Clinical effectiveness of biologics in clinical practice

TNF inhibitors are currently considered both effective and cost-effective in patients with active rheumatoid arthritis (RA), particularly in patients who have not responded fully to methotrexate. There is substantial doubt about the cost-effectiveness of TNF inhibitors as initial treatment for active RA. New data from the National Data Bank for Rheumatic Diseases now question the current consensus in methotrexate failures. The data suggest that in routine clinical practice TNF inhibitors provide only modest incremental benefits over best conventional therapy. If confirmed, these observational studies suggest that the economic argument underpinning the widespread use of TNF inhibitors in established RA is unsustainable.     

Mayday - integrative analytics for expression data

Background  

DNA Microarrays have become the standard method for large scale analyses of gene expression and epigenomics. The increasing complexity and inherent noisiness of the generated data makes visual data exploration ever more important. Fast deployment of new methods as well as a combination of predefined, easy to apply methods with programmer's access to the data are important requirements for any analysis framework. Mayday is an open source platform with emphasis on visual data exploration and analysis. Many built-in methods for clustering, machine learning and classification are provided for dissecting complex datasets. Plugins can easily be written to extend Mayday's functionality in a large number of ways. As Java program, Mayday is platform-independent and can be used as Java WebStart application without any installation. Mayday can import data from several file formats, database connectivity is included for efficient data organization. Numerous interactive visualization tools, including box plots, profile plots, principal component plots and a heatmap are available, can be enhanced with metadata and exported as publication quality vector files.     

The Effects of Copper Sulfate on Liver Histology and Biochemical Parameters of Term Ross Broiler Chicks

Copper is an essential trace element that is extremely toxic to organisms and organs at high doses. We have investigated the histological and biochemical effects of a toxic dose of copper sulfate on the liver of term Ross broiler chicks. Fertilized eggs were divided into three groups: experimental, injected with 50 mcg/0.1 ml copper sulfate in the air chambers on day 1; sham, injected with 0.1 ml saline; and control, no injection. Term chicks were killed and their livers investigated histologically, with hematoxylin–eosin-stained sections examined under light microscopy, and biochemically, for malondialdehyde and glutathione levels. Histological examinations showed copper-treated samples with granular degeneration and necrosis of hepatocytes and impairment to the cell lining of the remark cords. The samples had a congestive appearance, with blood in the vena centralis and sinusoids, slight connective tissue increase, and lymphocyte infiltration. Control and sham group sections had normal appearances. As oxidative damage parameters, in the copper-treated group, malondialdehyde levels were increased and glutathione levels decreased. In the sham and control groups, there were no significant differences. At this toxic dose, copper sulfate shows oxidative damage according to the histology of term chick liver that are confirmed biochemically by the changes in malondialdehyde and glutathione levels.     

Rabbit small intestine does not contain an annexin II/caveolin 1 complex as a target for 2-azetidinone cholesterol absorption inhibitors

Intestinal cholesterol absorption is specifically inhibited by the 2-azetidinone cholesterol absorption inhibitor ezetimibe. Photoreactive ezetimibe analogues specifically label a 145-kDa protein in the brush border membrane of enterocytes from rabbit small intestine identified as aminopeptidase N (CD13). In zebrafish and mouse small intestinal cytosol, a heterocomplex of M_r 52 kDa between annexin II and caveolin 1 was suggested as a target of ezetimibe. In contrast, in the cytosol and brush border membrane vesicles (BBMV) from rabbit small intestine of control animals or rabbits treated with the nonabsorbable cholesterol absorption inhibitor AVE 5530, both annexin II and caveolin 1 were exclusively present as monomers without any heterocomplex formation. Upon immunoprecipitation with annexin II a 52-kDa band was observed after immunostaining with annexin II antibodies, whereas no staining of a 52-kDa band occurred with anti-caveolin 1 antibodies. Vice versa, a 52-kDa band obtained by immunoprecipitation with caveolin 1 antibodies did not stain with annexin II-antibodies. The intensity of the 52-kDa band was dependent on the amount of antibody and was also observed with anti-actin or anti-APN antibodies suggesting that the 52-kDa band is a biochemical artefact. After incubation of cytosol or BBMV with radioactively labelled ezetimibe analogues, no significant amounts of the ezetimibe analogues could be detected in the immunoprecipitate with caveolin-1 or annexin II antibodies. Photoaffinity labelling of rabbit small intestinal BBMV with ezetimibe analogues did not result in labelling of proteins being immunoreactive with annexin II, caveolin 1 or a 52-kDa heterocomplex. These findings indicate that the rabbit small intestine does not contain an annexin II/caveolin 1 heterocomplex as a target for ezetimibe.     

Characterization of circadian oscillations in alanine dehydrogenase activity in non-dividing populations of Euglena gracilis (z)

Possible factors that could generate the circadian oscillations in alanine dehydrogenase (EC 1.4.1.1.) activity observed in cultures of non-dividing Euglena gracilis (Z) have been examined in an effort to learn more about the basic timekeeping mechanism of biological clocks. No differences in K_m, pH optimum or electrophoretic mobility could be demonstrated between enzyme extracted from the minimum part of the 24-h oscillation in activity and that extracted from the maximum part. Also, no evidence for the presence of activators or inhibitors was found in mixing experiments. The effect of cycloheximide on the rhythm was examined; it was shown that the oscillation ceases in the presence of the inhibitor, but that if the inhibitor is removed after 12 h, the rhythm resumes with no apparent change in phase. Analyses of gel scans of enzyme preparations partially purified by (NH₄)₂SO₄ fractionation and polyacrylamide gel electrophoresis indicated that there was more alanine dehydrogenase protein present at the maximum part of the cycle than there was at the minimum part. In view of these and other data, an operational model of a circadian biological clock is discussed.     

Global introductions of salmon and trout in the genus <Emphasis Type="Italic">Oncorhynchus</Emphasis>: 1870–2007

The purpose of this review is to provide a global perspective on Oncorhynchus salmonine introductions and put-and-take fisheries based on modern stocking programs, with special emphasis on freshwater ecosystems. We survey the global introductions of nine selected salmonines of the genus Oncorhynchus: golden trout, cutthroat trout, pink salmon, chum salmon, coho salmon, masu/cherry salmon, rainbow trout/steelhead, sockeye salmon/kokanee, and chinook salmon. The information is organized on a geographical basis by continent, and then by species and chronology. Two different objectives and associated definitions of ‘success’ for introductions are distinguished: (a) seed introduction: release of individuals with the purpose of creating a wild-reproducing, self-sustaining population; and (b) put-and-take introduction: release of individuals with the purpose of maintaining some level of wild population abundance, regardless of wild reproduction. We identify four major phenomena regarding global salmonine introductions: (1) general inadequacy of documentation regarding introductions; (2) a fundamental disconnect between management actions and ecological consequences of introductions; (3) the importance of global climate change on success of previous and future introductions; and (4) the significance of aquaculture as a key uncertainty in accidental introductions. We conclude this review with a recognition of the need to terminate ongoing stocking programs for introduced salmonines worldwide.     

Internal lipid synthesis and vesicle growth as a step toward self-reproduction of the minimal cell

One of the major properties of the semi-synthetic minimal cell, as a model for early living cells, is the ability to self-reproduce itself, and the reproduction of the boundary layer or vesicle compartment is part of this process. A minimal bio-molecular mechanism based on the activity of one single enzyme, the FAS-B (Fatty Acid Synthase) Type I enzyme from Brevibacterium ammoniagenes, is encapsulated in 1-palmitoyl-2oleoyl-sn-glycero-3-phosphatidylcholine (POPC) liposomes to control lipid synthesis. Consequently molecules of palmitic acid released from the FAS catalysis, within the internal lumen, move toward the membrane compartment and become incorporated into the phospholipid bilayer. As a result the vesicle membranes change in lipid composition and liposome growth can be monitored. Here we report the first experiments showing vesicles growth by catalysis of one enzyme only that produces cell boundary from within. This is the prototype of the simplest autopoietic minimal cell.