bluuebunny/crossref_metadata_2025 huggingface dataset:
Isolated trochlear nerve palsy as a presenting feature of primary polycythemia rubra vera
Authors: Jones Michael M , Clement Colin I , Rowe Dominic B
Published: June 2004

A case is reported where the onset of vertical diplopia secondary to a trochlear nerve palsy occurred as the presenting feature of polycythemia rubra vera. This may be the first report of an isolated trochlear nerve palsy secondary to polycythemia rubra vera and infarction of the fascicle or nerve.
Myopia: precedents for research in the twenty‐first century
Authors: Gilmartin Bernard
Published: June 2004

The myopic eye is generally considered to be a vulnerable eye and, at levels greater than 6 D, one that is especially susceptible to a range of ocular pathologies. There is concern therefore that the prevalence of myopia in young adolescent eyes has increased substantially over recent decades and is now approaching 10−25% and 60−80%, respectively, in industrialized societies of the West and East. Whereas it is clear that the major structural correlate of myopia is longitudinal elongation of the posterior vitreous chamber, other potential correlates include profiles of lenticular and corneal power, the relationship between longitudinal and transverse vitreous chamber dimensions and ocular volume. The most potent predictors for juvenile‐onset myopia continue to be a refractive error ≤+0.50 D at 5 years of age and family history. Significant and continuing progress is being made on the genetic characteristics of high myopia with at least four chromosomes currently identified. Twin studies and genetic modelling have computed a heritability index of at least 80% across the whole ametropic continuum. The high index does not, however, preclude an environmental precursor, sustained near work with high cognitive demand being the most likely. The significance of associations between accommodation, oculomotor dysfunction and human myopia is equivocal despite animal models that have demonstrated that sustained hyperopic defocus can induce vitreous chamber growth. Recent optical and pharmaceutical approaches to the reduction of myopia progression in children are likely precedents for future research, for example progressive addition spectacle lens trials and the use of the topical M1 muscarinic antagonist pirenzepine.
Optical analysis of crack tip stress fields: a comparative study
Authors: PATTERSON E. A. , OLDEN E. J.
Published: June 2004

Four optical techniques for evaluating stress intensity factors in opaque specimens are described in outline, and compared for both an artificial crack and a fatigue crack. The results are compared to a standard solution for the geometry considered. All the techniques gave acceptable results over a range of stress levels and crack lengths. The methods of caustics and strain gauges were less good, whilst photoelasticity gave consistent results over a wide range of stress levels. Comments on the ease of application and the resource implications are also made in order to assist practitioners.
Tutankhamun's chariots: secret treasures of engineering mechanics
Authors: SANDOR B. I.
Published: June 2004

The Tutankhamun‐class chariot is the earliest high‐performance machine, most likely developed via racing and thoughtful mechanistic modelling and testing, and made with exquisite craftsmanship. The complex suspension system of springs and dampers comprises simple elements that are useful by chance, and also some well‐designed and expensive components and subassemblies for advantages in structural dynamics and ride quality. These chariots' spokes and joints have aircraft‐like damage tolerance, and are more sophisticated than those of any veteran car with wooden wheels. A substantially better overall design with the ancient materials of construction is difficult to visualize even if we apply our knowledge and computerized methods. This makes the Egyptian chariot an excellent example of original and advanced design, and a formidable challenge in further engineering investigations aimed at a full understanding of the ancients' achievements.
The effect of porosity on the fatigue life of cast aluminium‐silicon alloys*
Authors: GAO Y. X. , YI J. Z. , LEE P. D. , LINDLEY T. C.
Published: June 2004

Fatigue strength optimization of cast aluminium alloys requires an understanding of the role of micropores resulting from the casting process. High cycle fatigue tests conducted on cast A356‐T6 show that the pore size and proximity to the specimen surface significantly influence fatigue crack initiation. This is supported by finite element analyses (both elastic and elastic–plastic) which demonstrate that high stress/strain concentration is induced by pores which are both large and near to the specimen surface. A new pore‐sensitive model based on a modified stress‐life approach has been developed which correlates fatigue life with the size of the failure‐dominant pore. The model prediction is in good agreement with experimental data.
Measuring stress intensity factors during fatigue crack growth using thermoelasticity
Authors: DÍAZ F. A. , PATTERSON E. A. , TOMLINSON R. A. , YATES J. R.
Published: June 2004

Thermoelastic stress analysis has been developed in recent years as a direct method of investigating the crack tip stresses in a structure under cyclic loading. This is a consequence of the fact that stress intensity factors obtained from thermoelastic experiments are determined from the cyclic stress field ahead of a fatigue crack, rather than inferred from measurement of the crack length and load range. In the present paper the results of fatigue crack growth tests performed on welded ferritic steel plates are reported. From the results it can be observed that the technique is sensitive to the effects of crack closure and the presence of tensile and compressive residual stresses due to welding.
Monitoring fatigue degradation in austenitic stainless steels
Authors: KALKHOF D. , GROSSE M. , NIFFENEGGER M. , LEBER H. J.
Published: June 2004

During cyclic loading of austenitic stainless steel, microstructural changes occurred, which affected both mechanical and physical properties. For certain steels, a strain‐induced martensitic phase transformation was observed. The investigations showed that for the given material and loading conditions the volume fraction of martensite depended on the cycle number, temperature and initial material state. It was found that the martensite content continuously increased with the cycle number. Therefore, the volume fraction of martensite was used for indication of the fatigue usage. The temperature dependence of the martensite formation was described by a Boltzmann function. The martensite content decreased with increasing temperature. Two different heats of the austenitic stainless steel X6CrNiTi18‐10 (AISI 321, DIN 1.4541) were investigated. The martensite formation rate was much higher for the cold‐worked material than for the solution‐annealed one. All applied techniques, neutron diffraction and advanced magnetic methods allowed the detection of martensite in the differently fatigued specimens.
Crack‐healing and mechanical behaviour of Al2O3/SiC composites at elevated temperature
Authors: ANDO K. , KIM B.‐S. , CHU M.‐C. , SAITO S. , TAKAHASHI K.
Published: June 2004

Alumina/silicon carbide (Al2O3/SiC) composite ceramics with large self‐crack‐healing ability, high strength and high heat‐resistance limit temperature for strength were developed and subjected to three‐point bending. A semicircular surface crack 100 μm in diameter was made on each sample. Crack‐healing behaviour was systematically studied, as functions of crack‐healing temperature and healing time, and the fatigue strengths of the crack‐healed sample at room temperature and 1373 K were investigated. Four main conclusions were drawn from the present study. (1) Al2O3/SiC composite ceramics have the ability to heal after cracking from 1273to 1673 K in air. (2) The heat‐resistance limit temperature for strength of the crack‐healed sample is ≅1573 K, and ≅68% of the samples fractured from outside the crack‐healed zone in the testing‐temperature range 873–1573 K. (3) The crack‐healed sample exhibited very high fatigue limit at room temperature and also 1373 K. (4) The large self‐crack‐healing ability is a desirable technique for the high structural integrity of ceramic component.
Synchrotron diffraction investigation of the distribution and influence of residual stresses in fatigue
Authors: JAMES M. N. , HATTINGH D. G. , HUGHES D. J. , WEI L.‐W. , PATTERSON E. A. , DA FONSECA J. QUINTA
Published: June 2004

This paper presents some results obtained from synchrotron diffraction investigations into two somewhat related areas of interest to the fatigue community. Firstly, the influence of fatigue cycling on the distribution and magnitude of residual strains and stresses and, secondly, the residual strains and stresses engendered around a growing fatigue crack. Its main premise is that modern tools such as automated synchrotron strain scanning offer the potential for more complete insight into the distribution of residual strains and stresses and their influence on fatigue performance. The first part of the work was accomplished using friction‐stir welded (FSW) and metal‐inert gas (MIG) welded specimens. The particular interest in these specimens was obtaining detailed knowledge regarding as‐welded variation in residual stresses between specimens, the location of peak values relative to local microstructure and stress concentrations, and of their modification during fatigue cycling. Such information may indicate a route forward to the selection of welding process parameters for optimised fatigue performance. The second part of the work considered an established fatigue crack in a compact tension (CT) specimen and examined the ability of synchrotron diffraction to characterize the stresses associated with the plastic enclave around a fatigue crack. This work is of interest in the context of better knowledge of crack‐tip shielding by plasticity‐induced closure and its incorporation into life prediction methodologies.
Time dependent effects in fatigue of titanium and nickel alloys
Authors: EVANS W. J.
Published: June 2004

The paper explores fatigue at both low and high temperature where creep and environmental damage interact with the normal cyclic processes of crack development. This is achieved by studying two contrasting material systems: the titanium alloys (Ti685, Ti834, Ti6246) and the nickel alloys (Udimet 720Li). Particular attention is given to both load and strain control fatigue response and crack development at stress concentration features. In each case there is an interesting balance between the beneficial effects of stress relaxation and the damaging effects of creep and environmental factors. On the crack growth side, the relative contributions of creep and environment are highlighted through measurements made in air and vacuum and by varying R value and dwell time. At the same time, any complications due to closure are removed by careful measurement of closure levels for each condition. The inadequacy of linear damage models for combining cyclic and time dependent effects is highlighted.
The adaptive da/dN method: a solution to the problem of processing crack growth data
Authors: VRIES S. BENEDICTUS‐DE , HORN C. H. L. J. TEN , AMENT P. C. H. , BAKKER A.
Published: June 2004

The standard fatigue data‐processing procedure, published in ASTM E647, is not adapted to the use of modern crack length measurement techniques. Because the use of this standard is usually required by journals, the raw data are often reduced to only a few data points. This way valuable information is simply thrown away and mathematical errors are unintentionally made. More importantly, the fact that no satisfactory reduction method exists, has led to destandardization of the processing procedure. Therefore, a new standard processing method is desired. In this paper a new data‐processing method, referred to as the ‘adaptive da/dN method’, is proposed and discussed. This method is suitable for both optical and modern (electrical or automated) measurement techniques as well as modern (computer‐assisted or ‐controlled) processing techniques. The adaptive da/dN method is validated both by data generated with a certain amount of scatter as well as actual experimental data. It shows a more accurate behaviour than the ASTM standards for all data types.
Reforming the Conventions Regarding Parliamentary Scrutiny of Ministerial Actions
Authors: Holland Ian
Published: June 2004

Parliamentary scrutiny of government ministers is limited by the convention that one house of parliament cannot compel a member of the other house to appear before it. This convention limits the Senate's capacity to examine ministers who are members of the House of Representatives. It has its origins in UK parliamentary practice, and is given alleged legal force in Australia by virtue of section 49 of Australia's constitution. That section effectively says that Australia's current parliamentary powers, privileges and immunities are those of the UK House of Commons in 1901.

However analysis of UK practice prior to the twentieth century reveals a surprising picture. Far from protecting members of one house from the other house's inquiries, it would seem that invitations issued by one chamber to a member of the other were never refused, an element of ‘custom and practice’ now conveniently overlooked. Furthermore, the purpose of the powers had nothing to do with protecting ministers. On the contrary, their origins He in a desire to ensure the strength of parliamentary accountability. If modern Australian practice is to be true to historical House of Commons practice, consideration should be given to ensuring that each chamber does have guaranteed access to ministers of the other house.
A Comparative Analysis of Entrepreneurial Approaches Within Public Healthcare Organisations
Authors: Rowe Patricia A. , Boyce Rosalie A. , Boyle Maree V. , O'Reilly Kathleen
Published: June 2004

This article examines the development of two distinct models of organising allied health professionals within two public sector health service organisations in Australia. The first case illustrated a mode of organising that facilitated a culture that focused on asset protection and whose external orientation was threat oriented because its disparate multiple identities operated as a fractured, fragmented and competitive set of profession disciplines. In this milieu, there was no evidence of entrepreneurial approaches being used. In contrast, the second case study illustrated a mode of organising that facilitated an entrepreneurial culture that focused on asset growth and an external orientation that was opportunity oriented because of the evolution of a strong superordinate allied health identity that operated as a single united health services stakeholder. This evolution was coupled with the emergence of a corporate boardroom model of management that is consonant with Savage et al. (1997) IDS/N model of management. Once this structure and strategy were in place, corporate entrepreneur ship became the modus operandi. Consequently, because the case study was a situation where corporate entrepreneurship existed in the public sector, it was possible to compare the factors that stimulate corporate entrepreneurship in Sadler's (2000) study with factors that were observed in our study.
‘Designing Better Health Care in the South’: A Case Study of Unsuccessful Transformational Change in Public Sector Health Service Reform
Authors: Hurley Catherine , Baum Fran , van Eyk Helen
Published: June 2004

This article presents a case study of a project known as ‘Designing Better Health Care in the South’ that attempted to transform four separately incorporated health services in southern Adelaide into a single regional health service. The project's efforts are examined using Kotter's (1996) model of the preconditions for transformational change in organisations and the areas in which it met or failed to meet these preconditions are analysed, using results from an evaluation that was commenced during the course of the attempted reform. The article provides valuable insights into an attempted major change by four public sector health organisations and the facilitators and barriers to such change. It also examines the way in which forces beyond the control of individual public sector agencies can significantly impact on attempts to implement organisational change in response to an identified need. This case study offers a rare glimpse into the micro detail of health care reform processes that are so widespread in contemporary health services but which are rarely systematically evaluated.
Denying Citizens Their Rights? Indigenous People, Mining Payments and Service Provision
Authors: O'Faircheallaigh Ciaran
Published: June 2004

Indigenous Australians have a growing capacity to extract monetary payments from mineral development on their traditional lands. Considerable controversy surrounds the possible use of these payments to fund services such as health, housing and education for the Indigenous groups concerned. Critics of such an approach argue that government should provide basic public services to all citizens, and that use of ‘mining payments’ for service provision denies Indigenous people specific compensation for the negative impacts of mining and an important opportunity to enhance their economic status. There is also a danger that government may reduce its existing spending on services, leaving Indigenous people no better off as a result of allowing mining to occur. This article argues that while there are certainly risks involved in using mining payments to fund services, Indigenous groups can generate substantial net benefits by doing so. Mining payments can leverage additional government spending; fund services at a level or of a sort that government will not provide; give Indigenous people greater control over service provision; and help develop Indigenous organisational skills and governance capacity. A strategic approach is required to minimise risk and maximise the available benefits, and the article identifies policy principles that can be applied to secure such an outcome.
The Tasmanian Electoral Roll Trial in the 2002 ATSIC Elections
Authors: Sanders Will
Published: June 2004

Aboriginal and Torres Strait Islander Commission (ATSIC) elections since 1990 have used the Commonwealth Electoral Roll (CER) as a large under‐specified list of potential voters. Dissatisfaction with this arrangement within the Tasmanian Aboriginal community led to a trial roll of Indigenous electors being drawn up for the 2002 ATSIC elections in that State. This paper recounts a number of contexts in which this trial was developed. It also recounts the experience of the trial itself, which did not work out as successfully as those who had promoted it had hoped. Finally it looks at lessons from the trial and options for the future.
Elections and Representation in Local Government: A Victorian Case Study
Authors: Burdess Neil , O'Toole Kevin
Published: June 2004

This article examines the application of different views of representation in the electoral systems at local government level: interest, corporate and mirror representation. The electoral framework underpins the process of representation, influencing both who are eligible to become voters and how their votes are collected and counted. The paper examines the interrelationship between representation and the electoral framework in local government in Victoria. We use a historical analysis, and identify a long period of interest representation; a short, relatively recent period of corporate representation; and an attempt to introduce some elements of mirror representation. We conclude by arguing that local electoral reform needs to take into account the multiple meanings of representation.
The Effect of the Reform of Canadian State‐Owned Enterprises on Major Corporate Governance Mechanisms
Authors: Bozec Richard , Zéghal Daniel , Boujenoui Ameur
Published: June 2004

Corporate governance is nowadays one of the most discussed topics by academics, practitioners and regulators. Most of the discussion is targeted at publicly held corporations. The present research deals with the issue of governance in the public sector and more specifically in state‐owned enterprises (SOEs). We investigate the effect of the reform of Canadian SOEs on the characteristics of boards and board committees.

Our results seem to confirm the presence of significant adjustments in board characteristics following two major events in the reform: commercialisation and privatisation. In both cases, boards have on average evolved towards a set of structures and mechanisms that have the potential to improve independence and governance. This study sheds new lights on the process of adjusting corporate governance mechanisms to new strategies and to new environments.
What do Australian Foundations Do – Who Knows and Who Cares?
Authors: Leat Diana
Published: June 2004

This article explores governance and accountability demands on foundations in Australia and compares these with requirements in the US. The article begins by discussing the meaning of, and rise of concern with, governance and accountability, the nature and variety of foundations and their status as organisations in the public domain. The second and third sections compare the formal and informal requirements relating to governance and accountability of foundations in the US and Australia. It is suggested that US foundations are both more closely regulated and more concerned with issues of governance and accountability than Australian foundations. The fourth section identifies the drivers of demand for better governance and accountability of foundations in the US and their relevance in Australia. Finally, some possible explanations of the relative lack of concern with foundation governance in Australia are considered.
Issues in Higher Education Quality Assurance
Authors: Blackmur Douglas
Published: June 2004

This article examines a range of policy issues which concern the quality assurance of higher education by regulatory bodies. There is a widespread consensus that the benefits of at least some forms of external quality assurance of higher education exceed the costs. This is probably a matter of faith more than the outcome of a considered analysis, but public policy in several countries has accepted it nevertheless.

There are important questions regarding the manner in which such quality assurance should be conducted. Issues to do with self‐regulation, the use of independent ratings agencies, the role of the courts, the establishment of a government agency, and the public funding of private quality assurance bodies all deserve consideration.

Process matters become important once structural issues have been decided. These include quality assurance principles, internationalisation and national jurisdiction; the role of a quality assurance system in qualifications' design and development; what precisely is to be ‘quality assured’ in higher education; the standards to be used in quality assurance; linkages between quality assurance and public funding of higher education; compliance costs; and the utility of a National Qualifications Framework (NQF).

This article places considerable emphasis on a discussion of the deficiencies of the NQF approach. It argues that the emphasis placed on the development of an NQF in several systems of educational quality assurance is misplaced: an NQF cannot embrace the complexity of contemporary qualifications systems.

Claims to the effect that an NQF is a valuable addition to the sources of information available to national and international labour markets must be treated with scepticism. There are logical and practical issues to be considered in this regard. An NQF is arguably likely to mislead labour markets seriously under existing circumstances.
THE COMING OF AGE OF ISLAND STUDIES
Authors: BALDACCHINO GODFREY
Published: June 2004

This paper presents insights into the emerging academic field of ‘island studies’, defined as the interdisciplinary study of islands on their own terms. This exposé is undertaken in two ways: conceptually, by means of a critical and judicious review of the literature across a number of disciplines; and analytically in relation to what is probably the most popular scholarly piece of non‐fiction based on an island society written to date –Coming of Age in Samoa by Margaret Mead.
THE BALLAD DANCE OF THE FAEROESE: ISLAND BIOCULTURAL GEOGRAPHY IN AN AGE OF GLOBALISATION
Authors: CLARK ERIC
Published: June 2004

Boundary issues are central to globalisation – the expansion and time‐space integration of human societies – and to both biological and cultural diversity. The latter are, in turn, intrinsically related in processes of coevolution that generate change in the patchwork quilt of cultural and natural landscapes. These processes are especially discernible in small island societies. This paper argues that island studies can enhance our understanding of globalisation processes and how these are involved in the displacement of boundaries and the historically unprecedented decline in both biological and cultural diversity.
ISLAND ECOLOGIES AND CARIBBEAN LITERATURES1
Authors: DELOUGHREY ELIZABETH
Published: June 2004

This paper examines the ways in which European colonialism positioned tropical island landscapes outside the trajectories of modernity and history by segregating nature from culture, and it explores how contemporary Caribbean authors have complicated this opposition. By tracing the ways in which island colonisation transplanted and hybridised both peoples and plants, I demonstrate how mainstream scholarship in disciplines as diverse as biogeography, anthropology, history, and literature have neglected to engage with the deep history of island landscapes. I draw upon the literary works of Caribbean writers such as Édouard Glissant, Wilson Harris, Jamaica Kincaid and Olive Senior to explore the relationship between landscape and power.
THROUGH A MIST ON THE OCEAN: HUMAN UNDERSTANDING OF ISLAND ENVIRONMENTS
Authors: NUNN PATRICK D.
Published: June 2004

Although generally distinct from continental environments, and therefore of interest in their own right, island environments have been generally misunderstood, misinterpreted, and mismanaged. The main reason is that they have been interpreted for management purposes largely by continent‐trained observers. An example of views towards island size is given. It is argued that the pejorative label ‘small’ should no longer be used to characterise islands. The ways in which island environments have been impacted by humans and their commensals is given. Questions of the sustainable development of island environments are also considered, including for whom these should be sustainable, how extraneous threats like sea‐level rise are best incorporated into such plans, and what threats are posed to the rest of the world by mega‐tsunami from certain island environments. Island environments are best managed by persons who understand their distinct character and who are committed to their future.
THE CONTEMPORARY LURE OF THE ISLAND
Authors: PÉRON FRANÇOISE
Published: June 2004

Islands have exercised a fascination on the human imagination. Yet today it is possible to identify a positive need for island experience – an island imperative – in whole sectors of society in developed countries. This condition invites the geographer to investigate the nature and fundamental causes of this ‘lure of the island’. In this paper, it is argued that the enhanced impact of islands on the human imagination is not a passing fad: there is rather an essential contribution of, and by, small islands and their inhabitants to the urban and globalised civilisation of our time.
Valproic acid reduces brain damage induced by transient focal cerebral ischemia in rats: potential roles of histone deacetylase inhibition and heat shock protein induction
Authors: Ren Ming , Leng Yan , Jeong MiRa , Leeds Peter R. , Chuang De‐Maw
Published: June 2004

Growing evidence from in vitro studies supports that valproic acid (VPA), an anti‐convulsant and mood‐stabilizing drug, has neuroprotective effects. The present study investigated whether VPA reduces brain damage and improves functional outcome in a transient focal cerebral ischemia model of rats. Subcutaneous injection of VPA (300 mg/kg) immediately after ischemia followed by repeated injections every 12 h, was found to markedly decrease infarct size and reduce ischemia‐induced neurological deficit scores measured at 24 and 48 h after ischemic onset. VPA treatment also suppressed ischemia‐induced neuronal caspase‐3 activation in the cerebral cortex. VPA treatments resulted in a time‐dependent increase in acetylated histone H3 levels in the cortex and striatum of both ipsilateral and contralateral brain hemispheres of middle cerebral artery occlusion (MCAO) rats, as well as in these brain areas of normal, non‐surgical rats, supporting the in vitro finding that VPA is a histone deacetylase (HDAC) inhibitor. Similarly, heat shock protein 70 (HSP70) levels were time‐dependently up‐regulated by VPA in the cortex and striatum of both ipsilateral and contralateral sides of MCAO rats and in these brain areas of normal rats. Altogether, our results demonstrate that VPA is neuroprotective in the cerebral ischemia model and suggest that the protection mechanisms may involve HDAC inhibition and HSP induction.
A non‐peptidyl neurotrophic small molecule for midbrain dopaminergic neurons
Authors: Lin Leu‐Fen H. , Rubin Lee L. , Xu Mei
Published: June 2004

A small organic molecule (CUR‐162590) that selectively enhances survival of midbrain dopaminergic neurons was identified by screening small molecule compound libraries. In embryonic midbrain cultures, CUR‐162590 increased dopamine uptake and the number of dopaminergic neurons without altering the number of total neurons or astroglia or the uptake of GABA or serotonin. CUR‐162590 reduced apoptosis of cultured dopaminergic neurons and protected against death induced by toxins such as MPP+. Several synthetic analogs of CUR‐162590 also had similar bioactivities. CUR‐162590 thus represents a new class of neurotrophic small molecules that may have utility in the treatment of Parkinson's disease, which is marked by degeneration of midbrain dopaminergic neurons.
Glycogen synthase kinase 3: a drug target for CNS therapies
Authors: Bhat Ratan V. , Budd Haeberlein Samantha L. , Avila Jesús
Published: June 2004

Glycogen synthase kinase3 (GSK3) is emerging as a prominent drug target in the CNS. The most exciting of the possibilities of GSK3 lies within the treatment of Alzheimer's disease (AD) where abnormal increases in GSK3 levels and activity have been associated with neuronal death, paired helical filament tau formation and neurite retraction as well as a decline in cognitive performance. Abnormal activity of GSK3 is also implicated in stroke. Lithium, a widely used drug for affective disorders, inhibits GSK3 at therapeutically relevant concentrations. Thus while the rationale remains testable, pharmaceutical companies are investing in finding a selective inhibitor of GSK3. In the present review, we summarize the properties of GSK3, and discuss the potential for such a therapy in AD, and other CNS disorders.
Could a loss of α‐synuclein function put dopaminergic neurons at risk?
Authors: Perez Ruth G. , Hastings Teresa G.
Published: June 2004

The α‐synuclein gene is implicated in Parkinson's disease, the symptoms of which occur after a marked loss of substantia nigra dopamine neurons. While the function of α‐synuclein is not entirely elucidated, one function appears to be as a normal regulatory protein that can bind to and inhibit tyrosine hydroxylase, the rate‐limiting enzyme in dopamine synthesis. Soluble α‐synuclein levels may be diminished in Parkinson's disease substantia nigra dopamine neurons both by reduced expression and by α‐synuclein aggregation as Lewy bodies and Lewy neurites form. The loss of functional α‐synuclein may then result in dysregulation of tyrosine hydroxylase, dopamine transport and dopamine storage, resulting in excess cytosolic dopamine. Because dopamine and its metabolites are reactive molecules capable of generating highly reactive quinones and reactive oxygen species, a failure to package dopamine into vesicles could cause irreversible damage to cellular macromolecules and contribute to resultant neurotoxicity. This review focuses on how a loss of normal α‐synuclein function may contribute to the dopamine‐related loss of substantia nigra neurons during Parkinson's disease pathogenesis.
Ceramide influences neurite outgrowth and neuroblastoma cell apoptosis regulated by novel protein kinase C isoforms
Authors: Schultz Anna , Larsson Christer
Published: June 2004

We have previously seen that protein kinase C (PKC) ε induces neurite outgrowth and that PKCδ and PKCθ elicit apoptosis in neuroblastoma cells. In this study we investigate the effects of cell‐permeable C2‐ceramide on these events in SK‐N‐BE(2) neuroblastoma cells. C2‐ceramide abolishes neurite formation induced by overexpression of PKCε and, in cells overexpressing PKCδ or PKCθ, ceramide treatment leads to apoptosis. Exposure to C2‐ceramide also suppressed neurite outgrowth induced by retinoic acid, but ceramide did not abrogate neurite induction by treatment with the ROCK inhibitor Y‐27632, demonstrating that C2‐ceramide is not a general inhibitor of neurite outgrowth. The neurite‐suppressing effect occurs independently of cell‐death. Furthermore, C2‐ceramide relocated PKCε and the isolated regulatory domain of PKCε from the cytosol to the perinuclear region. In contrast, neither the localization of PKCδ nor of PKCθ was affected by C2‐ceramide. Taken together, the data indicate that the neurite‐inhibiting effect of C2‐ceramide treatment may be caused by a re‐localization of PKCε and thus identify a functional consequence of ceramide effects on PKCε localization.
Alterations in hippocampal phospholipid profile by prenatal exposure to ethanol
Authors: Wen Zhiming , Kim Hee‐Yong
Published: June 2004

It has been suggested that hippocampus‐related cognitive processes are especially sensitive to ethanol. To provide an insight into the biochemical mechanisms underlying the hippocampus‐related functional deficits associated with prenatal ethanol exposure, we investigated the effects of chronic ethanol exposure on the phospholipid profile in developing rat hippocampi. High‐performance liquid chromatography/electrospray ionization–mass spectrometry analysis revealed that ethanol lowered the levels of total phosphatidylserine (PS) by 15–20% at all ages examined, primarily owing to the reduction in 1‐stearoyl‐2‐docosahexaenoyl‐PS (18:0,22:6n‐3‐PS) species. Ethanol exposure also led to a decrease in phosphatidylcholine (PC) and an increase in phosphatidylethanolamine (PE), but the total phospholipid content was not significantly changed. At the fatty acid level, ethanol exposure significantly decreased the 22:6n‐3 content at postnatal days 0 and 21, with a slight increase in 22:5n‐6, without changing the total fatty acid content significantly. In conclusion, ethanol depleted PS, especially 22:6‐containing species, and PC from hippocampal membranes with concomitant increase in PE. Alteration of the phospholipid profile in the hippocampus resulting from exposure to ethanol during prenatal and developmental stages may have significant implications with respect to the cognitive dysfunction observed in fetal alcohol syndrome.
Brain antioxidant systems in human methamphetamine users
Authors: Moszczynska Anna , Fitzmaurice Paul , Ang Lee , Kalasinsky Kathryn S. , Peretti Frank J. , Aiken Sally S. , Wickham Dennis J. , Sherwin Allan , Nobrega José N. , Forman Henry J. , Kish Stephen J.
Published: June 2004

Animal data suggest that the widely abused psychostimulant methamphetamine can damage brain dopamine neurones by causing dopamine‐dependent oxidative stress; however, the relevance to human methamphetamine users is unclear. We measured levels of key antioxidant defences [reduced (GSH) and oxidized (GSSG) glutathione, six major GSH system enzymes, copper–zinc superoxide dismutase (CuZnSOD), uric acid] that are often altered after exposure to oxidative stress, in autopsied brain of human methamphetamine users and matched controls. Changes in the total (n = 20) methamphetamine group were limited to the dopamine‐rich caudate (the striatal subdivision with the most severe dopamine loss) in which only activity of CuZnSOD (+ 14%) and GSSG levels (+ 58%) were changed. In the six methamphetamine users with severe (− 72 to − 97%) caudate dopamine loss, caudate CuZnSOD activity (+ 20%) and uric acid levels (+ 63%) were increased with a trend for decreased (− 35%) GSH concentration. Our data suggest that brain levels of many antioxidant systems are preserved in methamphetamine users and that GSH depletion, commonly observed during severe oxidative stress, might occur only with severe dopamine loss. Increased CuZnSOD and uric acid might reflect compensatory responses to oxidative stress. Future studies are necessary to establish whether these changes are associated with oxidative brain damage in human methamphetamine users.
Transfection of 2,6 and 2,3‐sialyltransferase genes and GlcNAc‐transferase genes into human glioma cell line U‐373 MG affects glycoconjugate expression and enhances cell death
Authors: Dawson G. , Moskal J. R. , Dawson S. A.
Published: June 2004

Human glioma cell line U‐373 MG expresses CMP‐NeuAc : Galβ1,3GlcNAc α2,3‐sialyltransferase [EC No. 2.4.99.6] (α2,3ST), UDP‐GlcNAc : β‐d‐mannoside β1,6‐N‐acetylglucosaminyltransferase V [EC 2.4.1.155] (GnT‐V) and UDP‐GlcNAc3: β‐d‐mannoside β1,4‐N‐acetylglucosaminyltransferase III [EC 2.4.1.144] (GnT‐III) but not CMP‐NeuAc : Galβ1,4GlcNAc α2,6‐sialyltransferase [EC 2.4.99.1] (α2,6ST) under normal culture conditions. We have previously shown that transfection of the α2,6ST gene into U‐373 cells replaced α2,3‐linked sialic acids with α2,6 sialic acids, resulting in a marked inhibition of glioma cell invasivity and a significant reduction in adhesivity. We now show that U‐373 cells, which are typically highly resistant to cell death induced by chemotherapeutic agents (< 10% death in 18 h), become more sensitive to apoptosis following overexpression of these four glycoprotein glycosyltransferases. U‐373 cell viability showed a three‐fold decrease (from 20 to 60% cell death) following treatment with staurosporine, C2‐ceramide or etoposide, when either α2,6ST and GnT‐V genes were stably overexpressed. Even glycosyltransferases typically raised in cancer cells, such as α2,3ST and GnT‐III, were able to decrease viability two‐fold (from 20 to 40% cell death) following stable overexpression. The increased susceptibility of glycosyltransferase‐transfected U‐373 cells to pro‐apoptotic drugs was associated with increased ceramide levels in Rafts, increased caspase‐3 activity and increased DNA fragmentation. In contrast, the same glycosyltransferase overexpression protected U‐373 cells against a different class of apoptotic drugs, namely the phosphatidylinositol 3‐kinase inhibitor LY294002. Thus altered surface protein glycosylation of a human glioblastoma cell line can lead to lowered resistance to chemotherapeutic agents.
Blood‐to‐retina transport of creatine via creatine transporter (CRT) at the rat inner blood–retinal barrier
Authors: Nakashima Toshihisa , Tomi Masatoshi , Katayama Kazunori , Tachikawa Masanori , Watanabe Masahiko , Terasaki Tetsuya , Hosoya Ken‐ichi
Published: June 2004

The purpose of this study was to elucidate the mechanisms of blood‐to‐retina creatine transport across the blood–retinal barrier (BRB) in vivo and in vitro, and to identify the responsible transporter(s). The creatine transport across the BRB in vivo and creatine uptake in an in vitro model of the inner BRB (TR‐iBRB2 cells) were examined using [14C]creatine. Identification and localization of the creatine transporter (CRT) were carried out by RT‐PCR, western blot, and immunoperoxidase electron microscopic analyses. An in vivo intravenous administration study suggested that [14C]creatine is transported from the blood to the retina against the creatine concentration gradient that exists between the retina and blood. [14C]Creatine uptake by TR‐iBRB2 cells was saturable, Na+‐ and Cl–‐dependent and inhibited by CRT inhibitors, suggesting that CRT is involved in creatine transport at the inner BRB. RT‐PCR and western blot analyses demonstrated that CRT is expressed in rat retina and TR‐iBRB2 cells. Moreover, using an immunoperoxidase electron microscopic analysis, CRT immunoreactivity was found at both the luminal and abluminal membranes of the rat retinal capillary endothelial cells. In conclusion, CRT is expressed at the inner BRB and plays a role in blood‐to‐retina creatine transport across the inner BRB.
Mitochondria dysfunction of Alzheimer's disease cybrids enhances Aβ toxicity
Authors: Cardoso Sandra M. , Santana Isabel , Swerdlow Russell H. , Oliveira Catarina R.
Published: June 2004

Alzheimer's disease (AD) brain reveals high rates of oxygen consumption and oxidative stress, altered antioxidant defences, increased oxidized polyunsaturated fatty acids, and elevated transition metal ions. Mitochondrial dysfunction in AD is perhaps relevant to these observations, as such may contribute to neurodegenerative cell death through the formation of reactive oxygen species (ROS) and the release of molecules that initiate programmed cell death pathways. In this study, we analyzed the effects of beta‐amyloid peptide (Aβ) on human teratocarcinoma (NT2) cells expressing endogenous mitochondrial DNA (mtDNA), mtDNA from AD subjects (AD cybrids), and mtDNA from age‐matched control subjects (control cybrids). In addition to finding reduced cytochrome oxidase activity, elevated ROS, and reduced ATP levels in the AD cybrids, when these cell lines were exposed to Aβ 1–40 we observed excessive mitochondrial membrane potential depolarization, increased cytoplasmic cytochrome c, and elevated caspase‐3 activity. When exposed to Aβ, events associated with programmed cell death are activated in AD NT2 cybrids to a greater extent than they are in control cybrids or the native NT2 cell line, suggesting a role for mtDNA‐derived mitochondrial dysfunction in AD degeneration.
Brain‐specific potential guanine nucleotide exchange factor for Arf, synArfGEF (Po), is localized to postsynaptic density
Authors: Inaba Yuji , Tian Qing Bao , Okano Akira , Zhang Jing‐Ping , Sakagami Hiroyuki , Miyazawa Shoko , Li Weidong , Komiyama Atsushi , Inokuchi Kaoru , Kondo Hisatake , Suzuki Tatsuo
Published: June 2004

We cloned from a rat brain cDNA library a novel cDNA and named it a potential synaptic guanine nucleotide exchange factor (GEF) for Arf (synArfGEF (Po)) (GenBank Accession no. AB057643) based on its domain structure and localization. The cloned gene was 7410 bases long with a 3585‐bp coding sequence encoding a protein of 1194 amino acids. The deduced protein contained a coiled‐coil structure in the N‐terminal portion followed by Sec7 and Plekstrin homology (PH) domains. Thus, the protein was a member of the Sec7 family of proteins, GEFs. Conservation of the ADP‐ribosylation factor (Arf)‐binding sequence suggested that the protein was a GEF for Arf. The gene was expressed specifically in the brain, where it exhibited region‐specific expression. The protein was highly enriched in the postsynaptic density (PSD) fraction prepared from the rat forebrain. Uniquely, the protein interacted with PSD‐95, SAP97 and Homer/Vesl 1/PSD‐Zip45 via its C‐terminal PDZ‐binding motif and co‐localized with these proteins in cultured cortical neurons. These results supported its localization in the PSD. The postsynaptic localization was also supported by immunohistochemical examination of the rat brain. The mRNA for the synArfGEF was also localized to dendrites, as well as somas, of neuronal cells. Thus, both the mRNA and the protein were localized in the postsynaptic compartments. These results suggest a postsynaptic role of synArfGEF in the brain.
Reduction of excitotoxicity and associated leukocyte recruitment by a broad‐spectrum matrix metalloproteinase inhibitor
Authors: Campbell Sandra J. , Finlay Malcolm , Clements John M. , Wells Graham , Miller Karen M. , Perry V. Hugh , Anthony Daniel C.
Published: June 2004

An important step in the cascade leading to neuronal cell death is degradation of laminin and other components of the brain extracellular matrix by microglia‐derived proteases. Excitotoxic cell death of murine hippocampal neurones in vivo can be prevented by inhibitors of tissue plasminogen activator (tPA) or by inhibitors of plasmin. Plasmin is a potent activator of the matrix metalloproteinases (MMPs), which are made by resident and recruited leukocytes following CNS injury. In this study, we show, using Taqman RT‐PCR, that MMP mRNAs, but not other calcium‐dependent proteases such as calpain mRNAs, are acutely up‐regulated after an excitotoxic challenge in vivo. α2‐antiplasmin or BB‐3103, a broad‐spectrum inhibitor of the MMPs, co‐injected with kainic acid into the striatum, inhibits excitotoxic cell death in the rat striatum, and reduces both the number of recruited macrophages and the size of the lesion. We also show that leukocyte populations differentially express MMPs, which may account, in part, for the expression profile we observe in the challenged brain. Our results show that inhibition of the MMPs in the rat will prevent kainic acid‐induced cell death in the brain. These studies suggest that MMP inhibitors have therapeutic potential for use in stroke, and support the increasing evidence that microglial activation may contribute to neuronal cell death.
4‐Hydroxy‐trans‐2‐nonenoic acid is a γ‐hydroxybutyrate receptor ligand in the cerebral cortex and hippocampus
Authors: Murphy Tonya C. , Poppe Claire , Porter James E. , Montine Thomas J. , Picklo Sr Matthew J.
Published: June 2004

Elevated production of 4‐hydroxy‐trans‐2‐nonenal (HNE) occurs in numerous neurological disorders involving oxidative damage. HNE is metabolized to the non‐toxic 4‐hydroxy‐trans‐2‐nonenoic acid (HNEAcid) by aldehyde dehydrogenases in the rat cerebral cortex. Based upon the structural similarity of HNEAcid to ligands of the γ‐hydroxybutyrate (GHB) receptor, we hypothesized that HNEAcid is an endogenous ligand for the GHB receptor. HNEAcid displaced the specific binding of the GHB receptor ligand 3H‐NCS382 (30 nm) in membrane preparations of human frontal cerebral cortex and whole rat cerebral cortex with IC50s of 3.9 ± 1.1 and 5.6 ± 1.2 µm, respectively. Inhibition was attenuated when the carboxyl group of HNEAcid was replaced with an aldehyde or an alcohol. HNEAcid (300 µm) did not displace the binding of β‐adrenergic receptor and GABAB receptor antagonists, demonstrating the selectivity of HNEAcid for the GHB receptor. HNEAcid is formed in homogenates of human frontal cortical gray matter in an NAD+‐dependent (VMax, 0.71 nmol/min/mg) and NADP+‐dependent (VMax, 0.12 nmol/min/mg) manner. Lastly, 3H‐NCS382 binding is elevated 2.7‐fold with age in the cerebral cortex of rats. Our data demonstrate that an HNE metabolite, formed in rat and human brain, is a signaling molecule analogous to other bioactive lipid peroxidation products.