into metastatic disease, androgen deprivation therapy is applied as the first-line treatment, and has been shown to be effective in most patients, leading to a decrease in serum prostate-specific antigen and relief of disease-related symptoms. However, advanced PCa almost inevitably progresses to a castration-resistant state, and is currently regarded as incurable. The large body of evidence indicates that PCa cells remain dependent on androgen receptor (AR) signaling even in an androgen-deprived environment. As such, development of drugs that target AR and AR signaling pathways have become one of the major milestones in treatment of castration-resistant PCa (CRPC). Nevertheless, currently available therapies that target AR signaling are still regarded as palliative and more potent therapies are in great need. Over the past few years, a wide range of novel therapies has entered clinical trial for treatment of CRPC, including androgen synthesis inhibitors (abiraterone acetate), chemotherapeutic agents (docetaxel and cabazitaxel), and immunotherapies (sipuleucel-T). In this context, enzalutamide (previously referred to as MDV3100) is a novel second generation antiandrogen that has been demonstrated to significantly improve survival in men with metastatic CRPC in several clinical trials. In this paper we summarize recently completed and ongoing clinical trials of enzalutamide, and briefly discuss the efficacy of the novel antiandrogen therapy and its limitations for treatment of CRPC

Interleukin-1beta and tumour necrosis factor-alpha impede neutral lipid turnover in macrophage-derived foam cells

<p>Abstract</p> <p>Background</p> <p>Pro-inflammatory cytokines can affect intracellular lipid metabolism. A variety of effects have been described for different cell types; hepatocyte lipid turnover pathways are inhibited during inflammation, whereas interleukin-1β (IL-1β) reduces intracellular cholesterol levels in fibroblasts. Levels of the pro-inflammatory cytokines IL-1β and tumour necrosis factor-α (TNF-α) are up-regulated at sites of formation of atherosclerotic plaques. Plaque formation is though to begin with infiltration of monocytes to the intimal layer of the vascular wall, followed by differentiation to macrophages and macrophage uptake of modified lipoproteins, resulting in accumulation of intracellular lipids. The lipid-filled cells are referred to as macrophage foam cells, a key feature of atherosclerotic plaques. We have investigated the effects of IL-1β and TNF-α on macrophage foam cells in order to assess whether presence of the pro-inflammatory cytokines improves or aggravates macrophage foam cell formation by affecting lipid accumulation and lipid turn-over in the cells.</p> <p>Results</p> <p>Differentiated primary human macrophages or THP-1 cells were lipid loaded by uptake of aggregated low density lipoproteins (AgLDL) or very low density lipoproteins (VLDL), and then incubated with IL-1β (0 – 5000 pg/ml) in lipoprotein-free media for 24 h. Cells incubated in absence of cytokine utilized accumulated neutral lipids, in particular triglycerides. Addition of exogenous IL-1β resulted in a dose-dependent retention of intracellular cholesterol and triglycerides. Exchanging IL-1β with TNF-α gave a similar response. Analysis of fatty acid efflux and intracellular fatty acid activation revealed a pattern of decreased lipid utilization in cytokine-stimulated cells.</p> <p>Conclusion</p> <p>IL-1β and TNF-α enhance macrophage foam cell formation, in part by inhibition of macrophage intracellular lipid catabolism. If present <it>in vivo</it>, these mechanisms will further augment the pro-atherogenic properties of the two cytokines.</p