Patterns in metabolite profile are associated with risk of more aggressive prostate cancer: A prospective study of 3,057 matched case–control sets from EPIC

Metabolomics may reveal novel insights into the etiology of prostate cancer, for which few risk factors are established. We investigated the association between patterns in baseline plasma metabolite profile and subsequent prostate cancer risk, using data from 3,057 matched case–control sets from the European Prospective Investigation into Cancer and Nutrition (EPIC). We measured 119 metabolite concentrations in plasma samples, collected on average 9.4 years before diagnosis, by mass spectrometry (AbsoluteIDQ p180 Kit, Biocrates Life Sciences AG). Metabolite patterns were identified using treelet transform, a statistical method for identification of groups of correlated metabolites. Associations of metabolite patterns with prostate cancer risk (OR_1SD) were estimated by conditional logistic regression. Supplementary analyses were conducted for metabolite patterns derived using principal component analysis and for individual metabolites. Men with metabolite profiles characterized by higher concentrations of either phosphatidylcholines or hydroxysphingomyelins (OR_1SD = 0.77, 95% confidence interval 0.66–0.89), acylcarnitines C18:1 and C18:2, glutamate, ornithine and taurine (OR_1SD = 0.72, 0.57–0.90), or lysophosphatidylcholines (OR_1SD = 0.81, 0.69–0.95) had lower risk of advanced stage prostate cancer at diagnosis, with no evidence of heterogeneity by follow-up time. Similar associations were observed for the two former patterns with aggressive disease risk (the more aggressive subset of advanced stage), while the latter pattern was inversely related to risk of prostate cancer death (OR_1SD = 0.77, 0.61–0.96). No associations were observed for prostate cancer overall or less aggressive tumor subtypes. In conclusion, metabolite patterns may be related to lower risk of more aggressive prostate tumors and prostate cancer death, and might be relevant to etiology of advanced stage prostate cancer.     

Involvement of angiotensin-converting enzyme inhibition in reversal of helpless behavior evoked by perindopril in rats

Several clinical investigations have suggested that captopril, an angiotensin-converting enzyme inhibitor (ACEI) currently used as an anti-hypertensive agent, exhibits antidepressant properties in humans. In the present study we evaluated the action of perindopril, another ACEI, and two of its metabolites, the di-acide form perindoprilat, which possesses ACE inhibitory properties, and BDM-4, an inactive metabolite, in the learned helplessness paradigm. In order to confirm a possible action of these drugs via dipeptidyl carboxypeptidase inhibition, we also investigated two inactive analogues of perindopril and perindoprilat. Perindopril (0.06-8 mg/kg per day) and perindoprilat (0.25-8 mg/kg per day) induced a reversal of escape deficits. BMD-4 and two analogues failed to reverse helpless behavior. These results support the hypothesis that ACE inhibition is a key factor in the behavioral antidepressant-like activity of perindopril and perindoprilat.     

Primary vesicoureteric reflux--our 20 years' experience.

AIM: The aim of this study is to compare the Lich-Gregoir procedure and antireflux ureterocystoneostomy at the vertex of the bladder (AUVB) based on 20 years' clinical experience. METHODS: Over a period of 20 years (1978 - 1998) 1280 children were operated on, 368 bilaterally, which resulted in 1648 antireflux ureterocystoneostomies being performed. Of the total of 1648 antireflux ureterocystoneostomies, AUVB was performed in 1032 ureteric units and the Lich-Gregoir procedure in 616 ureteric units. Between 1978 and 1992 we performed only AUVB, and from 1992, both AUVB and the Lich-Gregoir procedure. RESULTS: The final result was evaluated 2 years after the operation. Satisfactory results were achieved in 93.5 % with AUVB and in 96 % with the Lich-Gregoir procedure. The postoperative failure rate was 6.5 % for the AUVB and 4 % for the Lich-Gregoir operations. The recurrence rate was higher with AUVB (5 %) than with the Lich-Gregoir procedure (1.5 %), but postoperative stenosis was more frequent with the Lich-Gregoir procedure (2.5 %). CONCLUSIVE: Today, as the first operative method we prefer to employ the Lich-Gregoir procedure. If the result of the Lich-Gregoir procedure is unsatisfactory, we recommend the AUVB for the first and second recurrence operation. Finally, in cases of repeated VUR recurrence of postoperative stenosis, as the last operation we perform antireflux ureteroileocystoplasty with an intussuscepted segment of the ileum.     

Lipid-Protein-Wechselwirkungen menschlicher Apolipoproteine — Entwicklung von Lipoprotein-Modellen

Zusammenfassung Die menschlichen Plasmalipoproteine sind komplexe makromolekulare Strukturen, die eine entscheidende Rolle im Fettransport und im Energie- und Membranstoffwechsel tierischer Organismen spielen. Die strukturellen und funktionellen Wechselbeziehungen zwischen den einzelnen Lipoproteinklassen sind in den letzten Jahren eingehend untersucht worden. Ihre Proteinbestandteile, die sog. Apolipoproteine, konnten gereinigt und charakterisiert werden; die Primärstruktur von vier von ihnen ist bekannt. Erste Rekombinationsstudien deuteten darauf hin, daß das (unfraktionierte) Apoprotein ein beachtliches Lipid-Bindungsvermögen besitzt und daß dabei Partikel gebildet werden, die den nativen Lipoproteinen ähnlich sind. Spätere Bindungsexperimente, die in einer Reihe von Laboratorien mit den gereinigten A- und C-Apolipoproteinen und verschiedenen, physiko-chemisch gut definierten Lipiden durchgeführt wurden, haben zur Identifizierung von sog. Lipidbindungsstellen (lipid binding sites) innerhalb der Proteinmoleküle geführt. Bei und während der Wechselwirkung mit dem Lipid bilden sich dadurch sog. amphipathische Helices aus. Dieser für alle Apolipoproteine möglicherweise gleichermaßen gültige Mechanismus einer Lipid-Protein-Wechselwirkung bildet die Grundlage eines kürzlich vorgeschlagenen Modells einer der Lipoproteinklassen, nämlich der high density Lipoproteine (HDL). Die Bedeutung von Protein-Protein-Wechselwirkungen für die Bildung und Stabilisierung der Lipoproteine ist noch unbekannt. Ob eine Störung der Lipid-Protein-Wechselwirkungen zu strukturellen und/oder funktionellen Änderungen der entsprechenden Lipoproteine führen kann, wird noch diskutiert. Ob entsprechende Defekte zur Entstehung einer Hyperlipoproteinämie beitragen können, ist ebenfalls noch offen. Die einschlägige Literatur wird in der vorliegenden Arbeit besprochen, und die Fragen der physiologischen Relevanz dieser Studien und ihrer klinischen Aspekte werden diskutiert.     

Antigen-specific stimulation and trans-stimulation of T cells in long-term culture.

When T cells from antigen-primed lymph nodes are stimulated in vitro with antigen, they give rise to a proliferative response as high as that elicited by the polyclonal T cell activator concanavalin A. It is likely that in these conditions not only antigen-specific T cells proliferate. We have established an experimental system which demonstrates that large numbers of nonantigen-specific T cells are induced to proliferate as a result of antigen-specific T cells' confrontation with antigen. This phenomenon, which we call trans-stimulation is antigen-dependent and antigen-specific. Although the presence of antigen-specific T cells is required, these cells do not have to proliferate in order to induce trans-stimulation. In an attempt to enrich for antigen-specific T cells in vitro, we established conditions for culturing T cells in the presence of antigen for long periods of time (up to 6 weeks). High levels of antigen reactivity were observed upon antigen restimulation of “directly” stimulated T cells from long-term cultures. In contrast, long-term cultures of trans-stimulated cells were depleted of antigen reactivity. Neither type of long-term culture contained detectable alloreactive cells indicating that trans-stimulation is not reflected randomly upon bystander T cells.     

Patients affected with Fabry disease have an increased incidence of progressive hearing loss and sudden deafness: an investigation of twenty-two hemizygous male patients

Background  

Fabry disease (FD, OMIM 301500) is an X-linked inborn error of glycosphingolipid metabolism due to the deficient activity of alpha-galactosidase A, a lysosomal enzyme. While the progressive systemic deposition of uncleaved glycosphingolipids throughout the body is known to have protean clinical manifestations, few data are available regarding the cochlear involvement.