Sportmedizinische Aspekte kardialer Risikostratifizierung

The present study investigates the association of the predicted CHD-risk (PROCAM) with the individual endurance capacity and heart rate variability (HRV) in a population-based sample of sedentary elderly. After stratification, in 57 men (48.1+/-9.5 yrs.) with an overall PROCAM-risk <10% (28.7+/-10.9 points) and 22 men (54.5+/-7.7 yrs.) with a coronary 10-year risk > or =10% (50.8+/-5.6 points) cycle ergometries and short-term HRV analysis of time (RRMEAN, SDNN, RMSSD) and frequency domain parameters (LF, HF, TP, LF/HF) were conducted. Additionally the autonomic stress index (SI) was calculated. Nonparametric tests were used for statistical correlation analysis (Spearman rho) and group comparisons (Mann-Whitney). For endurance capacity [W/kg] (r=-0.469, p<0.001), SDNN (r=-0.302, p<0.05), RMSSD (r= -0.311, p<0.05), LF (r=-0.325, p<0.05), HF (r= -0.311, p<0.05) and TP (r= -0.307, p<0.05) negative monotone correlations with the coronary score-risk were determined. Significant positive correlations were calculated for SI (r=0.476, p<0.001). Except for RRMEAN and LF/HF significant group differences (p<0.05) were computed for SDNN (30.0+/-20.0 vs 20.0+/-10.0 ms), RMSSD (22.2+/-18.3 vs 18.0+/-8.7 ms), LF (90.9+/-241.5 vs 41.35+/-81.1 ms(2)), HF (43.0+/-105.1 vs 18.0+/-27.0 ms(2)) and TP (189.0+/-457.1 vs 100.0+/-157.6 ms(2)). Significant differences (p<0.01) were evaluated for exercise capacity (2.4+/-0.5 vs 1.8+/-0.3 W/kg) and SI (90+/-183 vs 322+/-291). The results underline the predictive value of HRV analysis in risk stratification and outline the interrelation of a decreased exercise capacity and autonomic function with a raised individual 10-year cardiac risk. As an independent parameter of the vegetative regulatory state the stress index may contribute to an increased practical relevance of short-time HRV analysis.     

Mechanisms of gold biomineralization in the bacterium Cupriavidus metallidurans

While the role of microorganisms as main drivers of metal mobility and mineral formation under Earth surface conditions is now widely accepted, the formation of secondary gold (Au) is commonly attributed to abiotic processes. Here we report that the biomineralization of Au nanoparticles in the metallophillic bacterium Cupriavidus metallidurans CH34 is the result of Au-regulated gene expression leading to the energy-dependent reductive precipitation of toxic Au(III)-complexes. C. metallidurans, which forms biofilms on Au grains, rapidly accumulates Au(III)-complexes from solution. Bulk and microbeam synchrotron X-ray analyses revealed that cellular Au accumulation is coupled to the formation of Au(I)-S complexes. This process promotes Au toxicity and C. metallidurans reacts by inducing oxidative stress and metal resistances gene clusters (including a Au-specific operon) to promote cellular defense. As a result, Au detoxification is mediated by a combination of efflux, reduction, and possibly methylation of Au-complexes, leading to the formation of Au(I)-C-compounds and nanoparticulate Au⁰. Similar particles were observed in bacterial biofilms on Au grains, suggesting that bacteria actively contribute to the formation of Au grains in surface environments. The recognition of specific genetic responses to Au opens the way for the development of bioexploration and bioprocessing tools.     

A role of the kinase mTOR in cellular transformation induced by the oncoproteins P3k and Akt

The oncoproteins P3k (homolog of the catalytic subunit of class IA phosphoinositide 3-kinase) and Akt (protein kinase B) induce oncogenic transformation of chicken embryo fibroblasts. The transformed cells show constitutive phosphorylation of the positive regulator of translation p70S6 kinase (S6K) and of the eukaryotic initiation factor 4E-BP1 binding protein (4E-BP1), a negative regulator of translation. Phosphorylation activates S6K and inactivates 4E-BP1. A mutant of Akt that retains kinase activity but does not induce phosphorylation of S6K or of 4E-BP1 fails to transform chicken embryo fibroblasts, suggesting a correlation between the oncogenicity of Akt and phosphorylation of S6K and 4E-BP1. The macrolide antibiotic rapamycin effectively blocks oncogenic transformation induced by either P3k or Akt but does not reduce the transforming activity of 11 other oncoproteins. Rapamycin inhibits the kinase mTOR, an important regulator of translation, and this inhibition requires binding of the antibiotic to the immunophilin FKBP12. Displacement of rapamycin from FKBP12 relieves the inhibition of mTOR and also restores P3k-induced transformation. These data are in accord with the hypothesis that transformation by P3k or Akt involves intervention in translational controls.     

Ca2+-channel blockers inhibit the action of recombinant platelet-derived growth factor in vascular smooth muscle cells.

Human platelet-derived growth factor (PDGF) is mainly composed of two polypeptide chains (PDGF-AB). All three possible dimeric forms of PDGF--i.e., PDGF-AA, PDGF-BB and PDGF-AB--exist in nature. We have used two recombinant PDGF homodimers to determine the roles of each isoform in the activation of phosphatidylinositol turnover in vascular smooth muscle cells (VSMC) isolated from rat thoracic aorta, their mitogenic effect on VSMC, and their vasoconstrictor effect on intact strips of aortic vascular tissue. Three Ca2+-channel blockers, nifedipine, verapamil, and diltiazem, were used as antagonists for investigating the PDGF-dependent changes mediated by the homodimers. PDGF-BB had a greater efficacy than PDGF-AA on inositol 1,4,5-trisphosphate release, on the formation of diacylglycerol, and on Ca2+ mobilization, which was also associated with vasoconstrictor activity and effective mitogenicity. PDGF-AA, on the other hand, was more potent than PDGF-BB in stimulating protein kinase C. In all instances, the activation of the phosphatidylinositol turnover by the two homodimers was inhibited by the Ca2+-channel blockers.     

Myelomonocytic antigen positive multiple myeloma

In a four year span, between 1983 and 1987, 215 bone marrow and cell culture samples from 125 myeloma patients were immunotyped and coexpression of myelomonocytic and plasma cell antigens occurred in 16 (13%). We employed both immunohistochemical and flow cytometry methods including coplots and double labelling. Three types of myeloma cases were found: (1) those with isolated myeloid antigen coexpression, usually Leu M1 or esterase (BE, CE) positive (11 cases); (2) those with multiple myeloid antigens (Leu M1, M3, M5, MY7, BE, CE) (four cases); and (3) one case beginning as 1 and ending as 2. Isolated myeloid antigen expression was generally associated with typical features of myeloma with survival close to the anticipated median (33 months), while multiple myeloid antigen expression was associated with more aggressive disease and shorter survival duration (median survival 16 months). The latter subgroup also had other poor prognostic factors including high labelling index and common acute lymphoblastic leukemia antigen (CALLA) positivity. Other features found overall were frequent abnormal karyotypes (seven of 12 abnormal) and coexpressed IgA (eight of 16); all IgA+ cases also coexpressed Leu M1. We conclude that there is an unusual and unexpected predilection for coexpression of myelomonocytic antigens in myeloma cells. The reasons are not immediately obvious. Whether the coexpression indicates that myeloma cells truly have latent multilineage potential or just aberrantly coexpress other hematopoietic antigens as a manifestation of malignancy remains to be explained. However, a cell line established from the bone marrow of one patient is a valuable scientific tool allowing detailed analysis of these questions.     

Early detection of antibodies against rDNA-produced HIV proteins with a flow cytometric assay

There is evidence that some human immunodeficiency virus (HIV)-infected individuals have prolonged periods of seronegativity. A flow cytometric immunoreactive bead (IRB) assay is described for quantitative, simultaneous, and early detection of antibodies to HIV. Polystyrene beads of four diameters, each size coated with a different HIV recombinant DNA-produced protein (p24, p31, gp41, or gp120), bound anti- HIV antibodies detected with fluorescent antiglobulin. The IRB assay was performed on a panel of blood donor samples, many giving consistently false-positive enzyme immunoassay (EIA) and indeterminant Western blot (WB) results. The IRB assay proved as sensitive and more specific than currently licensed EIA and WB tests. Results on serial samples from eight HIV-infected individuals indicated that quantitation of anti-p24 by IRB assay may be useful in monitoring disease progression. Sequential pre- and post-EIA seroconversion sera from 35 HIV-infected homosexual men were tested by the IRB assay using IgM- and IgG-specific fluorescent probes. All 35 cases were IRB assay positive for at least one rDNA-p either before (17 of 35, 49%) or at the time of EIA positivity. Eleven cases (31%) initially had only IgM anti-HIV, primarily to gp41 (17%). In two individuals, the IgM response was detected at least 18 months before EIA seroconversion. The IRB assay is a widely applicable analytic procedure, potentially useful in pretransfusion anti-HIV screening of blood.     

Programmed cell death protein 1 (PD-1)-inhibition in hepatocellular carcinoma (HCC): a single center experience

Abstract

Background

The prognosis for advanced Hepatocellular carcinoma (HCC)is still very poor. Despite initial usefulness of immune checkpoint inhibitor (PD-1), phase 3 trials failed to show significant benefit of PD-1 inhibition with nivolumab or pembrolizumab in the first and second line therapy of HCC. Clinical evidence of PD-1 inhibition in patients with advanced and heavily pretreated HCC outside clinical trials is extremely limited. In this study, we analyzed the clinical experience with PD-1 inhibition in patients with heavily pretreated HCC.