The Role of the Principle of Object-relatedness in the Theory of Activity

The present state of the theory of activity (by which we mean the concept developed by Leont'ev and his school) undoubtedly deserves serious discussion. Such a discussion must not be reduced, as often happens, to a critique of this theory by representatives of other schools and currents in psychology that are based on different theoretical positions (i.e., to a criticism from without), on the one hand, or to an unconditional acceptance of all of its postulates by proponents of this theory, on the other. In my view, the kind of critique of this theory that is most relevant and acutely necessary in terms of both its prospects of development and the extent to which its perceptions accord with other psychological currents is of another sort, namely, a critique from within, by which I mean analysis of its own laws, of the internal logic of development of the theory, and of its internal contradictions, which define its present status and the dynamics of its development. Such an analysis should enable us to stimulate more effectively the internal mechanism of development and self-development of the theory of activity and ensure a transition from a period of stagnation that has produced nothing of note to a progressive evolution of its content and its explanatory power.     

Conditioning studies in the Pavlov's laboratory during 75 years of its existence (on the 150th birthday of Ivan Petrovich Pavlov)

The paper reviews experimental and clinical data obtained on physiology and pathology of the higher nervous system by the Laboratory founded by I. P. Pavlov during 75 years of its existence: the principle of systemic organisation of the brain structures activity, the role of separate subcortical structures in organisation of behaviour, theoretical development of experimental pathology problems, inner inhibition, the role of sympathetic nervous system in conditioning, possible neurophysiological and neurochemical mechanisms of conditioning.     

Research in motion: the enigma of Parkinson's disease pathology spread

Neuropathological changes in Parkinson's disease progress slowly and spread according to a characteristic pattern. Recent papers have shed light on this progression of pathology by examining the fate of neurons grafted into the brains of patients with Parkinson's disease. Two of these studies demonstrate that grafted healthy neurons can gradually develop the same pathology as host neurons in the diseased brains. According to these studies, implanted neurons developed alpha-synuclein- and ubiquitin-positive Lewy bodies more than a decade after transplantation. We discuss the possible underlying mechanisms and their implications for how pathology spreads in Parkinson's disease.     

What systems biology can tell us about disease

A recent debate has touched upon the question of whether diseases can be understood as dysfunctional mechanisms or whether there are "pathological" mechanisms that deserve to be investigated and explained independently (Nervi 2010; Moghaddam-Taaheri 2011). Here I suggest that both views tell us something important about disease but that in many instances only a systemic view can shed light on the relationship between physiology and pathology. I provide examples from the literature in systems biology in support of my position. As a result of my analysis, I conclude that a perspective narrowly focusing on mechanisms is insufficient if the goal is to get a comprehensive picture of disease.     

Commentary: Deconstructing Critiques on the Internationalization of PTSD

When PTSD entered the DSM, advocacy for the diagnosis was a critical part of advocacy for Vietnam veterans. Over the next two decades, the range of contexts in which this clinical concept was applied increased dramatically. In a recent article in Culture, Medicine and Psychiatry, Breslau (2004) describes PTSD as a “prominent cultural model” to account for suffering as well as the synergy between human rights or political advocacy and traumatic stress advocacy. In this article I question the sequence of steps that Breslau took to critique the internationalization of the PTSD construct. I also question Breslau's critique on our work in Nepal. Finally, I will formulate some future challenges for psychiatry and anthropology to bridge their universalistic and relativistic points of view.     

The fallacy of the Principle of Procreative Beneficence

The claim that we have a moral obligation, where a choice can be made, to bring to birth the 'best' child possible, has been highly controversial for a number of decades. More recently Savulescu has labelled this claim the Principle of Procreative Beneficence. It has been argued that this Principle is problematic in both its reasoning and its implications, most notably in that it places lower moral value on the disabled. Relentless criticism of this proposed moral obligation, however, has been unable, thus far, to discredit this Principle convincingly and as a result its influence shows no sign of abating. I will argue that while criticisms of the implications and detail of the reasoning behind it are well founded, they are unlikely to produce an argument that will ultimately discredit the obligation that the Principle of Procreative Beneficence represents. I believe that what is needed finally and convincingly to reveal the fallacy of this Principle is a critique of its ultimate theoretical foundation, the notion of impersonal harm. In this paper I argue that while the notion of impersonal harm is intuitively very appealing, its plausibility is based entirely on this intuitive appeal and not on sound moral reasoning. I show that there is another plausible explanation for our intuitive response and I believe that this, in conjunction with the other theoretical criticisms that I and others have levelled at this Principle, shows that the Principle of Procreative Beneficence should be rejected.     

Guest Lecture 9.00–9.45 Wednesday 17 September 2003

The past decades have seen an explosion in our knowledge of the molecular events underpinning the pathogenesis of many disease processes. Furthermore, there have been enormous technical advances with the ability to identify, clone and sequence genes and to characterize their protein products now being common place in research settings. However, despite many claims as to the utility of molecular and biochemical methods in pathology only very few laboratories employ such methods in a clinical setting. Indeed the impact of molecular medicine has been more talked about than real. Why is this? The goal of this presentation is to address this question and present some perspectives on the future of Molecular Pathology. I shall overview, for the BSCC, the current state of the technology available for gene analysis and to explore the developments needed before the mirage of molecular pathology becomes a clinical reality.     

Nietzsche's aesthetic critique of Darwin

Despite his position as one of the first philosophers to write in the "post-Darwinian" world, the critique of Darwin by Friedrich Nietzsche is often ignored for a host of unsatisfactory reasons. I argue that Nietzsche's critique of Darwin is important to the study of both Nietzsche's and Darwin's impact on philosophy. Further, I show that the central claims of Nietzsche's critique have been broadly misunderstood. I then present a new reading of Nietzsche's core criticism of Darwin. An important part of Nietzsche's response can best be understood as an aesthetic critique of Darwin, reacting to what he saw as Darwin having drained life of an essential component of objective aesthetic value. For Nietzsche, Darwin's theory is false because it is too intellectual, because it searches for rules, regulations, and uniformity in a realm where none of these are to be found - and, moreover, where they should not be found. Such a reading goes furthest toward making Nietzsche's criticism substantive and relevant. Finally, I attempt to relate this novel explanation of Nietzsche's critique to topics in contemporary philosophy of biology, particularly work on the evolutionary explanation of culture.     

Pathogenesis of toxoplasmic retinochoroiditis

The protozoan parasite Toxoplasma gondii is an important cause of ocular disease both in immunosuppressed and immunocompetent individuals. Non-ocular infections are not usually serious in otherwise healthy adults. In contrast, toxoplasmic retinochoroiditis is a progressive, recurring disease that can cause severe morbidity. Here, Fiona Roberts and Rima McLeod review the demography, pathology and clinical findings of this disease. They discuss mechanisms of retinal destruction and disease recurrences, and the local immunological response at this immune-privileged site.     

Death,Biography, and the Mapuche Person

The amulpüllün biographical oratory which takes place at Mapuche funerals in southern Chile is said to ‘complete’ the person. Such a perspective challenges the assumption that mortuary practices necessarily constitute a form of analysis, a division of the component parts of the social person. In this paper I explore what it is about the Mapuche person which needs to be ‘completed,’ and how funeral oratory achieves this goal. Utilizing Bakhtin's concepts of consummation and transgredience, and Ricoeur's concepts of emplotment and narrative identity, I suggest that it is only from the position of outsidedness that the necessary totalization of the deceased's person can occur. These processes of synthesis and totalization cast light upon an apparent contradiction between the importance which Amerindians place upon biography as an oral form, and theoretical approaches which stress the instability and divisibility of an Amerindian personhood predicated upon the incorporation of the other. Rather than viewing the totalization which occurs in biography as a critique of such an approach, I see it as a solution to the ontological problem which such an approach describes.     

Age-related alteration of arginase activity impacts on severity of leishmaniasis

Background

The leishmaniases are a group of vector-borne parasitic diseases that represent a major international public health problem; they belong to the most neglected tropical diseases and have one of the highest rates of morbidity and mortality. The clinical outcome of infection with Leishmania parasites depends on a variety of factors such as parasite species, vector-derived products, genetics, behaviour, and nutrition. The age of the infected individuals also appears to be critical, as a significant proportion of clinical cases occur in children; this age-related higher prevalence of disease is most remarkable in visceral leishmaniasis. The mechanisms resulting in this higher incidence of clinical disease in children are poorly understood. We have recently revealed that sustained arginase activity promotes uncontrolled parasite growth and pathology in vivo. Here, we tested the hypothesis that arginase-mediated L-arginine metabolism differs with age.

Methodology

The age distribution of patients with visceral or cutaneous leishmaniasis was determined in cohorts of patients in our clinics in endemic areas in Ethiopia. To exclude factors that are difficult to control in patients, we assessed the impact of ageing on the manifestations of experimental leishmaniasis. We determined parasite burden, T cell responses, and macrophage effector functions in young and aged mice during the course of infection.

Results

Our results show that younger mice develop exacerbated lesion pathology and higher parasite burdens than aged mice. This aggravated disease development in younger individuals does not correlate with a change in T helper cytokine profile. To address the underlying mechanisms responsible for the more severe infections in younger mice, we investigated macrophage effector functions. Our results show that macrophages from younger mice do not have an impaired capacity to kill parasites; however, they express significantly higher levels of arginase 1 than aged mice and promote parasite growth more efficiently. Thus, our results demonstrate that ageing differentially impacts on L-arginine metabolism and subsequent effector functions of physiologically distinct macrophage subsets.

Conclusions

Here, we show that arginase-mediated L-arginine metabolism is modulated with age and affects the capacity of macrophages to express arginase; the increased capacity to upregulate this enzyme in younger individuals results in a more permissive environment for parasite growth, increased disease severity and pathology. These results suggest that the difference in arginase-mediated L-arginine catabolism is likely to be an important factor contributing to the increased incidence of clinical cases in children. Thus, targeting L-arginine metabolism might be a promising therapeutic strategy against leishmaniasis, especially in children and young adults.     

The Pathosome: A Dynamic Three‐Dimensional View of Disease–Environment Interaction

Most contemporary models of disease development consider the interaction between genotype and environment as static. The authors argue that because time is a key factor in genotype–environment interaction, this approach oversimplifies the pathology analysis and may lead to wrong conclusions. In reviewing the field, the authors suggest that the history of genotype–environment interactions plays an important role in the development of diseases and that this history may be analyzed using the phenotype as a proxy. Furthermore, a theoretical and experimental framework is proposed based on the assumption that phenotypes do not change from one to another randomly but are interconnected and follow certain phenotype trajectories. It then follows that analysis of such phenotype trajectories might be useful to predict the future phenotypes including the onset of disease. In addition, an analysis of phenotype trajectories can be subsequently used to choose better control subjects in comparative studies reducing noise and bias in studies investigating disease mechanisms.     

Mitochondrial DNA mutations in human disease

Since their first association with human disease in 1988, more than 250 pathogenic point mutations and rearrangements of the 16.6 kb mitochondrial genome (mtDNA) have been reported in a spectrum of clinical disorders which exhibit prominent muscle and central nervous system involvement. With novel mutations and disease phenotypes still being described, mtDNA disorders are recognized collectively as common, inherited genetic diseases although relatively little is still known concerning the precise pathophysiological mechanisms that lead to cell dysfunction and pathology. This review considers the basic principles of mitochondrial genetics which govern both the behaviour and investigation of pathogenic mtDNA mutations summarizing recent advances in this area, and an assessment of the ongoing debate into the role of somatic mtDNA mutations in neurodegenerative disease, ageing and cancer.     

Evolutionary Theory and the Social uses of Biology

Stephen Jay Gould is rightly remembered for many different kinds of contributions to our intellectual life. I focus on his criticisms of uses of evolutionary ideas to defend inegalitarian doctrines and on his attempts to expand the framework of Darwinian evolutionary theory. I argue that his important successes in the former sphere are applications of the idea of local critique, grounded in careful attention to the details of the inegalitarian proposals. As he became more concerned with the second project, Gould was inclined to suggest that the abuses of evolutionary ideas rested on an insufficiently expanded Darwinism. I suggest that what is valuable in Gould's contribution to general evolutionary theory is the original claim about punctuated equilibrium (advanced, with Niles Eldredge in1972), and the careful defense of that claim through the accumulation of paleontological evidence. I try to show that the more ambitious program of a hierarchical expansion of neo-Darwinism is misguided, and that the endeavor to go beyond local critique fails.     

Where do we stand on the autoimmunity hypothesis of Chagas disease?

The question posed in the title elicits as much controversy today as it did when I wrote about this subject in the first issue of Parasitology Today 20 years ago. A consensus is now emerging that Trypanosoma cruzi, the etiological agent of Chagas disease, bears primary responsibility for producing chagasic pathology. Whether one or more of the autoimmune events described in human and experimental Chagas disease can contribute to, or aggravate, this pathology is the current question.     

The Substance View: A Critique (Part 2)

In my initial critique of the substance view, I raised reductio‐style objections to the substance view's conclusion that the standard human fetus has the same intrinsic value and moral standing as the standard adult human being, among others. In this follow‐up critique, I raise objections to some of the premises invoked in support of this conclusion. I begin by briefly presenting the substance view as well as its defense. (For a more thorough presentation, see the first part of my critique.) I then raise objections to three claims involved in the substance view's defense: the claim that the standard human fetus's intrinsic value and moral standing is a function of its potentiality; the claim that the standard human fetus's intrinsic value and moral standing is a function of its essential properties; and the claim that it is the possession of the basic potential for rational moral agency that best accounts for the wrongness of killing the standard human fetus, among others.     

A missense mutation (I278T) in the cystathionine beta-synthase gene prevalent in pyridoxine-responsive homocystinuria and associated with mild clinical phenotype.

Cystathionine beta-synthase (CBS) deficiency is an autosomal recessive disorder characterized by homocystinuria and multisystem clinical disease. Patients responsive to pyridoxine usually have a milder clinical phenotype than do nonresponsive patients, and we studied the molecular pathology of this disorder in an attempt to understand the molecular basis of the clinical variation. We previously reported a T833C transition in exon 8 causing a substitution of threonine for isoleucine at codon 278 (I278T). By PCR amplification and sequencing of exon 8 from genomic DNA we have now detected the I278T mutation in 7 of 11 patients with in vivo pyridoxine responsiveness and in 0 of 27 pyridoxine-nonresponsive patients. Two pyridoxine-responsive patients are homozygous and five are heterozygous for I278T. We have now observed the I278T mutation in 41% (9 of 22) of the independent alleles in pyridoxine-responsive patients of varied ethnic backgrounds. In two of the compound heterozygotes we identified a novel mutation (G139R and E144K) in the other allele. The finding that the two patients who are homozygous for I278T have only ectopia lentis and mild bone demineralization suggests that this mutation is associated with both in vivo pyridoxine responsiveness and mild clinical disease. Compound heterozygous patients who have one copy of this missense mutation are likely to retain some degree of pyridoxine responsiveness.     

Mechanisms of Neural and Behavioral Dysfunction in Alzheimer’s Disease

This review critically examines progress in understanding the link between Alzheimer’s disease (AD) molecular pathogenesis and behavior, with an emphasis on the impact of amyloid-β. We present the argument that the AD research field requires more multifaceted analyses into the impacts of Alzheimer’s pathogenesis which combine simultaneous molecular-, circuit-, and behavior-level approaches. Supporting this argument is a review of particular research utilizing similar, “systems-level” methods in mouse models of AD. Related to this, a critique of common physiological and behavioral models is made—highlighting the likely usefulness of more refined and specific tools in understanding the relationship between candidate molecular pathologies and behavioral dysfunction. Finally, we propose challenges for future research which, if met, may greatly extend our current understanding of how AD molecular pathology impacts neural network function and behavior and possibly may lead to refinements in disease therapeutics.