Prognostic imaging biomarkers for diabetic kidney disease (iBEAt):study protocol

Background: Diabetic kidney disease (DKD) remains one of the leading causes of premature death in diabetes. DKD is classified on albuminuria and reduced kidney function (estimated glomerular filtration rate (eGFR)) but these have modest value for predicting future renal status. There is an unmet need for biomarkers that can be used in clinical settings which also improve prediction of renal decline on top of routinely available data, particularly in the early stages. The iBEAt study of the BEAt-DKD project aims to determine whether renal imaging biomarkers (magnetic resonance imaging (MRI) and ultrasound (US)) provide insight into the pathogenesis and heterogeneity of DKD (primary aim) and whether they have potential as prognostic biomarkers in DKD (secondary aim). Methods: iBEAt is a prospective multi-centre observational cohort study recruiting 500 patients with type 2 diabetes (T2D) and eGFR ≥30 ml/min/1.73m2. At baseline, blood and urine will be collected, clinical examinations will be performed, and medical history will be obtained. These assessments will be repeated annually for 3 years. At baseline each participant will also undergo quantitative renal MRI and US with central processing of MRI images. Biological samples will be stored in a central laboratory for biomarker and validation studies, and data in a central data depository. Data analysis will explore the potential associations between imaging biomarkers and renal function, and whether the imaging biomarkers improve the prediction of DKD progression. Ancillary substudies will: (1) validate imaging biomarkers against renal histopathology; (2) validate MRI based renal blood flow measurements against H2O15 positron-emission tomography (PET); (3) validate methods for (semi-)automated processing of renal MRI; (4) examine longitudinal changes in imaging biomarkers; (5) examine whether glycocalyx and microvascular measures are associated with imaging biomarkers and eGFR decline; (6) explore whether the findings in T2D can be extrapolated to type 1 diabetes. Discussion: iBEAt is the largest DKD imaging study to date and will provide valuable insights into the progression and heterogeneity of DKD. The results may contribute to a more personalised approach to DKD management in patients with T2D. Trial registration: Clinicaltrials.gov (NCT03716401)

Vascular Cellular Adhesion Molecule-1 (VCAM-1) Expression in Mice Retinal Vessels Is Affected by Both Hyperglycemia and Hyperlipidemia

BACKGROUND: Inflammation has been proposed to be important in the pathogenesis of diabetic retinopathy. An early feature of inflammation is the release of cytokines leading to increased expression of endothelial activation markers such as vascular cellular adhesion molecule-1 (VCAM-1). Here we investigated the impact of diabetes and dyslipidemia on VCAM-1 expression in mouse retinal vessels, as well as the potential role of tumor necrosis factor-α (TNFα). METHODOLOGY/PRINCIPAL FINDINGS: Expression of VCAM-1 was examined by confocal immunofluorescence microscopy in vessels of wild type (wt), hyperlipidemic (ApoE(-/-)) and TNFα deficient (TNFα(-/-), ApoE(-/-)/TNFα(-/-)) mice. Eight weeks of streptozotocin-induced diabetes resulted in increased VCAM-1 in wt mice, predominantly in small vessels (<10 µm). Diabetic wt mice had higher total retinal TNFα, IL-6 and IL-1β mRNA than controls; as well as higher soluble VCAM-1 (sVCAM-1) in plasma. Lack of TNFα increased higher basal VCAM-1 protein and sVCAM-1, but failed to up-regulate IL-6 and IL-1β mRNA and VCAM-1 protein in response to diabetes. Basal VCAM-1 expression was higher in ApoE(-/-) than in wt mice and both VCAM-1 mRNA and protein levels were further increased by high fat diet. These changes correlated to plasma cholesterol, LDL- and HDL-cholesterol, but not to triglycerides levels. Diabetes, despite further increasing plasma cholesterol in ApoE(-/-) mice, had no effects on VCAM-1 protein expression or on sVCAM-1. However, it increased ICAM-1 mRNA expression in retinal vessels, which correlated to plasma triglycerides. CONCLUSIONS/SIGNIFICANCE: Hyperglycemia triggers an inflammatory response in the retina of normolipidemic mice and up-regulation of VCAM-1 in retinal vessels. Hypercholesterolemia effectively promotes VCAM-1 expression without evident stimulation of inflammation. Diabetes-induced endothelial activation in ApoE(-/-) mice seems driven by elevated plasma triglycerides but not by cholesterol. Results also suggest a complex role for TNFα in the regulation of VCAM-1 expression, being protective under basal conditions but pro-inflammatory in response to diabetes

NFAT signaling in chronic and acute inflammation - A novel target for the treatment of diabetic vascular complications and acute pancreatitis?

Diabetic patients suffer from macro- and microvascular complications causing increased morbidity and mortality. How hyperglycemia provokes vascular damage remains unclear, but glucose is believed to fuel a harmful low-grade chronic inflammation of the vessel wall. Previous work showed that glucose activates the transcription factor Nuclear Factor of Activated T cells (NFAT) in arteries ex vivo. NFAT is a family of Ca2+-calcineurin-sensitive proteins first found to regulate inflammatory gene expression in T cells, but have since been demonstrated to play a role in other cell types, including vascular endothelium and smooth muscle cells. We hypothesized that NFAT proteins are activated by glucose in diabetic vessels where they regulate proinflammatory genes that contribute to diabetic atherosclerosis and retinopathy. We also hypothesized that NFAT proteins regulate the inflammatory disease acute pancreatitis (AP). In the thesis, we demonstrate that both acute and chronic hyperglycemia activate NFAT in large arteries and retinal microvessels of mice. We show that activation of NFAT promotes the expression of the pro-inflammatory cytokine osteopontin (OPN). In vivo inhibition of NFAT with the novel blocker A-285222 or genetic deletion of NFATc3 reduced diabetes-induced OPN expression in mouse aorta. Moreover, we showed that treatment with A-285222 abolished diabetes-induced atherosclerosis, but had no effect on atherosclerosis in non-diabetic mice. Specifically, A-285222 reduced aortic lipid and macrophage content and the expression of IL-6, OPN, monocyte chemotactic protein-1 (MCP-1), intercellular adhesion molecule 1 (ICAM-1), and tissue factor in the arterial wall. In retinal vessels in vivo, we show that both glucose and lipids up-regulate the expression of vascular cell adhesion molecule 1 ( VCAM-1), promoting endothelial activation. Furthermore, in these vessels, we demonstrate that NFAT is activated by glucose by a mechanism involving the local release of extracellular nucleotides (i.e. UTP, UDP). In vivo inhibition of NFAT prevented diabetes-induced reduction of anti-inflammatory IL-10 in whole retina and reduced OPN and ICAM-1 mRNA in retinal microvessels. Finally, in the context of the exocrine pancreas, we demonstrate that NFATc3 regulates trypsinogen activation, inflammation and tissue damage in two mouse models of AP, and that NFATc3 deletion prevents AP-induced damage. Taken together, this thesis establishes that NFAT plays important roles in diabetic vascular complications and AP. Targeting NFAT may represent a novel therapeutic approach in these inflamatory disorders

Barndom, kultur och politik : ett teaterpolitiskt forskningsprojekt. Forskarnas rapport

Föreliggande rapport sammanfattar reflektioner och tentativa slutsatser från ett samarbetsprojekt mellan ung scen/öst och tema Barn, Linköpings universitet under år 2011. Målet med verksamheten var tredelat och syftade till 1) att utveckla samarbete mellan forskning och konstnärlig verksamhet genom en modell byggd på metoden aktionsforskning, 2) att forskarna skulle återkoppla sina iakttagelser under repetitionsarbetet med betoning på att det skulle ske innan premiären, 3) att dramatikerna också önskade sig en kritisk analys av pjäsen som text. Forskarna har utforskat iscensättningsprocessen,reflekterat och analyserat återkopplingsprocesser mellan forskare och dramatiker, samt genomfört en genusteoretisk textläsning av pjäsen. Rapporten speglar dessa tre aspekter av samarbetet

Програма заходів Всеукраїнського фестивалю науки у Тернопільському національному технічному університеті імені Івана Пулюя 2010 року

Föreliggande rapport sammanfattar reflektioner och tentativa slutsatser från ett samarbetsprojekt mellan ung scen/öst och tema Barn, Linköpings universitet under år 2011. Målet med verksamheten var tredelat och syftade till 1) att utveckla samarbete mellan forskning och konstnärlig verksamhet genom en modell byggd på metoden aktionsforskning, 2) att forskarna skulle återkoppla sina iakttagelser under repetitionsarbetet med betoning på att det skulle ske innan premiären, 3) att dramatikerna också önskade sig en kritisk analys av pjäsen som text. Forskarna har utforskat iscensättningsprocessen,reflekterat och analyserat återkopplingsprocesser mellan forskare och dramatiker, samt genomfört en genusteoretisk textläsning av pjäsen. Rapporten speglar dessa tre aspekter av samarbetet

Frequency and examples of code breaches found by the IGM or NBL in antidepressant advertisements in the Swedish Medical Journal in 1994–2003.

<p>See <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0062609#pone.0062609.s003" target="_blank">Table S2</a> for complete list of relevant articles.</p>1<p>Refers to IGM/NBL cases. Note that some cases revealed more than one type of article breach: see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0062609#pone.0062609.s002" target="_blank">Table S1</a>.</p>2<p>A few ads had contents ruled in violation in multiple cases.</p>3<p>Case numbers in the IGM/NBL database are indicated.</p>4<p>Percentage in cell of total, e.g. 13% of IGM/NBL cases, 4.8% of unique ads, and 5.1% of total ads breached article 1.</p

Nuclear factor of activated T-cells transcription factors in the vasculature: the good guys or the bad guys?

PURPOSE OF REVIEW: The nuclear factor of activated T-cells (NFAT) proteins are a family of Ca/calcineurin-dependent transcription factors that were first characterized in T-lymphocytes as inducers of cytokine gene expression. Since then, NFAT proteins have been shown to play varied roles outside of the immune system, including in the cardiovascular system. Cells in the vessel wall display a diverse array of Ca signaling modalities, which are subject to change during disease. The fact that NFAT proteins are able to decode and translate these signals into changes in gene expression makes them potential regulators of vascular pathogenesis. RECENT FINDINGS: It is now clear that NFAT signaling is required for normal vascular patterning during embryogenesis and for vascular endothelial growth factor-induced angiogenesis. The overall role of NFAT signaling in the vasculature, however, is less clear during adult life. This review aims to give an update on mechanisms that regulate NFAT activation in vascular cells, with an emphasis on the role of mitochondria and of upstream activators such as lipids and glucose. It also addresses recent work implicating NFAT proteins as mediators of vascular disease. SUMMARY: A better understanding of the NFAT-signaling pathway in the vasculature may open up an unexplored area for the development of new therapeutic approaches for treating vascular disease

Statements in antidepressant advertisements advancing general or comparative efficacy in depression treatment, or professing monoamine theories.

1<p>Number of ads containing claims or theories/number of ads found in breach by the IGM/NBL for this, e.g. 16 unique ads professed general efficacy claims; zero were found to be in violation for this.</p>2<p>Percentage of ads containing claims or theories of total, e.g. 12.9% of 124 unique advertisements professed general efficacy claims.</p>3<p>Percentage of ads found in breach by the IGM/NBL of ads containing claims or theories, e.g. 16 unique ads professed general efficacy claims; zero percent were found to be in violation for this.</p>4<p>Italicized statements were found to breach the code by the IGM/NBL. Case number in the IGM/NBL database is indicated.</p

Lags in the system allowed for extended and substantial exposure to unethical antidepressant advertising.

<p>The instigator of each IGM/NBL case is indicated; HP (health professionals), MPA (Medical Products Agency). (A) Scatter plot of reaction times (i.e. the elapsed time between original publication date and date of ruling against wrongful claims) among IGM/NBL cases concerning antidepressant advertising in the Swedish Medical Journal in 1994–2003. Linear regression analysis shows that reaction times increased over the ten-year period (p = 0.041; β = 6.9 weeks/year; n = 23). (B) Scatter plot of the total number of violative advertisements in the Swedish Medical Journal per IGM/NBL case prior to date of ruling. Linear regression analysis shows that there was a borderline significant increase in the number of advertisements allowed in print over the period (p = 0.063; β = 1.4 ads/year; n = 23). (C) Reaction times and (D) number of violative advertisements among cases instigated by the IGM (i.e. via active monitoring of promotional material) and non-IGM (i.e. following voluntary complaints from industry, HP or the MPA), respectively. The median of each group is indicated by the bar. Differences between groups were analyzed with two-tailed Mann-Whitney test. There was a significant difference in reaction time between IGM and non-IGM cases (p = 0.007) (in C).</p