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.     

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.     

Osteopathien und Calcium-Phosphat-Stoffwechsel bei chronischer Hämodialyse

Zusammenfassung Unter chronischer Hämodialyse-Behandlung wurden 13 Fälle auf Knochenveränderungen unter Berücksichtigung des Calcium-Phosphat-Stoffwechsels untersucht. Die Knochenveränderungen wurden histomorphometrisch definiert. Bestimmt wurden die prozentualen Anteile der neutralen Oberflächen, des Osteoids, der aktivierten Osteoblasten, der Resorptionslacunen und der mehrkernigen Osteoclasten an den endostalen Oberflächen, sowie die mittlere Breite der Osteoidsäume. Außerdem wurden Formation und Resorption des Knochens mittels quantitativer Mikroradiographie sowie die volumetrische Dichte der Spongiosa gemessen.Beiallen Fällen konnten unterschiedlich schwere Knochenveränderungen nachgewiesen werden (60% schwere und 40% leichte), wobei die stets pathologisch erhöhte Knochenresorption als Ausdruck eines regulativen sekundären Hyperparathyreoidismus gewertet wurde. Eine direkte Beziehung zwischen Calciumspiegel und Schwere der renalen Osteopathie ließ sich nicht beweisen. Die Hyperphosphatämien, die bei allen Patienten unter der Hämodialyse-Behandlung unverändert blieben, ergaben mit den ansteigenden Serumcalciumwerten pathologische Calciumphosphatprodukte. Bei einem Teil der Patienten kam es zu extraossären Verkalkungen, die unter kontrollierter Behandlung mit Aluminiumhydroxyd und abfallendem Calciumphosphatprodukt eine erhebliche Rückbildungstendenz zeigten. Wegen der Gefahr derartiger Calcifizierungen verbot sich in unserem Krankengut eine Vitamin D-Behandlung. Die Indikation einer totalen oder subtotalen Parathyroidektomie wurde in Abhängigkeit vom Ausmaß der Osteopathie und einer möglichen Nierentransplantation erörtert.

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Bone Disease and Calcium-phosphate Metabolism in Chronic Hemodialysis

Summary 13 patients under chronic hemodialysis were studied for changes in the bone, whereby calcium and phosphorus metabolism were given special attention. The changes in the bone were defined histomorphometrically. The percentage of the neutral surfaces, the osteoid, the activated osteoblasts, the resorption lacunae and the polynuclear osteoclasts of the endosteal surfaces were determined as well as the medium width of the osteoid seams. Moreover, formation and resorption of the bone were assessed by quantitative microradiography and the volumetric density of the cancellous bone was measured. Inall cases, bone changes of various degree were observed (60% of serious and 40% of slight changes), whereby the constantly increased bone resorption was considered as expression of a regulative secondary hyperparathyroidism. A direct relationship between serum calcium levels and the degree of seriousness of renal osteopathy could not be established. Hyperphosphatemia remained unchanged and with increasing serum calcium levels, the calcium phosphorus product became abnormally high in all subjects under hemodialysis. Extraosseus calcifications developed in some cases and were reduced to a considerable degree by controlled treatment with aluminiumhydroxide in connection with a fall of the calcium phosphorus product. Because of the risk of such calcifications, vitamin D treatment were out of question. Total or subtotal parathyroidectomy was discussed in relation to the degree of osteopathy and the possibility of a kidney transplantation.

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Mit Unterstützung durch die Deutsche Forschungsgemeinschaft.     

Protroca: A Noninterventional Study on Prophylactic Lipegfilgrastim against Chemotherapy-Induced Neutropenia in Nonselected Breast Cancer Patients

BackgroundProtroca evaluated the efficacy and safety of primary and secondary prophylaxis of neutropenia with lipegfilgrastim (Lonquex®) in breast cancer patients receiving neoadjuvant or adjuvant chemotherapy (CT).Patients and MethodsOf the 255 patients enrolled, 248 patients were evaluable for the intent-to-treat (ITT) and 194 patients for the per-protocol set. Primary and secondary end points after lipegfilgrastim treatment were assessed.ResultsNine patients of the ITT set receiving lipegfilgrastim as primary prophylaxis (n = 222) had febrile neutropenia of grade 3–4 (5 patients) or infection of grade 3–4 (4 patients); 1/26 of those receiving secondary prophylaxis had an event. Dose reductions were performed in 9.5% of the patients. Postponement of cancer CT cycles for >3 days occurred in <15% of patients; 10.8% (92/851 AEs) and 8% (2/25 SAEs) of documented adverse events and serious adverse events, respectively, were related to lipegfilgrastim.ConclusionsApplication of lipegfilgrastim was effective as primary and secondary prophylaxis in the prevention of CT-induced neutropenia in breast cancer.     

Systemic effects of different perfluorochemical agents

Purpose: An intravitreal injection of Fluosol-DA leads to a higher alteration of the macrophage system of the retina than perfluorooctane and perfluorodecalin administered by the same route. The difference may be due to different kinds of oxidative damage caused by the three chemicals. To test the validity of this assumption, the degree of cell alteration, expressed as reduction of cytoplasmic motility, caused by these three perfluorochemicals was examined. Methods: Using the hepatic macrophage system of the rat, cell alteration was examined by magnetometry after intravenous application of various perfluorochemicals [emulsified perfluorodecalin (C₁₀F₁₈), perfluorooctane (C₈F₁₇Br) and Fluosol-DA (corresponding to a 20% emulsion of 70% perfluorodecalin and 30% perfluorotripropylamine, C₉F₂₁N)]. Results: After administration of high doses, all perfluorochemicals led to cytoskeleton alteration. This alteration, expressed as retardation of the relaxation period of ferromagnetic iron oxide particles, was most pronounced after administration of Fluosol-DA. Conclusion: The compromising effect of perfluoro-chemicals is dose dependent and differs among the three compounds tested, with Fluosol-DA showing the greatest decrease in cytoplasmic motility.