Asymmetric dimethylarginine determines the improvement of endothelium-dependent vasodilation by simvastatin: Effect of combination with oral L-arginine.

OBJECTIVES: We hypothesized that the level of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of endothelial nitric oxide (NO) synthase (eNOS), might determine the endothelial effects of statins. BACKGROUND: Endothelial NO synthase is up-regulated by statins. However, statins failed to improve endothelial function in some studies. Asymmetric dimethylarginine inhibits eNOS by a mechanism that is reversible by L-arginine. METHODS: Ninety-eight clinically asymptomatic elderly subjects had their plasma ADMA levels screened. Those in the highest (high ADMA, n = 15) and lowest quartiles of the ADMA distribution (low ADMA, n = 13) were eligible to receive, in a randomized order, simvastatin (40 mg/day), L-arginine (3 g/day), or a combination of both, each for 3 weeks. Endothelium-dependent vasodilation (EDD) was assessed by brachial artery ultrasound. RESULTS: Simvastatin had no effect on EDD in subjects with high ADMA (6.2 +/- 1.2% vs. 6.1 +/- 0.9%), whereas simvastatin plus L-arginine significantly improved EDD (9.8 +/- 1.5% vs. 5.3 +/- 0.8%; p < 0.01). In subjects with low ADMA, simvastatin improved endothelial function when given alone (9.5 +/- 3.2% vs. 6.1 +/- 3.8%; p < 0.001) or in combination with L-arginine (9.0 +/- 3.1% vs. 6.3 +/- 3.3%; p = 0.001). L-arginine alone improved endothelial function in both groups. Endothelium-independent vasodilation was not affected. CONCLUSIONS: Simvastatin does not enhance endothelial function in subjects with elevated ADMA, whereas it does so in patients with low ADMA. Combination of simvastatin with oral L-arginine improves endothelial function in subjects with high ADMA, but has no additional effect in subjects with low ADMA. As NO-mediated effects may play a major role in the therapeutic effects of statins, ADMA concentration is an important factor that influences the "pleiotropic" effects of simvastatin.     

Two new depsipeptides from the marine fungus Spicellum roseum

Investigation of the secondary metabolites of the marine-derived fungus Spicellum roseum yielded two new cyclohexadepsipeptides, spicellamide A (1) and spicellamide B (2). The structures of 1 and 2 were determined based on extensive evaluations of NMR and MS data. The absolute configuration was deduced after hydrolysis using Marfey's method, chiral chromatography, as well as NOESY and modeling data.     

Planning training seminars in palliative care: a cross-sectional survey on the preferences of general practitioners and nurses in Austria

Background  

Training in palliative care is frequently requested by health care professionals. However, little is known in detail about the subject matters and the educational preferences of physicians and staff or assistant nurses in this field.     

Combined TACE and PET for palliative treatment of unresectable hepatocellular carcinoma

AIM: To assess whether the effectiveness of a combination of transarterial chemoembolization (TACE) and percutaneous ethanol injection (PEI) in the treatment of unresectable hepatocellular carcinoma (HCC) is superior to TACE alone a randomized controlled trial was performed.METHODS: The effect of combination therapy on longterm survival rates and duration of hospitalization was evaluated in 52 previously untreated HCCs, randomly allocated to TACE-PEI (27 pts) or TACE alone (25 pts).RESULTS: The cumulative survival rate of the TACE group was 75.8% at 6 mo, 62.9% at 12 mo, and 18.0% at 24 mo and of the TACE-PEI group 76.9%, 61.5%, and 38.7%,respectively. Comparison of overall survival in both groups showed no statistically significant difference. Regarding the patients with HCCs Okuda stage I (n = 26), the median survival of the TACE-PEI group was significantly longer(＞24 mo, median not yet reached in the study period)compared to the TACE group (18.4 mo [range 11.6-21.7 mo];P = 0.04). TACE-PEI reduced the relative risk for mortality to 0.4 (95%CI 0.15-0.96) compared to patients who received TACE alone. Median survival in patients with HCCs Okuda stage Ⅱ or Ⅲ was 5.0 mo in the TACE group (1.7mo-not defined) compared to 10.4 mo in the TACE-PEI group.CONCLUSION: The combination TACE-PEI improved survival time compared to TACE alone. Our study revealed a statistically significant improved survival in HCCs Okuda stage I. Side effects were minor and the combination therapy did not prolong duration of hospitalization considerably.     

Interlaboratory comparison of a standardized toxicity test using the nematode Caenorhabditis elegans (ISO 10872)

A ring test was carried out within the standardization process of ISO 10872 to evaluate the precision of the toxicity test for the nematode Caenorhabditis elegans. Eight different laboratories tested aqueous solutions of the reference substance benzylcetyldimethylammonium chloride as well as native sediments and soils for toxic effects on the growth and reproduction of C. elegans. Validity criteria were met in all laboratories. Average median- and low-effect concentrations were determined to be 15.1 mg L(-1) (EC50) and 8.7 mg L(-1) (EC10) for growth and 7.5 mg L(-1) (EC50) and 3.8 mg L(-1) (EC10) for reproduction of C. elegans, with ECx values showing a high degree of reproducibility (CV(R) : <21% and <11% for EC10 and EC50, respectively) and repeatability (CV(r) : <20% and <7% for EC10 and EC50, respectively). The toxic effects of the sediments and soils revealed by the different laboratories were well related to each samples' degree of chemical contamination. Moreover, the effects showed an acceptable reproducibility (CV(R) : 5-33% and 0-28% for growth and reproduction, respectively) and repeatability (CV(r) : 3-13% and 0-12% for growth and reproduction, respectively). The present study confirms that the toxicity test with C. elegans according to ISO 10872 is a reliable and precise tool to assess the toxicity of aqueous media, freshwater sediments, and soils.     

The psychological assessment of candidates for reconstructive hand transplantation

Standardized psychological assessment of candidates for reconstructive hand transplantation (RHT) is a new approach in transplantation medicine. Currently, international guidelines and standardized criteria for the evaluation are not established. Patients suffering from the loss of a hand or an upper extremity have to cope with multiple challenges. For a selected group of patients, RHT represents an option for restoring natural function and for regaining daily living independence. The identification of at-risk patients and those requiring ongoing counseling due to poor coping or limited psychological resources are the primary focus of the psychological assessment. We have developed the 'Innsbruck Psychological Screening Program for Reconstructive Transplantation (iRT-PSP)' which utilizes a semi-structured interview and standardized psychological screening procedures and continuous follow-up ratings. Between January 2011 and October 2011, four candidates were evaluated using the iRT-PSP. Psychological impairments including social withdrawal, embarrassment, reduced self-esteem, and a depressive coping style were identified and poor quality of life was reported. The motivation for transplantation was diverse, depending on many factors such as bi- or unilateral impairment, native or accidental loss of hand, and social integration.     

Peptide-binding assays and HLA II transgenic Abeta degrees mice are consistent and complementary tools for identifying HLA II-restricted peptides

The identification of MHC class II-restricted peptides has become a priority for the development of peptide-based prophylactic and therapeutic vaccines. The aim of this study was to assess the correlations between peptide-binding assays on purified HLA II molecules and immunization of human HLA II transgenic mice deficient in murine class II molecules (Abeta degrees ). We used as models two MHC class II-restricted peptides, one derived from the HIV Nef regulatory protein (Nef (56-68)) and the other from the Schistosoma mansoni 28-kDa glutathione-S-transferase (Sm28GST (190-211)). High correlations were found between the two approaches, which showed that the Nef (56-68) and Sm28GST (190-211) peptides may represent promiscuous ligands for HLA-DQ and for HLA-DR molecules, respectively. We suggest a rational method based on the combination of peptide-binding assays and HLA II transgenic mice experiments as consistent and complementary tools for selecting T helper epitopes.     

Alpha-methylacyl-CoA racemase (AMACR/P504S) protein expression in urothelial carcinoma of the upper urinary tract correlates with tumour progression

Alpha-methylacyl-CoA racemase (AMACR/P504S) is a useful biomarker of prostate cancer. We evaluated the expression of AMACR in upper urinary tract urothelial carcinomas with respect to associations with tumour stage, grade and metastasis-free survival. A total of 268 tumours were investigated immunohistochemically using a tissue microarray technique. AMACR expression was noted in 127 of 261 (48.7%) evaluated tumours and was associated with high tumour stage [58 of 139 (41.7%) pTa/pT1 vs. 69 of 122 (56.6%) pT2–pT4, P=0.019] and high tumour grade [44 of 137 (32.1%) low vs. 83 of 124 (66.9%) high grade, P<0.001]. In addition, AMACR expression was associated with the presence of tumour necrosis (P<0.001) and marked stromal desmoplasia (P=0.0026). This correlation indicates that increased AMACR expression might be related to hypoxia-induced changes in cancer cell metabolism, such as increased dependence on fatty acid oxidation for energy generation. Progressive disease was observed in 73 of 183 (39.9%) patients with solitary invasive carcinomas and was associated with AMACR expression (P=0.017). Multivariate analysis, however, proved only pT-stage >1 (P<0.001) and high tumour grade (P<0.001) to be independent predictors of patient outcome. In conclusion, AMACR expression correlated with advanced tumour stage and grade and may serve as an additional prognostic indicator in upper urinary tract urothelial cancer.     

Activation of p38 mitogen-activated protein kinase and partial reactivation of the cell cycle by cis-4-methylsphingosine direct postmitotic neurons towards apoptosis

As shown before in three different cell types, cis-4-methylsphingosine is a synthetic, membrane permeable, pro-drug, that is taken up by cells and phosphorylated to a metabolically stable cis-4-methylsphingosine-phosphate. The synthetic compound mimicked the mitogenic effect of sphingosine-1-phosphate (S1P) in Swiss 3T3 fibroblasts, but induced apoptosis in B104 neuroblastoma cells. We now investigated its effect in differentiated primary cultured neurons. In contrast to S1P, which had no effect on growth of these postmitotic cells, cis-4-methylsphingosine-phosphate induced apoptosis. Interestingly, both compounds stimulated extracellular regulated kinase (ERK) and also p38 mitogen-activated protein kinase (MAPK). Additionally, both compounds induced an increased expression of cyclin D1 but not of cyclin E. Our results document that the different physiological effects, apoptosis in the case of the accumulating metabolically stable synthetic compound vs. no apoptosis in the case of the short-living S1P, rely only on nuances of impact. In other words both sphingoid phosphates affect similar pathways albeit in a sustained and more pronounced manner in case of the metabolically stable synthetic compound. Experiments with several pharmacological inhibitors indicate that cis-4-methylsphingosine-phosphate-induced neuronal apoptosis is mediated on the one hand by a caspase dependent and p38 MAPK forwarded pathway and on the other hand by an abortive reactivation of the cell cycle, a caspase independent process.