Human immune responses to porcine xenogeneic matrices and their extracellular matrix constituents in vitro.

Several tissue engineering approaches for the treatment of cardiovascular diseases are based on a xenogeneic extracellular matrix. However, the application of engineered heart valves has failed in some patients, causing severe signs of inflammation by so far undetermined processes. Therefore we investigated the immune-mediated responses to porcine valve matrices (native, decellularized and glutaraldehyde-fixed) and to purified xenogeneic extracellular matrix proteins (ECMp).

Characterization of streptavidin binding to biotinylated, binary self-assembled thiol monolayers--influence of component ratio and solvent.

Many biosensor applications are based on streptavidin (SA) binding to partially biotinylated self-assembled thiol monolayers (SAMs). In our study, binary SAMs on gold were prepared from solutions containing 16-mercapto-1-hexadecanol (thiol I) and N-(8-biotinyl-3,6-dioxa-octanamidyl)-16-mercaptohexadecanamide (thiol II) in varying component ratios. Either chloroform or ethanol was used as solvent.

Iron absorption and distribution in TNF(DeltaARE/+) mice, a model of chronic inflammation.

Hemizygous TNF(DeltaARE/+) mice are a murine model for chronic inflammation. We utilized these animals to study iron-kinetics and corresponding protein expression in an iron-deficient and iron-adequate setting. (59)Fe-absorption was determined in ligated duodenal loops in vivo.

[The dural arteriovenous fistula - an unimposing morphological correlate with imposing consequences].

Dural arteriovenous fistulas (DAVFs) are abnormal arteriovenous shunts located within the dura mater representing approximately 10 - 15 % of all arteriovenous shunts in the central nervous system. The aetiology of spontaneous DAVFs remains to be elucidated. The symptoms associated with DAVFs can be highly variable and dependent upon the direction of the blood flow, the amount of arteriovenous shunting and the specific location of the fistula.

Molecular footprints of a germinal center derivation of human IgM+(IgD+)CD27+ B cells and the dynamics of memory B cell generation.

The origin of IgM(+)CD27(+) B lymphocytes with mutated IgV genes, which account for approximately 20% of human peripheral blood (PB) B cells, is controversially discussed. A generation in a primary diversification pathway, in T cell-independent immune responses, or in T cell-dependent germinal center (GC) reactions has been proposed. We show here that IgM(+)IgD(+)CD27(+) and IgM(+)IgD(-/low)CD27(+) B cell subsets carry, like class-switched memory B cells, mutations in the Bcl6 gene as a genetic trait of a GC experience.

Growth differentiation factor 15 in anaemia of chronic disease, iron deficiency anaemia and mixed type anaemia.

Recently, the iron and erythropoiesis-controlled growth differentiation factor 15 (GDF15) has been shown to inhibit the expression of hepcidin in beta-thalassaemia patients, thereby increasing iron absorption despite iron overload. To access the diagnostic and pathogenic impact of GDF15 in inflammatory anaemia the association of GDF15 expression with serum iron parameters and hepcidin was studied in patients suffering from iron deficiency anaemia (IDA), anaemia of chronic disease (ACD) and ACD subjects with true iron deficiency (ACD/IDA). GDF15 was significantly increased in both ACD and ACD/IDA, but not in IDA subjects as compared to controls.

Analysis of elite swimmers' activity during an instrumented protocol.

The aim of this study was to examine swimmers' activity-technical device coupling during an experimental protocol (MAD-system). The study was conducted within a course-of-action theoretical and methodological framework. Two types of data were collected: (a) video recordings and (b) verbalizations during post-protocol interviews.

A comprehensive microarray-based DNA methylation study of 367 hematological neoplasms.

Background: Alterations in the DNA methylation pattern are a hallmark of leukemias and lymphomas. However, most epigenetic studies in hematologic neoplasms (HNs) have focused either on the analysis of few candidate genes or many genes and few HN entities, and comprehensive studies are required.

Methodology/principal Findings: Here, we report for the first time a microarray-based DNA methylation study of 767 genes in 367 HNs diagnosed with 16 of the most representative B-cell (n = 203), T-cell (n = 30), and myeloid (n = 134) neoplasias, as well as 37 samples from different cell types of the hematopoietic system.

Toward MSC in solid organ transplantation: 2008 position paper of the MISOT study group.

The following position paper summarizes the recommendations for early clinical trials and ongoing basic research in the field of mesenchymal stem cell-induced solid organ graft acceptance--agreed upon on the first meeting of the Mesenchymal Stem Cells In Solid Organ Transplantation (MISOT) study group in late 2008.

Inactivating SOCS1 mutations are caused by aberrant somatic hypermutation and restricted to a subset of B-cell lymphoma entities.

STATs are constitutively activated in several malignancies. In primary mediastinal large B-cell lymphoma and Hodgkin lymphoma (HL), inactivating mutations in SOCS1, an inhibitor of JAK/STAT signaling, contribute to deregulated STAT activity. Based on indications that the SOCS1 mutations are caused by the B cell-specific somatic hypermutation (SHM) process, we analyzed B-cell non-HL and normal B cells for mutations in SOCS1.

Absence of functional Hfe protects mice from invasive Salmonella enterica serovar Typhimurium infection via induction of lipocalin-2.

Mutations of HFE are associated with hereditary hemochromatosis, but their influence on host susceptibility to infection is incompletely understood. We report that mice lacking one or both Hfe alleles are protected from septicemia with Salmonella Typhimurium, displaying prolonged survival and improved control of bacterial replication. This increased resistance is paralleled by an enhanced production of the enterochelin-binding peptide lipocalin-2 (Lcn2), which reduces the availability of iron for Salmonella within Hfe-deficient macrophages.

Expression of 25-hydroxyvitamin D-1alpha-hydroxylase (1alphaOHase, CYP27B1) splice variants in HaCaT keratinocytes and other skin cells: modulation by culture conditions and UV-B treatment in vitro.

In vitro and in vivo studies have demonstrated that the biologically active vitamin D metabolite 1,25-dihydroxyvitamin D (1,25(OH)2D3, calcitriol) suppresses proliferation and induces differentiation in various cell types, including human keratinocytes and melanocytes. Vitamin D is synthesized in the skin from 7-dehydrocholesterol (7-DHC) by the action of UV-B. There are two principal enzymes involved in the formation of circulating 1,25(OH)2D3 from vitamin D, the hepatic microsomal or mitochondrial vitamin D-25-hydroxylase (CYP27A1) and the renal mitochondrial 25-hydroxyvitamin D-1alpha-hydroxylase (CYP27B1) for vitamin D and 25(OH)D3 (calcidiol), respectively.

Cross-talk between vitamin D receptor (VDR)- and peroxisome proliferator-activated receptor (PPAR)-signaling in melanoma cells.

The expression and signaling of the vitamin D receptor (VDR) and peroxisome proliferator-activated receptor (PPAR) alpha, delta, gamma was investigated in the melanoma cell line MeWo. Using real-time PCR, the mRNA of the nuclear receptors (NR) was detected. The strongest expression was found for the VDR, approximately 3-fold higher compared to the expression of PPARalpha or PPARdelta, and the weakest expression was for PPARgamma.

Serendipitous evidence of T lymphocyte activation in close female relatives of patients with systemic lupus erythematosus.

A well-recognized characteristic of the autoimmune disease, systemic lupus erythematosus (SLE), is the high level of activated T cells present in the blood. Because of the increased size and granularity of activated T cells, in flow cytometry one might expect to find increased numbers of cells falling outside a standard light-scatter lymphocyte gate, and indeed we now report that the percentage of T lymphocytes in the gate (% TiG) was below the normal range in 23 of 58 (40%) female patients because of increased scatter values. However, the surprising additional observation was made that 18 of 30 (60%) female first-degree relatives of the patients also fell below the normal % TiG range, suggesting the presence of T cell activation in these relatives.

Targeted scoring functions for virtual screening.

The benefit offered by virtual screening methods during the early drug discovery process is directly related to the predictivity of scoring functions that assess protein-ligand binding affinity. The scoring of protein-ligand complexes, however, is still a challenge: despite great efforts, a universal and accurate scoring method has not been developed up to now. Targeted scoring functions, in contrast, enhance virtual screening performance significantly.

Robust optimization of scoring functions for a target class.

Target-specific optimization of scoring functions for protein-ligand docking is an effective method for significantly improving the discrimination of active and inactive molecules in virtual screening applications. Its applicability, however, is limited due to the narrow focus on, e.g.

Acquired coarctation of the abdominal aorta related to umbilical artery catheterization.

Severe hypertension is rare in children, and often has a secondary cause. We review a case of a five year-old boy who presented with severe hypertension secondary to an acquired coarctation of the abdominal aorta. We hypothesize that this lesion resulted from endothelial damage caused by umbilical artery catheterization as a neonate.

Natural product inhibitors of protein-protein interactions mediated by Src-family SH2 domains.

In this Letter, we report the natural products salvianolic acid A, salvianolic acid B, and caftaric acid as inhibitors of the protein-protein interactions mediated by the SH2 domains of the Src-family kinases Src and Lck, two established disease targets. Moreover, we propose a binding mode for the inhibitors based on molecular modeling, which will facilitate chemical optimization efforts of these important lead structures for drug discovery.

Calcimimetic inhibits late-stage cyst growth in ADPKD.

In polycystic kidney disease (PKD), genetic mutations in polycystin 1 and 2 lead to defective intracellular trafficking of calcium, thereby decreasing intracellular calcium and altering cAMP signaling to favor proliferation. We hypothesized that calcimimetics, allosteric modulators of the calcium-sensing receptor, would reduce cyst growth by increasing intracellular calcium. We randomly assigned 20-wk-old male rats with a form of autosomal dominant PKD (heterozygote Cy/+) to one of four groups for 14 to 18 wk of treatment: (group 1) no treatment; (group 2) calcimimetic R-568 formulated in the diet; (group 3) R-568 plus calcium-supplemented drinking water (R-568 plus Ca); or (group 4) Ca-supplemented drinking water with a normal diet (Ca).

Utilizing gene pair orientations for HMM-based analysis of promoter array ChIP-chip data.

Motivation: Array-based analysis of chromatin immunoprecipitation (ChIP-chip) data is a powerful technique for identifying DNA target regions of individual transcription factors. The identification of these target regions from comprehensive promoter array ChIP-chip data is challenging. Here, three approaches for the identification of transcription factor target genes from promoter array ChIP-chip data are presented.

E2-mediated cathepsin D (CTSD) activation involves looping of distal enhancer elements.

Estrogen receptor alpha (ERalpha) is a ligand dependent transcription factor that regulates the expression of target genes through interacting with cis-acting estrogen response elements (EREs). However, only a minority of ERalpha binding sites are located within the proximal promoter regions of responsive genes. Here we report the characterization of an ERE located 9kbp upstream of the TSS of the cathepsin D gene (CTSD) that up-regulates CTSD expression upon estrogen stimulation in MCF-7 cells.

Regulation of iron homeostasis in anemia of chronic disease and iron deficiency anemia: diagnostic and therapeutic implications.

The anemia of chronic disease (ACD) is characterized by macrophage iron retention induced by cytokines and the master regulator hepcidin. Hepcidin controls cellular iron efflux on binding to the iron export protein ferroportin. Many patients, however, present with both ACD and iron deficiency anemia (ACD/IDA), the latter resulting from chronic blood loss.

R-568 reduces ectopic calcification in a rat model of chronic kidney disease-mineral bone disorder (CKD-MBD).

Background: Chronic kidney disease-mineral bone disorder (CKD-MBD), a newly defined disorder in patients with CKD, describes the interacting triad of (1) biochemical abnormalities of calcium, phosphorus and parathyroid hormone (PTH), (2) extraskeletal calcification and (3) abnormal bone.

Methods: We studied the effects of the calcimimetic R-568, R-568 with calcium (R-568 + Ca) or calcium (Ca) alone compared with control CKD rats on this triad in the Cy/+ male rat, a model of progressive CKD that spontaneously develops CKD-MBD on a normal phosphorus diet. Animals were treated for either 14 or 18 weeks beginning at 20 weeks of age (34-week and 38-week animals, respectively).

[Improving left ventricular contractility by stimulation during the absolute refractory period--cardiac contractility modulation (CCM)].

Cardiac contractility modulation (CCM) is a treatment option for patients with systolic ventricular dysfunction, independent of QRS duration, moderate to severe systolic heart failure and symptoms despite optimal medical therapy. In contrast to cardiac resynchronization therapy (CRT) which has been an established therapy in patients with wide QRS and ventricular asynchrony, CCM can enhance cardiac contractility in patients independent of QRS duration. Whereas inotropic drugs increase oxygen demand, CCM works without additional myocardial oxygen need and without reference to asynchrony.

Low immunogenicity of endothelial derivatives from rat embryonic stem cell-like cells.

Embryonic stem cells (ESC) are suggested to be immune-privileged, but they carry the risk of uncontrolled expansion and malignancy. Upon differentiation they lose their tumor-forming capacity, but they become immunogenic by the expression of a normal set of MHC molecules. This immunogenicity might trigger rejection after application in regenerative therapies.