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Kranendonk M.E.G.,University Utrecht | Kranendonk M.E.G.,Molecular Cancer Research | van Herwaarden J.A.,UMC Utrecht | Stupkova T.,University Utrecht | And 5 more authors.
Atherosclerosis | Year: 2015

Objective: Abdominal obesity is associated with insulin resistance and metabolic syndrome. However, specific contributions of distinct adipose tissue (AT) depots to metabolic complications of obesity are still unclear. In this study, the inflammatory profile of four distinct abdominal AT-depots and the relation between AT-characteristics and obesity-induced metabolic complications was evaluated. Methods: In 28 men undergoing abdominal aortic surgery, biopsies were collected from subcutaneous fat (SAT), and 3 visceral AT-depots: mesenteric (MAT), omental (OAT) and periaortic (PAT). The AT biopsies were characterized morphologically (adipocyte size, capillary density, CD68+macrophages and crown-like-structures (CLS)) and the exvivo adipokine secretion profile was determined by multiplex-immunoassay. The relation between depot-specific inflammatory characteristics and clinical parameters (waist circumference, insulin resistance and metabolic syndrome) was assessed by multivariable linear regression analysis. Results: PAT contained the smallest adipocytes, highest capillary density and secreted abundant amounts of adipokines. SAT contained the lowest amount of macrophages and adipokines, while MAT and OAT displayed a similar inflammatory profile. In contrast to the other depots, MAT inflammation was most strongly related to metabolic complications of obesity, as adipocyte size and CLS were related to insulin resistance (β2.0; 95%CI1.15-2.85 and β0.24; 95%CI0.06-0.43) and MAT adipocyte size was associated with 79% higher odds of having metabolic syndrome (OR1.79; 95% CI1.13-2.89). Conclusions: There are significant differences in the inflammatory profile of distinct abdominal fat depots, of which MAT characteristics were mostly associated with metabolic complications of obesity. These findings suggest a differential contribution of AT-depots to systemic metabolic dysfunction which precedes type 2 diabetes and vascular diseases. © 2015 Elsevier Ireland Ltd. Source

De Hoog V.C.,University Utrecht | Timmers L.,University Utrecht | Van Duijvenvoorde A.,University Utrecht | De Jager S.C.A.,University Utrecht | And 9 more authors.
Cardiovascular Research | Year: 2014

Aims Early reperfusion is mandatory for the treatment of acute myocardial infarction. This process, however, also induces additional loss of viable myocardium, called ischaemia-reperfusion (IR) injury. Complement activation plays an important role in IR injury, partly through binding of C5a to its major receptor (C5aR). We investigated the role of C5aR on infarct size and cardiac function in a model for myocardial IR injury. Methods and results BALB/c (WT) mice and C5aR-/- mice underwent coronary occlusion for 30 min, followed by reperfusion. Infarct size, determined 24 h after IR, was reduced in C5aR-/- mice compared with WT mice (28.5±2.1 vs. 35.7±2.5%, P = 0.017). Bone marrow (BM) chimaera experiments showed that this effect was due to the absence of C5aR on circulating leucocytes, since a similar reduction in infarct size was observed in WT mice with C5aR-deficient BM cells (25.3±2.2 vs. 34.6±2.8%, P < 0.05), but not in C5aR -/- mice withWTBM cells. Reduced infarct sizewas associated with fewer neutrophils, T cells, and macrophages in the infarcted area 24 h after IR in C5aR-/- mice, and also with lower levels of Caspase-3/7 indicating less inflammation and apoptosis. Echocardiography 4weeks after IR showed an improved ejection fraction in C5aR-/- mice (25.8±5.5 vs. 19.2±5.4%, P < 0.001). Conclusion The absence of C5aR on circulating leucocytes reduces infarct size, is associated with reduced leucocyte infiltration and with less apoptosis in the infarcted myocardium, and improves cardiac function in a mouse model of myocardial IR injury. Selective blocking of C5aR might be a promising strategy to prevent myocardial IR injury. © The Author 2014. Source

van Montfrans J.,University Utrecht | Schulz L.,University Utrecht | Versluys B.,University Utrecht | de Wildt A.,University Utrecht | And 7 more authors.
Biology of Blood and Marrow Transplantation | Year: 2015

Acute graft-versus-host disease (aGVHD) can be triggered by inflammatory conditions, including infections and mucositis. We investigated the association between PCR positivity for gastrointestinal (GI) viruses in stool before hematopoietic cell transplantation (HCT) and intestinal aGVHD using Cox proportional hazard models. We included 48 consecutive HCT patients (28 with malignancies and 20 with nonmalignancies) without GI symptoms before HCT. Fifteen patients were GI virus positive: 9 adenovirus, 3 norovirus, 2 parechovirus, and 1 astrovirus. Overall survival was 58%±8%. The cumulative incidence of aGVHD grade 2 to 4 was 43%±8% (n=18) after a median of 47days (range, 14 to 140). In univariate analysis, GI virus PCR positivity was the only predictor for aGVHD (P=008): within the group of GI virus PCR-positive patients, the cumulative incidence of aGVHD 2 to 4 was 70%±12% versus 29±8% in the PCR-negative group (P=004). In conclusion, GI virus PCR positivity before HCT predicted development of intestinal aGVHD. These results may ultimately affect monitoring, aGVHD prophylaxis, and treatment, as well as rescheduling of elective HCTs. © 2015 American Society for Blood and Marrow Transplantation. Source

Koenig J.,University College London | Werdehausen R.,University College London | Werdehausen R.,Heinrich Heine University Dusseldorf | Linley J.E.,University College London | And 11 more authors.
PLoS ONE | Year: 2015

The Nav1.7 voltage-gated sodium channel, encoded by SCN9A, is critical for human pain perception yet the transcriptional and post-transcriptional mechanisms that regulate this gene are still incompletely understood. Here, we describe a novel natural antisense transcript (NAT) for SCN9A that is conserved in humans and mice. The NAT has a similar tissue expression pattern to the sense gene and is alternatively spliced within dorsal root ganglia. The human and mouse NATs exist in cis with the sense gene in a tail-to-tail orientation and both share sequences that are complementary to the terminal exon of SCN9A/Scn9a. Over-expression analyses of the human NAT in human embryonic kidney (HEK293A) and human neuroblastoma (SH-SY5Y) cell lines show that it can function to downregulate Nav1.7 mRNA, protein levels and currents. The NAT may play an important role in regulating human pain thresholds and is a potential candidate gene for individuals with chronic pain disorders that map to the SCN9A locus, such as Inherited Primary Erythromelalgia, Paroxysmal Extreme Pain Disorder and Painful Small Fibre Neuropathy, but who do not contain mutations in the sense gene. Our results strongly suggest the SCN9A NAT as a prime candidate for new therapies based upon augmentation of existing antisense RNAs in the treatment of chronic pain conditions in man. © 2015 Koenig et al.This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Source

Otten H.G.,Laboratory for Translational Immunology | Hilbrands L.B.,RadboudUMC | Baas M.,RadboudUMC | Spierings E.,Laboratory for Translational Immunology | And 27 more authors.
Transplant Immunology | Year: 2014

Kidney transplantation is the best treatment option for patients with end-stage renal failure. At present, approximately 800 Dutch patients are registered on the active waiting list of Eurotransplant. The waiting time in the Netherlands for a kidney from a deceased donor is on average between 3 and 4. years. During this period, patients are fully dependent on dialysis, which replaces only partly the renal function, whereas the quality of life is limited. Mortality among patients on the waiting list is high. In order to increase the number of kidney donors, several initiatives have been undertaken by the Dutch Kidney Foundation including national calls for donor registration and providing information on organ donation and kidney transplantation. The aim of the national PROCARE consortium is to develop improved matching algorithms that will lead to a prolonged survival of transplanted donor kidneys and a reduced HLA immunization. The latter will positively affect the waiting time for a retransplantation. The present algorithm for allocation is among others based on matching for HLA antigens, which were originally defined by antibodies using serological typing techniques. However, several studies suggest that this algorithm needs adaptation and that other immune parameters which are currently not included may assist in improving graft survival rates. We will employ a multicenter-based evaluation on 5429 patients transplanted between 1995 and 2005 in the Netherlands. The association between key clinical endpoints and selected laboratory defined parameters will be examined, including Luminex-defined HLA antibody specificities, T and B cell epitopes recognized on the mismatched HLA antigens, non-HLA antibodies, and also polymorphisms in complement and Fc receptors functionally associated with effector functions of anti-graft antibodies. From these data, key parameters determining the success of kidney transplantation will be identified which will lead to the identification of additional parameters to be included in future matching algorithms aiming to extend survival of transplanted kidneys and to diminish HLA immunization. Computer simulation studies will reveal the number of patients having a direct benefit from improved matching, the effect on shortening of the waiting list, and the decrease in waiting time. © 2014. Source

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