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)

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)

Previous studies have identified the critical role of the left fusiform cortex in visual word form processing, learning, and memory. However, this so-called visual word form area's other functions are not clear. In this study, we used fMRI and the subsequent memory paradigm to examine whether the putative VWFA was involved in the processing and successful memory encoding of faces as well as words. Twenty-two native Chinese speakers were recruited to memorize the visual forms of faces and Chinese words. Episodic (...) memory for the studied material was tested 3. h after the scan with a recognition test. The fusiform face area and the VWFA were functionally defined using separate localizer tasks. We found that, both within and across subjects, stronger activity in the VWFA was associated with better recognition memory of both words and faces. Furthermore, activation in the VWFA did not differ significantly during the encoding of faces and words. Our results revealed the important role of the so-called VWFA in face processing and memory and supported the view that the left mid-fusiform cortex plays a general role in the successful processing and memory of different types of visual objects. © 2010 Elsevier Inc. (shrink)

There are differences in caregivers’ literacy and health literacy levels that may affect their ability to consent to children participating in clinical research trials. This study aimed to explore the effectiveness, and caregivers’ understandings, of the process of informed consent that accompanied their child’s participation in a dental randomized control trial (RCT). Telephone interviews were conducted with a convenience sample of ten caregivers who each had a child participating in the RCT. Pre-tested closed and open-ended questions were used, and the (...) findings were produced from an inductive analysis of the latter and a descriptive analysis of the former. Participants had limited understanding of the purpose of the RCT and rated the readability of the consent form more highly than they rated their understanding of the research. All felt that informed consent was vital, but some caregivers had not read the consent documents. Some caregivers enrolled their child in the RCT because they trusted the researchers, and the majority wanted to improve dental care for children. The informed consent process was not always effective despite high readability of the informed consent documents. Researchers must consider the health literacy of the study group, and actively engaging with caregivers to achieve meaningful informed consent may be challenging. Future research could explore participants’ perspectives of informed consent in populations with low health literacy and assess whether an underlying expectation not to comprehend health-related information may be a barrier to informed consent. (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)

Our paper contributes to the rapidly expanding body of experimental research on transformative decision making, and in the process, marks out a novel empirical interpretation for assessments of subjective value in transformative contexts. We start with a discussion of the role of subjective value in transformative decisions, and then critique extant experimental work that explores this role, with special attention to Reuter and Messerli (2018). We argue that current empirical treatments miss a crucial feature of practical deliberation manifesting across a (...) variety of everyday decisions: often, people attach more weight to decision criteria that they can know—a phenomenon known as the “evaluability bias.” In transformative contexts, if people cannot know the subjective value of an option, they are unlikely to attach it much weight. Despite this, people may care very much about such value. We then use this point to develop and present new empirical results that, in addition to supporting our concerns about evaluability bias, support the hypothesis that people care about subjective value. Our work enriches the current philosophical understanding of transformative decisions and helps to frame the emerging experimental paradigm for the empirical dimensions of the debate. (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)

Volume 20, Issue 6, June 2020, Page 33-35.

Bioethics is best viewed as both a second-order discipline and also part of public discourse. Since their goals differ, some bioethical activities are more usefully viewed as advancing public discourse than academic disciplines. For example, the “Universal Declaration on Bioethics and Human Rights” sponsored by the United Nations Educational, Scientific, and Cultural Organization seeks to promote ethical guidance on bioethical issues. From the vantage of philosophical ethics, it fails to rank or specify its stated principles, justify controversial principles, clarify key (...) terms, or say what is meant by calling potentially conflicting norms “foundational.” From the vantage of improving the public discourse about bioethical problems and seeking ethical solutions in the public arena, however, this document may have an important role. The goals and relations between bioethics as a second-order discipline and public discourse are explored. (shrink)

What should be the content of a package of health care services that we would want to guarantee to all Americans? This question cannot be answered adequately apart from also addressing the issue of fair health care rationing. Consequently, as I argue in this essay, appeal to the language of "basic," "essential," "adequate," "minimally decent," or "medically necessary" for purposes of answering our question is unhelpful. All these notions are too vague to be useful. Cost matters. Effectiveness matters. The clinical (...) circumstances of a patient matters. But what we must ultimately determine is what we mutually agree are the just claims to needed health care of each American in a relatively complex range of clinical circumstances. Answering this question will require a public moral conversation, a fair process of rational democratic deliberation aimed at defining both just claims to needed health care and just limits. (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)

Many years ago, when Michael was lecturing in Oxford on the Philosophy of Physics and was trying to explain the logic of Aspect's experiments in Paris, he turned to me to expound the correct doctrine of counter-factual truth. I was flummoxed. It had been much discussed in late- and postmediaeval times, especially in the Iberian peninsula, and had recently enjoyed a revival in the Eastern United States. But Middle Knowledge, as the Schoolmen called it, was beyond my comprehension, and I (...) could only exemplify once again the truism that philosophers were better at raising problems than resolving them. (shrink)

Adolescence is an important developmental period marked by a transition from primarily parental-controlled eating to self-directed and peer-influenced eating. During this period, adolescents gain autonomy over their individual food choices and eating behavior in general. While parent-feeding practices have been shown to influence eating behaviors in children, little is known about how these relationships track across adolescent development as autonomy expands. The purpose of this qualitative study was to identify factors that impact food decisions and eating autonomy among adolescents. Using (...) the food choice process model as a guide, four focus groups were conducted with 34 adolescents. Focus group discussion was semi-structured, asking teens about influences on their food choices across different food environments, their involvement with food purchasing and preparation, and perceived control over food their choices. Focus group transcripts were analyzed using deductive and inductive code creation and thematic analysis. This study found six leading influences on adolescents' food choices and identified additional factors with prominence within specific environmental contexts. This study distinguished a broader spectrum of factors influencing adolescent food choice that extend beyond “convenience” and “taste” which have previously been identified as significant contributors. The degree of control that teens reported differed by eating location, occasion, and social context. Finally, adolescents demonstrated various levels of engagement in behaviors related to their eating autonomy. Identifying the emergent themes related to adolescent autonomy was the first step toward the goal of developing a scale to evaluate adolescent eating autonomy. (shrink)

In this paper we focus on the modularity of visual functions in the human visual cortex, that is, the specific problems that the visual system must solve in order to achieve recognition of objects and visual space. The computational theory of early visual functions is briefly reviewed and is then used as a basis for suggesting computational constraints on the higher-level visual computations. The remainder of the paper presents neurological evidence for the existence of two visual systems in man, one (...) specialized for spatial vision and the other for object vision. We show further clinical evidence for the computational hypothesis that these two systems consist of several visual modules, some of which can be isolated on the basis of specific visual deficts which occur after lesions to selected areas in the visually responsive brain. We will provide examples of visual modules which solve information processing tasks that are mediated by specific anatomic areas. We will show that the clinical data from behavioral studies of monkeys (Ungerleider and Mishkin 1984) supports the distinction between two visual systems in monkeys, the 'what' system, involved in object vision, and the 'where' system, involved in spatial vision. (shrink)

This paper focuses on natural dualities for varieties of bilattice-based algebras. Such varieties have been widely studied as semantic models in situations where information is incomplete or inconsistent. The most popular tool for studying bilattices-based algebras is product representation. The authors recently set up a widely applicable algebraic framework which enabled product representations over a base variety to be derived in a uniform and categorical manner. By combining this methodology with that of natural duality theory, we demonstrate how to build (...) a natural duality for any bilattice-based variety which has a suitable product representation over a dualisable base variety. This procedure allows us systematically to present economical natural dualities for many bilattice-based varieties, for most of which no dual representation has previously been given. Among our results we highlight that for bilattices with a generalised conflation operation. Here both the associated product representation and the duality are new. Finally we outline analogous procedures for pre-bilattice-based algebras. (shrink)

Volume 24, Issue 8, August 2024, Page 116-118.

The best-interests standard is a widely used ethical, legal, and social basis for policy and decision-making involving children and other incompetent persons. It is under attack, however, as self-defeating, individualistic, unknowable, vague, dangerous, and open to abuse. The author defends this standard by identifying its employment, first, as a threshold for intervention and judgment (as in child abuse and neglect rulings), second, as an ideal to establish policies or prima facie duties, and, third, as a standard of reasonableness. Criticisms of (...) the best-interests standard are reconsidered after clarifying these different meanings. (shrink)

This edition of Giraldus Odonis' Logica for the first time gives access to an important and original treatise, which has unduly been neglected since the author's death. It is also important in that it gives evidence of interesting achievements in the field of logic outside the anti-metaphysical circle surrounding Ockham.

The connection between similarity logic and the theory of closure operators is examined. Indeed one proves that the consequence relation defined in [14] can be obtained by composing two closure operators and that the resulting operator is still a closure operator. Also, we extend any similarity into a similarity which is compatible with the logical equivalence, and we prove that this gives the same consequence relation.