| 11. |
- Kjaergaard, Benedict, et al.
(författare)
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Low plasma potassium in deep hypothermic cardiac arrest indicates that cardiac arrest is secondary to hypothermia : a porcine study
- 2010
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Ingår i: European journal of emergency medicine. - 0969-9546 .- 1473-5695. ; 17:3, s. 131-135
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: In accidental hypothermia, normal signs of death are unreliable. It is generally accepted that a lifeless person is beyond the limits of rescue if plasma potassium (P-potassium) is higher than10 mmol/l. However, the rate of increase in potassium or in other markers after cardiac arrest has not been carefully studied in hypothermic individuals. The aim of this animal study was to assess biochemical changes after anoxic circulatory arrest at hypothermia and at normothermia followed by external cooling. METHODS: Five pigs were treated with heparin and extracorporeal circulation and cooled to 20 degrees C (primary hypothermia group). The animals were weaned from extracorporeal circulation, suffered cardiac arrest, and were cooled externally with ice to mimic victims found in a cold environment. With the use of intermittent external cardiac compressions mixing the blood, arterial P-potassium was followed after cardiac arrest until the level exceeded 10 mmol/l. Another group of five pigs (anoxic cardiac arrest group) were treated with heparin and killed by anoxia at normothermia and were thereafter treated and followed similarly to the primary hypothermia group. RESULTS: In primary hypothermia P-potassium exceeded 10 mmol/l after median 3.5 h, whereas in anoxic cardiac arrest P-potassium exceeded 10 mmol/l after median 1 h. CONCLUSION: This study shows that if cardiac arrest occurs before hypothermia is established, P-potassium increases quickly in contrast to the situation when hypothermia induces cardiac arrest. Thus, a low P-potassium in a hypothermic individual with cardiac arrest indicates that cardiac arrest occurred recently or was secondary to the hypothermic event.
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| 12. |
- Kristensen, Lars Erik, et al.
(författare)
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Is Swollen to Tender Joint Count Ratio a New and Useful Clinical Marker for Biologic Drug Response in Rheumatoid Arthritis? Results From a Swedish Cohort
- 2014
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Ingår i: Arthritis Care and Research. - : Wiley. - 2151-4658 .- 2151-464X. ; 66:2, s. 173-179
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Tidskriftsartikel (refereegranskat)abstract
- ObjectiveTo study the impact of swollen to tender joint count ratio (STR) and other baseline characteristics on treatment response to a first course of anti-tumor necrosis factor (anti-TNF) therapy in rheumatoid arthritis (RA) patients. MethodsPatients with RA initiating their first course of anti-TNF treatment were included in a structured clinical followup protocol. Based on pragmatic thresholds and plausibility, patients were categorized as having low (STR <0.5), moderate (0.5 STR 1.0), or high (STR >1.0) joint count ratios. The data were collected and followed during the period of March 1999 through December 2010. ResultsA total of 2,507 patients were included in the study (median age 56 years, 78% women). Of these patients, 344 (14%) had a low STR, 1,180 (47%) had a moderate STR, and 983 (39%) had a high STR. According to these STR thresholds, 23% of patients (95% confidence interval [95% CI] 18-29%) with low, 39% (95% CI 35-43%) with moderate, and 40% (95% CI 36-44%) with high STR achieved the American College of Rheumatology criteria for 50% improvement (ACR50) response at 6 months after initiation. Correlation tests showed that STR was associated with ACR50 response independent of both swollen and tender joint counts. Logistic regression analysis consistently showed that moderate STR, high STR, not using prednisolone, high baseline Disease Activity Score in 28 joints, and low baseline Health Assessment Questionnaire scores were significantly associated with favorable ACR50 response with odds ratios of 1.93 (P < 0.01), 2.82 (P < 0.01), 0.65 (P < 0.01), 1.49 (P < 0.01), and 0.47 (P < 0.01), respectively. ConclusionSTR is a new and feasible predictor of treatment response in RA. RA patients with a moderate to high STR have a 2- to 3-fold increased likelihood of responding according to ACR50 criteria.
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| 13. |
- Ladenson, Paul W, et al.
(författare)
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Use of the Thyroid Hormone Analogue Eprotirome in Statin-Treated Dyslipidemia
- 2010
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Ingår i: NEW ENGLAND JOURNAL OF MEDICINE. - 0028-4793 .- 1533-4406. ; 362:10, s. 906-916
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND Dyslipidemia increases the risk of atherosclerotic cardiovascular disease and is incompletely reversed by statin therapy alone in many patients. Thyroid hormone lowers levels of serum low-density lipoprotein (LDL) cholesterol and has other potentially favorable actions on lipoprotein metabolism. Consequently, thyromimetic drugs hold promise as lipid-lowering agents if adverse effects can be avoided. METHODS We performed a randomized, placebo-controlled, double-blind, multicenter trial to assess the safety and efficacy of the thyromimetic compound eprotirome (KB2115) in lowering the level of serum LDL cholesterol in patients with hypercholesterolemia who were already receiving simvastatin or atorvastatin. In addition to statin treatment, patients received either eprotirome (at a dose of 25, 50, or 100 mu g per day) or placebo. Secondary outcomes were changes in levels of serum apolipoprotein B, triglycerides, and Lp(a) lipoprotein. Patients were monitored for potential adverse thyromimetic effects on the heart, bone, and pituitary. RESULTS The addition of placebo or eprotirome at a dose of 25, 50, or 100 mu g daily to statin treatment for 12 weeks reduced the mean level of serum LDL cholesterol from 141 mg per deciliter (3.6 mmol per liter) to 127, 113, 99, and 94 mg per deciliter (3.3, 2.9, 2.6, and 2.4 mmol per liter), respectively, (mean reduction from baseline, 7%, 22%, 28%, and 32%). Similar reductions were seen in levels of serum apolipoprotein B, triglycerides, and Lp(a) lipoprotein. Eprotirome therapy was not associated with adverse effects on the heart or bone. No change in levels of serum thyrotropin or triiodothyronine was detected, although the thyroxine level decreased in patients receiving eprotirome. CONCLUSIONS In this 12-week trial, the thyroid hormone analogue eprotirome was associated with decreases in levels of atherogenic lipoproteins in patients receiving treatment with statins.
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| 14. |
- Ladenson, Paul W, et al.
(författare)
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Use of the Thyroid Hormone Analogue Eprotirome in Statin-Treated Dyslipidemia
- 2010
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Ingår i: Obstetrical and Gynecological Survey. - : Lippincott Williams & Wilkins. - 0029-7828 .- 1533-9866. ; 65:8, s. 512-513
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Statins effectively reduce levels of serum cholesterol and lower the risk of cardiovascular disease, but have limited effectiveness if stringent goals for serum low-density lipoprotein (LDL) cholesterol levels are not met or adverse effects develop, requiring a dose reduction or drug discontinuation. Previous studies have shown that thyroid hormone and some of its metabolites reduce levels of serum LDL cholesterol and have potentially favorable actions on other lipoproteins. The studies were discontinued because of reports of adverse effects on heart and bone, and possible deaths. In a recent report, eprotirome, a thyromimetic compound with minimal uptake in nonhepatic-tissues, was shown to reduce levels of serum total and LDL cholesterol and apolipoprotein B without apparent side effects in patients not receiving statin therapy. This randomized, placebo-controlled, double-blind, multicenter trial investigated the safety and efficacy of eprotirome in lowering the level of serum LDL cholesterol in patients with hypercholesterolemia who already were receiving simvastatin or atorvastatin. The aim of the study was to determine whether adding eprotirome to statin therapy would provide additional lipid-lowering actions without producing adverse extrahepatic thyromimetic effects. Patients were randomly assigned to receive daily oral doses of 25, 50, or 100 mcg of eprotirome or a placebo for 12 weeks. The primary study outcome was changes in serum LDL cholesterol. The potential adverse thyromimetic effects on the heart, bone, and pituitary were examined. Treatment of patients for 12 weeks already receiving statins with either placebo or eprotirome at a dose of 25, 50, or 100 mu g reduced the mean level of serum LDL cholesterol from 141 mg per deciliter (3.6 mmol per liter) at baseline to 127, 113, 99, and 94 mg per deciliter (3.3, 2.9, 2.6, and 2.4 mmol per liter), respectively; this represented a mean reduction from baseline of 7%, 22%, 28%, and 32%, respectively. Similar reductions were found in the secondary study outcomes, which included serum levels of apolipoprotein B, triglycerides, and Lp(a) lipoprotein. No evidence of adverse effects of eprotirome on the heart, bone, or pituitary was noted. Although reductions in serum levels of thyroxine occurred in some patients who received eprotirome, there were no changes in levels of thyrotropin or triiodothyronine. These findings demonstrate that the addition of eprotirome to statin therapy produces substantial further reductions in serum LDL cholesterol, non-high-density lipoprotein cholesterol, and apolipoprotein B. The drug appears to have an excellent safety profile.
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| 15. |
- Liljefors, Max, et al.
(författare)
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Atrocity Media: Negotiating the Abject in Images of Torture and Death
- 2013
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Ingår i: Transvisuality: the Cultural Dimension of Visuality. Volume 1: Boundaries and Creative Openings. - 9781846318917 ; , s. 185-206
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Bokkapitel (refereegranskat)abstract
- This essay discusses the dissemination of atrocity images in contemporary mass media, from the photographs of mass-graves in the Nazi concentration camps to the pictures of torture of Iraqi prisoners in Abu Ghraib. The central question is one of distances: the distance between the image and the event, between the picture and the beholder, and between the destroyed human body and the cultural forms through which it is represented. These distances, their upholding and overcoming, are analyzed through the works of three visual artists that have dealt with atrocity imagery in their art: in 1945, an Italian artist encountering the Nazi camps in 1945; a Holocaust survivor merging mass-grave photographs with pornography in the 1960s; and in 2002, a Taiwanese video artist re-enacting a century-old photograph of Chinese torture. The article interprets these artworks as reflecting processes of abjection at work in the mediatization of atrocities throughout late modern society. Julia Kristeva's theory of the abject underpins the argument, that the media, while bringing atrocities to the public’s attention, also establish a reassuring distance to the scenes of atrocity, and enthrall the viewer in a fascination with the images themselves. In the end, this tension between distance and proximity may open for critical reflection and political action.
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| 16. |
- Malm, Jan, et al.
(författare)
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Implementation of a new CSF dynamic device: a multicenter feasibility study in 562 patients
- 2012
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Ingår i: Acta Neurologica Scandinavica. - : John Wiley and Sons. - 0001-6314 .- 1600-0404. ; 125:3, s. 199-205
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Tidskriftsartikel (refereegranskat)abstract
- Objectives - The cerebrospinal fluid (CSF) infusion test is frequently used when selecting hydrocephalus patients for shunt surgery. Very little has been reported regarding adverse events. We present a prospective feasibility study. Methods -Standardized devices for measuring CSF dynamics were built and 562 patients investigated: Needles were placed by lumbar puncture (LP). An automatic CSF infusion protocol was performed. Course of events during the investigation as well as adverse events were registered. Results Preoperative evaluation of normal-pressure hydrocephalus was the most common indication (63%), followed by evaluation of shunt function (23%) and intracranial pressure recordings (14%). The LP was successfully performed in all but nine cases with 24 patients (4.3%) reporting major discomfort. Ringer infusion was performed in 474 investigations, and a valid measurement of the outflow resistance was received in 439 (93%). During the infusion phase, 17 (4%) patients reported severe headache. Infusion volume was significantly higher in patients having subjective symptoms during the infusion phase compared with those without adverse events. During 269 preoperative CSF tap tests, six (2%) patients had severe headache. Postinvestigational headache was reported by 83 (15%) patients at the 24-h follow-up. No serious adverse events were observed. Conclusion Infusion testing was safe and without serious adverse events with a high rate of successful procedures. The investigation was associated with expected mild to moderate discomfort.
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| 17. |
- Muggerud, Aslaug Aa, et al.
(författare)
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Frequent aberrant DNA methylation of ABCB1, FOXC1, PPP2R2B and PTEN in ductal carcinoma in situ and early invasive breast cancer
- 2010
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Ingår i: Breast Cancer Research. - : Springer Science and Business Media LLC. - 1465-5411 .- 1465-542X. ; 12:1, s. R3-
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: Ductal carcinoma in situ (DCIS) is a non-invasive lesion of the breast that is frequently detected by mammography and subsequently removed by surgery. However, it is estimated that about half of the detected lesions would never have progressed into invasive cancer. Identifying DCIS and invasive cancer specific epigenetic lesions and understanding how these epigenetic changes are involved in triggering tumour progression is important for a better understanding of which lesions are at risk of becoming invasive. METHODS: Quantitative DNA methylation analysis of ABCB1, CDKN2A/p16INK4a, ESR1, FOXC1, GSTP1, IGF2, MGMT, MLH1, PPP2R2B, PTEN and RASSF1A was performed by pyrosequencing in a series of 27 pure DCIS, 28 small invasive ductal carcinomas (IDCs), 34 IDCs with a DCIS component and 5 normal breast tissue samples. FOXC1, ABCB1, PPP2R2B and PTEN were analyzed in 23 additional normal breast tissue samples. Real-Time PCR expression analysis was performed for FOXC1. RESULTS: Aberrant DNA methylation was observed in all three diagnosis groups for the following genes: ABCB1, FOXC1, GSTP1, MGMT, MLH1, PPP2R2B, PTEN and RASSF1A. For most of these genes, methylation was already present at the DCIS level with the same frequency as within IDCs. For FOXC1 significant differences in methylation levels were observed between normal breast tissue and invasive tumours (P < 0.001). The average DNA methylation levels were significantly higher in the pure IDCs and IDCs with DCIS compared to pure DCIS (P = 0.007 and P = 0.001, respectively). Real-time PCR analysis of FOXC1 expression from 25 DCIS, 23 IDCs and 28 normal tissue samples showed lower gene expression levels of FOXC1 in both methylated and unmethylated tumours compared to normal tissue (P < 0.001). DNA methylation levels of FOXC1, GSTP1, ABCB1 and RASSF1A were higher in oestrogen receptor (ER) positive vs. ER negative tumours; whereas methylation levels of FOXC1, ABCB1, PPP2R2B and PTEN were lower in tumours with a TP53 mutation. CONCLUSIONS: Quantitative methylation analysis identified ABCB1, FOXC1, PPP2R2B and PTEN as novel genes to be methylated in DCIS. In particular, FOXC1 showed a significant increase in the methylation frequency in invasive tumours. Low FOXC1 gene expression in both methylated and unmethylated DCIS and IDCs indicates that the loss of its expression is an early event during breast cancer progression.
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| 18. |
- Pedersen, Soren W., et al.
(författare)
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Probing backbone hydrogen bonding in PDZ/ligand interactions by protein amide-to-ester mutations
- 2014
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 5, s. 3215-
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Tidskriftsartikel (refereegranskat)abstract
- PDZ domains are scaffolding modules in protein-protein interactions that mediate numerous physiological functions by interacting canonically with the C-terminus or non-canonically with an internal motif of protein ligands. A conserved carboxylate-binding site in the PDZ domain facilitates binding via backbone hydrogen bonds; however, little is known about the role of these hydrogen bonds due to experimental challenges with backbone mutations. Here we address this interaction by generating semisynthetic PDZ domains containing backbone amide-to-ester mutations and evaluating the importance of individual hydrogen bonds for ligand binding. We observe substantial and differential effects upon amide-to-ester mutation in PDZ2 of postsynaptic density protein 95 and other PDZ domains, suggesting that hydrogen bonding at the carboxylate-binding site contributes to both affinity and selectivity. In particular, the hydrogen-bonding pattern is surprisingly different between the non-canonical and canonical interaction. Our data provide a detailed understanding of the role of hydrogen bonds in protein-protein interactions.
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| 19. |
- Persson, Fredrik, 1979, et al.
(författare)
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Local conformation of confined DNA studied using emission polarization anisotropy
- 2010
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Ingår i: Biophysical Society 54th Annual Meeting.
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- When confined in nanochannels with dimensions smaller than the DNA radius of gyration, DNA will extend along the channel. We investigate long DNA confined in nanochannels, using fluorescence microscopy and intercalated dyes. Studies of the dynamics and statics of DNA in such nanoscale confinements as a function of e.g. degree of confinement and ionic strength have yielded new insights into the physical properties of DNA with relevance for applications in genomics as well as fundamental understanding of DNA packaging in vivo. Our work extends the field by not only studying the location of the emitting dyes along a confined DNA molecule but also monitoring the polarization of the emitted light. By measuring the emission polarized parallel and perpendicular to the extension axis of the stretched DNA, information on the local spatial distribution of the DNA backbone can be obtained. Comparing polarizations in two directions for DNA confined in channels of effective diameters of 85 nm and 170 nm reveals a striking difference. Whereas the DNA in the larger channels shows an isotropic polarization of the emitted light, the light is to a large extent polarized perpendicular to the elongation of the DNA in the smaller channels. We expect this technique to have a large impact on the studies of changes in DNA conformation induced by protein binding or during DNA compactation as well as in fundamental polymer physics studies of DNA in confined environments, for example in bacterial spores and viruses.
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| 20. |
- Persson, Fredrik, 1979, et al.
(författare)
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Local conformation of confined DNA studied using emission polarization anisotropy
- 2010
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Ingår i: NanoBioTech-Montreux 2009.
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- In nanochannels with dimensions smaller than the DNA radius of gyration, DNA will extend along the channel. We investigate long DNA confined in nanochannels using fluorescence microscopy and intercalated dyes. Studies of the dynamics and statics of the DNA extension or position in such nanoscale confinements as a function of e.g. DNA contour length, degree and shape of confinement as well as ionic strength have yielded new insights in the physical properties of DNA with relevance for applications in genomics as well as fundamental understanding of DNA packaging in vivo. Our work extends the field by not only studying the location of the emitting dyes along a confined DNA molecule but also monitoring the polarization of the emitted light. We use intercalating dyes (YOYO-1) whose emission is polarized perpendicular to the DNA extension axis, and by measuring the emission polarized parallel and perpendicular to the extension axis of the stretched DNA, information on the local spatial distribution of the DNA backbone can be obtained. The results obtained are analogous to linear dichroism (LD) but on a single-molecule level, and obtained in a highly parallel fashion. We will discuss results in shallow (60 nm) and deep (180 nm) channels and describe an example of how the technique can be used to investigate non-uniform stretching of DNA on the single molecule level. Comparing polarizations in two directions for DNA confined in channels of effective diameters of 85 nm and 170 nm reveals a striking difference. Whereas the DNA in the larger channels shows an isotropic polarization of the emitted light, the light is to a large extent polarized perpendicular to the elongation of the DNA in the smaller channels. The ratio of the polarization parallel and perpendicular to the elongation direction, I|| / I⊥, is a measure of the relative local orientation of the DNA backbone. We believe that this technique will have a large impact on the studies of changes in DNA conformation induced by protein binding or during DNA compactation as well as in fundamental polymer physics studies of DNA in confined environments, for example in bacterial spores and viruses.
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