bluuebunny/crossref_metadata_2025 huggingface dataset:
A Study of Industry Evolution in the Face of Major Environmental Disturbances: Group and Firm Strategic Behaviour of Spanish Banks, 1983–1997*
Authors: Zúñiga‐Vicente JoséÁngel , De La Fuente‐Sabaté Juan Manuel , Rodríguez‐Puerta Julio
Published: August 2004

This paper examines the story of the evolution of a specific industry through the application of dynamic strategic group analysis. In particular, we analyse the relationship between major environmental disturbances and changes that have occurred over time in the competitive structure of the industry regarding two closely related central questions. First, the way in which these environmental transformations have influenced group patterns and stability, and second, the way in which such environmental disturbances has affected the strategic positioning of individual firms. We resort to alternative theoretical perspectives in an attempt to answer both questions. The empirical setting is the population of Spanish banks over the period 1983–1997. We make use of a new grouping algorithm – the Model‐based Clustering or MCLUST – which may be enormously fruitful in future empirical works on strategic groups. This method allows researchers to obtain the optimal number of groupings over time in a much more objective way than the cluster techniques used until now. Compared to previous dynamic studies that only consider the largest firms, our research illustrates how a richer analysis of an industry dynamics can be obtained by using a dynamic analysis of strategic groups. Our results show that while there have been no industry‐wide identical groupings year to year, there is an important strategic stability at group and firm‐level punctuated by a high degree of strategic instability at times of major environmental disturbances.
Gender and Employee Attitudes: The Role of Organizational Justice Perceptions
Authors: Ramamoorthy N. , Flood P. C.
Published: August 2004

In this study, using path analysis, we tested whether procedural justice perceptions mediated the relationship between gender and distributive justice perceptions. Furthermore, we also tested whether the two forms of commitment (affective and normative) mediated the relationships between justice perceptions (distributive and procedural) and tenure intent. One hundred and eighty‐three employees from Irish manufacturing organizations participated in the study. As hypothesized, we found support for the mediating role of procedural justice perception on the relationship between gender and distributive justice perception. Results also indicated that affective commitment mediated the relationships between justice perceptions and tenure intent and affective commitment. Finally, normative commitment did not mediate the relationships between justice perceptions and tenure intent. Further analysis using moderated regression analysis showed that gender moderated the relationships between distributive justice perceptions and affective commitment only. Gender did not have any moderating effect on normative commitment or tenure intent. Implications for research and practice are discussed.
Women and Part‐time Work: The Careers of Part‐time NHS Nurses
Authors: Lane Nikala
Published: August 2004

This paper examines theoretical explanations of the employment disadvantage experienced by many female part‐time workers. Data from a survey of 643 qualified National Health Service (NHS) nurses is used to establish employment profiles of respondents. Employment profiles reveal that, contrary to many predictions, part‐time female nurses do not ‘invest less’ in their careers than their full‐time counterparts in terms of qualifications and experience. Neither are part‐time nurses relatively ‘uncommitted’ to their careers compared to full‐time nurses. It is found that the organizational context affects how opportunities are structured for part‐time nurses. The management implications of the findings for the NHS are also considered.
Bridging the Gap between Rhetoric and Reality: Line Managers and the Protection of Job Security for Ill Workers in the Modern Workplace
Authors: Cunningham Ian , James Philip , Dibben Pauline
Published: August 2004

In the light of the long‐standing concern in management regarding the gap that can arise between organizational policy prescriptions and line‐management practice, the purpose of this article is to provide insights into the nature and causes of that gap. The particular focus of analysis is the line manager's role in facilitating the employment security of employees who have contracted serious illness, injuries or disabilities. More specifically, the article presents findings from four case‐study organizations in the UK, and identifies a number of factors that militate against the ability of line managers to comply with organizational policies on the provision of workplace adjustments and employment security for ill or disabled workers. These factors include: contradictory policy requirements, weaknesses in training, lack of support from relevant internal and external specialists and various work and budgetary pressures. The authors suggest four areas of action that may begin to reduce the potential for conflicts between management and employees, and minimize the legal vulnerability of organizations in an area of increasing domestic and international regulation.
Why I Believe in Science and Believe in God: A Credo
Authors: Laszlo Ervin
Published: August 2004

Abstract. The conflict between science and religion is not irremediable: the world concept of science is changing, and the change brings about a rapprochement with religious beliefs in some fundamental areas. One such area is the question of original creation. Recent findings regarding the nature of the universe show the improbability of its having arisen in the course of a random process. The perennial religious intuition of a transcendental act of creation is a logical entailment of the randomly entirely improbable fine tuning of the natural laws and processes that the observed universe manifests.
What Does Silicon Valley Have to Do with Jerusalem?
Authors: Peterson Gregory R.
Published: August 2004

Abstract. Adapted from the introductory chapter of Minding God: Theology and the Cognitive Sciences (Peterson 2003), I here lay out a general approach for a dialogue between theology and cognitive science. Key to this task is an understanding of theology as the science or study of meaning and purpose. I give reasons why theology should be thought of in this sense and the potential fruitfulness of this approach.
Do Split Brains Listen to Prozac?
Authors: Peterson Gregory R.
Published: August 2004

Abstract.Cognitive science challenges our understandings of self and freedom. In this article, adapted from a chapter inMinding God: Theology and the Cognitive Sciences(Peterson 2003), I review some of the scientific literature with regard to issues of self and freedom. I argue that our sense of self is a construct and heavily dependent on the kind of brain that we have. Furthermore, understanding the issue of freedom requires an understanding of the findings of cognitive science. Human beings are constrained to be free; our biology in no small way determines the kinds of freedom that we are able to have.
Freedom in the Body: The Physical, the Causal, and the Possibility of Choice
Authors: Spezio Michael L.
Published: August 2004

Abstract. In Minding God Gregory Peterson takes a careful look at the kind of freedom that human persons have. He concludes that humans are constrained to be free and unpacks this into a version of compatibilism. That is, humans are not metaphysically free under current existence because of the causal determination inherent in their physical nature, but they can take credit for the origination of selfforming decisions because the causes occur inside of us. Peterson does advocate an eschatological hope looking forward to the breaking of causal determination by God's own action. Thus, Minding God presents an eschatologically limited compatibilism. Compatibilism of any kind, however, presents serious challenges to most Christian theologies and to many religious traditions broadly considered. After I interpret Peterson's position I make the argument that compatibilism is neither desirable nor required for a theological anthropology intent on serious engagement of cognitive science.
Three Questions aboutMinding God
Authors: Bielfeldt Dennis
Published: August 2004

Abstract.Gregory Peterson'sMinding Goddoes an excellent job of introducing the cognitive sciences to the general reader and drawing preliminary connections between these disciplines and some of the loci of theology. The book less successfully articulates how the cognitive sciences should impact the future of theology. In this article I pose three questions: (1) What semantics is presupposed in relating the languages of theology and the cognitive sciences? How do the truth conditions of these disparate disciplines relate? (2) What precisely does theology gain from what is central to cognitive science: the emphasis on information processing, inner representation, and the computer model of the mind? What exactly does cognitive science offer to theology beyond the now‐standard rejection of Cartesian dualism, the affirmation of an embodied mind, and the repudiation of reduction? (3) What can the cognitive sciences offer in tackling crucial questions in the theology‐science discussion such as divine agency and divine causation? Finally, I point to a possible begging of the question in the claim that cognitive science relates to theology because theology deals with meaning and purpose, and a particular interpretation of cognitive science grants more meaning and purpose to human beings than antecedent post‐Cartesian positions in the philosophy of mind.
Minding Minding God: A Response to Spezio and Bielfeldt
Authors: Peterson Gregory R.
Published: August 2004

Abstract. Michael Spezio and Dennis Bielfeldt have each raised important issues with regard to my positions in Minding God: Theology and the Cognitive Sciences. In this article I respond to several of their criticisms, including issues of the nature of theology, my stance on epistemology and realism, and issues of physicalism, freedom, and determinism.
Natural Law and Divine Action: The Search for an Expanded Theory of Causation
Authors: Clayton Philip
Published: August 2004

Abstract. Talk of divine action faces its greatest obstacle when it confronts natural law and efficient causation. If all valid explanations involve deterministic laws, and only microphysical causes actively trigger change, claims for divine action can serve no explanatory role. But science does not in fact require the limitation to downwardly deterministic laws and efficient causes. Evidence supports the existence of emergent systems of phenomena, which, though dependent on physical law, also display emergent causal powers not reducible to their subvenient systems. Careful study of top‐down causation in biology and of mental causation in psychology offers analogies that are helpful for making sense of the notion of divine action. Theists' ascription of a causal role to God cannot be proven from science or identified with scientific forms of causality. Nevertheless, if the emergence hypothesis is correct, theistic explanations do not need to conflict with science, and a plausible model of divine influence may even be derived from emergent causation. In this article I offer an expanded theory of causation that reduces the distance between two types of causal forces that are often held to be incommensurable.
Resolving Multiple Visions of Nature, Science, and Religion
Authors: Proctor James D.
Published: August 2004

Abstract.I argue for the centrality of the concepts of biophysical and human nature in science‐and‐religion studies, consider five different metaphors, or “visions,” of nature, and explore possibilities and challenges in reconciling them. These visions include (a) evolutionary nature, built on the powerful explanatory framework of evolutionary theory; (b) emergent nature, arising from recent research in complex systems and self‐organization; (c) malleable nature, indicating both the recombinant potential of biotechnology and the postmodern challenge to a fixed ontology; (d) nature as sacred, a diffuse popular concept fundamental to cultural analysis; and (e) nature as culture, an admission of epistemological constructivism. These multiple visions suggest the famous story of the blind men and the elephant, in which each man made the classic mistake of part‐whole substitution in believing that what he grasped (the tail, for example) represented the elephant as a whole. Indeed, given the inescapability of metaphor, we may have to admit that the ultimate truth about the “elephant” (nature, or the reality toward which science and religion point) is a mystery, and the best we can hope for is to confess the limitations of any particular vision.
Was Thomas Aquinas a Sociobiologist? Thomistic Natural Law, Rational Goods, and Sociobiology
Authors: Boyd Craig A.
Published: August 2004

Abstract.Traditional Darwinian theory presents two difficulties for Thomistic natural‐law morality: relativism and essentialism. The sociobiology of E. O. Wilson seems to refute the idea of evolutionary relativism. Larry Arnhart has argued that Wilson's views on sociobiology can provide a scientific framework for Thomistic natural‐law theory. However, in his attempt to reconcile Aquinas's views with Wilson's sociobiology, Arnhart fails to address a critical feature of Aquinas's ethics: the role of rational goods in natural law. Arnhart limits Aquinas's understanding of rationality to the Humean notion of economic rationality–that “reason is and ought to be the slave of the passions.” On Aquinas's view, rationality discovers goods that transcend the merely biological, viz., the pursuit of truth, virtue, and God. I believe that Aquinas's natural‐law morality is consistent with some accounts of sociobiology but not the more ontologically reductionist versions like the one presented by Wilson and defended by Arnhart. Moreover, Aquinas's normative account of rationality is successful in refuting the challenges of evolutionary relativism as well as the reductionism found in most sociobiological approaches to ethics.
Altruistic Celibacy, Kin‐Cue Manipulation, and The Development of Religious Institutions
Authors: Qirko Hector
Published: August 2004

Abstract. Building on a model first proposed by Gary Johnson, it is hypothesized that religious institutions demanding celibacy and other forms of altruism from members take advantage of human predispositions to favor genetic relatives in order to maintain and reinforce these desired behaviors in non‐kin settings. This is accomplished through the institutionalization of practices to manipulate cues through which such relatives are regularly identified. These cues are association, phenotypic similarity, and the use of kin terms. In addition, the age of recruits and their contact with actual kin are factors that relate to kinship recognition and that are similarly manipulated by institutions in order to reinforce altruistic behavior directed toward non‐kin. Support for this set of predictions is presented from historical and ethnographic sources on monastic life in Buddhism, Christianity, and Hinduism, as well as Islamic dervish groups, the Essenes, Shakers, and others. Potential implications of the model for understanding the development of religious institutions are preliminarily explored by reviewing Joachim Wach's model of religious developmental stages as well as some of the literature on the relationship between individualism and communalism in incipient religious organizations, in light of the kin‐cue manipulation model.
The Scientific Study of Religion: Its Contribution to the Study of the Bhagavadg?tā
Authors: Sharma Arvind
Published: August 2004

Abstract. The Bhagavadg?tā is a popular Hindu text containing eighteen chapters. It begins with the hero, Arjuna, showing a marked unwillingness to engage in combat on the eve of battle. He is finally persuaded to do so by Krishna, who is an incarnation of God. Krishna actually reveals himself as such to an amazed Arjuna in the eleventh chapter. The fact that Arjuna does not immediately heed Krishna's advice to engage in battle after Krishna's sensational self‐disclosure has long puzzled students of the text. It is only at the end of the eighteenth chapter that Arjuna finally shows his readiness to fight. In this essay I argue that the discussion of the nine primary sensory states by Eugene d'Aquili may help resolve this issue and thus provide an instance of a case in which modern scientific study of religion enhances our understanding of a religious phenomenon, as a corrective to the usual charge that it must invariably diminish it.
Young Offenders: Children in Need of Protection*
Authors: Arthur Raymond
Published: August 2004

The Institute of Public Policy Research recommended that the government in England and Wales should establish a unified youth justice system, based on the Scottish Reporter system, for assessing the nature of intervention needed by young offenders. This article examines the Scottish youth justice system, the French youth justice system, and the youth justice system in England and Wales. The article contends that in England and Wales there already exists an agency and a legislative framework, similar to the Scottish and French examples, which has the power to assess the nature of intervention needed by young offenders and which has the authority to require that appropriate welfare or support services be provided. Therefore a new legislative framework is unnecessary; instead attention should be paid to the proper resourcing of the current system.
Corruption and Regulatory Structures*
Authors: Ogus Anthony
Published: August 2004

The methods of constraining corruption typically adopted in Western industrialized societies, increasing the transparency and accountability of decision‐making, and intensifying the enforcement of criminal justice prohibitions, have not always proved to be effective in developing countries. This is not surprising, given that in many of them the resources available for law enforcement are relatively modest, and corruption is deeply embedded culturally. In this paper, I suggest a strategy of reducing the opportunities for corruption, rather than attempting to suppress it altogether. I focus on regulatory institutions and procedures, identifying key aspects to these arrangements, which, if appropriately designed, can achieve this goal. Some of the design strategies that I advocate are inconsistent with the models of regulatory arrangements that Western institutions have been urging developing countries to adopt.
At the Crossroads of Policymaking: Executive Politics, Administrative Action, and Judicial Deference by the DC Circuit Court of Appeals (1985–1996)*
Authors: Caruson Kiki , Bitzer J. Michael
Published: August 2004

This study seeks to expand our understanding of judicial deference to administrative agencies within the context of one particularly important legal forum – the U.S. Court of Appeals for the District of Columbia. The DC circuit functions as a key venue for administrative law cases and the opinions of the court constitute a growing body of common law in the field of administrative law. We investigate the importance of several agency‐centered and judge‐centered variables in explaining judicial deference to administrative agencies in cases before the DC circuit court during a twelve‐year period (1985–1996). We find that an integrated model of judicial deference, combining both legal and attitudinal factors, best explains judicial deference. Like judges on so many other courts, judges on the DC circuit are politically motivated, but their political activism is tempered by agency‐centered factors such as the type of case before the court, and environmental factors such as the composition of the judicial panel reviewing the case and the behavior of the Supreme Court.
Online Financial Information: Law and Technological Change*
Authors: Bradley Caroline
Published: August 2004

Two contrasting narratives about the impact of the Internet on investors point to different responses by regulators: a narrative of empowerment suggests that regulators should encourage investors to make investment decisions for themselves. But a narrative of vulnerability suggests that these investors may not be able to use the information that is available, and may be at increased risk of loss. Regulators should aim to promote investor empowerment while taking due account of investor vulnerabilities.

Three characteristics (immediacy, interactivity, and interjurisdictionality) distinguish online investment information from offline investment information and have implications for the regulation of online information.
Technologies of Risk? Regulating Online Investing in Canada*
Authors: Condon Mary
Published: August 2004

This paper places the development of regulatory strategies dealing with the growth of online investing in Canada in the context of theoretical debates about governance through risk. It examines aspects of this emerging regulation relating to (i) use of the Internet by issuers for document delivery; (ii) application of investment suitability rules to online trading; (iii) emergence of new electronic‐trading markets. These regulatory developments are considered in terms of the extent to which they exhibit features suggesting: (a) an increased decentring of the state; (b) a shift to risk governance as an end of regulating. The paper argues for the need to pay careful attention to the politics of decentring and risk governance in assessing the emerging regulation of online investing.
Beyond the Rule of Law? Decentered Regulation in Online Investing*
Authors: Smith Dimity Kingsford
Published: August 2004

This paper considers online investing regulation that displays decentered (as opposed to state‐centric) characteristics with varying intensity. Though such regulation responds to the contemporary demand for regulation to be flexible, facilitative, and effective, it is short on democracy in creation and implementation. It lacks traditional mechanisms of accountability and so may be seen as less legitimate. These difficulties are investigated by reflecting on the degree to which decentered regulation conforms to the rule‐of‐law ideal, or to the values underlying the ideal. There is some reason to hope for functional equivalence with rule‐of‐law values in decentered mechanisms close to the state. However, those further away lack the institutional development to deliver political or legal accountability being particularly weak in the recognition and support of individual rights. Here, we should try to design state law to connect decentered forms to public justice and debate.
Regulatory Innovation and the Online Consumer*
Authors: Scott Colin
Published: August 2004

The explosion of usage of the Internet has caused considerable anxiety concerning the capacity of states to fulfil the functions they have developed in protecting consumers. Online business is booming in many sectors. Key examples, investigated in this article, are online investing, Internet gambling, and e‐shopping (sale of goods via the Internet). The article suggests that the high‐level discourse of regulatory reform and innovation has been focused on what may be done with state instruments and agencies to address the problems. We argue for adjusting the focus and offer an analysis of examples of non‐state mechanisms and actors with the potential to enhance regulatory protections.
Capacity to consent to participate in research – a recontextualization
Authors: Dye Linda , Hendy Steve , Hare Dougal Julian , Burton Mark
Published: August 2004

Capacity to consent is an important concept when working with people with learning disabilities. The current concept of consent is based on a dichotomous categorization: people either have or do not have capacity to consent. Several research studies have focused on the assessment of capacity to consent and these studies report a range from 0 to 65% of people with learning disabilities identified as having capacity to consent. Findings from these studies reflect several limitations with the current concept of consent. A recontextualization is needed in order to address these limitations. This should include the concept of risk and benefit assessment, i.e. the seriousness of the consequences involved determines the level of capacity needed for a specific decision. Moreover, the emergence of participatory research paradigms in the field of learning disabilities further challenges the validity of such concepts of consent. Therefore, it is proposed that it is more helpful to present the concept of capacity to consent within a broader contextual framework rather than as a unitary dichotomous categorization.
Hidden learning disability
Authors: Whitaker Simon
Published: August 2004

Although it has been suggested that about 2.5% of the population as a whole should be regarded as having a mild‐to‐moderate learning disability, only about 0.25% of the population is registered as having a learning disability. This paper considers why this disparity exists. It is suggested that although 2.5% of the population may be a good estimate for people with IQs less than 70, a better estimate of the proportion of the population who reach a dual criteria of having both a low IQ and social/skill defects is about 1%. It is pointed out that even if true prevalence rate of learning disability is nearer to 1% rather than 2.5%, services still only know of a small proportion of people who could be considered to have a learning disability, and there are probably a large number of people with unidentified learning disabilities. It is also noted that the term ‘learning disability’ can be very confusing as it is not clear if it refers to people who have IQs below 70, people with both intellectual and adaptive disabilities or people who have been given a learning disability label. The implications of this for services and research are discussed.
Delirium in learning disability: case series and literature review
Authors: Van Waarde Jeroen A. , Van Der Mast Rose C.
Published: August 2004

Although predisposing and facilitating factors for delirium are common in learning disabled patients, little is known about the occurrence of delirium in these patients. This paper presents three case reports and results of a manual and computer (Medline, Embase Psychiatry) search. In the literature only two case reports of delirium in learning disabled patients were found. These data were added to those of our three cases. The respective age of the patients was 16, 17, 51, 55 and 78 years. Delirium was associated with eye surgery, anticholinergic overdose, urinary infection, Alzheimer's disease and pulmonary infection, respectively. All patients had predisposing factors for delirium. The literature on delirium in learning disability is scarce. A reason for this may be that the diagnosis is often missed. Delirium is very distressing and raises morbidity and mortality. However, it is treatable, so more attention should be given to diagnosis and treatment, especially in these vulnerable patients. A practice guideline for the assessment and treatment of delirium in learning disability is given.
Use of an in‐patient psychiatric service by learning disabled children
Authors: Hepper Felicity , Rose Gillian
Published: August 2004

Despite recent political commitment to increasing access to all levels of health service provision for learning disabled people, there is still limited access to in‐patient child psychiatric care for learning disabled children. This article describes the experiences of an in‐patient unit integrating learning disabled children into a peer group, the majority of whom have normal intellectual function. A case note review was undertaken of all children with a global learning disability admitted to the Collingham Gardens in‐patient Unit between January 2000 and December 2001. We discuss how similar services may be developed to be more inclusive for learning disabled children.
The use of social stories in a psychology service for children with learning disabilities: a case study of a sleep problem
Authors: Moore P. S.
Published: August 2004

This paper overviews the phenomena of social stories in conveying social messages to children with autistic spectrum disorder and learning disabilities. The use of social stories in a clinical psychology service for children with predominantly severe learning disabilities is discussed. A case study is presented describing the use of a social story as part of a conventional behavioural intervention on a boy presenting problems surrounding sleep behaviours.
Prevalence of hearing impairment in a community population of adults with learning disability: access to audiology and impact on behaviour
Authors: Timehin C. , Timehin E.
Published: August 2004

There is a paucity of studies exploring the frequency of problem behaviours in people with learning disability and hearing impairment. Deafness in learning disability has been described as a ‘double jeopardy‘ because the difficulties are compounded to be more than the sum of their parts. The aim of the study was to ascertain the prevalence of hearing impairment in a community population of adults with learning disability and then investigate their access to audiology. We also aimed to collect information on the prevalence of problem behaviours in this population and explore links between hearing impairment and the use of hearing aids and problem behaviours. The prevalence of hearing impairment was 9.2%, 70% had been seen by audiology services at some time in their life but only 24% had ongoing assessments and hearing‐aid maintenance. Sixty‐two percent of the population had problem behaviours and 34% had self‐injurious behaviour. The high prevalence of problem behaviours and self‐injurious behaviour found in this population compared with other studies suggests a need for further research. These findings also reveal that the hearing status of people with a learning disability continues to be overlooked as the deafness often gets lost among their other problems.
Learning disability nursing
Authors: Mitchell Duncan
Published: August 2004

Learning disability nursing has had an interesting history over recent decades. Despite many predictions of it being replaced it has survived to engage in a variety of roles in contemporary learning disability services. This paper acknowledges the anomalous position of the profession and discusses its current position within nursing, and within learning disability services.
Mitochondrial uncoupling proteins: from mitochondria to the regulation of energy balance
Authors: Ricquier Daniel , Bouillaud Frédéric
Published: August 2004

The coupling of oxygen consumption to ADP phosphorylation is incomplete, as is particularly evident in brown adipocyte mitochondria which use a regulated uncoupling mechanism to dissipate heat produced by substrate oxidation. In brown adipose tissue, uncoupling is effected by a specific protein in the inner mitochondrial membrane referred to as uncoupling protein‐1 (UCP1). UCP1 gene disruption in mice has confirmed UCP1′s role in cold‐induced thermogenesis. Genetic analysis of human cohorts has suggested that UCP1 plays a minor role in the control of fat content and body weight. The recent cloning of UCP2 and UCP3, two homologues of UCP1, has boosted research on the importance of respiration control in metabolic processes, metabolic diseases and energy balance. UCP2 is widely expressed in different organs whereas UCP3 is mainly present in skeletal muscle. The chromosomal localization of UCP2 as well as UCP2 mRNA induction by a lipid‐rich diet in obesity‐resistant mice suggested that UCP2 is involved in diet‐induced thermogenesis. A strong linkage between markers in the vicinity of human UCP2 and UCP3 (which are adjacent genes) and resting metabolic rate was calculated. UCPs are known or supposed to participate in basal and regulatory thermogenesis, but their exact biochemical and physiological functions have yet to be elucidated. UCPs may constitute novel targets in the development of drugs designed to modulate substrate oxidation. However, very recent data suggest an important role for the UCPs in the control of production of free radicals by mitochondria, and in response to oxidants.
Mitochondrial intermembrane junctional complexes and their role in cell death
Authors: Crompton Martin
Published: August 2004

A mitochondrial complex comprising the voltage‐dependent anion channel (outer membrane), the adenine nucleotide translocase (inner membrane) and cyclophilin‐D (matrix) assembles at contact sites between the inner and outer membranes. Under pathological conditions associated with ischaemia and reperfusion the junctional complex ‘deforms’ into the permeability transition (PT) pore, which can open transiently, allowing free permeation of low Mr solutes across the inner membrane. This may be a critical step in the pathogenesis of lethal cell injury in ischaemia and reperfusion. Moreover, it is argued, the degree of pore opening may be an important determinant of the relative extent of apoptosis and necrosis under these conditions. In addition, mitochondria are the major sites of action of Bax and other apoptotic regulatory proteins of the Bcl‐2 family. These proteins control a mitochondrial amplificatory loop in the apoptotic signalling pathway in which cytochrome c and other apoptogenic proteins of the mitochondrial intermembrane space are released into the cytosol. There are indications that the junctional complex, or components of it, may also mediate the action of Bax, but in a way that does not involve PT pore formation.
Pathophysiological and protective roles of mitochondrial ion channels
Authors: O'Rourke Brian
Published: August 2004

Mitochondria possess a highly permeable outer membrane and an inner membrane that was originally thought to be relatively impermeable to ions to prevent dissipation of the electrochemical gradient for protons. Although recent evidence has revealed a rich diversity of ion channels in both membranes, the purpose of these channels remains incompletely determined. Pores in the outer membrane are fundamental participants in apoptotic cell death, and this process may also involve permeability transition pores on the inner membrane. Novel functions are now being assigned to other ion channels of the inner membrane. Examples include protection against ischaemic injury by mitochondrial KATP channels and the contribution of inner membrane anion channels to spontaneous mitochondrial oscillations in cardiac myocytes. The central role of mitochondria in both the normal function of the cell and in its demise makes these channels prime targets for future research and drug development.
Mitochondria as all‐round players of the calcium game
Authors: Rizzuto Rosario , Bernardi Paolo , Pozzan Tullio
Published: August 2004

Although it has been known for over three decades that mitochondria are endowed with a complex array of Ca2+ transporters and that key enzymes of mitochondrial metabolism are regulated by Ca2+, the possibility that physiological stimuli that raise the [Ca2+] of the cytoplasm could trigger major mitochondrial Ca2+ uptake has long been considered unlikely, based on the low affinity of the mitochondrial transporters and the limited amplitude of the cytoplasmic [Ca2+] rises. The direct measurement of mitochondrial [Ca2+] with highly selective probes has led to a complete reversion of this view, by demonstrating that, after cell stimulation, the cytoplasmic Ca2+ signal is always paralleled by a much larger rise in [Ca2+] in the mitochondrial matrix. This observation has rejuvenated the study of mitochondrial Ca2+ transport and novel, unexpected results have altered long‐standing dogmas in the field of calcium signalling. Here we focus on four main topics: (i) the current knowledge of the functional properties of the Ca2+ transporters and of the thermodynamic constraints under which they operate; (ii) the occurrence of mitochondrial Ca2+ uptake in living cells and the key role of local signalling routes between the mitochondria and the Ca2+ sources; (iii) the physiological consequences of Ca2+ transport for both mitochondrial function and the modulation of the cytoplasmic Ca2+ signal; and (iv) evidence that alterations of mitochondrial Ca2+ signalling may occur in pathophysiological conditions.
Mitochondrial signals in glucose‐stimulated insulin secretion in the beta cell
Authors: Maechler Pierre , Wollheim Claes B.
Published: August 2004

Glucose‐induced insulin secretion is determined by signals generated in the mitochondria. The elevation of ATP is necessary for the membrane‐dependent increase in cytosolic Ca2+, the main trigger of insulin exocytosis. Beta cells depleted of mitochondrial DNA fail to respond to glucose while still secreting insulin in response to membrane depolarisation. This cell model resembles the situation of defective insulin secretion in patients with mitochondrial diabetes. On the other hand, infants with activating mutations in the mitochondrial enzyme glutamate dehydrogenase are characterised by hyperinsulinism and hypoglycaemia. We have recently proposed that glutamate, generated by this enzyme, participates in insulin secretion as a glucose‐derived metabolic messenger. In this model, glutamate acts downstream of the mitochondria by sensitising the exocytotic process to Ca2+. The evidence in favour of such a role for glutamate is discussed in the present review.
Mitochondria and calcium: from cell signalling to cell death
Authors: Duchen Michael R.
Published: August 2004

While a pathway for Ca2+accumulation into mitochondria has long been established, its functional significance is only now becoming clear in relation to cell physiology and pathophysiology. The observation that mitochondria take up Ca2+during physiological Ca2+signalling in a variety of cell types leads to four questions: (i) ‘What is the impact of mitochondrial Ca2+uptake on mitochondrial function?’ (ii) ‘What is the impact of mitochondrial Ca2+uptake on Ca2+signalling?’ (iii) ‘What are the consequences of impaired mitochondrial Ca2+uptake for cell function?’ and finally (iv) ‘What are the consequences of pathological [Ca2+]csignalling for mitochondrial function?’ These will be addressed in turn. Thus: (i) accumulation of Ca2+into mitochondria regulates mitochondrial metabolism and causes a transient depolarisation of mitochondrial membrane potential. (ii) Mitochondria may act as a spatial Ca2+buffer in many cells, regulating the local Ca2+concentration in cellular microdomains. This process regulates processes dependent on local cytoplasmic Ca2+concentration ([Ca2+]c), particularly the flux of Ca2+through IP3‐gated channels of the endoplasmic reticulum (ER) and the channels mediating capacitative Ca2+influx through the plasma membrane. Consequently, mitochondrial Ca2+uptake plays a substantial role in shaping [Ca2+]csignals in many cell types. (iii) Impaired mitochondrial Ca2+uptake alters the spatiotemporal characteristics of cellular [Ca2+]csignalling and downregulates mitochondrial metabolism. (iv) Under pathological conditions of cellular [Ca2+]coverload, particularly in association with oxidative stress, mitochondrial Ca2+uptake may trigger pathological states that lead to cell death. In the model of glutamate excitotoxicity, microdomains of [Ca2+]care apparently central, as the pathway to cell death seems to require the local activation of neuronal nitric oxide synthase (nNOS), itself held by scaffolding proteins in close association with the NMDA receptor. Mitochondrial Ca2+uptake in combination with NO production triggers the collapse of mitochondrial membrane potential, culminating in delayed cell death.
The machinery of local Ca2+ signalling between sarco‐endoplasmic reticulum and mitochondria
Authors: Hajnóczky György , Csordás György , Madesh Muniswamy , Pacher Pál
Published: August 2004

Growing evidence suggests that propagation of cytosolic [Ca2+] ([Ca2+]c) spikes and oscillations to the mitochondria is important for the control of fundamental cellular functions. Delivery of [Ca2+]c spikes to the mitochondria may utilize activation of the mitochondrial Ca2+ uptake sites by the large local [Ca2+]c rise occurring in the vicinity of activated sarco‐endoplasmic reticulum (SR/ER) Ca2+ release channels. Although direct measurement of the local [Ca2+]c sensed by the mitochondria has been difficult, recent studies shed some light onto the molecular mechanism of local Ca2+ communication between SR/ER and mitochondria. Subdomains of the SR/ER are in close contact with mitochondria and display a concentration of Ca2+ release sites, providing the conditions for an effective delivery of released Ca2+ to the mitochondrial targets. Furthermore, many functional properties of the signalling between SR/ER Ca2+ release sites and mitochondrial Ca2+ uptake sites, including transient microdomains of high [Ca2+], saturation of mitochondrial Ca2+ uptake sites by released Ca2+, connection of multiple release sites to each uptake site and quantal transmission, are analogous to the features of the coupling between neurotransmitter release sites and postsynaptic receptors in synaptic transmission. As such, Ca2+ signal transmission between SR/ER and mitochondria may utilize discrete communication sites and a closely related functional architecture to that used for synaptic signal propagation between cells.
Inhibition of Rho‐associated kinase blocks agonist‐induced Ca2+ sensitization of myosin phosphorylation and force in guinea‐pig ileum
Authors: Swärd Karl , Dreja Karl , Susnjar Marija , Hellstrand Per , Hartshorne David J. , Walsh Michael P.
Published: August 2004

Ca2+ sensitization of smooth muscle contraction involves the small GTPase RhoA, inhibition of myosin light chain phosphatase (MLCP) and enhanced myosin regulatory light chain (LC20) phosphorylation. A potential effector of RhoA is Rho‐associated kinase (ROK).

The role of ROK in Ca2+ sensitization was investigated in guinea‐pig ileum.

Contraction of permeabilized muscle strips induced by GTPγS at pCa 6.5 was inhibited by the kinase inhibitors Y‐27632, HA1077 and H‐7 with IC50 values that correlated with the known Ki values for inhibition of ROK. GTPγS also increased LC20 phosphorylation and this was prevented by HA1077. Contraction and LC20 phosphorylation elicited at pCa 5.75 were, however, unaffected by HA1077.

Pre‐treatment of intact tissue strips with HA1077 abolished the tonic component of carbachol‐induced contraction and the sustained elevation of LC20 phosphorylation, but had no effect on the transient or sustained increase in [Ca2+]i induced by carbachol.

LC20 phosphorylation and contraction dynamics suggest that the ROK‐mediated increase in LC20 phosphorylation is due to MLCP inhibition, not myosin light chain kinase activation.

In the absence of Ca2+, GTPγS stimulated 35S incorporation from [35S]ATPγS into the myosin targeting subunit of MLCP (MYPT). The enhanced thiophosphorylation was inhibited by HA1077. No thiophosphorylation of LC20 was detected.

These results indicate that ROK mediates agonist‐induced increases in myosin phosphorylation and force by inhibiting MLCP activity through phosphorylation of MYPT. Under Ca2+‐free conditions, ROK does not appear to phosphorylate LC20in situ, in contrast to its ability to phosphorylate myosin in vitro. In particular, ROK activation is essential for the tonic phase of agonist‐induced contraction.
Human ageing and the sympathoadrenal system
Authors: Seals Douglas R. , Esler Murray D.
Published: August 2004

Over the past three decades the changes in sympathoadrenal function that occur with age in healthy adult humans have been systematically studied using a combination of neurochemical, neurophysiological and haemodynamic experimental approaches. The available experimental evidence indicates that tonic whole‐body sympathetic nervous system (SNS) activity increases with age. The elevations in SNS activity appear to be region specific, targeting skeletal muscle and the gut, but not obviously the kidney. The SNS tone of the heart is increased, although this appears to be due in part to reduced neuronal reuptake of noradrenaline (norepinephrine). In contrast to SNS activity, tonic adrenaline (epinephrine) secretion from the adrenal medulla is markedly reduced with age. This is not reflected in plasma adrenaline concentrations because of reduced plasma clearance. Despite widely held beliefs to the contrary, sympathoadrenal responsiveness to acute stress is not exaggerated with age in healthy adults. Indeed, adrenaline release in response to acute stress is substantially attenuated in older men. The mechanisms underlying the age‐associated increases in SNS activity have not been established, but our preliminary data are consistent with increased subcortical central nervous system (CNS) sympathetic drive. These changes in sympathoadrenal function with advancing age may have a number of important physiological and pathophysiological consequences for human health and disease.
Ca2+‐activated non‐selective cation current in rabbit ventricular myocytes
Authors: Wu Yuejin , Anderson Mark E.
Published: August 2004

Oscillatory currents (OCs) were studied in isolated rabbit ventricular myocytes with whole cell mode voltage clamp using Na+‐free intracellular and extracellular solutions under conditions where K+ currents were anticipated to be eliminated or minimized.

All OCs were dependent on release of Ca2+ from the sarcoplasmic reticulum (SR) because they were associated with intracellular Ca2+ ([Ca2+]i) transients, and were suppressed by high concentrations of BAPTA (20 mmol l−1) or pretreatment with the SR antagonist agents ryanodine (10 μmol l−1) or thapsigargin (1 μmol l−1).

The reversal potential (Vrev) for OCs shifted with changes in the calculated Vrev for Cl− (ECl) but was between ECl and the calculated Vrev for elemental monovalent cations (ECat), indicating that more than one Ca2+‐activated current contributed to OCs.

Addition of the Ca2+‐activated Cl− current (ICl(Ca)) antagonist, niflumic acid, shifted the OC Vrev to ECat, suggesting that ICl(Ca) and a Ca2+‐activated non‐selective cation current (ICAN) contributed to the observed OCs.

A reduced niflumic acid‐insensitive Ca2+‐activated OC persisted following marked symmetrical reduction of Cl− in the intracellular and extracellular solutions. Subsequent removal of all extracellular monovalent cations, by N‐methyl‐D‐glucamine (NMDG) substitution, eliminated OCs and the inward holding current suggesting that ICAN and ICl(Ca) accounted for all or most of the Ca2+‐activated OC in the absence of Na+.

The OC Vrev was equal to ECl in the absence of monovalent elemental cations. Under these conditions niflumic acid eliminated all OCs.

Macroscopic OC is partially due to ICAN in rabbit ventricular myocytes.