18 research outputs found
Low- but not high-dose FK506 treatment confers atheroprotection due to alternative macrophage activation and unaffected cholesterol levels
No full textPrevious studies showed both pro- and anti-atherogenic effects of immunosuppressant drug FK506 on atherosclerosis. As these divergent/paradoxical results of FK506 may at least in part be attributable to differences in FK506 dosing, we have, in the current study, assessed dose-dependent effects of FK506 on atherosclerotic lesion formation as well as on inflammatory parameters relevant to atherosclerosis. Unlike low-dose FK506, high-dose FK506 did not protect against atherosclerosis in ApoE-/- mice. The high-dose induced hypercholesterolaemia, whereas the low-dose did not. Both low- and high-dose FK506 treatment significantly reduced systemic CD3(+) and CD4(+)CD25(+) T-cell populations, and showed similar suppression of FoxP3 regulatory 1-cell populations. Increased IL-4+ CD4+ T-cells and decreased IgG-MDA-LDL antibody titres pointed to a selective, albeit modest Th2 skewing in the high-dose treatment group, despite the advanced stage of atherosclerosis. Low concentrations of FK506, however, skewed bone marrow-derived macrophage polarisation towards a M2 macrophage phenotype, whereas high concentration did not. A low-dose FK506 treatment regime protected against atherosclerosis by suppressing T-cell activation and favouring (M2) macrophage polarisation. Although a high-dose FK506 treatment effected a similar T-cell suppressive effect, with an even more pronounced shift towards Th2 type immune responses, this did not translate in atheroprotection due to the hypercholesterolaemia and absent M2 skewing
Is immunohistochemical analysis of oestrogen and progesterone receptors in endometrial carcinoma superior to the radioligand binding assay?
No full textSemigroup presentations
No full textIn this thesis we consider in detail the following two fundamental problems for
semigroup presentations:
1. Given a semigroup find a presentation defining it.
2. Given a presentation describe the semigroup defined by it.
We also establish two links between these two approaches: semigroup constructions
and computational methods.
After an introduction to semigroup presentations in Chapter 3, in Chapters 4
and 5 we consider the first of the two approaches. The semigroups we examine in
these two chapters include completely O-simple semigroups, transformation semigroups,
matrix semigroups and various endomorphism semigroups. In Chapter 6
we find presentations for the following semi group constructions: wreath product,
Bruck-Reilly extension, Schiitzenberger product, strong semilattices of monoids,
Rees matrix semigroups, ideal extensions and subsemigroups. We investigate in
more detail presentations for subsemigroups in Chapters 7 and 10, where we prove
a number of Reidemeister-Schreier type results for semigroups. In Chapter 9
we examine the connection between the semi group and the group defined by the
same presentation. The general results from Chapters 6, 7, 9 and 10 are applied
in Chapters 8, 11, 12 and 13 to subsemigroups of free semigroups, Fibonacci
semigroups, semigroups defined by Coxeter type presentations and one relator
products of cyclic groups. Finally, in Chapter 14 we describe the Todd-Coxeter
enumeration procedure and introduce three modifications of this procedure
Plasmacytoid dendritic cells protect against atherosclerosis by tuning t-cell proliferation and activity
No full textRationale: Unlike conventional dendritic cells, plasmacytoid DCs (PDC) are poor in antigen presentation and critical for type 1 interferon response. Though proposed to be present in human atherosclerotic lesions, their role in atherosclerosis remains elusive. Objective: To investigate the role of PDC in atherosclerosis. Methods and Results: We show that PDC are scarcely present in human atherosclerotic lesions and almost absent in mouse plaques. Surprisingly, PDC depletion by 120G8 mAb administration was seen to promote plaque T-cell accumulation and exacerbate lesion development and progression in LDLr(-/-) mice. PDC depletion was accompanied by increased CD4(+) T-cell proliferation, interferon-gamma expression by splenic T cells, and plasma interferon-gamma levels. Lymphoid tissue PDC from atherosclerotic mice showed increased indoleamine 2,3-dioxygenase (IDO) expression and IDO blockage abrogated the PDC suppressive effect on T-cell proliferation. Conclusions: Our data reveal a protective role for PDC in atherosclerosis, possibly by dampening T-cell proliferation and activity in peripheral lymphoid tissue, rendering PDC an interesting target for future therapeutic interventions. (Circ Res. 2011;109:1387-1395.
Chemokines CCL3/MIP1α, CCL5/RANTES and CCL18/PARC are independent risk predictors of short-term mortality in patients with acute coronary syndromes
No full textCytokines play an important role in ischemic injury and repair. However, little is known about their prognostic value in cardiovascular disease. The aim of this study was to investigate the prognostic importance of chemokines CCL3/MIP-1α, CCL5/RANTES and CCL18/PARC for the risk of future cardiovascular events in patients with acute coronary syndromes (ACS). Baseline levels of CCL3/MIP-1α, CCL5/RANTES and CCL18/PARC were determined in ACS patients from the Bad Nauheim ACS II registry (n = 609). During the following 200 days, patients were monitored for the occurrence of fatal and non-fatal cardiovascular events. Patients with CCL3/MIP1α, CCL5/RANTES and CCL18/PARC concentrations in the highest tertile were associated with an increased risk of a fatal event during follow-up (HR: 2.19, 95%CI: 1.04–4.61 for CCL3/MIP1α, HR: 3.45, 95%CI: 1.54–7.72 for CCL5/RANTES and HR: 3.14, 95%CI: 1.33–7.46 for CCL18/PARC). This risk was highest for patients with all three biomarkers concentrations in the upper tertile (HR: 2.52, 95%CI: 1.11–5.65). Together with known risk predictors of cardiovascular events, CCL3/MIP-1α, CCL5/RANTES and CCL18/PARC combined improved the c-statistics from 0.74 to 0.81 (p = 0.007). In conclusion, CCL3/MIP-1α, CCL5/RANTES and CCL18/PARC are independently associated with the risk of short-term mortality in ACS patients. Combining all three biomarkers further increased their prognostic value
Noninvasive diagnosis of ruptured peripheral atherosclerotic lesions and myocardial infarction by antibody profiling
No full textNovel biomarkers, such as circulating (auto)antibody signatures, may improve early detection and treatment of ruptured atherosclerotic lesions and accompanying cardiovascular events, such as myocardial infarction. Using a phage-display library derived from cDNAs preferentially expressed in ruptured peripheral human atherosclerotic plaques, we performed serological antigen selection to isolate displayed cDNA products specifically interacting with antibodies in sera from patients with proven ruptured peripheral atherosclerotic lesions. Two cDNA products were subsequently evaluated on a validation series of patients with peripheral atherosclerotic lesions, healthy controls, and patients with coronary artery disease at different stages. Our biomarker set was able to discriminate between patients with peripheral ruptured lesions and patients with peripheral stable plaques with 100% specificity and 76% sensitivity. Furthermore, 93% of patients with an acute myocardial infarction (AMI) tested positive for our biomarkers, whereas all patients with stable angina pectoris tested negative. Moreover, 90% of AMI patients who initially tested negative for troponin T, for which a positive result is known to indicate myocardial infarction, tested positive for our biomarkers upon hospital admission. In conclusion, antibody profiling constitutes a promising approach for noninvasive diagnosis of atherosclerotic lesions, because a positive serum response against a set of 2 cDNA products showed a strong association with the presence of ruptured peripheral atherosclerotic lesions and myocardial infarctio
Hazard Ratios (95% confidence intervals) for a future cardiovascular event<sup>1</sup> during follow-up in patients with the acute coronary syndrome, according to the number of chemokines (CCL3/MIP-1α, CCL5/RANTES and CCL18/PARC) in the highest tertile, Bad Nauheim ACS II registry.
No full text<p>HR: hazard ratio; CI: confidence interval.</p>1<p>A cardiovascular event is defined as the occurrence of death, an acute myocardial infarction or an urgent revascularization procedure.</p>2<p>Adjusted for age, sex, diabetes, smoking, family history of cardiovascular disease and baseline levels of NT-proBNP, CK-MB and TnT.</p>3<p>All three chemokines concentrations in the lowest tertile.</p
Hazard Ratios (95% confidence intervals) for a fatal future cardiovascular event during follow-up in patients with the acute coronary syndrome, according to baseline levels of CCL3/MIP-1α, CCL5/RANTES and CCL18/PARC, Bad Nauheim ACS II registry.
No full text<p>HR: hazard ratio; CI: confidence interval.</p>1<p>Tertile boundaries for CCL3/MIP-1α: 18.7–33.3 pg/ml, CCL5/RANTES: 16.2–134.15 ng/ml, CCL18/PARC: 43.0–70.9 ng/ml.</p>2<p>Adjusted for age, sex, diabetes, smoking, family history of cardiovascular disease and baseline levels of NT-proBNP, CK-MB and TnT.</p
Receiver operating characteristics curves and c-statistics for logistic regression models predicting fatal events during follow-up in a subgroup of patients with acute coronary syndromes for CCL3/MIP-1α (A), CCL5/RANTES (B), CCL18/PARC (C) and all markers combined (D).
No full text<p>Established risk predictors include age, sex, diabetes, smoking, family history of cardiovascular disease, baseline levels of NT-proBNP, CK-MB, and TnT.</p
Kaplan-Meier curves for the occurrence of fatal and non-fatal events in patients with acute coronary syndromes of the Bad-Nauheim ACS II registry.
No full text<p>P<0.001 for the comparison of both event functions by the log-rank test.</p
