Metaphor, indeterminacy, and intention

David Cooper has argued that it is a constraint on any acceptable theory of metaphor that it account for the 'indeterminacy' of metaphorical content, that is, the sense that many metaphors admit of more than one acceptable interpretation, none of which can be uniquely demonstrated to be correct. He further argues that the 'speaker's meaning' model of metaphorical content proposed by Searle and others cannot meet this constraint, and thus must be disregarded as a prospective account of such content. In this paper I argue firstly that Cooper's characterisation of the proposed constraint is misguided, and that we should be careful to distinguish the role that intention plays in determining metaphorical content from the question of whether we can have satisfying interpretations of metaphors that do not take speaker intention into account. I then give my own characterisation of the problem, relating it to a more general tension between the intuition that first person ascriptions of intentions carry a certain authority, and the fact that it seems to misrepresent the phenomenology of metaphor production to ascribe to the speaker a pre-existing and precise cognitive content which his metaphorical utterance is intended to convey. I go on to argue that we can resolve this tension by following Crispin Wright in viewing self ascriptions of intention as essentially response dependent; with our best judgements constituting rather than tracking the facts about what we intend. I conclude that while such an account must be refined in order to distinguish intentions related to specifically metaphorical content from the literal case, the general shape of the account is sufficient to remove the intuitions that Cooper's objection trades on

Moral facts and suitably informed subjects

The nature of moral facts, and their relationship to rationality, imagination and sentiment, have been central and pressing issues in recent moral philosophy. In this paper, I discuss and criticise a meta-ethical theory put forward by Alison Denham, which views moral facts as being constituted by the responses of ideal, empathetic agents. I argue that Denham's account is radically unstable, in that she has given us an account of the nature of such agents which is inconsistent with an independently plausible principle relating to concept acquisition. I go on to discuss one line of defence that Denham might employ, but argue that taking such a line entails abandoning what she takes to be an important advantage of her account over rival ideal-observer theories such as Michael Smith's

C1q-targeted inhibition of the classical complement pathway prevents injury in a novel mouse model of acute motor axonal neuropathy

Introduction Guillain-Barré syndrome (GBS) is an autoimmune disease that results in acute paralysis through inflammatory attack on peripheral nerves, and currently has limited, non-specific treatment options. The pathogenesis of the acute motor axonal neuropathy (AMAN) variant is mediated by complement-fixing anti-ganglioside antibodies that directly bind and injure the axon at sites of vulnerability such as nodes of Ranvier and nerve terminals. Consequently, the complement cascade is an attractive target to reduce disease severity. Recently, C5 complement component inhibitors that block the formation of the membrane attack complex and subsequent downstream injury have been shown to be efficacious in an in vivo anti-GQ1b antibody-mediated mouse model of the GBS variant Miller Fisher syndrome (MFS). However, since gangliosides are widely expressed in neurons and glial cells, injury in this model was not targeted exclusively to the axon and there are currently no pure mouse models for AMAN. Additionally, C5 inhibition does not prevent the production of early complement fragments such as C3a and C3b that can be deleterious via their known role in immune cell and macrophage recruitment to sites of neuronal damage. Results and Conclusions In this study, we first developed a new in vivo transgenic mouse model of AMAN using mice that express complex gangliosides exclusively in neurons, thereby enabling specific targeting of axons with anti-ganglioside antibodies. Secondly, we have evaluated the efficacy of a novel anti-C1q antibody (M1) that blocks initiation of the classical complement cascade, in both the newly developed anti-GM1 antibody-mediated AMAN model and our established MFS model in vivo. Anti-C1q monoclonal antibody treatment attenuated complement cascade activation and deposition, reduced immune cell recruitment and axonal injury, in both mouse models of GBS, along with improvement in respiratory function. These results demonstrate that neutralising C1q function attenuates injury with a consequent neuroprotective effect in acute GBS models and promises to be a useful new target for human therapy

Differential binding patterns of anti-sulfatide antibodies to glial membranes

Sulfatide is a major glycosphingolipid in myelin and a target for autoantibodies in autoimmune neuropathies. However neuropathy disease models have not been widely established, in part because currently available monoclonal antibodies to sulfatide may not represent the diversity of anti-sulfatide antibody binding patterns found in neuropathy patients. We sought to address this issue by generating and characterising a panel of new anti-sulfatide monoclonal antibodies. These antibodies have sulfatide reactivity distinct from existing antibodies in assays and in binding to peripheral nerve tissues and can be used to provide insights into the pathophysiological roles of anti-sulfatide antibodies in demyelinating neuropathies

Low Soluble Syndecan-1 Precedes Preeclampsia

Introduction Syndecan-1 (Sdc1; CD138) is a major transmembrane heparan sulfate proteoglycan expressed on the extracellular, luminal surface of epithelial cells and syncytiotrophoblast, thus comprising a major component of the glycocalyx of these cells. The "soluble" (shed) form of Sdc1 has paracrine and autocrine functions and is normally produced in a regulated fashion. We compared plasma soluble Sdc1 concentrations, in relation to placental Sdc1 expression, in uncomplicated (control) and preeclamptic pregnancies. Methods We evaluated soluble Sdc1 across uncomplicated pregnancy, and between preeclamptic, gestational hypertensive and control patients at mid-pregnancy (20 weeks) and 3rd trimester by ELISA. Placental expression level of Sdc1 was compared between groups in relation to pre-delivery plasma soluble Sdc1. Participants were recruited from Magee-Womens Hospital. Results In uncomplicated pregnancy, plasma soluble Sdc1 rose significantly in the 1st trimester, and reached an approximate 50-fold increase at term compared to post pregnancy levels. Soluble Sdc1 was lower at mid-pregnancy in women who later developed preeclampsia (P<0.05), but not gestational hypertension, compared to controls, and remained lower at late pregnancy in preeclampsia (P<0.01) compared to controls. Sdc1 was prominently expressed on syncytiotrophoblast of microvilli. Syncytiotrophoblast Sdc1 immunostaining intensities, and mRNA content in villous homogenates, were lower in preeclampsia vs. controls (P<0.05). Soluble Sdc1 and Sdc1 immunostaining scores were inversely associated with systolic blood pressures, and positively correlated with infant birth weight percentile

Chemical Reaction Dynamics at Surfaces

Contains reports on four research projects.National Science Foundation (Grant DMR81-19292)National Science Foundation (Grant CHE82-06422)Research CorporationCamille and Henry Dreyfus FoundationMonsant

A prospective study of consecutive emergency medical admissions to compare a novel automated computer-aided mortality risk score and clinical judgement of patient mortality risk

YesObjectives: To compare the performance of a validated automatic computer-aided risk of mortality (CARM) score versus medical judgement in predicting the risk of in-hospital mortality for patients following emergency medical admission. Design: A prospective study. Setting: Consecutive emergency medical admissions in York hospital. Participants: Elderly medical admissions in one ward were assigned a risk of death at the first post-take ward round by consultant staff over a 2-week period. The consultant medical staff used the same variables to assign a risk of death to the patient as the CARM (age, sex, National Early Warning Score and blood test results) but also had access to the clinical history, examination findings and any immediately available investigations such as ECGs. The performance of the CARM versus consultant medical judgement was compared using the c-statistic and the positive predictive value (PPV). Results: The in-hospital mortality was 31.8% (130/409). For patients with complete blood test results, the c-statistic for CARM was 0.75 (95% CI: 0.69 to 0.81) versus 0.72 (95% CI: 0.66 to 0.78) for medical judgements (p=0.28). For patients with at least one missing blood test result, the c-statistics were similar (medical judgements 0.70 (95% CI: 0.60 to 0.81) vs CARM 0.70 (95% CI: 0.59 to 0.80)). At a 10% mortality risk, the PPV for CARM was higher than medical judgements in patients with complete blood test results, 62.0% (95% CI: 51.2 to 71.9) versus 49.2% (95% CI: 39.8 to 58.5) but not when blood test results were missing, 50.0% (95% CI: 24.7 to 75.3) versus 53.3% (95% CI: 34.3 to 71.7). Conclusions: CARM is comparable with medical judgements in discriminating in-hospital mortality following emergency admission to an elderly care ward. CARM may have a promising role in supporting medical judgements in determining the patient's risk of death in hospital. Further evaluation of CARM in routine practice is required.Supported by the Health Foundation, National Institute for Health Research (NIHR) Yorkshire and Humberside Patient Safety Translational Research Centre (NIHR YHPSTRC)

Guillain-Barré syndrome: a century of progress

In 1916, Guillain, Barré and Strohl reported on two cases of acute flaccid paralysis with high cerebrospinal fluid protein levels and normal cell counts — novel findings that identified the disease we now know as Guillain–Barré syndrome (GBS). 100 years on, we have made great progress with the clinical and pathological characterization of GBS. Early clinicopathological and animal studies indicated that GBS was an immune-mediated demyelinating disorder, and that severe GBS could result in secondary axonal injury; the current treatments of plasma exchange and intravenous immunoglobulin, which were developed in the 1980s, are based on this premise. Subsequent work has, however, shown that primary axonal injury can be the underlying disease. The association of Campylobacter jejuni strains has led to confirmation that anti-ganglioside antibodies are pathogenic and that axonal GBS involves an antibody and complement-mediated disruption of nodes of Ranvier, neuromuscular junctions and other neuronal and glial membranes. Now, ongoing clinical trials of the complement inhibitor eculizumab are the first targeted immunotherapy in GBS

Radius and chirality dependent conformation of polymer molecule at nanotube interface

Temperature dependent conformations of linear polymer molecules adsorbed at carbon nanotube (CNT) interfaces are investigated through molecule dynamics simulations. Model polyethylene (PE) molecules are shown to have selective conformations on CNT surface, controlled by atomic structures of CNT lattice and geometric coiling energy. PE molecules form entropy driven assembly domains, and their preferred wrapping angles around large radius CNT (40, 40) reflect the molecule configurations with energy minimums on a graphite plane. While PE molecules prefer wrapping on small radius armchair CNT (5, 5) predominantly at low temperatures, their configurations are shifted to larger wrapping angle ones on a similar radius zigzag CNT (10, 0). A nematic transformation around 280 K is identified through Landau-deGennes theory, with molecule aligning along tube axis in extended conformationsComment: 19 pages, 7 figure2, submitted to journa