Differential Gene Expression Analysis of Placentas with Increased Vascular Resistance and Pre-Eclampsia Using Whole-Genome Microarrays

Pre-eclampsia is a pregnancy complication characterized by hypertension and proteinuria. There are several factors associated with an increased risk of developing pre-eclampsia, one of which is increased uterine artery resistance, referred to as “notching”. However, some women do not progress into pre-eclampsia whereas others may have a higher risk of doing so. The placenta, central in pre-eclampsia pathology, may express genes associated with either protection or progression into pre-eclampsia. In order to search for genes associated with protection or progression, whole-genome profiling was performed. Placental tissue from 15 controls, 10 pre-eclamptic, 5 pre-eclampsia with notching, and 5 with notching only were analyzed using microarray and antibody microarrays to study some of the same gene product and functionally related ones. The microarray showed 148 genes to be significantly altered between the four groups. In the preeclamptic group compared to notch only, there was increased expression of genes related to chemotaxis and the NF-kappa B pathway and decreased expression of genes related to antigen processing and presentation, such as human leukocyte antigen B. Our results indicate that progression of pre-eclampsia from notching may involve the development of inflammation. Increased expression of antigen-presenting genes, as seen in the notch-only placenta, may prevent this inflammatory response and, thereby, protect the patient from developing pre-eclampsia

Differential Effect of LPS on Glucose, Lactate and Inflammatory Markers in the Lungs of Normal and Diabetic Mice

Elevation of blood glucose results in increased glucose in the fluid that lines the surface of the airways and this is associated with an increased susceptibility to infection with respiratory pathogens. Infection induces an inflammatory response in the lung, but how this is altered by hyperglycemia and how this affects glucose, lactate and cytokine concentrations in the airway surface liquid is not understood. We used Wild Type (WT) and glucokinase heterozygote (GK+/-) mice to investigate the effect of hyperglycemia, with and without LPS-induced inflammatory responses, on airway glucose, lactate, inflammatory cells and cytokines measured in Bronchoalveolar Lavage Fluid (BALF). We found that glucose and lactate concentrations in BALF were elevated in GK+/-compared to WT mice and that there was a direct correlation between blood glucose and BALF glucose concentrations. LPS challenge increased BALF inflammatory cell numbers and this correlated with decreased glucose and increased lactate concentrations although the effect was less in GK+/- compared to WT mice. All cytokines measured (except IL-2) increased in BALF with LPS challenge. However, concentrations of TNFa, INFg, IL-1band IL-2 were less in GK+/- compared to WT mice. This study shows that the normal glucose/lactate environment of the airway surface liquid is altered by hyperglycemia and the inflammatory response. These data indicate that inflammatory cells utilize BALF glucose and that production of lactate and cytokines is compromised in hyperglycemic GK+/-mice

Rules, Norms and Practices – A Comparative Study Exploring Disposal Practices and Facilities in Northern Europe

We identify and analyse practices and management regimes around burial and handling of ashes across eight case study towns within six Northern European countries. We analyse management of cemeteries and crematoria gardens, majority practices and provision for minority communities, including various burial types, cremated remains, the re-use of graves, and costs for interments. Comparative data is drawn from analysis of national and local regulations, interviews with stakeholders, and observations at cemeteries and crematoria gardens. The findings show significant variation in national and local regulations and practices for burial and cremation particularly around the re-use of graves, handling of ashes and costs for grave space and cremation. We identify the opportunities and constraints of these variations in terms of accessibility, diversity and equality; and argue for national directions to avoid unequal treatment within nations. Furthermore, we stress the importance of a liberal and inclusive management of European cemeteries and crematoria gardens

Universal cross-over behavior of a magnetic impurity and consequences for doping in spin-1/2 chains

We consider a magnetic impurity in the antiferromagnetic spin-1/2 chain which is equivalent to the two-channel Kondo problem in terms of the field theoretical description. Using a modification of the transfer-matrix density matrix renormalization group (DMRG) we are able to determine local and global properties in the thermodynamic limit. The cross-over function for the impurity susceptibility is calculated over a large temperature range, which exhibits universal data-collapse. We are also able to determine the local susceptibilities near the impurity, which show an interesting competition of boundary effects. This results in quantitative predictions for experiments on doped spin-1/2 chains, which could observe two-channel Kondo physics directly.Comment: 5 pages in revtex format including 3 embedded figures (using epsf). The latest version in PDF format is available from http://fy.chalmers.se/~eggert/papers/crossover.pdf . Accepted by PR

Designing a memorial place

The design and selection of a memorial stone and the site of the grave, both of which represent the deceased, can be a central issue for people bereaved by traffic accidents. This was revealed in an interview survey of recent Swedish roadside memorials and other memorial places. In this article we consider the design and selection of the memorial stone and gravesite as expressions of continuing care for the deceased and as a way to offer comfort to the bereaved. Materiality, representation and presence will be discussed as crucial parts of the link between the living and the dead. Communicative, spatial and physical values are important also in the professional's design of common public memorial places. Of specific interest for this text are two design practice-based terms, memory object and passage landscape, which may be used by landscape architects when designing memorial places, such as cemeteries and public monuments. Throughout this text, we argue that memorial places like these are capable of bridging the gap between the space of life and the space of death, as well as supporting the regeneration of present memories and the construction of future ones

Dapagliflozin-lowered blood glucose reduces respiratory Pseudomonas aeruginosa infection in diabetic mice.

BACKGROUND AND PURPOSE: Hyperglycaemia increases glucose concentrations in airway surface liquid and increases the risk of pulmonary Pseudomonas aeruginosa infection. We determined whether reduction of blood and airway glucose concentrations by the anti-diabetic drug dapagliflozin could reduce P. aeruginosa growth/survival in the lungs of diabetic mice. EXPERIMENTAL APPROACH: The effect of dapagliflozin on blood and airway glucose concentration, the inflammatory response and infection were investigated in C57BL/6J (wild type, WT) or leptin receptor-deficient (db/db) mice, treated orally with dapagliflozin prior to intranasal dosing with LPS or inoculation with P. aeruginosa. Pulmonary glucose transport and fluid absorption were investigated in Wistar rats using the perfused fluid-filled lung technique. KEY RESULTS: Fasting blood, airway glucose and lactate concentrations were elevated in the db/db mouse lung. LPS challenge increased inflammatory cells in bronchoalveolar lavage fluid from WT and db/db mice with and without dapagliflozin treatment. P. aeruginosa colony-forming units (CFU) were increased in db/db lungs. Pretreatment with dapagliflozin reduced blood and bronchoalveolar lavage glucose concentrations and P. aeruginosa CFU in db/db mice towards those seen in WT. Dapagliflozin had no adverse effects on the inflammatory response in the mouse or pulmonary glucose transport or fluid absorption in the rat lung. CONCLUSION AND IMPLICATIONS: Pharmacological lowering of blood glucose with dapagliflozin effectively reduced P. aeruginosa infection in the lungs of diabetic mice and had no adverse pulmonary effects in the rat. Dapagliflozin has potential to reduce the use, or augment the effect, of antimicrobials in the prevention or treatment of pulmonary infection

Effects of Three Months of Low Molecular Weight Heparin (dalteparin) Treatment After Bypass Surgery for Lower Limb Ischemia—A Randomised Placebo-controlled Double Blind Multicentre Trial

AbstractObjectivesTo test the hypothesis that long-term postoperative dalteparin (Fragmin®, Pharmacia Corp) treatment improves primary patency of peripheral arterial bypass grafts (PABG) in lower limb ischemia patients on acetylsalicylic acid (ASA) treatment.DesignProspective randomised double blind multicenter study.Materials and methodsUsing a computer algorithm 284 patients with lower limb ischemia, most with pre-operative ischemic ulceration or partial gangrene, from 12 hospitals were randomised, after PABG, to 5000IU dalteparin or placebo injections once daily for 3 months. All patients received 75mg of ASA daily for 12 months. Graft patency was assessed at 1, 3 and 12 months.ResultsAt 1 year, 42 patients had died or were lost to follow-up. Compliance with the injection schedule was 80%. Primary patency rate, in the dalteparin versus the control group, respectively, was 83 versus 80% (n.s.) at 3 months and 59% for both groups at 12 months. Major complication rates and cardiovascular morbidity were not different between the two groups.ConclusionsIn patients on ASA treatment, long-term postoperative dalteparin treatment did not improve patency after peripheral artery bypass grafting. Therefore, low molecular weight heparin treatment cannot be recommended for routine use after bypass surgery for critical lower limb ischemia

Assessment and optimisation of normalisation methods for dual-colour antibody microarrays

<p>Abstract</p> <p>Background</p> <p>Recent advances in antibody microarray technology have made it possible to measure the expression of hundreds of proteins simultaneously in a competitive dual-colour approach similar to dual-colour gene expression microarrays. Thus, the established normalisation methods for gene expression microarrays, e.g. loess regression, can in principle be applied to protein microarrays. However, the typical assumptions of such normalisation methods might be violated due to a bias in the selection of the proteins to be measured. Due to high costs and limited availability of high quality antibodies, the current arrays usually focus on a high proportion of regulated targets. Housekeeping features could be used to circumvent this problem, but they are typically underrepresented on protein arrays. Therefore, it might be beneficial to select invariant features among the features already represented on available arrays for normalisation by a dedicated selection algorithm.</p> <p>Results</p> <p>We compare the performance of several normalisation methods that have been established for dual-colour gene expression microarrays. The focus is on an invariant selection algorithm, for which effective improvements are proposed. In a simulation study the performances of the different normalisation methods are compared with respect to their impact on the ability to correctly detect differentially expressed features. Furthermore, we apply the different normalisation methods to a pancreatic cancer data set to assess the impact on the classification power.</p> <p>Conclusions</p> <p>The simulation study and the data application demonstrate the superior performance of the improved invariant selection algorithms in comparison to other normalisation methods, especially in situations where the assumptions of the usual global loess normalisation are violated.</p

Genotype of metabolic enzymes and the benefit of tamoxifen in postmenopausal breast cancer patients

BACKGROUND: Tamoxifen is widely used as endocrine therapy for oestrogen-receptor-positive breast cancer. However, many of these patients experience recurrence despite tamoxifen therapy by incompletely understood mechanisms. In the present report we propose that tamoxifen resistance may be due to differences in activity of metabolic enzymes as a result of genetic polymorphism. Cytochrome P450 2D6 (CYP2D6) and sulfotransferase 1A1 (SULT1A1) are polymorphic and are involved in the metabolism of tamoxifen. The CYP2D6*4 and SULT1A1*2 genotypes result in decreased enzyme activity. We therefore investigated the genotypes of CYP2D6 and SULT1A1 in 226 breast cancer patients participating in a trial of adjuvant tamoxifen treatment in order to validate the benefit from the therapy. METHODS: The patients were genotyped using PCR followed by cleavage with restriction enzymes. RESULTS: Carriers of the CYP2D6*4 allele demonstrated a decreased risk of recurrence when treated with tamoxifen (relative risk = 0.28, 95% confidence interval = 0.11–0.74, P = 0.0089). A similar pattern was seen among the SULT1A1*1 homozygotes (relative risk = 0.48, 95% confidence interval = 0.21–1.12, P = 0.074). The combination of CYP2D6*4 and/or SULT1A1*1/*1 genotypes comprised 60% of the patients and showed a 62% decreased risk of distant recurrence with tamoxifen (relative risk = 0.38, 95% confidence interval = 0.19–0.74, P = 0.0041). CONCLUSION: The present study suggests that genotype of metabolic enzymes might be useful as a guide for adjuvant endocrine treatment of postmenopausal breast cancer patients. However, results are in contradiction to prior hypotheses and the present sample size is relatively small. Findings therefore need to be confirmed in a larger cohort