A strategy for designing inhibitors of alpha-synuclein aggregation and toxicity as a novel treatment for Parkinson's disease and related disorders.

Convergent biochemical and genetic evidence suggests that the formation of alpha-synuclein (alpha-syn) protein deposits is an important and, probably, seminal step in the development of Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). It has been reported that transgenic animals overexpressing human alpha-syn develop lesions similar to those found in the brain in PD, together with a progressive loss of dopaminergic cells and associated abnormalities of motor function. Inhibiting and/or reversing alpha-syn self-aggregation could, therefore, provide a novel approach to treating the underlying cause of these diseases. We synthesized a library of overlapping 7-mer peptides spanning the entire alpha-syn sequence, and identified amino acid residues 64-100 of alpha-syn as the binding region responsible for its self-association. Modified short peptides containing alpha-syn amino acid sequences from part of this binding region (residues 69-72), named alpha-syn inhibitors (ASI), were found to interact with full-length alpha-syn and block its assembly into both early oligomers and mature amyloid-like fibrils. We also developed a cell-permeable inhibitor of alpha-syn aggregation (ASID), using the polyarginine peptide delivery system. This ASID peptide was able to inhibit the DNA damage induced by Fe(II) in neuronal cells transfected with alpha-syn(A53T), a familial PD-associated mutation. ASI peptides without this delivery system did not reverse levels of Fe(II)-induced DNA damage. Furthermore, the ASID peptide increased (P

A model for developing, implementing and evaluating a strategy to improve nursing and midwifery care

Background: Health care organizations world wide are faced with the need to develop and implement strategic organizational plans to meet the challenges of modern health care. There is a need for models for developing, implementing and evaluating strategic plans that engage practitioners, and make a measurable difference to the patients that they serve. This article describes the development of such a model to underpin a strategy for nursing and midwifery in an acute hospital trust. An integrated model: The processes for strategy development (values clarification, critical companionship and focus groups) are discussed, together with the development of processes for implementation, based upon a modification of the PARIHS (Promoting Action on Research Implementation in Health Services) conceptual framework. Finally, the methods for evaluating the strategy (a pre-test/post-test approach measuring the quality of nursing care, the degree to which the organization supports professional nursing care, the leadership styles of ward managers, and patient satisfaction with care) are described. Conclusion: The model is offered as one that may be of use to others who wish to develop an integrated approach to strategic change; an approach in which the development, implementation and evaluation of strategic plans are informed by the core values of nurses and midwives.

Dynamic, in situ optical, magnetic and magneto-optical monitoring of the growth of Co/Au and Pd/Co/Au multilayer systems

The growth of magnetron sputtered Co/Au and Pd/Co/Au superlattices on Au and Pd buffer layers, deposited onto glass substrates, has been monitored optically and magneto-optically in real time, using rotating analyser ellipsometry and Kerr polarimetry, at a wavelength of 633 nm. The magneto-optical traces, combined with ex situ and in situ hysteresis loops, provide a detailed and informative fingerprint of the optical and magnetic properties of the films as they evolve during growth. For Co/Au, oscillations in the polar magneto-optical effect developed during the deposition of An overlayers on Co and these may be attributed to quantum well states. However, the hysteresis measurements show that the magnetic field required to maintain saturation magnetization throughout the experiment was larger than available in situ, introducing a degree of confusion concerning the interpretation of the data. This problem was overcome by the incorporation of Pd layers into the Co/Au structure, thereby eliminating variation in magnetic orientation during growth of the Au layers as a contributory factor to the observations.

The Sustainability Balanced Scorecard. Linking Sustainability Management to Business Strategy.

The Balanced Scorecard of Kaplan and Norton is a management tool that supports the successful implementation of corporate strategies. It has been discussed and considered widely in both practice and research. By linking operational and non-financial corporate activities with causal chains to the firm's long-term strategy, the Balanced Scorecard supports the alignment and management of all corporate activities according to their strategic relevance. The Balanced Scorecard makes it possible to take into account non-monetary strategic success factors that significantly impact the economic success of a business. The Balanced Scorecard is thus a promising starting-point to also incorporate environmental and social aspects into the main management system of a firm. Sustainability management with the Balanced Scorecard helps to overcome the shortcomings of conventional approaches to environmental and social management systems by integrating the three pillars of sustainability into a single and overarching strategic management tool. After a brief discussion of the different possible forms of a Sustainability Balanced Scorecard the article takes a closer look at the process and steps of formulating a Sustainability Balanced Scorecard for a business unit. Before doing so, the basic conventional approach of the Balanced Scorecard and its suitability for sustainability management will be outlined in brief.

Proteasome inhibitors: a therapeutic strategy for haematological malignancy

The proteasome is a multicatalytic enzyme complex responsible for the regulated degradation of intracellular proteins. In recent years, inhibition of proteasome function has emerged as a novel anti-cancer therapy. Proteasome inhibition is now established as an effective treatment for relapsed and refractory multiple myeloma and offers great promise for the treatment of other haematological malignancies, when used in combination with conventional therapeutic agents. Bortezomib is the first proteasome inhibitor to be used clinically and a second generation of proteasome inhibitors with differential pharmacological properties are currently in early clinical trials. This review summarises the development of proteasome inhibitors as therapeutic agents and describes how novel assays for measuring proteasome activity and inhibition may help to further delineate the mechanisms of action of different proteasome inhibitors. This will allow for the optimized use of proteasome inhibitors in combination therapies and provide the opportunity to design more potent and therapeutically efficacious proteasome inhibitors.