Activating the ERK pathway (extracellular signal‐regulated kinase pathway) has proven beneficial in several models of Huntington's disease (HD), and drugs that are protective in HD models have recently been found to activate ERK. Thus, the ERK cascade may be a potential target for therapeutic intervention in this currently untreatable disorder. HD is caused by an expanded polyglutamine repeat in the huntingtin (Htt) protein that actuates a diverse set of pathogenic mechanisms. In response to mutant Htt, ERK is activated and directs (...) a protective transcriptional response and inhibits caspase activation. Paradoxically, Htt also interferes with several signaling events of the ERK pathway. Mutant Htt compromises the ERK‐dependent transcriptional response to corticostriatal BDNF signaling. Mutant Htt also hinders glutamate uptake from the synaptic cleft by down‐regulating ERK‐dependent expression of glutamate transporters, leaving cells vulnerable to excitotoxicity. Some of this cellular complexity can be capitalized on to achieve selective activation of ERK, which can be protective. (shrink)

Neurodegenerative diseases are becoming increasingly common as life expectancy increases. Recent years have seen tremendous progress in the identification of genes that cause these diseases. While mutations have been found and cellular processes defined that are altered in the disease state, the identification of treatments and cures has proven more elusive. The process of finding drugs and therapies to treat human diseases can be slow, expensive and frustrating. Can model organisms such as Drosophila speed the process of finding cures and (...) treatments for human neurodegenerative diseases? We pose three questions, (1) can one mimic the essential features of human diseases in an organism like Drosophila, (2) can one cure a model organisms of human disease and (3) will these efforts accelerate the identification of useful therapies for testing in mice and ultimately humans? Here we focus on the use of Drosophila to identify potential treatments for neurodegenerative diseases such as Huntington's and we discuss how well these therapies translate into mammalian systems. BioEssays 26:485–496, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

Disputes regarding the ethics of work by children have intensified in recent years, with little resolution. The impasses stem from failure to recognize the diverse forms of child work and a lack of empirical research regarding its causes and consequences. We report on data gathered in Brazil’s export-oriented shoe industry, which is notorious for the employment of children. Central findings are: 1) the causes of child work have less to do with backwardness and more to do with how shoe workers (...) are integrated into the global order; 2) local employers and children regard this work as benign, but the U.S. government sees it as hazardous to children and unfair to U.S. producers; 3) efforts to remove children from the shoe industry have been frustrated by local resistance and raise ethical questions; and 4) in certain circumstances, efforts to eliminate hazards from the workplace are morally superior to campaigns to remove childworkers from employment. (shrink)

The large numbers of children working in developing countries continue to provoke calls for an end to such employment. However, many reformers argue that efforts should focus on ending the exploitation of children rather than depriving them of all opportunities to work. This posture reflects recognition of the multiplicity of needs children have and the diversity of situations in which they work. Unfortunately, research typically neglects these complexities and fails to distinguish between types of labor market jobs, dismisses household chores (...) as irrelevant, and conceptualizes children’s needs largely in terms of the education they require for successful careers. Based on data collected in schools in Franca, Brazil, where children often combine school with work in the shoe industry, this study first examined the implications of labor market jobs and household work for their health, life satisfaction, and education. Analyses suggested that both forms of work negatively affected children’s welfare, but the effects of household work were more extensive, especially for girls. The second part focused on children with labor market jobs and examined how facets of their jobs as well as their after-work household duties affected their welfare. A lack of discretion on the job undermined the health of both boys and girls, higher pay adversely affected boys’ education, and housework had detrimental effects on all indicators of girls’ welfare. This paper discusses the implications of these findings for further research and suggests the needs for attention to different forms of work activities within families. It concludes with suggestions for multinationals sourcing in developing areas that go beyond the usual calls for ridding their facilities and supply networks of child workers. (shrink)

Disputes regarding the ethics of work by children have intensified in recent years, with little resolution. The impasses stem from failure to recognize the diverse forms of child work and a lack of empirical research regarding its causes and consequences. We report on data gathered in Brazil’s export-oriented shoe industry, which is notorious for the employment of children. Central findings are: 1) the causes of child work have less to do with backwardness and more to do with how shoe workers (...) are integrated into the global order; 2) local employers and children regard this work as benign, but the U.S. government sees it as hazardous to children and unfair to U.S. producers; 3) efforts to remove children from the shoe industry have been frustrated by local resistance and raise ethical questions; and 4) in certain circumstances, efforts to eliminate hazards from the workplace are morally superior to campaigns to remove childworkers from employment. (shrink)

The large numbers of children working in developing countries continue to provoke calls for an end to such employment. However, many reformers argue that efforts should focus on ending the exploitation of children rather than depriving them of all opportunities to work. This posture reflects recognition of the multiplicity of needs children have and the diversity of situations in which they work. Unfortunately, research typically neglects these complexities and fails to distinguish between types of labor market jobs, dismisses household chores (...) as irrelevant, and conceptualizes children’s needs largely in terms of the education they require for successful careers. Based on data collected in schools in Franca, Brazil, where children often combine school with work in the shoe industry, this study first examined the implications of labor market jobs and household work for their health, life satisfaction, and education. Analyses suggested that both forms of work negatively affected children’s welfare, but the effects of household work were more extensive, especially for girls. The second part focused on children with labor market jobs and examined how facets of their jobs as well as their after-work household duties affected their welfare. A lack of discretion on the job undermined the health of both boys and girls, higher pay adversely affected boys’ education, and housework had detrimental effects on all indicators of girls’ welfare. This paper discusses the implications of these findings for further research and suggests the needs for attention to different forms of work activities within families. It concludes with suggestions for multinationals sourcing in developing areas that go beyond the usual calls for ridding their facilities and supply networks of child workers. (shrink)

Dissociative experiences have been associated with diachronic disunity. Yet, this work is in its infancy. Dissociative identity disorder is characterized by different identity states reporting their own relatively continuous sense of self. The degree to which patients in dissociative identity states experience diachronic unity has not been empirically explored. This study examined the degree to which patients in dissociative identity states experienced diachronic unity. Participants were DID adults assessed in adult and child identity states, adults with a psychotic illness, adults (...) from the general population, children from the general population and adults imagining themselves as children. They completed the Diachronic Disunity Scale, the Dissociative Experiences Scale, and the Self-Concept Clarity Scale. Diachronic disunity was not limited to psychiatric groups, but evident to some degree in all adult and child samples. The DID adult sample experienced more dissociation and self-confusion than the psychosis and adult comparison groups, but did not differ on the diachronic measure. DID patients in their child identity states and child comparisons showed disunity and were significantly different from child simulators, who showed relatively more unity. Results suggest that DID patients in either adult or child dissociative identity states, like those in other samples, do not universally experience themselves as having a consistent sense of self over time. (shrink)

Jnanasrimitra (975-1025) was regarded by both Buddhists and non-Buddhists as the most important Indian philosopher of his generation. His theory of exclusion combined a philosophy of language with a theory of conceptual content to explore the nature of words and thought. Jnanasrimitra's theory informed much of the work accomplished at Vikramasila, a monastic and educational complex instrumental to the growth of Buddhism. His ideas were also passionately debated among successive Hindu and Jain philosophers. This volume marks the first English translation (...) of Jnanasrimitra's Monograph on Exclusion, a careful, critical investigation into language, perception, and conceptual awareness. Featuring the rival arguments of Buddhist and Hindu intellectuals, among other thinkers, the Monograph reflects more than half a millennium of competing claims while providing an invaluable introduction to a crucial philosopher. Lawrence J. McCrea and Parimal G. Patil familiarize the reader with the author, themes, and topics of the text and situate Jnanasrimitra's findings within his larger intellectual milieu. Their clear, accessible, and accurate translation proves the influence of Jnanasrimitra on the foundations of Buddhist and Indian philosophy. (shrink)

Erich Fromm was a political activist, psychologist, psychoanalyst, philosopher, and one of the most important intellectuals of the twentieth century. Known for his theories of personality and political insight, Fromm dissected the sadomasochistic appeal of brutal dictators while also eloquently championing love--which, he insisted, was nothing if it did not involve joyful contact with others and humanity at large. Admired all over the world, Fromm continues to inspire with his message of universal brotherhood and quest for lasting peace. The first (...) systematic study of Fromm's influences and achievements, this biography revisits the thinker's most important works, especially _Escape from Freedom_ and _The Art of Loving_, which conveyed important and complex ideas to millions of readers. The volume recounts Fromm's political activism as a founder and major funder of Amnesty International, the National Committee for a Sane Nuclear Policy, and other peace groups. Consulting rare archival materials across the globe, Lawrence J. Friedman reveals Fromm's support for anti-Stalinist democratic movements in Central and Eastern Europe and his efforts to revitalize American democracy. For the first time, readers learn about Fromm's direct contact with high officials in the American government on matters of war and peace while accessing a deeper understanding of his conceptual differences with Freud, his rapport with Neo-Freudians like Karen Horney and Harry Stack Sullivan, and his association with innovative artists, public intellectuals, and world leaders. Friedman elucidates Fromm's key intellectual contributions, especially his innovative concept of "social character," in which social institutions and practices shape the inner psyche, and he clarifies Fromm's conception of love as an acquired skill. Taking full stock of the thinker's historical and global accomplishments, Friedman portrays a man of immense authenticity and spirituality who made life in the twentieth century more humane than it might have been. (shrink)

Erich Fromm was a political activist, psychologist, psychoanalyst, philosopher, and one of the most important intellectuals of the twentieth century. Known for his theories of personality and political insight, Fromm dissected the sadomasochistic appeal of brutal dictators while also eloquently championing love--which, he insisted, was nothing if it did not involve joyful contact with others and humanity at large. Admired all over the world, Fromm continues to inspire with his message of universal brotherhood and quest for lasting peace. The first (...) systematic study of Fromm's influences and achievements, this biography revisits the thinker's most important works, especially _Escape from Freedom_ and _The Art of Loving_, which conveyed important and complex ideas to millions of readers. The volume recounts Fromm's political activism as a founder and major funder of Amnesty International, the National Committee for a Sane Nuclear Policy, and other peace groups. Consulting rare archival materials across the globe, Lawrence J. Friedman reveals Fromm's support for anti-Stalinist democratic movements in Central and Eastern Europe and his efforts to revitalize American democracy. For the first time, readers learn about Fromm's direct contact with high officials in the American government on matters of war and peace while accessing a deeper understanding of his conceptual differences with Freud, his rapport with Neo-Freudians like Karen Horney and Harry Stack Sullivan, and his association with innovative artists, public intellectuals, and world leaders. Friedman elucidates Fromm's key intellectual contributions, especially his innovative concept of "social character," in which social institutions and practices shape the inner psyche, and he clarifies Fromm's conception of love as an acquired skill. Taking full stock of the thinker's historical and global accomplishments, Friedman portrays a man of immense authenticity and spirituality who made life in the twentieth century more humane than it might have been. (shrink)

This volume marks the first English translation of Jnanasrimitra's Monograph on Exclusion, a careful, critical investigation into language, perception, and conceptual awareness.

We report an experiment investigating the “special-process” theory of insight problem solving, which claims that insight arises from non-conscious, non-reportable processes that enable problem re-structuring. We predicted that reducing opportunities for speech-based processing during insight problem solving should permit special processes to function more effectively and gain conscious awareness, thereby facilitating insight. We distracted speech-based processing by using either articulatory suppression or irrelevant speech, with findings for these conditions supporting the predicted insight facilitation effect relative to silent working or thinking (...) aloud. The latter condition was included to investigate the currently contested effect of “verbal overshadowing” on insight, whereby thinking aloud is claimed to hinder the operation of special, non-reportable processes. Whilst verbal overshadowing was not evident in final solution rates, there was nevertheless support for verbal overshadowing up to and beyond.. (shrink)

In this paper, we will consider the neuro-cognitive systems involved in mediating morality. Five main claims will be made. First, that there are multiple, partially separable neuro-cognitive architectures that mediate specific aspects of morality: social convention, care-based morality, disgust-based morality and fairness/justice. Second, that all aspects of morality, including social convention, involve affect. Third, that the neural system particularly important for social convention, given its role in mediating anger and responding to angry expressions, is ventrolateral prefrontal cortex. Fourth, that the (...) neural systems particularly important for care-based morality are the amygdala and medial orbital frontal cortex. Fifth, that while Theory of Mind is not a prerequisite for the development of affect-based 'automatic moral attitudes', it is critically involved in many aspects of moral reasoning. (shrink)

The report of the President's Council on Bioethics, Human Cloning and Human Dignity, addresses the central ethical, political, and policy issue in human embryonic stem cell research: the moral status of extracorporeal human embryos. The Council members were in sharp disagreement on this issue and essentially failed to adequately engage and respectfully acknowledge each others' deepest moral concerns, despite their stated commitment to do so. This essay provides a detailed critique of the two extreme views on the Council (i.e., embryos (...) have full moral status or they have none at all) and then gives theoretical grounding for our judgment about the intermediate moral status of embryos. It also supplies an account of how to address profound moral disagreements in the public arena, especially by way of constructing a middle ground that deliberately pays sincere respect to the views of those with whom it has deep disagreements. (shrink)

_Intersubjective Processes and the Unconscious _looks at how the minds of the therapist and the patient interact with each other in a profound and unconscious way: a concept first described by Freud. This book expands Freud’s ideas further and examines how these have been greatly elaborated by contributions from the Kleinian School as well as from the work of Bion. It explores how, together, patient and therapist co-create a narrative through these unconscious intersubjective processes. Topics of discussion include: the unconscious (...) dimensions of intersubjective processes an historical overview of Freudian, Kleinian and Bionian contributions an integrated theory of the nature of unconscious intersubjective processes the central importance of dreaming in intersubjective processes the clinical implications of this intersubjective model The author offers in-depth clinical examples and case vignettes to illustrate the application of these principles when working with trauma, countertransference dreams and supervision. As such, this book will be invaluable to all psychoanalysts and psychotherapists interested in the topic of intersubjectivity as well as those who want to learn more about the interactional dimensions of Freud, Klein and Bion. (shrink)

Ras proteins function as critical relay switches that regulate diverse signaling pathways between cell surface receptors and the nucleus. Over the past 2‐3 years researchers have identified many components of these pathways that mediate Ras activation and effector function. Among these proteins are several guanine nucleotide exchange factors (GEFs), which are responsible for directly interacting with and activating Ras in response to extracellular stimuli. Analogous GEFs regulate Ras‐related proteins that serve other diverse cellular functions. In particular, a growing family of (...) proteins (Dbl homology proteins) has recently been identified, which may function as GEFs for the Rho family of Ras‐related proteins. This review summarizes our current knowledge of the structure, biochemistry and biology of Ras and Rho family GEFs. Additionally, we describe mechanisms of GEF activation of Ras in signal transduction and address the potential that deregulated GEFs might contribute to malignant transformation through chronic Ras protein activation. (shrink)

This paper reports data and scholarly opinion that support the perception of systemic flaws in the management of scientific professions and the research enterprise; explores the responsibility that professional status places on the scientific professions, and elaborates the concept of the responsible conduct of research (RCR). Data are presented on research misconduct, availability of research guidelines, and perceived research quality.

The pull to coordinate with other individuals is fundamental, serving as the basis for our social connectedness to others. Discussed is a dynamical and ecological perspective to joint action, an approach that embeds the individual’s mind in a body and the body in a niche, a physical and social environment. Research on uninstructed coordination of simple incidental rhythmic movement, along with research on goal‐directed, embodied cooperation, is reviewed. Finally, recent research is discussed that extends the coordination and cooperation studies, examining (...) how synchronizing with another, and how emergent social units of perceiving and acting are reflected in people’s feelings of connection to others. (shrink)

It probably should not be surprising, in this time of soaring medical costs and proliferating technology, that an intense debate has arisen over the concept of medical futility. Should doctors be doing all the things they are doing? In particular, should they be attempting treatments that have little likelihood of achieving the goals of medicine? What are the goals of medicine? Can we agree when medical treatment fails to achieve such goals? What should the physician do and not do under (...) such circumstances? Exploring these issues has forced us to revisit the doctor-patient relationship and the relationship of the medical profession to society in a most fundamental way. Medical futility has both a quantitative and qualitative component. I maintain that medical futility is the unacceptable likelihood of achieving an effect that the patient has the capacity to appreciate as a benefit. Both emphasized terms are important. A patient is neither a collection of organs nor merely an individual with desires. Rather, a patient (from the word to suffer ) is a person who seeks the healing (meaning to make whole ) powers of the physician. The relationship between the two is central to the healing process and the goals of medicine. Medicine today has the capacity to achieve a multitude of effects, raising and lowering blood pressure, speeding, slowing, and even removing and replacing the heart, to name but a minuscule few. But none of these effects is a benefit unless the patient has at the very least the capacity to appreciate it. Sadly, in the futility debate wherein some critics have failed or refused to define medical futility an important area of medicine has in large part been neglected, not only in treatment decisions at the bedside, but in public discussions—comfort care—the physician’s obligation to alleviate suffering, enhance well being and support the dignity of the patient in the last few days of life. (shrink)

The concept of “public participation” is currently one of great interest to researchers and policy makers. In response to a perceived need for greater public involvement in decision making and policy formation processes on the part of both policymakers and the general public, a variety of novel mechanisms have been developed, such as the consensus conference and citizens jury, to complement traditional mechanisms, such as the public meeting. However, the relative effectiveness of the various mechanisms is unclear, as efforts at (...) evaluation have been sparse. In this article, the authors describe an evaluation of a two-day “deliberative conference” on the topic of radiation dose assessment. The authors detail the evaluation framework that they adopt and describe the instruments that they have developed to determine the attainment of the evaluationcriteria stipulated in that framework. They then describe the participation exercise that they have evaluated. Finally, they apply the instruments to assess the effectiveness of the exercise, and discuss the results and their implications for the conduct of evaluations and the use of this particular participation mechanism. (shrink)

This book explores what anyone interested in ethics can draw from Heidegger's thinking. Heidegger argues for the radical finitude of being. But finitude is not only an ontological matter; it is also located in ethical life. Moral matters are responses to finite limit-conditions, and ethics itself is finite in its modes of disclosure, appropriation, and performance. With Heidegger's help, Lawrence Hatab argues that ethics should be understood as the contingent engagement of basic practical questions, such as how should human (...) beings live? (shrink)

U.S. politicians and policymakers have been preoccupied with how to pay for health care. Hardly any thought has been given to what should be paid for—as though health care is a commodity that needs no examination—or what health outcomes should receive priority in a just society, i.e., rationing. I present a rationing proposal, consistent with U.S. culture and traditions, that deals not with “health care,” the terminology used in the current debate, but with the more modest and limited topic of (...) medical care. Integral to this rationing proposal—which allows scope to individual choice and at the same time recognizes the interdependence of the individual and society—is a definition of a “decent minimum,” the basic package of medical treatments everyone should have access to in a just society. I apply it to a specific example, diabetes mellitus, and track it through a person's life span. (shrink)

In this book, Lawrence Hatab provides an accessible and provocative exploration of one of the best-known and still most puzzling aspects of Nietzsche's thought: eternal recurrence, the claim that life endlessly repeats itself identically in every detail. Hatab argues that eternal recurrence can and should be read literally, in just the way Nietzsche described it in the texts. The book offers a readable treatment of most of the core topics in Nietzsche's philosophy, all discussed in the light of the (...) consummating effect of eternal recurrence. Although Nietzsche called eternal recurrence his most fundamental idea, most interpreters have found it problematic or needful of redescription in other terms. For this reason, Hatab's book is an important and challenging contribution to Nietzsche scholarship. (shrink)

This short note attempts to shed light on some of the surgical procedures referred to in Martial's epigram 10.56 by consulting pertinent Graeco-Roman medical texts. A fuller understanding of one such intervention supports Martial's text as transmitted.

How is it that sounds from the mouth or marks on a page—which by themselves are nothing like things or events in the world—can be world-disclosive in an automatic manner? In this fascinating and important book, Lawrence J. Hatab presents a new vocabulary for Heidegger’s early phenomenology of being-in-the-world and applies it to the question of language. He takes language to be a mode of dwelling, in which there is an immediate, direct disclosure of meanings, and sketches an extensive (...) picture of proto-phenomenology, how it revises the posture of philosophy, and how this posture applies to the nature of language. Representational theories are not rejected but subordinated to a presentational account of immediate disclosure in concrete embodied life. The book critically addresses standard theories of language, such that typical questions in the philosophy of language are revised in a manner that avoids binary separations of language and world, speech and cognition, theory and practise, realism and idealism, internalism and externalism. (shrink)