Current status of drug-eluting stents

First-generation drug-eluting stents (DES) with controlled release of sirolimus or paclitaxel from durable polymers compared with bare-metal stents have been consistently shown to reduce the risk of repeat revascularization procedures due to restenosis. The superior efficacy was found across a wide range of patients and lesion subsets and persisted up to 5 years whereas similar outcomes have been observed in terms of death and myocardial infarction. Newer generation DES have been developed with the goal to further improve upon the safety profile of first-generation DES while maintaining efficacy. These platforms include DES with improved and more biocompatible durable polymers, DES using bioabsorbable polymers for drug release, DES with polymer-free drug release, and fully bioabsorbable DES. Newer generation DES with durable polymers such as zotarolimus-eluting or everolimus-eluting XIENCE V stents have been directly compared with first-generation DES. Most recent results of large scale clinical trials are encouraging in terms of similar or increased efficacy while improving safety by reducing the rates of myocardial infarctions and stent thrombosis. DES using biodegradable polymers for drug release represent the next technological modification and preliminary results are favorable and demonstrate similar angiographic and clinical efficacy as first-generation DES, but only longer term follow-up and investigation in larger patient cohorts will determine whether their use is associated with improved long-term safety. Fully bioabsorbable stents represent another innovative approach. Whether this innovative concept will enter into clinical routine remains yet to be determined.

Comparison of biolimus eluted from an erodible stent coating with bare metal stents in acute ST-elevation myocardial infarction (COMFORTABLE AMI trial): rationale and design

Compared with bare metal stents (BMS), early generation drug-eluting stents (DES) reduce the risk of revascularisation in patients with ST-elevation myocardial infarction (STEMI) at the expense of an increased risk of very late stent thrombosis (ST). Durable polymer coatings for controlled drug release have been identified as a potential trigger for these late adverse events and this has led to the development of newer generation DES with durable and biodegradable polymer surface coatings with improved biocompatibility. In a recent all-comers trial, biolimus-eluting stents with a biodegradable polymer surface coating were found to reduce the risk of very late ST by 80% compared with sirolimus-eluting stents with durable polymer, which also translated into a lower risk of cardiac death and myocardial infarction (MI) beyond one year.

Aberrant low expression level of bovine beta-lactoglobulin is associated with a C to A transversion in the BLG promoter region

Beta-lactoglobulin (beta-LG) is the major whey protein in cow's milk. It is well established that the predominant 2 genetic variants, beta-LG A and B, are differentially expressed. Extensive investigation of the genetic variation in the promoter region of the BLG gene revealed the existence of specific haplotypes associated with the A and B variants, respectively. However, the genetic basis for the differential expression of BLG A and B alleles is still elusive. We have previously reported a quantitative beta-LG B variant, characterized by a very low beta-LG protein expression level. Here, we report that the corresponding BLG allele (BLG B*) shows a correspondingly low mRNA expression level. Comparative DNA sequencing of 7,670 bp of the BLG B* allele and the established BLG B allele revealed a unique difference of a C to A transversion at position 215 bp upstream of the translation initiation site (g.-215C>A). This mutation segregated perfectly with the differential phenotypic expression in a paternal half-sib family and could be confirmed in 2 independent cases. The sequence of the BLG B allele in the region of the mutation is highly conserved among 4 related ruminant species. The site of the mutation corresponds to a putative consensus-binding sequence for the transcription factors c-Rel and Elk-1 as predicted by searching the TRANSFAC database. The beta-LG B* site might be relevant in the natural production of milk of low beta-LG content.

Nitric oxide down-regulates the expression of the catalytic NADPH oxidase subunit Nox1 in rat renal mesangial cells

Glomerular mesangial cells can produce high amounts of nitric oxide (NO) and reactive oxygen species (ROS). Here we analyzed the impact of NO on the ROS-generating system, particularly on the NADPH oxidase Nox1. Nox1 mRNA and protein levels were markedly decreased by treatment of mesangial cells with the NO-releasing compound DETA-NO in a concentration- and time-dependent fashion. By altering the cGMP signaling system with different inhibitors or activators, we revealed that the effect of NO on Nox1 expression is at least in part mediated by cGMP. Analysis of a reporter construct comprising the 2547 bp of the nox1 promoter region revealed that a stimulatory effect of IL-1beta on nox1 transcription is counteracted by an inhibitory effect of IL-1beta-evoked endogenous NO formation. Moreover, pretreatment of mesangial cells with DETA-NO attenuated platelet-derived growth factor (PDGF)-BB or serum stimulated production of superoxide as assessed by real-time EPR spectroscopy and dichlorofluorescein formation. Transfection of mesangial cells with siRNAs directed against Nox1 and Nox4 revealed that inhibition of Nox1, but not Nox4 expression, is responsible for the reduced ROS formation by NO. Obviously, there exists a fine-tuned crosstalk between NO and ROS generating systems in the course of inflammatory diseases.

The evolutionary diversification of parrots supports a taxon pulse model with multiple trans-oceanic dispersal events and local radiations

Vicariance is thought to have played a major role in the evolution of modern parrots. However, as the relationships especially of the African taxa remained mostly unresolved, it has been difficult to draw firm conclusions about the roles of dispersal and vicariance. Our analyses using the broadest taxon sampling of old world parrots ever based on 3219 bp of three nuclear genes revealed well-resolved and congruent phylogenetic hypotheses. Agapornis of Africa and Madagascar was found to be the sister group to Loriculus of Australasia and Indo-Malayasia and together they clustered with the Australasian Loriinae, Cyclopsittacini and Melopsittacus. Poicephalus and Psittacus from mainland Africa formed the sister group Of the Neotropical Arini and Coracopsis from Madagascar and adjacent islands may be the closest relative of Psittrichas from New Guinea. These biogeographic relationships are best explained by independent colonization of the African continent via trans-oceanic dispersal from Australasia and Antarctica in the Paleogene following what may have been vicariance events in the late Cretaceous and/or early Paleogene. Our data support a taxon pulse model for the diversification of parrots whereby trans-oceanic dispersal played a more important role than previously thought and was the prerequisite for range expansion into new continents. (C) 2009 Elsevier Inc. All rights reserved

Genetic relationships of Aeromonas strains inferred from 16S rRNA, gyrB and rpoB gene sequences

Genetic relationships among bacterial strains belonging to the genus Aeromonas were inferred from 16S rRNA, gyrB and rpoB gene sequences. Twenty-eight type or collection strains of the recognized species or subspecies and 33 Aeromonas strains isolated from human and animal specimens as well as from environmental samples were included in the study. As reported previously, the 16S rRNA gene sequence is highly conserved within the genus Aeromonas, having only limited resolution for this very tight group of species. Analysis of a 1.1 kb gyrB sequence confirmed that this gene has high resolving power, with maximal interspecies divergence of 15.2 %. Similar results were obtained by sequencing only 517 bp of the rpoB gene, which showed maximal interspecies divergence of 13 %. The topologies of the gyrB- and rpoB-derived trees were similar. The results confirm the close relationship of species within the genus Aeromonas and show that a phylogenetic approach including several genes is suitable for improving the complicated taxonomy of the genus.

Safety and efficacy of drug-eluting stents in women: a patient-level pooled analysis of randomised trials

BACKGROUND The safety and efficacy of drug-eluting stents (DES) in the treatment of coronary artery disease have been assessed in several randomised trials. However, none of these trials were powered to assess the safety and efficacy of DES in women because only a small proportion of recruited participants were women. We therefore investigated the safety and efficacy of DES in female patients during long-term follow-up. METHODS We pooled patient-level data for female participants from 26 randomised trials of DES and analysed outcomes according to stent type (bare-metal stents, early-generation DES, and newer-generation DES). The primary safety endpoint was a composite of death or myocardial infarction. The secondary safety endpoint was definite or probable stent thrombosis. The primary efficacy endpoint was target-lesion revascularisation. Analysis was by intention to treat. FINDINGS Of 43,904 patients recruited in 26 trials of DES, 11,557 (26·3%) were women (mean age 67·1 years [SD 10·6]). 1108 (9·6%) women received bare-metal stents, 4171 (36·1%) early-generation DES, and 6278 (54·3%) newer-generation DES. At 3 years, estimated cumulative incidence of the composite of death or myocardial infarction occurred in 132 (12·8%) women in the bare-metal stent group, 421 (10·9%) in the early-generation DES group, and 496 (9·2%) in the newer-generation DES group (p=0·001). Definite or probable stent thrombosis occurred in 13 (1·3%), 79 (2·1%), and 66 (1·1%) women in the bare-metal stent, early-generation DES, and newer-generation DES groups, respectively (p=0·01). The use of DES was associated with a significant reduction in the 3 year rates of target-lesion revascularisation (197 [18·6%] women in the bare-metal stent group, 294 [7·8%] in the early-generation DES group, and 330 [6·3%] in the newer-generation DES group, p<0·0001). Results did not change after adjustment for baseline characteristics in the multivariable analysis. INTERPRETATION The use of DES in women is more effective and safe than is use of bare-metal stents during long-term follow-up. Newer-generation DES are associated with an improved safety profile compared with early-generation DES, and should therefore be thought of as the standard of care for percutaneous coronary revascularisation in women. FUNDING Women in Innovation Initiative of the Society of Cardiovascular Angiography and Interventions.

GATA-4 and GATA-6 modulate tissue-specific transcription of the human gene for P450c17 by direct interaction with Sp1.

Cytochrome P450c17 catalyzes steroidogenic 17alpha-hydroxylase and 17,20 lyase activities. Expression of the gene for P450c17 is cAMP dependent, tissue specific, developmentally programmed, and varies among species. Binding of Sp1, Sp3, and NF1-C (nuclear factor 1-C) to the first 227 bp of 5'flanking DNA (-227/LUC) is crucial for basal transcription in human NCI-H295A adrenal cells. Human placental JEG-3 cells contain Sp1, Sp3, and NF1, but do not express -227/LUC, even when transfected with a vector expressing steroidogenic factor 1 (SF-1). Therefore, other factors are essential for basal expression of P450c17. Deoxyribonuclease I footprinting and EMSAs identified a GATA consensus site at -64/-58 and an SF-1 site at -58/-50. RT-PCR identified GATA-4, GATA-6, and SF-1 in NCI-H295A cells and GATA-2 and GATA-3, but not GATA-4, GATA-6, or SF-1 in JEG-3 cells. Cotransfection of either GATA-4 or GATA-6 without SF-1 activated -227/LUC in JEG-3 cells, but cotransfection of GATA-2 or GATA-3 with or without SF-1 did not. Surprisingly, mutation of the GATA binding site in -227/LUC increased GATA-4 or GATA-6 induced activity, whereas mutation of the Sp1/Sp3 site decreased it. Furthermore, promoter constructs including the GATA site, but excluding the Sp1/Sp3 site at -196/-188, were not activated by GATA-4 or GATA-6, suggesting an interaction between Sp1/Sp3 and GATA-4 or GATA-6. Glutathione-S-transferase pull-down experiments and coimmunoprecipitation demonstrated interaction between GATA-4 or GATA-6 and Sp1, but not Sp3. Chromatin immunoprecipitation assays confirmed that this GATA-4/6 interaction with Sp1 occurred at the Sp site in the P450c17 promoter in NCI-H295A cells. Demethylation with 5-aza-2-deoxycytidine permitted JEG-3 cells to express endogenous P450c17, SF-1, GATA-4, GATA-6, and transfected -227/LUC. Thus, GATA-4 or GATA-6 and Sp1 together regulate expression of P450c17 in adrenal NCI-H295A cells and methylation of P450c17, GATA-4 and GATA-6 silence the expression of P450c17 in placental JEG-3 cells.

Zu den Ergebnissen des Modellprojektes der Techniker-Krankenkasse zum Qualitätsmonitoring in der ambulanten Psychotherapie - eine Replik des wissenschaftlichen Beirats

Zur Versachlichung der Diskussion über die TK-Studie zum Effekt eines Qualitätsmonitorings in der ambulanten Psychotherapie hat der wissenschaftliche Beirat die Ergebnisse aus seiner Sichtweise dargestellt. Zur Hauptfragestellung wird der Abschlussbericht zitiert, der bestätigt, dass es sich um eine konfirmatorische Untersuchung handelte. Im Kern sollte sie die Hypothesen zur Überlegenheit des TK-Modells gegenüber dem Verfahren der Gutachterverfahren überprüfen. Beim TK-Modell handelt es sich um eine „Komplexintervention“, die aus mehreren Bausteinen bestand. Die Studienergebnisse lassen somit nur die Aussage zu, dass diese Komplexintervention in ihrer Kombination keine Überlegenheit gezeigt hat. Ob einzelne Bausteine Wirksamkeit hatten, bedarf weiterer Forschung. Schließlich werden das Repräsentativitäts- und das Selektivitätsproblem der Studie bzw. der verwertbaren Stichproben erläutert und mit Verweis auf die Literatur wird deren Relevanz dargelegt.