Radiation therapy generates platelet-activating factor agonists

Pro-oxidative stressors can suppress host immunity due to their ability to generate oxidized lipid agonists of the platelet-activating factor-receptor (PAF-R). As radiation therapy also induces reactive oxygen species, the present studies were designed to define whether ionizing radiation could generate PAF-R agonists and if these lipids could subvert host immunity. We demonstrate that radiation exposure of multiple tumor cell lines in-vitro, tumors in-vivo, and human subjects undergoing radiation therapy for skin tumors all generate PAF-R agonists. Structural characterization of radiation-induced PAF-R agonistic activity revealed PAF and multiple oxidized glycerophosphocholines that are produced non-enzymatically. In a murine melanoma tumor model, irradiation of one tumor augmented the growth of the other (non-treated) tumor in a PAF-R-dependent process blocked by a cyclooxygenase-2 inhibitor. These results indicate a novel pathway by which PAF-R agonists produced as a byproduct of radiation therapy could result in tumor treatment failure, and offer important insights into potential therapeutic strategies that could improve the overall antitumor effectiveness of radiation therapy regimens

Glucocorticoids with different chemical structures but similar glucocorticoid receptor potency regulate subsets of common and unique genes in human trabecular meshwork cells

<p>Abstract</p> <p>Background</p> <p>In addition to their well-documented ocular therapeutic effects, glucocorticoids (GCs) can cause sight-threatening side-effects including ocular hypertension presumably via morphological and biochemical changes in trabecular meshwork (TM) cells. In the present study, we directly compared the glucocorticoid receptor (GR) potency for dexamethasone (DEX), fluocinolone acetonide (FA) and triamcinolone acetonide (TA), examined the expression of known GRα and GRβ isoforms, and used gene expression microarrays to compare the effects of DEX, FA, and TA on the complete transcriptome in two primary human TM cell lines.</p> <p>Methods</p> <p>GR binding affinity for DEX, FA, and TA was measured by a cell-free competitive radio-labeled GR binding assay. GR-mediated transcriptional activity was assessed using the GeneBLAzer beta-lactamase reporter gene assay. Levels of GRα and GRβ isoforms were assessed by Western blot. Total RNA was extracted from TM 86 and TM 93 cells treated with 1 μM DEX, FA, or TA for 24 hr and used for microarray gene expression analysis. The microarray experiments were repeated three times. Differentially expressed genes were identified by Rosetta Resolver Gene Expression Analysis System.</p> <p>Results</p> <p>The GR binding affinity (IC₅₀) for DEX, FA, and TA was 5.4, 2.0, and 1.5 nM, respectively. These values are similar to the GR transactivation EC₅₀of 3.0, 0.7, and 1.5 nM for DEX, FA, and TA, respectively. All four GRα translational isoforms (A-D) were expressed in TM 86 and TM 93 total cell lysates, however, the C and D isoforms were more highly expressed relative to A and B. All four GRβ isoforms (A-D) were also detected in TM cells, although GRβ-D isoform expression was lower compared to that of the A, B, or C isoforms. Microarray analysis revealed 1,968 and 1,150 genes commonly regulated by DEX, FA, and TA in TM 86 and TM 93, respectively. These genes included RGC32, OCA2, ANGPTL7, MYOC, FKBP5, SAA1 and ZBTB16. In addition, each GC specifically regulated a unique set of genes in both TM cell lines. Using Ingenuity Pathway Analysis (IPA) software, analysis of the data from TM 86 cells showed that DEX significantly regulated transcripts associated with RNA post-transcriptional modifications, whereas FA and TA modulated genes involved in lipid metabolism and cell morphology, respectively. In TM 93 cells, DEX significantly regulated genes implicated in histone methylation, whereas FA and TA altered genes associated with cell cycle and cell adhesion, respectively.</p> <p>Conclusion</p> <p>Human trabecular meshwork cells in culture express all known GRα and GRβ translational isoforms, and GCs with similar potency but subtly different chemical structure are capable of regulating common and unique gene subsets and presumably biologic responses in these cells. These GC structure-dependent effects appear to be TM cell-lineage dependent.</p

Endogenous VEGF Is Required for Visual Function: Evidence for a Survival Role on Müller Cells and Photoreceptors

Vascular endothelial growth factor (VEGF) is well known for its role in normal and pathologic neovascularization. However, a growing body of evidence indicates that VEGF also acts on non-vascular cells, both developmentally as well as in the adult. In light of the widespread use of systemic and intraocular anti-VEGF therapies for the treatment of angiogenesis associated with tumor growth and wet macular degeneration, systematic investigation of the role of VEGF in the adult retina is critical.Using immunohistochemistry and Lac-Z reporter mouse lines, we report that VEGF is produced by various cells in the adult mouse retina and that VEGFR2, the primary signaling receptor, is also widely expressed, with strong expression by Müller cells and photoreceptors. Systemic neutralization of VEGF was accomplished in mice by adenoviral expression of sFlt1. After 14 days of VEGF neutralization, there was no effect on the inner and outer retina vasculature, but a significant increase in apoptosis of cells in the inner and outer nuclear layers. By four weeks, the increase in neural cell death was associated with reduced thickness of the inner and outer nuclear layers and a decline in retinal function as measured by electroretinograms. siRNA-based suppression of VEGF expression in a Müller cell line in vitro supports the existence of an autocrine role for VEGF in Müller cell survival. Similarly, the addition of exogenous VEGF to freshly isolated photoreceptor cells and outer-nuclear-layer explants demonstrated VEGF to be highly neuroprotective.These results indicate an important role for endogenous VEGF in the maintenance and function of adult retina neuronal cells and indicate that anti-VEGF therapies should be administered with caution

Branch Retinal Vein Occlusion: Pathogenesis, Visual Prognosis, and Treatment Modalities

In branch retinal vein occlusion (BRVO), abnormal arteriovenous crossing with vein compression, degenerative changes of the vessel wall and abnormal hematological factors constitute the primary mechanism of vessel occlusion. In general, BRVO has a good prognosis: 50–60% of eyes are reported to have a final visual acuity (VA) of 20/40 or better even without treatment. One important prognostic factor for final VA appears to be the initial VA. Grid laser photocoagulation is an established treatment for macular edema in a particular group of patients with BRVO, while promising results for this condition are shown by intravitreal application of steroids or new vascular endothelial growth factor inhibitors. Vitrectomy with or without arteriovenous sheathotomy combined with removal of the internal limiting membrane may improve vision in eyes with macular edema which are unresponsive to or ineligible for laser treatment

Cause of Death and Predictors of All-Cause Mortality in Anticoagulated Patients With Nonvalvular Atrial Fibrillation : Data From ROCKET AF

M. Kaste on työryhmän ROCKET AF Steering Comm jäsen.Background-Atrial fibrillation is associated with higher mortality. Identification of causes of death and contemporary risk factors for all-cause mortality may guide interventions. Methods and Results-In the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) study, patients with nonvalvular atrial fibrillation were randomized to rivaroxaban or dose-adjusted warfarin. Cox proportional hazards regression with backward elimination identified factors at randomization that were independently associated with all-cause mortality in the 14 171 participants in the intention-to-treat population. The median age was 73 years, and the mean CHADS(2) score was 3.5. Over 1.9 years of median follow-up, 1214 (8.6%) patients died. Kaplan-Meier mortality rates were 4.2% at 1 year and 8.9% at 2 years. The majority of classified deaths (1081) were cardiovascular (72%), whereas only 6% were nonhemorrhagic stroke or systemic embolism. No significant difference in all-cause mortality was observed between the rivaroxaban and warfarin arms (P=0.15). Heart failure (hazard ratio 1.51, 95% CI 1.33-1.70, P= 75 years (hazard ratio 1.69, 95% CI 1.51-1.90, P Conclusions-In a large population of patients anticoagulated for nonvalvular atrial fibrillation, approximate to 7 in 10 deaths were cardiovascular, whereasPeer reviewe

Konzeption fuer eine oekosystemare Umweltbeobachtung. Wissenschaftlich-fachlicher Ansatz. T. 1 und 2 Strategien fuer eine oekosystemare Umweltbeobachtung. Naturschutzfachliche Praezesierung der Konzeption fuer eine oekosystemare Umweltbeobachtung

In spite of in part considerable expenditure on environmental protection and of heightened efforts in the sectors environmental research and monitoring, there is increasing incidence of environmental damage with partly global impact. The latter is due inter alia to the fact that early detection of such damage is inadequate. The Federal Environmental Office, therefore, in order to come up with a conceptual frame for the recommendations given by the council of experts on environmental issues (''SRU''), has carried out the study ''Concept for ecosystemal environmental observation - pilot project for biosphere reserves''. In an exemplary manner, this study hammered out a transferable concept for ecosystemal environmental observation, based on types of ecosystems, for the terrestrian- and limnic-type biosphere reserves in Germany. (orig./SR)Trotz erheblicher Aufwendungen fuer Umweltschutz und verstaerkter Anstrengungen in den Bereichen der Umweltforschung und -ueberwachung treten zunehmend Umweltschaeden mit zum Teil globalen Auswirkungen auf, die unter anderem auf mangelnde Frueherkennung zurueckzufuehren sind. Das Umweltbundesamt hat daher zur konzeptionellen Ausgestaltung der Empfehlungen des Rats von Sachverstaendigen fuer Umweltfragen das F+E-Vorhaben ''Konzeption fuer eine oekosystemare Umweltbeobachtung - Pilotprojekt fuer Biosphaerenreservate'' durchgefuehrt. Dort wurde exemplarisch eine uebertragbare Konzeption fuer eine oekosystemare Umweltbeobachtung auf der Ebene von Oekosystemtypen fuer die terrestrisch und limnisch gepraegten Biosphaerenreservate (BR) in Deutschland erarbeitet. (orig./SR)Available from TIB Hannover: RN 8422(1997,32) / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekSIGLEBundesministerium fuer Umwelt, Naturschutz und Reaktorsicherheit, Bonn (Germany)DEGerman

COMBINED INTRAVITREAL BEVACIZUMAB AND TRIAMCINOLONE IN EXUDATIVE AGE-RELATED MACULAR DEGENERATION

ABSTRACT. Purpose: We report on thè combined application of intravitreal bevacizumab and triamcinolone acetonide for treatment of exudative age-related macular degeneration (AMD). Methods: The clinical interventional case-series study included 16 patients (16 eyes) with exudative AMD who had previously received 3.5 ±1. 8 mono-injec-tions of bevacizumab (1.5 mg) without significant improvement in visual acuity (VA) or reduction in macular exudation. AH patients underwent a combined intravitreal injection of bevacizumab (1.5 mg) and triamcinolone acetonide (about 20 mg). Main outcome measures were VA and macular thickness as determined by optical coherence tomography. AH patients were re-examined at 2-3 months after thè intervention. Results: Visual acuity improved significantly (p = 0.03) from 0.80 ± 0.40 logMAR prior to thè combined injection to 0.65 ± 0.42 logMAR at 3 months after thè injection. An improvement of > 1 Snellen line was found in eight sub-jects, an increase of > 2 lines in five subjects, and an improvement of > 3 lines in two subjects. One patient lost 1 line and one patient lost 3 lines. Central retinal thickness decreased significantly from 272 ± 62 ^m to 220 ± 47 firn (p = 0.03). At thè 6-month follow-up examination, centrai retinal thickness had increased again to 319 ± 142 fan, which was not significantly (p = 0.30) different from baseline measurements. Conclusions: The combined intravitreal application of bevacizumab and triam-cinolone may temporarily be helpful in thè treatment of exudative AMD if previous intravitreal bevacizumab mono-injections bave failed to improve vision and reduce macular oedema

Nachwachsende Rohstoffe statt Stillegung? Rentabilitaet - Vorschriften - Anbau und Verwertung

Der Anbau nachwachsender Rohstoffe kann die Umwelt entlasten. Beim Wachstum der Pflanzen wird CO_2 gebunden. Wenn es spaeter z.B. bei thermischer Nutzung wieder freigesetzt wird, entsteht ein Kreislauf im Gegensatz zur Nutzung fossiler Energie, bei deren Verbrennung die Atmosphaere mit CO_2 angereichert wird. Zu nachwachsenden Rohstoffen koennen sowohl ganze Pflanzen als auch bestimmte Inhaltsstoffe wie Staerke, Fett, Oel, Zellulose oder Zucker verarbeitet werden. Fuer die Verwendung ganzer Pflanzen steht in der Regel die thermische Nutzung im Vordergrund. Dagegen ist die Palette der Verwendungsmoeglichkeiten verschiedener Inhaltsstoffe sehr breit. So koennen Pflanzenoel und Fett z.B. Rohstoffe sein, die bisherige Schmiermittel, Farben und Kunststoffe ersetzen. Durch biochemische Prozesse kann Staerke zu Bioalkohol vergoren werden. (orig./EF)The cultivation of renewable resources can relieve the environmental pollution burden. During their growth the plants fix CO_2. When it is later released again during the process of combustion a cycle contrary to the use of fossil energies is created, where combustion results in the enrichment of CO_2 in the atmosphere. Renewable energies can be made both from whole plants and certain plant constituents such as starch, fat, oil, cellulose or sugar. Whole plants are mostly used as fuels in power generation. By contrast, the range of uses of different plant constituents is very broad. For instance, vegetable oils and fat may be used as substitutes for conventional lubricants, dyes and plastics. By biochemical processes, starch can be made into bioalcohol. (orig./EG)SIGLEAvailable from TIB Hannover: RA 9919(44) / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekDEGerman

Concept for integrated environmental monitoring. Scientific approach

Despite considerable expenditures for environmental protection and intensified efforts in the areas of environmental research and monitoring, environmental damage increasingly occurs, sometimes with global effects, largely due to the lack of early diagnosis. In the past few years various institutions have therefore demanded improvements in environmental monitoring. The Council of Experts on Environmental Issues ('Rat von Sachverstaendigen fuer Umweltfragen', SRU), in particular, in its 'Environmental Report' of 1987 and in its Special Report on 'General Ecological Environmental Monitoring' (1990) presented far-reaching demands for a nationwide ecological early warning system which should integrate the various local, regional, national, and even global monitoring levels, and which should encompass an environmental monitoring of entire ecosystems at representative locations. This is aimed at creating the prerequisites for - detection of long-term gradual environmental change, -confirmation of refutation of initial assumptions regarding the causes of these environmental changes, - permitting decisions on preventive actions to stabilize or improve environmental conditions and - making it possible to assess the success of environmental protection policies. This report includes an abbreviated version and documentation of the conference on the 'Concept for Integrated Environmental Monitoring' and the final report 'Specification of the Concept for Integrated Environmental Monitoring from the Perspective of Nature Conservation'. (orig.)English translation by M.N.L. SeamanSIGLEAvailable from TIB Hannover: RN 8422(1998,55) / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekBundesministerium fuer Umwelt, Naturschutz und Reaktorsicherheit, Bonn (Germany)DEGerman