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The availability of Piero Sraffa’s unpublished manuscripts and correspondence at Trinity College Library, Cambridge, has made it possible to begin to set out a more complete account of Sraffa’s philosophical thinking than previously could be done with only his published materials and the few comments and suggestions made by others about his ideas, especially in connection with their possible impact on Ludwig Wittgenstein’s later thinking. This makes a direct rather than indirect examination of Sraffa’s philosophical thinking possible, and also shifts the focus from his relationship to Wittgenstein to his own thinking per se. I suggest that the previous focus, necessary as it may have been prior to the availability of the unpublished materials, involved some distortion of Sraffa’s thinking by virtue of its framing in terms of Wittgenstein’s concerns as reflected in the concerns of scholars primarily interested in the change in the his thinking. This paper seeks to locate these early convictions in this historical context, and then go on to treat the development of Sraffa’s philosophical thinking as a process beginning from this point, arguing that his thinking underwent one significant shift around 1931, but still retained its early key assumptions. Thus the approach I will take to Sraffa’s philosophical thinking is to explain it as a process of development largely within a single framework defined by his view of how modern science determines the scope and limits upon economic theorizing.

Glial growth factors (GGFs) were purified from bovine pituitaries using an in vitro rat Schwann cell mitogenesis assay. In addition to an approximately 34-kDa species termed GGF-I, similar in molecular mass to a previously identified molecule (Lemke, G. E., and Brockes, J. P. (1984) J. Neuroscience 4, 75-83), two species named GGF-II and GGF-III were characterized with apparent molecular masses of approximately 59 and approximately 45 kDa, respectively. Highly purified preparations of all species share a similar dose-dependent stimulation of Schwann cell DNA synthesis at nanomolar concentrations. Forskolin synergizes with all three GGFs, shifting their dose dependence 3-8-fold into the sub-nanomolar range. The GGFs, which contain N-linked carbohydrate groups not essential for their in vitro mitogenic effects, are three distinct members of a novel family of glial cell mitogens.

David Ricardo's “On Machinery” chapter continues to interest theorists and historians of economic thought (Blaug 1958, Hollander 1979, Kurz 1984, Samuelson, 1988, 1989, Morishima 1989, Negishi 1990). Yet the addition of the chapter to the third edition of Ricardo's Principles of Political Economy and Taxation arguably overturns much of the view for which Ricardo is so well known (Davis 1989). In the added chapter Ricardo allows, contrary to his original view in the first two editions, that the introduction of machinery is indeed injurious to the class of laborers. More interestingly, because machinery substitutes for labor, wages cannot rise and profits are no longer threatened by rising rents. Effectively the contest between capitalists and landlords of the first two editions of the Principles is replaced in the final edition by one between capitalists and laborers. However, not only does the “On Machinery“ chapter substantially change the distributional argument customarily attributed to the Principles, but it also permits an examination of Ricardo's thinking about distribution in two distinct, but related frameworks. The discussion here compares the distributional analysis in the first two editions with that of the third to explain the general nature of the Ricardo's theory of profit. It does so by providing a novel interpretation of Ricardo's characterization of profit as a residual, and by emphasizing the historical context in which distribution occurred in the beginning of the nineteenth century.

The influence of Sraffa' early commitments to Gramscian Marxism on his subsequent economic analysis have been little investigated by Sraffa scholars. The discussion here argues for a philosophical connection. Specifically, it is argued that organicist ideas found their way into Sraffa's thinking about interdependence in his 1926 critique of Marshall, in his reported critique of Wittgenstein's early philosophy, and in his 1960 Production of commodities. In each instance, atomist views were challenged in an understanding of agent or sectoral interdependence that made use a single criterion for agent or sectoral autonomy: that such autonomy depends upon the fulfilment of identify conditions for the individuation of autonomous agents or sectors. It is suggested that Sraffa's thinking in this regard ses the attempted fulfilment of these conditions in neoclassical theory as self-contradictory, thus allowing the characterization of his thinking as a form of impossibility logic. This impossibility logic is contra...

This book examines the different conceptions of the individual that have emerged in recent new approaches in economics, including behavioral economics, experimental economics, social preferences approaches, game theory, neuroeconomics, evolutionary and complexity economics, and the capability approach. These conceptions are classified according to whether they seek to revise the traditional atomist individual conception, put new emphasis on interaction and relations between individuals, account for individuals as evolving and self-organizing, and explain individuals in terms of capabilities. The method of analysis uses two identity criteria for distinguishing and re-identifying individuals to determine whether these different individual conceptions successfully identify individuals. Successful individual conceptions account for sub-personal and supra-personal bounds on single individual explanations. The former concerns the fragmentation of individuals into multiple selves; the latter concerns the dissolution of individuals into the social. The book develops an understanding of bounded individuality, seen as central to the defense of human rights.

Individuals construct their own identity, but they do not construct their identity just as they please; they do not construct it under circumstances chosen by themselves, but under circumstances encountered, given and transmitted from the past. (Darity, Mason, and Stewart 2006, 290) Identity can’t be compartmentalized. You can’t divide it up into halves or thirds or any other separate segments. I haven’t got several identities: I’ve got just one, made up of many components in a mixture that is unique of me, just as other people’s identity is unique to them as individuals. (Maalouf 1998 [2000], 2) The Economics of Identity What is the “economics of identity?” In fact, the meaning of that expression is ambiguous and contested (Kirman and Teschl 2004; Fine 2009). Many nonetheless associate it with Akerlof and Kranton’s (2000) proposal to introduce the concept of social identity into economics by expanding the traditional Homo economicus utility function to include a set of self-images associated with the individual’s different social identities. On that view, people gain or lose utility according to how their social identity self-images are affected by their interaction with others. However, this does not explain the role that individuals have in determining which social identities they wish to have. That would entail having some account of how individuals choose certain social identities and also some explanation of the extent to which they are influential in determining what social identities they have. That is, it would entail having some understanding of the relationship between who they are, or what their personal identity involves, and their many social identities. Akerlof and Kranton, though they do not refer to personal identity, implicitly equate it with the individual’s utility function. However, because the utility function only tells us how people are affected by their social identities, it does not allow us to say how they influence their determination, thus making it the choice of the economic modeler to say what social identities individuals have. That is, with no real account of personal identity, they are unable to explain the relationship between personal identity and social identity. I argued in the previous chapter that on a capabilities conception of the individual people’s development of their capabilities goes hand in hand with their development of a special personal identity capability that allows them to keep narrative accounts of themselves. If one capability they develop, then, is of being able to elect particular social identities, how they keep narrative accounts of themselves constitutes a way of explaining the relationship between personal identity and social identity. Yet it would be a mistake to say that their doing this gives people complete freedom to determine what social identities they will have. Recall from Chapter 3, then, that in contrast to the psychology’s social identity approach and Turner’s self-categorization theory (Turner 1985) that Akerlof and Kranton draw on, the sociological approach to identity assumes that individuals and social groups mutually influence one another. On this view, the personal and social identities of individuals and also the identities of social groups are all mutually determined. On the one hand, the social construction and assignment of social categories to individuals influences what social groups they belong to and thus what social identities they elect. This in turn influences their personal identities. On the other hand, the social groups individuals belong to and the social identities they elect influences the formation of social groups and the construction of social categories used to represent those social groups. This frames the evolutionary-relational side of the individual conception developed previously in much broader terms that allow us to begin to capture the more indirect social influences that operate on individuality. In effect, what we try to do here, then, is locate that individual conception in an “identity dynamics” (Potts 2008) that operates across individuals and groups.

Neuroinflammation and the activation of inducible nitric oxide synthase (iNOS) have been proposed to play a role in the pathogenesis of Parkinson disease (PD). In this study we investigated the effects of the selective iNOS inhibitor GW274150 in the 6-OHDA model of PD. 6-OHDA administration was associated with increased numbers of cells expressing iNOS. Administration of the iNOS inhibitor twice daily for 7 days, beginning 2 days after the 6-OHDA lesioning, led to a significant neuroprotection as shown by assessment of the integrity of the nigrostriatal system by tyrosine hydroxylase immunocytochemistry and HPLC assessment of striatal dopamine content. However, GW274150 displayed a bell-shaped neuroprotective profile, being ineffective at high doses. 6-OHDA lesioning was associated with an increase in microglial activation as assessed by the MHC II antigen OX-6 and the number of matrix metalloproteinase 9 (MMP-9)-immunopositive cells. NO is a known modulator of MMP-9, and iNOS inhibition was associated with decreased numbers of MMP-9-immunopositive cells, culminating in a reduction in the numbers of reactive microglia. Withdrawal of GW274150 for a further 7 days negated any neuroprotective effects of iNOS inhibition, suggesting that the damaging effects of inflammation last beyond 7 days in this model and the continued administration of the drug may be required.

Background Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear hormone receptor that has been shown to have anti-inflammatory and matrix metalloproteinase (MMP) inhibitor properties. PPARγ agonists have been shown to have neuroprotective effects in various neurodegeneration models where inflammation is implicated, including models of Parkinson's disease. However, no studies have looked at the effects of partial PPARγ agonists. Experimental approach The neuroprotective effects of the PPARγ full agonist, pioglitazone (20 mg/kg), partial PPARγ agonist GW855266X (15 mg/kg) and PPAR-δ full agonist GW610742X (10 mg/kg) were investigated in the 6-hydroxydopamine (6-OHDA) model of Parkinson's disease when administered prior to or post 6-OHDA lesioning. The integrity of the nigrostriatal system was assessed by assessing the numbers dopaminergic neurons in the substantia nigra (SN) and by assessing striatal dopamine content. The degree of microglia activation in the SN was also immunohistochemistry assessed utilizing the marker OX-6 for activated microglia and CD-68 a marker for phagocytic microglia. Additionally we performed immunocytochemistry for MMP3 in the SN. Finally, we investigated whether a period of drug withdrawal for a further 7 days affected the neuroprotection produced by the PPARγ agonists. Key results Both Pioglitazone and GW855266X protected against 6-OHDA induced loss of dopaminergic neurons in the substantia nigra and depletion of striatal dopamine when administered orally twice daily for either 1) 7 day prior to and 7 days post lesioning or 2) for 7 days starting 2 days post lesioning when neurons will be severely traumatized. 6-OHDA lesioning was associated with an increase in microglia activation and in numbers of MMP-3 immunoreactive cells which was attenuated by pioglitazone and GW855266X. Neuroprotective effects were not replicated using the PPARδ agonist GW610742X. Subsequent withdrawal of both Pioglitazone and GW855266X, for a further 7 days negated any neuroprotective effect suggesting that long-term administration may be required to attenuate the inflammatory response. Conclusions and implications For the first time a partial PPAR-γ agonist has been shown to be neuroprotectory when administered post lesioning in a Parkinsonian model. Effects may be via the inhibition of microglial and MMP activation and support further research.

Explores Keynes′s long‐term policy proposals as social reform. Using early unpublished philosophical papers of Keynes, the argument is that Keynes′s long‐term policy proposals focused on reconciling “being good” and “doing good”. The socialization of investment was meant to bring about this reconciliation.

Interleukin-6 (IL-6) is a key mediator of inflammation. Inhibitors of IL-6 or of its signal transducing receptor gp130 constitute a novel class of anti-inflammatory drugs, which raise great hopes for improved treatments of painful inflammatory diseases such as rheumatoid arthritis. IL-6 and gp130 may enhance pain not only indirectly through their proinflammatory actions but also through a direct action on nociceptors (i.e., on neurons activated by painful stimuli). We found indeed that the IL-6/gp130 ligand-receptor complex induced heat hypersensitivity bothin vitroandin vivo. This process was mediated by activation of PKC-δ via Gab1/2/PI3K and subsequent regulation of TRPV1, a member of the transient receptor potential (TRP) family of ion channels. To assess the relevance of this direct pain promoting effect of IL-6, we generated conditional knock-out mice, which lackgp130specifically in nociceptors, and tested them in models of inflammatory and tumor-induced pain. These mice showed significantly reduced levels of inflammatory and tumor-induced pain but no changes in immune reactions or tumor growth. Our results uncover the significance of gp130 expressed in peripheral pain sensing neurons in the pathophysiology of major clinical pain disorders and suggest their use as novel pain relieving agents in inflammatory and tumor pain.

Recent work on the theory of teams and team reasoning in game interactive settings is due principally to the late Michael Bacharach (Bacharach, 2006), who offers a conception of the individual as a team member, and also to Martin Hollis (1998) and Robert Sugden and Natalie Gold (Sugden, 2000; Gold & Sugden, 2007), and is motivated by the conflict between what ordinary experience suggests people often to do and what rationality prescribes for them, such as in prisoner's dilemma games where individuals can choose to cooperate or defect. The source of the conflict, they suggest, is an ambiguity in the syntax of standard game theory, which is taken to pose the question individuals in games ask themselves as, "what should I do?," but which might be taken to pose the question, particularly when individuals are working together with others as, "what should we do?" When taken in the latter way, each individual chooses according to what best promotes the team's objective and then performs the role appropriate as a member of that team or group. Bacharach understood this change in focus in terms of the different possible cognitive frames that individuals use to think about the world and developed a variable frame theory for rational play in games in which the frame adopted for a decision problem determines what counts as rational play (Janssen, 2001; Casajus, 2001).In order to explain how someone acts, we have to take account of the representation or model of her situation that she is using as she thinks what to do. The model varies with the cognitive frame in which she does her thinking. Her frame stands to her thoughts as a set of axes does to a graph; it circumscribes the thoughts that are logically possible for her (not ever, but at that time). (Bacharach, 2006, p. 69)Sugden understands this framing idea in terms of the theory of focal points following Thomas Schelling's emphasis on the role of salience in coordination games (Schelling, 1960), and his theory similarly ties decision-making to the way the game is understood (Sugden, 1995). This all recalls what Tversky and Kahneman (1981, 1986) termed standard's theory's description invariance assumption, whose abandonment makes it possible to bring a variety of the insights from psychology to bear on rationality in economics.

This paper examines the connections between democracy and education, particularly as it concerns economics. We adopt a pluralist proceduralist view of democracy, and argue that this requires a view of individuals as active decision-makers able to deliberate and reflect on their different ideas and opinions – a view not available to mainstream economics with its preference-based view of the individual. The paper examines the nature of learning and its implications for teaching, and then applies this to economics education. An important aspect of this is students' exploration of their values. We argue this approach requires a pluralist educational philosophy.

This paper analyzes three of John Maynard Keynes's unpublished apostles papers, "Ethics in Relation to Conduct," "Miscellanea Ethica," and "Egoism," and the philosophical discussion in the first chapters of the Treatise on Probability. It argues that Keynes's philosophical development before and in the Treatise can be understood as an effort to make sense of the concept of intuition. Specifically, it is argued that Keynes abandoned a two-fold view of intuition in the early papers for a two-tier epistimology of acquaintance and knowledge in the Treatise, only to return to the two-fold view later in The General Theory. Copyright 1991 by Oxford University Press.

Historians of economics and philosophy have noted Georg Wilhelm Fredrich Hegel's debt to Adam Smith and have suggested that Hegel's analysis of civil society rests on a Smithian foundation. Laurence Dickey recognized that “Hegel's interest in the Scots coincided with the late eighteenth-century German interest in the relationship between socioeconomic processes in history and the development of civil institutions” (Dickey 1987, p. 194). Georg Lukacs emphasized that “it is highly probable that the study of Adam Smith was a turning-point in Hegel's evolution” (Lukacs 1976, p. 172). In his study of The Formation of the Economic Thought of Karl Marx, Ernest Mandel maintained that Marx discovered political economy and its importance to philosophy in his reading of Hegel. Says Mandel

Recent advances in clinical, pathological and neuroscience studies have identified disease-modifying therapeutic approaches for Alzheimer's disease that are now in clinical trials. This has highlighted the need for reliable and convenient biomarkers for both early disease diagnosis and a rapid signal of drug efficacy. We describe the identification and assessment of a number of candidate biomarkers in patients with Alzheimer's disease and the correlation of those biomarkers with rosiglitazone therapeutic efficacy, as represented by a change in the Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog). Plasma from 41 patients with Alzheimer's disease were analysed by open platform proteomics at baseline and after receiving 8 mg rosiglitazone for 24 weeks. From a comparison of protein expression following treatment with rosiglitazone, 97 proteins were observed to be differentially expressed with a p-value

5-HT4 agonists are currently being developed for the treatment of Alzheimer’s disease and have previously been demonstrated to improve cognitive performance in a variety of tests but none that specifically test attention. Here we characterise the 5-HT4 partial agonist SL65.0155 compared to the reference drug, nicotine, in a test that is used to measure attention in rats, the five-choice serial reaction time task (5CSRTT). SL65.0155 (0.1 or 1 mg/kg s.c) and nicotine (0.2 mg/kg s.c.) were tested in protocols using fixed or variable stimulus durations. SL65.0155 improved performance by virtue of reducing incorrect responses and increasing % correct trials. Perseverative responses were reduced by SL65.0155, and latency during incorrect trials was increased following treatment with 0.1 mg/kg SL65.0155. Nicotine, as previously reported, improved performance in several parameters in the 5CSRTT, including response latencies, errors of omission and correct responses in both the baseline and variable stimulus protocol. These data suggest 5-HT4 agonists may have beneficial effects on attention and thereby may be useful for the treatment of cognitive deficits.

6-Phenylnicotinamide (2) was previously identified as a potent TRPV1 antagonist with activity in an in vivo model of inflammatory pain. Optimization of this lead through modification of both the biaryl and heteroaryl components has resulted in the discovery of 6-(4-fluorophenyl)-2-methyl-N-(2-methylbenzothiazol-5-yl)nicotinamide (32; SB-782443) which possesses an excellent overall profile and has been progressed into pre-clinical development.

To provide a tool to investigate the mechanisms inducing and maintaining cancer-related pain and hyperalgesia, a soft tissue tumor/metastasis model was developed that is applicable in C57BL/6J wild-type and transgenic mice. We show that the experimental tumor-induced heat hyperalgesia and nociceptor sensitization were prevented by systemic treatment with the tumor necrosis factor α (TNFα) antagonist etanercept. In naive mice, exogenous TNFα evoked heat hyperalgesiain vivoand sensitized nociceptive nerve fibers to heatin vitro. TNFα enhanced the expression of the nociceptor-specific heat transducer ion channel transient receptor potential vanilloid 1 (TRPV1) and increased the amplitudes of capsaicin and heat-activated ionic currents via p38/MAP (mitogen-activated protein) kinase and PKC (protein kinase C). Deletion of the tumor necrosis factor receptor type 2 (TNFR2) gene attenuated heat hyperalgesia and prevented TRPV1 upregulation in tumor-bearing mice, whereas TNFR1 gene deletion played a minor role. We propose endogenous TNFα as a key player in cancer-related heat hyperalgesia and nociceptor sensitization that generates TRPV1 upregulation and sensitization via TNFR2.

This paper offers an account of how individuals act as agents when we employ a narrative approach to explaining their personal identities. It applies Korsgaard's idea of a "reflective structure of consciousness" to provide foundations for a richer account of the individual economic agent, and uses this to explain and distinguish the concepts of personal identity, individual identity, and social identity. The paper argues that individuals' personal identities may be in conflict with their socially constructed individual identities. Individuals' social identities are represented as a link between personal identity and individual identity. The overall framework is proposed as an alternative to the atomistic individual conception and a contribution to the socially embedded individual conception.

Publisher Summary This chapter focuses on some of the new approaches that are in clinical development and therefore offer the exciting prospect of new treatments for patients within the next 5–10 years. It discusses new symptomatic approaches that offer advances in efficacy, adverse event profile, or additional disease-modifying benefits. The chapter also concentrates on the amyloid lowering approaches that will test the “amyloid hypothesis” and offer a real prospect of disease modification. The chapter emphasizes that the cognitive and behavioral diversity of AD provides a basis for extensive dialogue between preclinical scientists and clinical researchers in search of new therapies. The chapter concludes that in future it is expected that further advances in the design of mechanism-based, symptomatic or disease modifying treatments will arise from progress in basic science research, improvement of animal models, development of cognitive and behavioral clinical measures relevant to AD, and a better understanding of previous clinical measure or molecule related failures.

This paper examines the relationship between the individual conception in economics and the justification of economic rights as human rights. It briefly describes the nature of economic rights, and argues that the Homo economicus conception constitutes a barrier to justifying them. The paper then offers an alternative conception of the individual as socially embedded, and argues that it offers an adequate basis for the justification of economic rights. On this alternative conception individuals are enduring beings who have personal identities.

This paper examines conceptions of the individual in recent economics (including prospect theory, preference reversal/construction approaches, social preference theory, Bacharach's team view, Ross's neuroeconomics view, and the Sugden/Bruni civil happiness approach). The first three are classified as internalist; the last three as externalist. Internalist conceptions are argued to draw on the standard atomistic view of the individual in economics, itself seen to be circular. The externalist conceptions reviewed here are treated as relational views of individuals, are seen to individuate persons, but encounter problems in explaining individuals as enduring.

Rat sciatic nerve Schwann cells in culture respond to a limited range of mitogens, including glial growth factor, transforming growth factors beta-1 and beta-2 (TGF-beta 1, TGF-beta 2), some cell membrane-associated factors, and to agents such as cholera toxin and forskolin which raise intracellular levels of cAMP. These responses require the presence of FCS, which exhibits little or no mitogenic activity in the absence of other factors. However, we recently found that forskolin greatly potentiates the mitogenic signal from TGFs-beta 1 and beta 2, raising the possibility that cAMP might couple other factors to mitogenesis. We have therefore screened a range of candidate mitogens using DNA synthesis assays. Other than TGFs-beta and glial growth factor, none of the factors tested were mitogenic in the presence of 10% serum alone. With the addition of forskolin, however, porcine PDGF, human PDGF, acidic and basic FGF were potent mitogens for rat Schwann cells, stimulating DNA synthesis and increasing cell number. Cholera toxin and dibutyrylcyclicAMP, but not 1,9-dideoxyforskolin, can substitute for forskolin indicating that the mitogenic effect is mediated via adenylyl cyclase activation. Porcine PDGF gave half-maximal stimulation at 15 pM, and human PGDF an equivalent response at 1 nM. Basic FGF was half maximal at 5 pM, acidic FGF at 1 nM. The recognition of PDGFs and FGFs as mitogens for Schwann cells has many implications for the study of Schwann cell proliferation in the development and regeneration of nerves, and in Schwann cell tumorigenesis.

In a recent examination of the origins of ordinal utility theory in neoclassical economics, Robert D. Cooter and Peter Rappoport argue that the ordinalist revolution of the 1930s, after which most economists abandoned interpersonal utility comparisons as normative and unscientific, constituted neither unambiguous progress in economic science nor the abandonment of normative theorizing, as many economists and historians of economic thought have generally believed (Cooter and Rappoport, 1984). Rather, the widespread acceptance of ordinalism, with its focus on Pareto optimality, simply represented the emergence of a new neoclassical research agenda that, on the one hand, defined economics differently than had the material welfare theorists of the cardinal utility school and, on the other, adopted a positivist methodology in contrast to the less restrictive empiricism of the cardinalists.

Karl Marx's social theory has often been thought to raise ethical questions at the outset. Yet many economists and social scientists believe social theory should be value-free and positive. Louis Althusser takes this view in arguing against the humanist interpretation of Marx. He advances a theory of reading for interpretation of Marx, and concludes that the “problematic” of Marx's later thought—as it arises from Marx's own distinctive philosophy—is inconsistent with the humanist interpretation. The article argues against this reading via this same philosophy, and defends a revised humanist view of Marx.

Emerging disease modifying therapeutic strategies for Alzheimer's disease (AD) have generated a critical need for biomarkers of early stage disease. Here, we describe the identification and assessment of a number of candidate biomarkers in patients with mild to moderate probable AD. Plasma from 47 probable Alzheimer's patients and 47 matched controls were analysed by proteomics to define a significant number of proteins whose expression appeared to be associated with AD. These were compared to a similar proteomic comparison of a mouse transgenic model of amyloidosis, which showed encouraging overlap with the human data. From these studies a prioritised list of 31 proteins were then analysed by immunoassay and/or functional assay in the same human cohort to verify the changes observed. Eight proteins continued to show significance by either immunoassay or functional assay in the human plasma and these were tested in a further set of 100 probable AD patients and 100 controls from the original cohort. From our data it appeared that two proteins, serpin F1 (pigment epithelium-derived factor) and complement C1 inhibitor are down-regulated in plasma from AD patients.

6-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methyl-3-pyridinecarboxamide hydrochloride (GSK189254) is a novel histamine H(3) receptor antagonist with high affinity for human (pK(i) = 9.59 -9.90) and rat (pK(i) = 8.51-9.17) H(3) receptors. GSK189254 is >10,000-fold selective for human H(3) receptors versus other targets tested, and it exhibited potent functional antagonism (pA(2) = 9.06 versus agonist-induced changes in cAMP) and inverse agonism [pIC(50) = 8.20 versus basal guanosine 5'-O-(3-[(35)S]thio)triphosphate binding] at the human recombinant H(3) receptor. In vitro autoradiography demonstrated specific [(3)H]GSK189254 binding in rat and human brain areas, including cortex and hippocampus. In addition, dense H(3) binding was detected in medial temporal cortex samples from severe cases of Alzheimer's disease, suggesting for the first time that H(3) receptors are preserved in late-stage disease. After oral administration, GSK189254 inhibited cortical ex vivo R-(-)-alpha-methyl[imidazole-2,5(n)-(3)H]histamine dihydrochloride ([(3)H]R-alpha-methylhistamine) binding (ED(50) = 0.17 mg/kg) and increased c-Fos immunoreactivity in prefrontal and somatosensory cortex (3 mg/kg). Microdialysis studies demonstrated that GSK189254 (0.3-3 mg/kg p.o.) increased the release of acetylcholine, noradrenaline, and dopamine in the anterior cingulate cortex and acetylcholine in the dorsal hippocampus. Functional antagonism of central H(3) receptors was demonstrated by blockade of R-alpha-methylhistamine-induced dipsogenia in rats (ID(50) = 0.03 mg/kg p.o.). GSK189254 significantly improved performance of rats in diverse cognition paradigms, including passive avoidance (1 and 3 mg/kg p.o.), water maze (1 and 3 mg/kg p.o.), object recognition (0.3 and 1 mg/kg p.o.), and attentional set shift (1 mg/kg p.o.). These data suggest that GSK189254 may have therapeutic potential for the symptomatic treatment of dementia in Alzheimer's disease and other cognitive disorders.

John Rawls', "A Theory of Justice", project of arguing from individuals to social outcomes is examined from the perspective of experimental methods in economics and complex adaptive systems simulations. The first section discusses the book's main argument regarding the original position, and the justice principle selection process is explained as Rawls' representation of a hypothetical experiment. This hypothetical experiment, however, falls short of satisfying reasonable experimental controls, particularly as reflects the conception of the individual it employs. The second section of the paper then goes beyond the usual focus on Rawls' original position argument, and discusses the differences between his conception of rational persons in the first and third parts of the book, associated with his distinction between thin and full theories of the good. The third section uses his fuller conception of rational persons in the third part of the book to offer an alternative view of the selection process understood as a complex adaptive system. The fourth section turns to a topic raised by this alternative complex system approach, namely, the status of normative reasoning in political-economic systems. The fifth section gives brief summary remarks.

The concept of identity was introduced into the neoclassical utility maximising framework by Akerlof and Kranton in an analysis which draws directly from social psychology's social identity approach and self-categorisation theory. This paper examines their analysis, and compares the social identity approach and an alternative social psychology identity framework called the sociological approach to identity. Using this comparison, the paper argues that their treating identity as an argument in the utility function leaves unaddressed how individuals' different social identities are related. The paper suggests a framework for addressing this issue by embedding their utility function in a personal identity objective function. The general context for the paper is the Akerlof-Kranton analysis as an example of 'recent economics' defined as a collection of new competing research programmes that make departures from neoclassical economics.

This paper examines change on the economics research frontier, and asks whether the current competition between new research programs may be supplanted by a new single dominant approach in the future. The paper discusses whether economics tends to be dominated by a single approach or reflect a pluralism of approaches, and argues that historically it has alternated between the two. It argues that orthodoxy usually emerges from heterodoxy, and interprets the division between orthodoxy and heterodoxy in terms of a core-periphery distinction. Regarding recent economics, the paper maps out two different types of combinations of new research programs as being synchronic or diachronic in nature. It treats the new research programs as a new kind of heterodoxy, and asks how a new orthodoxy might arise out of this new heterodoxy and traditional heterodoxy. It discusses this question by advancing two views regarding how the two different types of combinations in the new research programs might consolidate along the lines of three shared commitments with traditional heterodoxy to form a new orthodoxy in economics.