Sigma-2 ligands induce tumour cell death by multiple signalling pathways.

BACKGROUND: The sigma-2 receptor has been identified as a biomarker of proliferating cells in solid tumours. In the present study, we studied the mechanisms of sigma-2 ligand-induced cell death in the mouse breast cancer cell line EMT-6 and the human melanoma cell line MDA-MB-435. METHODS: EMT-6 and MDA-MB-435 cells were treated with sigma-2 ligands. The modulation of multiple signaling pathways of cell death was evaluated. RESULTS: Three sigma-2 ligands (WC-26, SV119 and RHM-138) induced DNA fragmentation, caspase-3 activation and PARP-1 cleavage. The caspase inhibitor Z-VAD-FMK partially blocked DNA fragmentation and cytotoxicity caused by these compounds. These data suggest that sigma-2 ligand-induced apoptosis and caspase activation are partially responsible for the cell death. WC-26 and siramesine induced formation of vacuoles in the cells. WC-26, SV119, RHM-138 and siramesine increased the synthesis and processing of microtubule-associated protein light chain 3, an autophagosome marker, and decreased the expression levels of the downstream effectors of mammalian target of rapamycin (mTOR), p70S6K and 4EBP1, suggesting that sigma-2 ligands induce autophagy, probably by inhibition of the mTOR pathway. All four sigma-2 ligands decreased the expression of cyclin D1 in a time-dependent manner. In addition, WC-26 and SV119 mainly decreased cyclin B1, E2 and phosphorylation of retinoblastoma protein (pRb); RHM-138 mainly decreased cyclin E2; and 10 µM siramesine mainly decreased cyclin B1 and pRb. These data suggest that sigma-2 ligands also impair cell-cycle progression in multiple phases of the cell cycle. CONCLUSION: Sigma-2 ligands induce cell death by multiple signalling pathways.

[Left ventricular functional parameters: comparison of 16-slice spiral CT with MRI]. / Bestimmung linksventrikulärer Funktionsparameter: Vergleich von 16-Zeilen-Mehrschicht-CT mit der MR-Tomographie.

PURPOSE: The quantitative measurement of left ventricular functional parameters using multislice computed tomography (MSCT) with retrospective ECG-gating and comparison of the results with magnetic resonance imaging (MRI). MATERIALS AND METHODS: Thirty-one patients with suspected or known coronary artery disease underwent MSCT angiography with retrospective ECG-gating (Sensation 16, Siemens). Based on the CT data set, short axis reformations of the left ventricle were performed for functional analysis. On a commercially available workstation, end-diastolic- (EDV), end-systolic- (ESV), stroke volume (SV), ejection fraction (EF) and myocardial mass (MM) were calculated from MSCT (temporal resolution 105 - 210 ms) data according to the modified Simpson's rule and compared to MRI (1.5 T scanner, temporal resolution 48 ms) using a 2D TrueFISP cine sequence with respiration hold. RESULTS: In all cases, the quality was adequate for both MSCT and MRI. MSCT and MRI had an excellent correlation for EDV (r = 0.86), ESV (r = 0.91), EF (r = 0.87) and MM (r = 0.88), and a good correlation for SV (r = 0.70). The mean difference was 13.2 +/- 21.9 ml for EDV, 8.7 +/- 15.9 ml for ESV, 4.6 +/- 12.3 ml for SV, 1.4 +/- 5.2 % for EF, and 11.9 +/- 13.8 g for MM. However, EDV (p = 0.002), ESV (p = 0.005), SV (p = 0.048), and MM (p < 0.0001) were significantly overestimated with MSCT compared to MRI. For EF, no significant difference between MSCT and MRI was found (p = 0.15). CONCLUSION: For left ventricular functional parameters, MSCT of the heart with retrospective ECG-gating showed a high correlation with MRI, which has an important implication when using MSCT for non-invasive cardiac imaging. Despite the high correlation, overestimation of EDV, EVS, SV, and MM with MSCT has to be taken into account when applying this technology in clinical practice. EF was not significantly different between both modalities.

Socioeconomic evaluation of rheumatoid arthritis and osteoarthritis: a literature review.

Limited resources and the need to improve the cost-effectiveness of medical procedures underlie the increasing importance of socioeconomic evaluations of health care. A search of MEDLINE was conducted to identify publications on the socioeconomic aspects of the two most important joint diseases: rheumatoid arthritis (RA) and osteoarthritis (OA). Analysis of the retrieved publications focused on three areas: (1) description of the socioeconomic effects of these diseases; (2) methodological approaches of the economic analyses; and (3) discussion from the perspective of patients, clinicians, or public health policy-makers. Of 52 publications dealing with cost data for RA and OA, 44 presented original and recently collected and developed data. Twenty-six were classified as cost analyses, three as cost-benefit analyses, and 11 as cost-effectiveness analyses (four did not fit into any of these classifications). Eight established methodological criteria were used to test for "full economic evaluation"; none of the reviewed studies fulfilled all eight, and only one study fulfilled seven. The gap between the importance of the socioeconomic effects of RA and OA and the research conducted in this field is considerable. A quality standard could be developed to serve as a guideline for further research.

[Current legislation in public health--an example for post-modern social ethics?]. / Aktuelle Gesetzgebung im Gesundheitswesen--ein Beispiel für postmoderne Sozialethik?

Social ethics of affirmative postmodernists are discussed in relation to recent German health care legislation. It could be shown that: 1. the health care legislation 1989 and 1993 only partially fulfills the postmodern call for "cultivation of individual responsibility", 2. both laws largely fail to enforce the principle of subsidiarity, and 3. postmodernist thinking is weak on the question of global strategies but strong In the area of individualism and subjectivity. We conclude that postmodern social ethics are useful to compensate areas largely neglected by recent German health care legislation, rather than that the legislation is an example of postmodern social ethics.