Development and functional consequences of LPS tolerance in sinusoidal endothelial cells of the liver.

Kupffer cells and liver sinusoidal endothelial cells (LSEC) clear portal venous blood from gut-derived bacterial degradation products such as lipopolysaccharide (LPS) without inducing a local inflammatory reaction. LPS tolerance was reported for Kupffer cells, but little is known whether sensitivity of LSEC toward LPS is dynamically regulated. Here, we demonstrate that LSEC react to LPS directly as a function of constitutive Toll-like receptor 4 (TLR4)/CD14 expression but gain a LPS-refractory state upon repetitive stimulation without loss of scavenger activity.

The role of regulatory T cells in antigen-induced arthritis: aggravation of arthritis after depletion and amelioration after transfer of CD4+CD25+ T cells.

It is now generally accepted that CD4+CD25+ Treg cells play a major role in the prevention of autoimmunity and pathological immune responses. Their involvement in the pathogenesis of chronic arthritis is controversial, however, and so we examined their role in experimental antigen-induced arthritis in mice. Depletion of CD25-expressing cells in immunized animals before arthritis induction led to increased cellular and humoral immune responses to the inducing antigen (methylated bovine serum albumin; mBSA) and autoantigens, and to an exacerbation of arthritis, as indicated by clinical (knee joint swelling) and histological scores.

Dendritic cells govern induction and reprogramming of polarized tissue-selective homing receptor patterns of T cells: important roles for soluble factors and tissue microenvironments.

Tissue-selective homing is established during naive T cell activation by the tissue microenvironment and tissue-specific dendritic cells (DC). The factors driving induction and maintenance of T cell homing patterns are still largely unknown. Here we show that soluble factors produced during the interaction of T cells with CD11c(+) DC isolated from skin- or small intestine-associated tissues differentially modulate expression of the corresponding tissue-selective homing receptors (E-selectin ligands and alpha4beta7 integrin/CCR9, respectively) on murine CD8(+) T cells.

Differences in phenotype and function between spontaneously occurring melan-A-, tyrosinase- and influenza matrix peptide-specific CTL in HLA-A*0201 melanoma patients.

Melanoma-specific T cells can occur spontaneously or in response to vaccination or other therapies, but the frequency is much lower than observed in viral infections. The presence of tumor-specific T cells does not necessarily translate into clinical regressions for a variety of reasons such as an insufficient frequency, activation state or homing capacity of the T cells or escape strategies of the tumor. Having screened melanoma patients prior to inclusion in vaccination trials for spontaneous tumor-specific T cells either by Elispot or tetramer-staining, we have identified 3 patients with sufficient numbers of tumor-reactive T cells to more than 1 TAA and at least 1 virus-antigen to perform phenotypic and functional analysis directly ex vivo.

Decreased plasma lipoprotein lipase in hypoadiponectinemia: an association independent of systemic inflammation and insulin resistance.

Objective: Adiponectin is a plasma protein expressed in adipose tissue. Hypoadiponectinemia is associated with low HDL cholesterol and high plasma triglycerides, which also characterize lipoprotein lipase (LPL) deficiency syndromes. Recently, dramatically increased LPL activity was reported in mice overexpressing adiponectin.

[Oral diabetes treatment. Which substance is indicated at which time?].

The prevalence of type 2 diabetes continues to show a clear upward trend in Germany. In earlier days it was considered the "harmless diabetes of old age," but has become increasingly recognized as a disease carrying a high risk of vascular sequelae as well as shortening the diabetic's remaining life expectancy if adequate therapy is not initiated. In addition to correcting hyperglycemia, treatment consists in effective management of concomitant risk factors such as hypertension, dyslipidemia, and adiposity resulting from faulty nutrition and lack of exercise.

Genetic analysis of spore killing in the filamentous ascomycete Podospora anserina.

In the present study, we analysed different Podospora anserina strains for their ability to induce spore killing and identified three new killer strains. Test crosses of killer strains with different sensitive strains revealed different second division segregation ratios suggesting an influence of the sensitive strain on the crossing-over frequency. In crosses of killer strain O with a sensitive strain, the frequency of two-spored asci was found to vary extremely from perithecium to perithecium.

The composition of intrahepatic lymphocytes: shaped by selective recruitment?

Intrahepatic lymphocytes have a distinct subset composition and phenotype. Compared with lymphoid tissues, the frequency of natural killer (NK) cells, NKT cells and gammadelta T cells among total lymphocytes is increased within the liver, and alphabeta T cells are predominantly effector/memory cells. Divergent hypotheses on the origin of intrahepatic T cells have emerged to explain this; in these hypotheses, either local development or selective recruitment of cells into the liver dominates.

Reduction of postprandial hyperglycemia in patients with type 2 diabetes reduces NF-kappaB activation in PBMCs.

Aims/hypothesis: Short-lasting hyperglycemia results in activation of the transcription factor NF-kappaB in peripheral blood mononuclear cells. We therefore studied whether the postprandial increase in glucose is sufficient to induce mononuclear NF-kappaB activation and whether blunting postprandial hyperglycemia with the alpha-glucosidase inhibitor acarbose reduces NF-kappaB activation.

Methods: 20 patients with type 2 diabetes were included in a double-blind randomized trial receiving 100 mg acarbose or placebo three times a day over a period of eight weeks.

Variants in the human beta 1-, beta 2-, and beta 3-adrenergic receptor genes are not associated with morbid obesity in children and adolescents.

Aim: beta-adrenergic receptors (beta-ARs) are of key importance for the regulation of lipolysis and thermogenesis by catecholamines. Genetic defects in expression or function of beta(1)- beta(2)- and/or beta(3)-AR could affect energy homeostasis and predispose an individual towards the development of obesity. We therefore investigated the possible association of polymorphisms in the beta-adrenergic receptor genes with early onset obesity.

Expression of selectin ligands on murine effector and IL-10-producing CD4+ T cells from non-infected and infected tissues.

Endothelial selectins are crucial for the recruitment of leukocytes into sites of inflammation. On T cells, ligands for selectins become induced upon differentiation into the effector/memory stage. Initial in vitro studies suggested a correlation between the Th1 phenotype and ligand expression, but whether this also holds true in vivo remained uncertain.

Bone marrow microenvironment facilitating dendritic cell: CD4 T cell interactions and maintenance of CD4 memory.

This study shows that bone marrow (BM) stroma expresses constitutively multiple adhesion molecules (ICAM-1, VCAM-1, MadCAM-1, P-selectin) relevant for the homing and infiltration of BM by blood derived T lymphocytes, and also the co-stimulatory molecule CD80, relevant for T cell activation. T cells were capable of homing to BM but not to thymus. Homing to BM involved the integrins LFA-1alpha and alpha4 which interact with the above constitutively expressed cell adhesion molecules (CAMs).

Tissue and serum levofloxacin concentrations in diabetic foot infection patients.

Objectives: Levofloxacin has a high bioavailability and a broad antibacterial spectrum which covers the common pathogens found in acute and chronic diabetic foot infections. The purpose of our study was to determine the serum and tissue concentrations of levofloxacin when administered orally in patients with infected diabetic foot ulcers and to compare these values with microbiological findings.

Patients And Methods: Ten outpatients with diabetes and ulcerations of the lower extremity were included.

[AGE-RAGE: a hypothesis or a mechanism?].

Acausal relation between hyperglycemia and accelerated atherosclerosis has been recently suggested. The AGE-RAGE interaction is a potential mechanism underlying the accelerated atherosclerosis. Hyperglycemia causes via nonenzymatic glycation the formation of AGEs (advanced glycation endproducts).

Differential regulation of P-selectin ligand expression in naive versus memory CD4+ T cells: evidence for epigenetic regulation of involved glycosyltransferase genes.

Lymphocytes are targeted to inflamed sites by specific "homing" and chemokine receptors. Most of them, including ligands for P- and E-selectin, are absent from naive CD4(+) T cells and become induced after activation and differentiation in effector/memory cells. Polarized effector cells are characterized by the rapid production of distinct cytokines upon restimulation.

Atorvastatin improves diabetic dyslipidemia and increases lipoprotein lipase activity in vivo.

A major factor contributing to cardiovascular mortality in type 2 diabetes is dyslipidemia, characterized by low HDL cholesterol and high triglycerides, rather than elevated LDL cholesterol. Lipoprotein lipase (LPL) is the rate-limiting enzyme of triglyceride removal from plasma and has been implicated in atherosclerosis. Since treatment with statins significantly reduces cardiovascular morbidity in diabetes, we analyzed the lipid profile and LPL activities in 61 patients with type 2 diabetes before and 8 weeks after initiation of atorvastatin (40 mg) or placebo treatment.

Lack of association between polymorphisms of the toll-like receptor 4 gene and cerebral ischemia.

Toll-like receptor-4 (TLR4), an important mediator of the innate immune response, is expressed in atherosclerotic lesions. The common single nucleotide exchange (Asp299Gly) of the TLR4 gene has been previously reported to impair TLR4 function and to be associated with a decreased risk of carotid atherosclerosis. Therefore, we aimed to detect the potential impact of TLR4 genotypes on the risk of cerebral ischemia.

[Thyroid hormones and the function of the vascular endothelium].

Numerous clinical studies point towards connections between cardiovascular morbidity and mortality and disorders of the thyroid function. This does not only apply to clinically manifest functional disorders, but also to their subclinical stages. The present review discusses in detail some of the most important endothelial changes, open questions and future developments.

CC chemokine receptor 7 expression by effector/memory CD4+ T cells depends on antigen specificity and tissue localization during influenza A virus infection.

The lung is an important entry site for respiratory pathogens such as influenza A virus. In order to combat such invading infectious agents, effector/memory T cells home to the lung and other peripheral tissues as well as lymphoid organs. In this process, chemokines and their receptors fulfill important roles in the guidance of T cells into such organs and specialized microenvironments within tissues.

The spectrum of lymphoid subsets preferentially recruited into the liver reflects that of resident populations.

Intrahepatic lymphocytes (IHL) differ phenotypically from cells found in the peripheral blood or in lymphoid organs. The liver contains T-cells that are also found in lymphoid organs but a higher proportion of these T-cells compared to those in lymphoid organs express activation or memory markers and very few naïve T-cells are present within the liver. Furthermore, subsets such as NK and NK T-cells, which are detected at comparably lower levels within the lymphoid organs are increased within the liver.

Rosuvastatin and fenofibrate alone and in combination in type 2 diabetes patients with combined hyperlipidaemia.

The aim of this study was to evaluate the effects of rosuvastatin and fenofibrate alone and in combination in type 2 diabetes associated with combined hyperlipidaemia. A total of 216 patients with total cholesterol >/=200 mg/dl (>/=5.17 mmol/l) and triglycerides >/=200 and <800 mg/dl (>/=2.

A 63bp deletion in the promoter of rage correlates with a decreased risk for nephropathy in patients with type 2 diabetes.

Several polymorphisms have been identified in the RAGE-promoter region that might modulate the outcome of disease. Here we analyse the association of a 63bp deletion (delta63) spanning from bp - 407 to bp - 345 with diabetic nephropathy. The deletion was determined using the polymerase chain reaction (PCR) in a cross-sectional study with 1087 patients with type 1 diabetes (n = 559) and type 2 diabetes (n = 528).

Effect of thiol antioxidant on body fat and insulin reactivity.

Insulin signaling is enhanced by moderate concentrations of reactive oxygen species (ROS) and suppressed by persistent exposure to ROS. Diabetic patients show abnormally high ROS levels and a decrease in insulin reactivity which is ameliorated by antioxidants, such as N-acetylcysteine (NAC). A similar effect of NAC has not been reported for non-diabetic subjects.