Anticonvulsant,antiepileptogenic, and antiictogenic pharmacostrategies

Pharmacological concepts tailored to status epilepticus, to epileptogenesis following acquired brain insults, and to ictogenesis in established epilepsy vary considerably and should ideally be directed at those pathophysiological mechanisms that presumably underly these conditions. Currently known important molecular targets include voltage-gated sodium and calcium channels, the γ-aminobutyric acid (GABA) system and ionotropic glutamate receptors. Metabotropic glutamate receptors, potassium channels, and neurotransmitters such as acetylcholine, glycine, and monoamines are beyond the scope of this review. In status epilepticus, immediate failure of GABAergic inhibition occurs, and administration of benzodiazepines and barbiturates displays the pharmacostrategic mainstay. In epileptogenesis within limbic structures, the most important underlying pathophysiological mechanisms currently discussed are transient loss of inhibition and aberrant mossy fiber sprouting. Both processes may be facilitated by N-methy-d-aspartat (NMDA) receptor regulation. NMDA antagonists may exhibit antiepileptogenic properties in experimental animals, but reliable data in humans are lacking. In established epilepsy, voltage-gated ion channels and impairment of GABAergic functions contribute to mechanisms facilitating ictogenesis. Blockade of sodium and calcium channels and enhancement of GABAergic inhibition are currently the most important tools to prevent the occurrence of seizures. Received 16 January 2007; received after revision 7 March 2007; accepted 17 April 2007     

Chromosome 13 dementias

The importance of cerebral amyloid deposition in the mechanism of neurodegeneration is still debatable. Classic arguments are usually centered on amyloid β(Aβ) and its role in the neuronal loss characteristic of Alzheimer’s disease, the most common form of human cerebral amyloidosis. Two non-Aβ cerebral amyloidoses, familial British and Danish dementias (FBD and FDD), share many aspects of Alzheimer’s disease, including the presence of neurofibrillary tangles, parenchymal preamyloid and amyloid deposits, cerebral amyloid angiopathy and a variety of amyloid-associated proteins and inflammatory components. Both early-onset conditions are linked to specific mutations at or near the stop codon of the chromosome 13 gene BRI2 that cause generation of longer-than-normal protein products. Furin-like processing of these longer precursors releases two de novo-created peptides, ABri and ADan, which deposit as amyloid fibrils in FBD and FDD, respectively. Due to the similar pathology generated by completely unrelated amyloid subunits, FBD and FDD, collectively referred to as chromosome 13 dementias, constitute alternative models for studying the role of amyloid deposition in the mechanism of neuronal cell death.Received 4 March 2005; received after revision 24 April 2005; accepted 26 April 2005     

Mechanism-based targeting of NMDA receptor functions

NMDA receptors (NRs) are key signaling proteins in the central nervous system and represent important targets for drug development in several neurologic disorders. They are critically involved with fundamental brain processes, and thus indiscriminate pharmacological suppression of NR currents has seen only modest therapeutic success so far. Targeting harmful NR receptor activities while sparing the receptor’s vital functions requires a better understanding of the complexity of NR activation reaction; of the range of mechanisms that modulate discrete receptor activities; and of the consequences of this modulation on specific receptor functions. A quantitative account of the NR activation pathway was recently proposed and validated. It describes the gating reaction as a sequential, multi-step process rather than a binary, on-off switch. Alongside isoform-specific modulators, state-specific modulators may represent sophisticated interventions with high potential for narrow, functional specifi city. Here I review physiologic mechanisms that control NR responses; the salient features of the NR activation reaction; and discuss the model’s validity and its implications for drug development and characterization.Submitted 25 May 2005; accepted 29 June 2005     

Protein phosphatases and their potential implications in neuroprotective processes

Several neurological disorders such as stroke, amyotrophic lateral sclerosis and epilepsy result from excitotoxic events and are accompanied by neuronal cell death. These processes engage multiple signalling pathways and recruit numerous molecular components, in particular several families of protein kinases and protein phosphatases. While many investigations have examined the importance of protein kinases in excitotoxicity, protein phosphatases have not been well studied in this context. However, recent advances in understanding the functions of protein phosphatases have suggested that they may play a neuroprotective role. In this review, we summarize some of the recent findings that illustrate the pleiotropic and complex functions of tyrosine and serine/threonine protein phosphatases in the cascade of events leading to neuronal cell death, and highlight their potential intervention in limiting the extent of neuronal death.Received 8 January 2005; received after revision 3 March 2005; accepted 14 March 2005     

Synaptic dysfunction in Huntington’s disease: a new perspective

Huntington’s disease (HD) is caused by a polyglutamine expansion in the protein huntingtin and is characterized by intraneuronal inclusions and widespread neuronal death at the late stage of the disease. In research, most of the emphasis has been on understanding the cell death and its mechanisms. Until recently, it was believed that the vast majority, if not all, of the symptoms in HD are a direct consequence of neurodegeneration. However, increasing evidence shows that subtle alterations in synaptic function could underlie the early symptoms. It is of particular interest to understand the nature of this neuronal dysfunction. Normal huntingtin interacts with various cytoskeletal and synaptic vesicle proteins that are essential for exocytosis and endocytosis. Altered interactions of mutant huntingtin with its associated partners could contribute to abnormal synaptic transmission in HD. This review describes recent advances in understanding synaptic dysfunction in HD.Received 2 March 2005; received after revision 13 April 2005; accepted 19 April 2005     

Oxidation and tyrosine phosphorylation: synergistic or antagonistic cues in protein tyrosine phosphatases

Protein tyrosine phosphatases (PTPs) have been generally recognised as key modulators of cell proliferation, differentiation, adhesion and motility. During signalling, several PTPs undergo two posttranslational modifications that greatly affect their enzymatic activity: tyrosine phosphorylation and cysteine oxidation. Although these modifications share their reversibility depending on the intracellular environment, their effects on enzymatic activity are opposite, tyrosine phosphorylation being correlated to enzyme activation and thiol oxidation to complete inactivation. Several papers have suggested that both these modifications occur in response to the same stimuli i.e. cell proliferation induced by numerous growth factors and cytokines. Conversely, the possibility that these two regulation mechanisms act simultaneously on PTPs has not been established and very few reports investigated this dual regulation of PTPs. To underline the relevance of the question, we discuss several possibilities: (i) that tyrosine phosphorylation and cysteine oxidation of PTPs may share the same target molecules but with different kinetics; (ii) that PTP phosphorylation and oxidation may take place on different subcellular pools of the same protein and (iii) that these two modifications, although having divergent effects on enzyme activity, cooperate in the integrated and coordinated function of PTPs during receptor tyrosine kinase signalling. We believe that our perspective will open new perspectives on an ancient problem – the apparent contradiction of opposing enzymatic regulation of many PTPs – thus clarifying their role as positive or negative transducers (or both) of many extracellular stimuli.Received 11 October 2004; received after revision 26 January 2005; accepted 10 February 2005 Available online 29 March 2005     

Trading zones and interactional expertise

The phrase ‘trading zone’ is often used to denote any kind of interdisciplinary partnership in which two or more perspectives are combined and a new, shared language develops. In this paper we distinguish between different types of trading zone by asking whether the collaboration is co-operative or coerced and whether the end-state is a heterogeneous or homogeneous culture. In so doing, we find that the voluntary development of a new language community—what we call an inter-language trading zone—represents only one of four possible configurations. In developing this argument we show how different modes of collaboration result in different kinds of trading zone, how different kinds of trading zone may be ‘nested’ inside each other and discuss how a single collaboration might move between different kinds of trading zone over time. One implication of our analysis is that interactional expertise is a central component of at least one class of trading zone.     

Predictivism and the periodic table

This is a comment on the paper by Barnes (2005) and the responses from Scerri (2005) and Worrall (2005), debating the thesis (‘predictivism’) that a fact successfully predicted by a theory is stronger evidence than a similar fact known before the prediction was made. Since Barnes and Scerri both use evidence presented in my paper on Mendeleev’s periodic law (Brush, 1996) to support their views, I reiterate my own position on predictivism. I do not argue for or against predictivism in the normative sense that philosophers of science employ, rather I describe how scientists themselves use facts and predictions to support their theories. I find wide variations, and no support for the assumption that scientists use a single ‘Scientific Method’ in deciding whether to accept a proposed new theory.     

Human selenoproteins at a glance

The public perception of selenium has changed significantly over the last decades. Originally mainly known for its high toxicity, it was later recognized as an essential trace element and is now (despite its narrow therapeutic window) almost being marketed as a lifestyle drug. Indeed, some clinical and preclinical studies suggest that selenium supplementation may be beneficial in a large number of clinical conditions. However, its mode of action is unresolved in most of these cases. Selenocysteine – identified as the 21^st amino acid used in ribosome-mediated protein synthesis – is incorporated in at least 25 specific, genetically determined human selenoproteins, many of which have only recently been discovered. Restoration of normal selenoprotein levels may be – apart from direct supranutritional effects – one possible explanation for the effects of selenium supplements. In this review we provide a brief but up-to-date overview of what is currently known about these 25 acknowledged human selenoproteins and their synthesis. Received 30 March 2005; received after revision 4 July 2005; accepted 13 July 2005     

The ontology of artefacts: the hard problem

We examine to what extent an adequate ontology of technical artefacts can be based on existing general accounts of the relation between higher-order objects and their material basis. We consider two of these accounts: supervenience and constitution. We take as our starting point the thesis that artefacts have a ‘dual nature’, that is, that they are both material bodies and functional objects. We present two criteria for an adequate ontology of artefacts, ‘Underdetermination’ (UD) and ‘Realizability Constraints’ (RC), which address aspects of the dual nature thesis. Assessing supervenience accounts, we find them either wanting with respect to these criteria or insufficiently informative. Next, we argue that a recent application of Lynne Rudder Baker’s constitution view to artefacts cannot (yet) meet our criteria, although the broader view leaves room for improvement. Based on our evaluation of the most promising candidates, we conclude that so far general metaphysical views fail to address the most salient features of artefacts. Although they can account for the fact that artefacts have a ‘dual nature’, they do not offer the conceptual resources needed to describe the relation between these natures; this relation raises a hard problem in metaphysics.     

Scientific realism bit by bit: part I. Kitcher on reference

In this paper, I consider Kitcher’s (1993) account of reference for the expressions of past science. Kitcher’s case study is of Joseph Priestley and his expression ‘dephlogisticated air’. There is a strong intuitive case that ‘dephlogisticated air’ referred to oxygen, but it was underpinned by very mistaken phlogiston theory, so concluding either that dephlogisticated air referred straightforwardly or that it failed to refer both have unpalatable consequences. Kitcher argues that the reference of such terms is best considered relative to each token—some tokens refer, and others do not. His account thus relies crucially on how this distinction between tokens can be made good—a puzzle I call the discrimination problem. I argue that the discrimination problem cannot be solved. On any reading of Kitcher’s defence of the distinction, the grounds provided are either insufficient or illegitimate. On the first reading, Kitcher violates the principle of humanity by making Priestley’s referential success a matter of the mental contents of modern speakers. The second reading sidesteps the problem of beliefs by appealing to mind-independent facts, but I argue that these are insufficient to achieve reference because of the indeterminacy introduced by the qua problem. On the third and final reading, Priestley’s success is given by what he would say in counterfactual circumstances. I argue that even if there are facts about what Priestley would say, and there is reason for doubt, there is no motivation to think that such facts determine how Priestley referred in the actual world.     

The glycinergic control of spinal pain processing

Alterations in synaptic transmission within the spinal cord dorsal horn play a key role in the development of pathological pain. While N-methyl-D-aspartate (NMDA) receptors and activity-dependent synaptic plasticity have been the focus of research for many years, recent evidence attributes very specific functions to inhibitory glycinergic and γ-aminobutyric acid (GABA)-ergic neurotransmission in the generation of inflammatory and neuropathic pain. The central component of inflammatory pain originates from a disinhibition of dorsal horn neurons, which are relieved from glycinergic neurotransmission by the inflammatory mediator prostaglandin E₂ (PGE₂). PGE₂ activates prostaglandin E receptors of the EP2 subtype and leads to a protein kinase A-dependent phosphorylation and inhibition of glycine receptors containing the α3 subunit (GlyRα3). This GlyRα3 is distinctly expressed in the superficial dorsal horn, where nociceptive afferents terminate. Other but probably very similar disinhibitory mechanisms may well contribute to abnormal pain occurring after peripheral nerve injury.Received 11 March 2005; received after revision 1 April 2005; accepted 19 April 2005     

Worlds in the Everett interpretation

This is a discussion of how we can understand the world-view given to us by the Everett interpretation of quantum mechanics, and in particular the rôle played by the concept of ‘world’. The view presented is that we are entitled to use ‘many-worlds’ terminology even if the theory does not specify the worlds in the formalism; this is defended by means of an extensive analogy with the concept of an ‘instant’ or moment of time in relativity, with the lack of a preferred foliation of spacetime being compared with the lack of a preferred basis in quantum theory. Implications for identity of worlds over time, and for relativistic quantum mechanics, are discussed.     

Intersubjective corroboration

How are we to understand the use of probability in corroboration functions? Popper says logically, but does not show we could have access to, or even calculate, probability values in a logical sense. This makes the logical interpretation untenable, as Ramsey and van Fraassen have argued.If corroboration functions only make sense when the probabilities employed therein are subjective, however, then what counts as impressive evidence for a theory might be a matter of convention, or even whim. So isn’t so-called ‘corroboration’ just a matter of psychology?In this paper, I argue that we can go some way towards addressing this objection by adopting an intersubjective interpretation, of the form advocated by Gillies, with respect to corroboration. I show why intersubjective probabilities are preferable to subjective ones when it comes to decision making in science: why group decisions are liable to be superior to individual ones, given a number of plausible conditions. I then argue that intersubjective corroboration is preferable to intersubjective confirmation of a Bayesian variety, because there is greater opportunity for principled agreement concerning the factors involved in the former.     

‘Physics and fashion’: John Tyndall and his audiences in mid-Victorian Britain

This paper explores how the physicist John Tyndall transformed himself from humble surveyor and schoolmaster into an internationally applauded icon of science. Beginning with his appointment as Professor of Natural Philosophy at the Royal Institution in 1853, I show how Tyndall’s worries about his social class and Irish origins, his painstaking attention to his lecturing performance and skilled use of the material and architectural resources of the Royal Institution were vital to his eventual success as a popular expositor and ambassador for science. Secondly I explore the implications of Tyndall’s ‘popularity’ with respect to debates over the meaning and value of scientific ‘popularisation’. In support of recent work challenging diffusionist models of science communication, I show how Tyndall’s interactions with his audiences illustrate the symbiotic relationship between producer and consumer of ‘popular’ science. By examining the views of Tyndall’s critics—notably the ‘North British’ group of physicists—and his defenders and rivals in the domain of popular scientific lecturing, I show that disputes over Tyndall’s authority reflected anxieties about what constituted popular science and the transient boundaries between instruction and entertainment. The term ‘popularisation’ enjoyed many different uses in these debates, not least of all as a rheorical device with which to either exalt or destroy a scientist’s credibility.     

The power of images: mathematics and metaphysics in Hobbes's optics

This paper deals with Hobbes's theory of optical images, developed in his optical magnum opus, ‘A Minute or First Draught of the Optiques’ (1646), and published in abridged version in De homine (1658). The paper suggests that Hobbes's theory of vision and images serves him to ground his philosophy of man on his philosophy of body. Furthermore, since this part of Hobbes's work on optics is the most thoroughly geometrical, it reveals a good deal about the role of mathematics in Hobbes's philosophy. The paper points to some difficulties in the thesis of Shapin and Schaffer, who presented geometry as a ‘paradigm’ for Hobbes's natural philosophy. It will be argued here that Hobbes's application of geometry to optics was dictated by his metaphysical and epistemological principles, not by a blind belief in the power of geometry. Geometry supported causal explanation, and assisted reason in making sense of appearances by helping the philosopher understand the relationships between the world outside us and the images it produces in us. Finally the paper broadly suggests how Hobbes's theory of images may have triggered, by negative example, the flourishing of geometrical optics in Restoration England.     

Looking for structure in all the wrong places: Ramsey sentences, multiple realisability, and structure

‘Epistemic structural realism’ (ESR) insists that all that we know of the world is its structure, and that the ‘nature’ of the underlying elements remains hidden. With structure represented via Ramsey sentences, the question arises as to how ‘hidden natures’ might also be represented. If the Ramsey sentence describes a class of realisers for the relevant theory, one way of answering this question is through the notion of multiple realisability. We explore this answer in the context of the work of Carnap, Hintikka and Lewis. Both Carnap and Hintikka offer clear structuralist perspectives which, crucially, accommodate the openness inherent in theory change. Unfortunately there is little purchase for a viable form of realism in either case. Lewis’s approach, on the other hand, offers more scope for realism but, as we shall see, concerns arise as to whether a relevant form of structuralism can be maintained. In particular his thesis of Ramseyan humility undermines certain conceptions of scientific laws that the structural realist might naturally cleave to. Our overall conclusion is that the representational device of Ramsey sentence plus multiple realisability can accommodate either the structuralist or realist aspects of ESR but has difficulties capturing both.     

Pierre Duhem’s virtue epistemology

Duhem’s concept of ‘good sense’ is central to his philosophy of science, given that it is what allows scientists to decide between competing theories. Scientists must use good sense and have intellectual and moral virtues in order to be neutral arbiters of scientific theories, especially when choosing between empirically adequate theories. I discuss the parallels in Duhem’s views to those of virtue epistemologists, who understand justified belief as that arrived at by a cognitive agent with intellectual and moral virtues, showing how consideration of Duhem as a virtue epistemologist offers insights into his views, as well as providing possible answers to some puzzles about virtue epistemology. The extent to which Duhem holds that the intellectual and moral virtues of the scientist determine scientific knowledge has not been generally noticed.     

Saving the Strong Programme: a critique of Stephen Kemp’s recent paper

In this paper I intend to discuss some of the views put forward by Stephen Kemp in his recent critique of the Strong Program (Kemp, 2005). In particular I will try to defend David Bloor’s SSK against the charge of weak idealism brought up by Stephen Kemp in his paper. The widely held accusation, namely, according to which the social constructionist approach to scientific knowledge is strongly idealist, is already rejected by Kemp himself. He argues, however that Bloor’s attempts to divert the charge of idealism from the Strong Programme were not successful with respect to the kind of idealism that Kemp calls ‘weak idealism’, that is, treating scientific discourse as free-floating and unrelated to the world of things. I intend to argue that Kemp’s charges are unfounded when levelled at Bloor’s views on meaning and reference. Kemp deals with two issues of the Bloorian program: with the social constructionist approach to concepts as self-referential social institutions, and with the actor/analyst distinction introduced by the Strong Programmers. I will focus only on the first issue in my paper.