Apolipoprotein E*3-Leiden transgenic mice as a test model for hypolipidaemic drugs

PURPOSE: We report an investigation into the distribution of proteoglycans (PGs) in normal, organ-cultured and dextran-treated human corneas. METHODS: Immunogold labeling was carried out at the electron microscope level to localize keratan sulphate (KS), chondroitin sulphate (CS), and heparan sulphate (HS) PGs. RESULTS: High levels of labeling for CS was found in the epithelium, endothelium, and keratocytes, with light labelling present in the basement membranes and the corneal stroma. Labeling for HS was present in the epithelium, endothelium, and keratocytes, with intense labeling present at the endothelium/Descemet's membrane interface and the epithelium/Bowman's layer interface. Large filaments were also observed in these regions in cuprolinic blue-stained specimens. Keratan sulphate was present at high levels in the stroma and the basement membranes with low levels present within the keratocytes, epithelium, and endothelium. The pattern of KS labeling along the collagen fibrils in the stroma sometimes showed evidence of periodicity. Organ-cultured corneas had extensive collagen-free "lakes," the interior of which immunolabeled positively for KS and showed staining with cuprolinic blue. The lakes were greatly reduced in the dextran-treated samples. CONCLUSION: This investigation determined the ultrastructural distribution of KS, CS, and HS PGs in human cornea and showed that organ culture is associated with a change in distribution of stromal PGs.     

Angiogenesis-inhibiting drugs--a future therapeutic option

In order to grow beyond 2-3 mm in size, a primary tumour or metastasis must induce angiogenesis, the formation of new blood vessels. Tumour capillary content is an independent prognostic factor, usually measured as the mean of three counts in capillary-rich areas of the histological section. Either as single drugs or in combination with other treatment, angiostatic agents probably represent the future of cancer treatment.     

Blast furnace ironmaking: view on future developments

Within many industries, there is a constant drive to reduce environmental impact and energy costs thereby ensuring maximum energy re-use. Within the iron and steel industry, the ironmaking processes are acknowledged to be the focus area when the topic of energy saving arises. A lot of attention has been applied to the ironmaking processes with regards to environment and energy saving, with established technologies being in place to reach these goals such that the process per se is now at or very close to theoretical limits. The following areas of the blast furnace process are currently the focus of Primetals activity with regard the target to further improve energy saving with incremental improvements: flue gas recycling within blast furnace stoves, MERIM dry gas cleaning process and dry slag granulation including heat recovery. This paper will present the concepts and latest status of the above technologies. The paper will review the progress to date of these development activities and thus present ideas on options for energy saving and reuse within the ironmaking system.     

Current developments and future directions in computerized personality assessment.

Contends, on the basis of a review of current examples of computer usage in personality assessment, that there is wide acceptance of automated clerical tasks such as test scoring and administration. The computer is also writing narrative interpretive reports from test results. Three proposed strategies (countdown, adaptive typological, and a strategy borrowed from ability testing) for developing computerized adaptive personality tests are described. (50 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Nuclear transfer in mammals: recent developments and future perspectives

A clone can be defined as a set of genetically identical animals. Small clones of two or occasionally up to four identical animals can be obtained by embryo splitting or blastomere separation. Embryo cloning by nuclear transfer involves the transfer of genetic material from a donor cell (karyoplast) to the cytoplasm of an oocyte or zygote from which the genetic material has been removed (cytoplast). In farm animals, metaphase II oocytes are most widely used as cytoplasts. There are now many factors known to influence the efficiency of embryo cloning by nuclear transfer. These include stage of development and cell cycle of donor cells, the choice of the recipient cell, the methods for activation of oocytes, the cell cycle coordination between donor cell and recipient cytoplast, and the method for fusion between nuclear donor and recipient cytoplast. Recent progress in cloning embryos and animals from cultured cells of embryonic, fetal, or adult origin offers a wide spectrum of potential applications of nuclear transfer, such as the unlimited multiplication of elite embryos or animals from selected matings and the potential for precise genetic modification of farm animals for gene farming or xenotransplantation.     

N-glycoprotein biosynthesis in plants: recent developments and future trends

This review summarizes the evolution of ideas concerning insulin signal transduction, the current information on protein ser/thr kinase cascades as signalling intermediates, and their status as participants in insulin regulation of energy metabolism. Best characterized is the Ras-MAPK pathway, whose input is crucial to cell fate decisions, but relatively dispensable in metabolic regulation. By contrast the effectors downstream of PI-3 kinase, although less well elucidated, include elements indispensable for the insulin regulation of glucose transport, glycogen and cAMP metabolism. Considerable information has accrued on PKB/cAkt, a protein kinase that interacts directly with Ptd Ins 3'OH phosphorylated lipids, as well as some of the elements further downstream, such as glycogen synthase kinase-3 and the p70 S6 kinase. Finally, some information implicates other erk pathways (e.g. such as the SAPK/JNK pathway) and Nck/cdc42-regulated PAKs (homologs of the yeast Ste 20) as participants in the cellular response to insulin. Thus insulin recruits a broad array of protein (ser/thr) kinases in its target cells to effectuate its characteristic anabolic and anticatabolic programs.     

Amyloidosis: a review of recent diagnostic and therapeutic developments

Amyloid deposition is associated with a diverse range of disorders that includes Alzheimer's disease, type II diabetes mellitus and dialysis arthropathy. Although less common, systemic AA and AL amyloidosis remain important because effective treatments have increasingly become available. The pathology in all forms of amyloidosis involves the extracellular deposition of protein as characteristic fibrillar aggregates which interfere with tissue structure and function. Amyloid fibrils are derived from different unrelated proteins in the different forms of the disease but share many common properties, including the capacity to bind the normal plasma protein serum amyloid P component (SAP). This is the basis for our development of radiolabelled SAP as a nuclear medicine tracer for the diagnosis and quantitative monitoring of amyloid. Serial studies have shown that the deposits are far from inert but are actually turned over quite rapidly in many patients. The treatment of amyloidosis involves supportive measures whilst every effort is made to reduce the supply of the respective fibril precursor protein. Under favourable circumstances further amyloid deposition will be prevented. existing deposits will regress and improvement of organ function will occur. Since this strategy is not always possible or may fail, new approaches to inhibit fibril formation and promote regression of amyloid are being pursued.     

The plasma membrane calcium pump: recent developments and future perspectives

The Ca2+ pump of the plasma membrane (PMCA) is regulated by a number of agents. The most important is calmodulin (CaM), which binds to a domain located in the C-terminal portion of the pump, removing it from an autoinhibitory site next to the active site. The CaM-binding domain is preceded by an acidic sequence which contains a hidden signal for endoplasmic reticulum (ER) retention. Chimeras of the PMCA and endoplasmic reticulum (SERCA) pumps have revealed the presence of a strong signal for ER retention in the first 45 residues of the SERCA pump. Four gene products of the PMCA pump are known: two of them (1 and 4) are ubiquitously expressed, two (2 and 3) are specific for nerve cells and may be induced by their activation. Mutagenesis work has identified four residues in three of the transmembrane domains of the pump which may be components of the trans-protein Ca2+ path. The mutation of two of these residues alters the membrane targeting of the pump.     

Prevention of transplant rejection: current treatment guidelines and future developments

In the past 2 decades, progressive improvements in the results of organ transplantation as a therapeutic strategy for patients with end-stage organ disease have been achieved due to greater insight into the immunobiology of graft rejection and better measures for surgical and medical management. It is now known that T cells play a central role in the specific immune response of acute allograft rejection. Strategies to prevent T cell activation or effector function are thus all potentially useful for immunosuppression. Standard immunosuppressive therapy in renal transplantation consists of baseline therapy to prevent rejection and short courses of high-dose corticosteroids or monoclonal or polyclonal antibodies as treatment of ongoing rejection episodes. Triple-drug therapy with the combination of cyclosporin, corticosteroids and azathioprine is now the most frequently used immunosuppressive drug regimen in cadaveric kidney recipients. The continuing search for more selective and specific agents has become, in the past decade, one of the priorities for transplant medicine. Some of these compounds are now entering routine clinical practice: among them are tacrolimus (which has a mechanism of action similar to that of cyclosporin), mycophenolate mofetil and mizoribine (which selectively inhibit the enzyme inosine monophosphate dehydrogenase, the rate-limiting enzyme for de novo purine synthesis during cell division), and sirolimus (rapamycin) [which acts on and inhibits kinase homologues required for cell-cycle progression in response to growth factors, like interleukin-2 (IL-2)]. Other new pharmacological strategies and innovative approaches to organ transplantation are also under development. Application of this technology will offer enormous potential not only for the investigation of mechanisms and mediators of graft rejection but also for therapeutic intervention.     

Trends and future developments in the pharmacological treatment of acute ischaemic stroke

Stroke stands as the third leading cause of death. It makes great demands on patients, who must not only survive the complications of the acute stages, but must cope then with the great physical and economic costs of long-term disabilities. Therefore, there is urgent need to establish generally useful regimens for the acute treatment of ischaemic stroke. Three treatment approaches are based upon pathophysiologic concepts derived from experimental work with focal cerebral ischaemia. These include pharmacologic strategies for arterial recanalisation, inhibition of inflammatory processes and neural protection. Focal cerebral ischaemia secondary to occlusion of a brain-supplying artery initiates neuronal and microvascular events, and the simultaneous processes of inflammation which further injure tissue. The use of plasminogen activators to mediate thrombus and lysis in the acute setting has been shown to be clinically beneficial. Further work with arterial reperfusion strategies is under way. Early clinical studies with polymorphonuclear leukocyte-dependent endothelial adhesion receptor antagonists are being completed, but a strategy has yet to emerge. A large effort examining the potential efficacy of agents which may stabilise or protect neurons from ischaemic injury has shown promise in experimental models, and has been translated into clinical trials. Experimental work, and limited clinical experience, have indicated that: (a) the time window for intervention is important in limiting ischaemic and inflammatory injury, and for reducing the risk of haemorrhagic transformation; (b) putative neuroprotective strategies may potentially elongate the time interval for treatment; and (c) limitations from the adverse effects of plasminogen activators and of agents which beneficially affect neuronal dysfunction during ischaemia must yet be overcome. This review surveys pharmacological approaches currently undergoing evaluation which provide the goal of establishing effective strategies for the treatment of patients with acute cerebral ischaemia.     

Overview No. 87 Solidification microstructures: Recent developments and future directions

During solidification a great variety of microstructures can form. These are plane front (and its related instabilities), cells, densrites and eutectic. Recent progress and future directions of research in this rapidly moving field are summarized. This overview is based on the critical assessment of the field made at an interdisciplinary workshop held in Zermatt during July 1988.     

Attitudes to current oral contraceptive use and future developments: the women's perspective

OBJECTIVES: The study was planned to determine current trends in contraceptive usage and to examine the attitudes, needs and preferences of women with respect to oral contraceptives. METHODS: Semi-structured interviews were carried out with women (n = 1201, aged 16-45 years) in Germany, the UK and France. RESULTS: The study revealed that oral contraceptives were the most popular method of contraception employed, followed by condoms, and that the majority of respondents were aged 16-19 years when they first used an oral contraceptive. An important finding of the study was that an oral contraceptive was first used only after having sexual intercourse for the first time (within 1 year), emphasizing the importance of effective contraceptive information and education for adolescents. Regarding non-contraceptive health benefits, protection from ovarian and endometrial cancer was perceived by respondents to be of the greatest importance; however, few women were spontaneously aware of this benefit. When given a number of different oral contraceptive intake options to assess, the established 'once daily for 21 consecutive days' option remained the most popular, although a 'once weekly' alternative was cited by many women. When asked about the preferred frequency of menstrual bleeding, there was a polarization between women favoring the normal monthly bleed and those wanting a 'no-bleed' regimen. CONCLUSION: Women are poorly informed about oral contraceptive use, and are largely unaware of the important long-term non-contraceptive benefits. Many women would prefer alternative pill intake options and a significant number would favor a 'no-bleed' regimen.     

Adenosine receptors: new opportunities for future drugs

This review summarises current knowledge on adenosine receptors, an important G protein-coupled receptor. The four known adenosine receptor subtypes A1, A2A, A2B, and A3 are discussed with special reference to the opportunities for drug development.     

双相不锈钢的发展现状及未来市场趋势

从不同角度叙述双相不锈钢发展史,介绍合金设计,以及过去和现有的合金牌号。讨论了合金设计的基本原则,介绍了新的双相不锈钢。对于双相不锈钢的主要性能,也作了介绍,并着重强调其在新的应用领域具有极大的增长潜力。从所提供的数据中,也引伸出一些开放性的课题。这些课题将进一步推进2010年在法国博恩(Beaune)举办的双相不锈钢大会上的研讨。