Although activated spinal cord glia contribute importantly to neuropathic pain, how nerve injury activates glia remains controversial. It has recently been proposed, on the basis of genetic approaches, that toll-like receptor 4 may be a key receptor for initiating microglial activation following L5 spinal nerve injury. The present studies extend this idea pharmacologically by showing that TLR4 is key for maintaining neuropathic pain following sciatic nerve chronic constriction injury. Established neuropathic pain was reversed by intrathecally delivered TLR4 receptor antagonists derived (...) from lipopolysaccharide. Additionally, -naltrexone, -naloxone, and -naloxone, which we show here to be TLR4 antagonists in vitro on both stably transfected HEK293-TLR4 and microglial cell lines, suppressed neuropathic pain with complete reversal upon chronic infusion. Immunohistochemical analyses of spinal cords following chronic infusion revealed suppression of CCI-induced microglial activation by -naloxone and -naloxone, paralleling reversal of neuropathic pain. Together, these CCI data support the conclusion that neuron-to-glia signaling through TLR4 is important not only for initiating neuropathic pain, as suggested previously, but also for maintaining established neuropathic pain. Furthermore, these studies suggest that the novel TLR4 antagonists -naloxone and -naloxone can each fully reverse established neuropathic pain upon multi-day administration. This finding with -naloxone is of potential clinical relevance. This is because -naloxone is an antagonist that is inactive at the -opioid selective receptors on neurons that produce analgesia. Thus, these data suggest that -opioid antagonists such as -naloxone may be useful clinically to suppress glial activation, yet -opioid agonists suppress pain. (shrink)

PURPOSE:To report the localization of a gene causing drusen and macular degeneration in a previously undescribed North American family. METHODS:Genetic mapping studies were performed using linkage analysis in a single family with drusen and atrophic macular degeneration. RESULTS:The clinical manifestations in this family ranged from fine macular drusen in asymptomatic middle-aged individuals to atrophic macular lesions in two children and two elderly patients. We mapped the gene to chromosome 6q14 between markers D6S2258 and D6S1644. CONCLUSIONS:In a family with autosomal dominant (...) drusen and atrophic macular degeneration, the gene maps to a 3.2-cM region on chromosome 6q14. This locus appears to be distinct from, but adjacent to, the loci for cone-rod dystrophy 7 (CORD7) and North Carolina macular dystrophy (MCDR1). Future identification of the gene responsible for the disease in this family will provide a better understanding of macular degeneration. (shrink)

Coronavirus disease 2019 can lead to respiratory failure. Some patients require extracorporeal membrane oxygenation support. During the current pandemic, health care resources in some cities have been overwhelmed, and doctors have faced complex decisions about resource allocation. We present a case in which a pediatric hospital caring for both children and adults seeks to establish guidelines for the use of extracorporeal membrane oxygenation if there are not enough resources to treat every patient. Experts in critical care, end-of-life care, bioethics, and (...) health policy discuss if age should guide rationing decisions. (shrink)

This clinical case report illustrates the potential dilemmas that can arise from knowledge gained through genetic analysis. These conflicts require careful ethical analysis of presumed duties to protect patient privacy and maintain confidentiality, the duty to warn a second party of a health risk, and the duty of veracity. While the questions raised by genetic testing of one individual for disease that reveals potentially important information about relatives, such as risk for Huntington chorea or breast cancer, have been discussed, the (...) continuing expansion in our capacity for sophisticated genetic analysis continues to present new and challenging situations. The resolution of this case and others like it requires close collaboration among the treatment team, geneticists, and clinical ethicists. (shrink)

© 2015, Springer-Verlag Berlin Heidelberg.Genetic studies have identified single nucleotide polymorphisms associated with the risk of prostate cancer. It remains unclear whether such genetic variants are associated with disease aggressiveness. The NCI-SPORE Genetics Working Group retrospectively collected clinicopathologic information and genotype data for 36 SNPs which at the time had been validated to be associated with PC risk from 25,674 cases with PC. Cases were grouped according to race, Gleason score and aggressiveness. Statistical analyses were used to compare the frequency (...) of the SNPs between different disease cohorts. After adjusting for multiple testing, only PC-risk SNP rs2735839 was significantly and inversely associated with aggressive and high-grade disease in European men. Similar associations with aggressive and high-grade disease were documented in African-American subjects. The G allele of rs2735839 was associated with disease aggressiveness even at low PSA levels in both European and African-American men. Our results provide further support that a PC-risk SNP rs2735839 near the KLK3 gene on chromosome 19q13 may be associated with aggressive and high-grade PC. Future prospectively designed, case-case GWAS are needed to identify additional SNPs associated with PC aggressiveness. (shrink)

The completeness of the modal logic S4 for all topological spaces as well as for the real line , the n-dimensional Euclidean space and the segment etc. was proved by McKinsey and Tarski in 1944. Several simplified proofs contain gaps. A new proof presented here combines the ideas published later by G. Mints and M. Aiello, J. van Benthem, G. Bezhanishvili with a further simplification. The proof strategy is to embed a finite rooted Kripke structure for S4 into a subspace (...) of the Cantor space which in turn encodes . This provides an open and continuous map from onto the topological space corresponding to . The completeness follows as S4 is complete with respect to the class of all finite rooted Kripke structures. (shrink)

In this 1974 book a practising scientist and gifted expositor sets forth an exciting point of view on the nature of science and how it works.

Theodor W. Adorno is best known for his contributions to aesthetics and social theory. Critics have always complained about the lack of a practical, political or ethical dimension to Adorno's philosophy. In this highly original contribution to the literature on Adorno, J. M. Bernstein offers the first attempt in any language to provide an account of the ethical theory latent in Adorno's writings. Bernstein relates Adorno's ethics to major trends in contemporary moral philosophy. He analyses the full range of Adorno's (...) major works, with a special focus on Dialectic of Enlightenment, Minima Moralia and Negative Dialectics. In developing his account Bernstein lays particular stress on Adorno's contention that the event of Auschwitz demands a new categorical imperative. This book will be widely acknowledged as the standard work on Adorno's ethics and as such will interest professionals and students of philosophy, political theory, sociology, history of ideas, art history and music. (shrink)

Malthus did not leave us with a systematic treatment of colonization, but from remarks scattered throughout his publications and correspondence it is possible to assemble a fairly coherent account of his views on the advantages and disadvantages of colonies, and on the reasons why some have failed and others succeeded. Included in these scattered remarks are some comparisons between his own views on colonies and those of Adam Smith. The question of the relationship between Malthus and Adam Smith is a (...) rather complex and subtle one, and cannot be given the full consideration it deserves in one short paper. But, as a general summary, it can be said that Malthus had a high regard for Smith and considered himself a follower and disciple of Smith, by contrast with Ricardo, James Mill, and McCulloch etc., whom he considered as exponents of a ‘New System of Political Economy”. His own Principles of Political Economy was conceived as a collection of ‘tracts or essays”, not as a new systematic treatise replacing the Wealth of Nations, Joseph Gamier in his article ‘Malthus” in the Dictionnaire de l'Economie Politique, 1852, saw that the title of the Principles was in fact a misnomer: ‘Malgré son titre, le livre sur les Principes n'est point un traité complet, mais seulement une collection de dissertations.” In what was probably intended as a criticism of Ricardo's Principles of Political Economy and Taxation, 1817, Malthus stated that the ‘present period … seems to be unpropitious to the publication of a new systematic treatise on political economy”, and, referring to Smith's work, stated that ‘the treatise which we already possess is still of the very highest value”. Nevertheless, despite professing his affiliation, Malthus did not hesitate to criticize Smith when he disagreed with him. He recognized that the Wealth of Nations contained ‘controverted points” and that it would require some ‘additions … which the more advanced stage of the science has rendered necessary”. (shrink)

Theodor Adorno's Aesthetic Theory offers one of the most powerful and comprehensive critiques of art and of the discipline of aesthetics ever written. The work offers a deeply critical engagement with the history and philosophy of aesthetics and with the traditions of European art through the middle of the 20th century. It is coupled with ambitious claims about what aesthetic theory ought to be. But the cultural horizon of Adorno's Aesthetic Theory was the world of high modernism, and much has (...) happened since then both in theory and in practice. Adorno's powerful vision of aesthetics calls for reconsideration in this light. Must his work be defended, updated, resisted, or simply left behind? This volume gathers new essays by leading philosophers, critics, and theorists writing in the wake of Adorno in order to address these questions. They hold in common a deep respect for the power of Adorno's aesthetic critique and a concern for the future of aesthetic theory in response to recent developments in aesthetics and its contexts. (shrink)

John and Mary have fully consensual sex, but they do not want to have a child, so they use contraception with the intention of avoiding pregnancy. Unfortunately, although they used the contraception in the way in which it is supposed to be used, Mary has become pregnant. The couple decides to have the baby, whom they name ‘Ernie’. Now we fill in the story a bit. The universe is causally deterministic, and 30 years later Ernie performs some action A and (...) thereby brings about event E. We also stipulate that Ernie meets plausible compatibilist conditions for acting freely . That is, we suppose that there are no uncontroversially freedom- and responsibility-undermining conditions present in the context in which Ernie performs A, and, further, that Ernie meets plausible compatibilist conditions for acting freely. Let us say, for example, that one adopts the theory according to which the freedom-relevant condition on moral responsibility is that the agent exhibits ‘guidance control’ of his action and . On this approach, one acts freely in so far as one acts from one's own, suitably reasons-responsive mechanism. We can then simply stipulate that, in the relevant context, Ernie acts from his own, suitably reasons-responsive mechanism . If one prefers a different set of compatiblist-friendly conditions for acting freely, one can simply stipulate that Ernie meets them; indeed, the plausible compatibilist-friendly conditions seem to be compatible with each other, and thus Ernie could presumably meet all of them in the relevant context. In such a case, and given that the epistemic condition on acting freely and moral responsibility is met, I am inclined to say that Ernie …. (shrink)

Advances in intracranial electroencephalography and neurophysiology have enabled the study of previously inaccessible brain regions with high fidelity temporal and spatial resolution. Studies of iEEG have revealed a rich neural code subserving healthy brain function and which fails in disease states. Machine learning, a form of artificial intelligence, is a modern tool that may be able to better decode complex neural signals and enhance interpretation of these data. To date, a number of publications have applied ML to iEEG, but clinician (...) awareness of these techniques and their relevance to neurosurgery, has been limited. The present work presents a review of existing applications of ML techniques in iEEG data, discusses the relative merits and limitations of the various approaches, and examines potential avenues for clinical translation in neurosurgery. One-hundred-seven articles examining artificial intelligence applications to iEEG were identified from 3 databases. Clinical applications of ML from these articles were categorized into 4 domains: i) seizure analysis, ii) motor tasks, iii) cognitive assessment, and iv) sleep staging. The review revealed that supervised algorithms were most commonly used across studies and often leveraged publicly available timeseries datasets. We conclude with recommendations for future work and potential clinical applications. (shrink)

We examine metonymy at psycho- and neurolinguistic levels, seeking to adjudicate between two possible processing implementations. We compare highly conventionalized systematic metonymy to lesser-conventionalized circumstantial metonymy. Whereas these two metonymy types differ in terms of contextual demands, they each reveal a similar dependency between the named and intended conceptual entities. We reason that if each metonymy yields a distinct processing time course and substantially non-overlapping preferential localization pattern, it would not only support a two-mechanism view but would suggest that conventionalization (...) acts as a linguistic categorizer. By contrast, a similar behavior in time course and localization would support a one-mechanism view and the inference that conventionalization acts instead as a modulator of contextual felicitousness, and that differences in interpretation introduced by conventionalization are of degree, not of kind. Results from three paradigms: self-paced reading, event-related potentials, and functional magnetic resonance imaging, reveal the following: no main effect by condition for either metonymy type immediately after the metonymy trigger, and a main effect for only the Circumstantial metonymy one word post-trigger ; a N400 effect across metonymy types and a late positivity for Circumstantial metonymy ; and a highly overlapping activation connecting the left ventrolateral prefrontal cortex and the left dorsolateral prefrontal cortex. Altogether, the pattern observed does not reach the threshold required to justify a two-mechanism system. Instead, the pattern is more naturally understood as resulting from the implementation of a generalized referential dependency mechanism, modulated by degree of context dependence/conventionalization, thus supporting architectures of language whereby “lexical” and “pragmatic” meaning relations are encoded along a cline of contextual underspecification. (shrink)

In this paper we study the relations between the fragment L of classical logic having just conjunction and disjunction and the variety D of distributive lattices, within the context of Algebraic Logic. We prove that these relations cannot be fully expressed either with the tools of Blok and Pigozzi's theory of algebraizable logics or with the use of reduced matrices for L. However, these relations can be naturally formulated when we introduce a new notion of model of a sequent calculus. (...) When applied to a certain natural calculus for L, the resulting models are equivalent to a class of abstract logics (in the sense of Brown and Suszko) which we call distributive. Among other results, we prove that D is exactly the class of the algebraic reducts of the reduced models of L, that there is an embedding of the theories of L into the theories of the equational consequence (in the sense of Blok and Pigozzi) relative to D, and that for any algebra A of type (2,2) there is an isomorphism between the D-congruences of A and the models of L over A. In the second part of this paper (which will be published separately) we will also apply some results to give proofs with a logical flavour for several new or well-known lattice-theoretical properties. (shrink)

While N6‐methyladenosine (m6A) is a well‐known epigenetic modification in bacterial DNA, it remained largely unstudied in eukaryotes. Recent studies have brought to fore its potential epigenetic role across diverse eukaryotes with biological consequences, which are distinct and possibly even opposite to the well‐studied 5‐methylcytosine mark. Adenine methyltransferases appear to have been independently acquired by eukaryotes on at least 13 occasions from prokaryotic restriction‐modification and counter‐restriction systems. On at least four to five instances, these methyltransferases were recruited as RNA methylases. Thus, (...) m6A marks in eukaryotic DNA and RNA might be more widespread and diversified than previously believed. Several m6A‐binding protein domains from prokaryotes were also acquired by eukaryotes, facilitating prediction of potential readers for these marks. Further, multiple lineages of the AlkB family of dioxygenases have been recruited as m6A demethylases. Although members of the TET/JBP family of dioxygenases have also been suggested to be m6A demethylases, this proposal needs more careful evaluation. (shrink)

Despite optimistic reports about the results of amputation for advanced vascular disease, the patient’s assessment of advantages and disadvantages is seldom acknowledged. A detailed social study of 67 amputees has revealed considerable disparity between the patient’s views and those of the medical staff. About a third of the patients are forced to retire from active work by the amputation; about three-quarters report a serious decline in their social activities; only about half are really independent with prostheses in the long term; (...) a quarter report severe and intractable symptoms related to their amputation stumps; only about a quarter feel that the amputation was definitely beneficial; and only about one in five feel that the medical staff have provided adequate support during their hospital stay. Amputees face physical and financial disability, isolation, and discomfort. Every effort must be made to explain the implications of amputation honestly and realistically and to ensure continuing patient assessment and support. (shrink)

The theory of emotion developed by William James has been subject to four criticisms. First, it is held that Jamesian emotion is without function, that it plays no role in cognition and behavior. Second, that James ignores the role of experience in emotion. Third, that James overstated the role of physical processes in emotion. Fourth, that James’ theory of emotion has been experimentally demonstrated to be false. A fifth point, less an explicit criticism than an assumption, holds that James has (...) nothing to offer a social psychology of emotions. It will be shown in this paper that not one of these criticisms of James' theory of emotion can be sustianed. (shrink)

Book reviewed in this article: Just War Tradition and the Restraint of War: A Moral and Historical Inquiry. By James Turner Johnson.