The YAP/TAZ family of transcriptional co‐activators drives cell proliferation in epithelial tissues and cancers. Yet, how YAP and TAZ are physiologically regulated remains unclear. Here we review recent reports that YAP and TAZ act primarily as sensors of epithelial cell polarity, being inhibited when cells differentiate an apical membrane domain, and being activated when cells contact the extracellular matrix via their basal membrane domain. Apical signalling occurs via the canonical Crumbs/CRB‐Hippo/MST‐Warts/LATS kinase cascade to phosphorylate and inhibit YAP/TAZ. Basal signalling occurs (...) via Integrins and Src family kinases to phosphorylate and activate YAP/TAZ. Thus, YAP/TAZ is localised to the nucleus in basal stem/progenitor cells and cytoplasm in differentiated squamous cells or columnar cells. In addition, other signals such as mechanical forces, tissue damage and possibly receptor tyrosine kinases (RTKs) can influence MST‐LATS or Src family kinase activity to modulate YAP/TAZ activity. (shrink)

Despite some clinical promise, using fetal transplants for degenerative and traumatic brain injury remains controversial and a number of issues need further attention. This response reexamines a number of questions. Issues addressed include: temporal factors relating to neural grafting, the role of behavioral experience in graft outcome, and the relationship of rebuilding of neural circuitry to functional recovery. Also discussed are organization and type of transplanted tissue, the of transplant viability, and whether transplants are really needed to obtain functional (...) recovery after brain damage. (shrink)

Ex-vivo tissue engineering is a quickly developing medical technology aiming to regenerate tissue through the introduction of an ex-vivo created tissue construct instead of restoring the damaged tissue to some level of functionality. Tissue engineering is considered by some as a new medical paradigm. We analyse this claim and identify tissue engineering’s fundamental characteristics, focusing on the aim of the intervention and on the complexity and continuity of the process. We inquire how these features (...) have an impact not only on the scientific research itself but also on the ethical evaluation of this research. We suggest that viewing tissue engineering as a new medical paradigm allows us to develop a wider perspective for successful investigation instead of focusing on isolated steps of the tissue engineering process in an anecdotal way, which may lead to an inadequate ethical evaluation. We argue that the concept of tissue engineering as a paradigm may benefit the way we address the ethical challenges presented by tissue engineering. (shrink)

This article reviews and discusses emerging evidence suggesting an evolutionarily‐conserved connection between injury‐associated exposure of cytoskeletal proteins and the induction of tolerance to infection, repair of tissue damage and restoration of homeostasis. While differences exist between vertebrates and invertebrates with respect to the receptor(s), cell types, and effector mechanisms involved, the response to exposed cytoskeletal proteins appears to be protective and to rely on a conserved signaling cassette involving Src family kinases, the nonreceptor tyrosine kinase Syk, and tyrosine (...) phosphatases. A case is made for research programs that integrate different model organisms in order to increase the understanding of this putative response to tissue damage. (shrink)

Commodification is a broad and crosscutting issue that spans debates in ethics (from prostitution to global market practices) and bioethics (from the sale of body parts to genetic enhancement). There has been disagreement, however, over what constitutes commodification, whether it is happening, and whether it is of ethical import. This chapter focuses on one area of the discussion in bioethics – the commodification of human tissue – and addresses these questions – about the characteristics of commodification, its pervasiveness, and (...) ethical significance – in order to clarify and map the commodificatory debate. The chapter does this in three parts. First, it defines commodification as the shift from “persons” to “things” and from “relationships” to services for “contract.” Second, using examples of kidney and gamete sale and commercial surrogacy, it argues that commodification is rife in bioethics. Third, it contends that commodification is an ethical problem for three key reasons: First, because it leads to exploitation; second, because some things should not be for sale; and third, because it damages social goods. The chapter concludes that commodification and commodificatory practices should be resisted. (shrink)

Grafts of embryonic neural tissue into the brains of adult patients are currently being used to treat Parkinson's disease and are under serious consideration as therapy for a variety of other degenerative and traumatic disorders. This target article evaluates the use of transplants to promote recovery from brain injury and highlights the kinds of questions and problems that must be addressed before this form of therapy is routinely applied. It has been argued that neural transplantation can promote functional recovery (...) through the replacement of damaged nerve cells, the reestablishment of specific nerve pathways lost as a result of injury, the release of specific neurotransmitters, or the production of factors that promote neuronal growth. The latter two mechanisms, which need not rely on anatomical connections to the host brain, are open to examination for nonsurgical, less intrusive therapeutic use. Certain subjective judgments used to select patients who will receive grafts and in assessment of the outcome of graft therapy make it difficult to evaluate the procedure. In addition, little long-term assessment of transplant efficacy and effect has been done in nonhuman primates. Carefully controlled human studies, with multiple testing paradigms, are also needed to establish the efficacy of transplant therapy. (shrink)

Oxidised bases, such as 8-oxo-guanine, occur in cellular DNA as a result of attack by oxygen free radicals. The cancer-protective effect of vegetables and fruit is attributed to the ability of antioxidants in them to scavenge free radicals, preventing DNA damage and subsequent mutation. Antioxidant supplements (e.g., β-carotene, vitamin C) increase the resistance of lymphocytes to oxidative damage, and a negative correlation is seen between antioxidant concentrations in tissues and oxidised bases in DNA. Large-scale intervention trials with β-carotene (...) have, however, led to increases in cancer. Recent measurements of the frequency of oxidised DNA bases indicate that earlier estimates were greatly exaggerated; there may be only a few thousand 8-oxo-guanines per cell. Convincing evidence for mutations resulting from oxidative damage, in tumours or cultured cells, is lacking. It seems that efficient antioxidant defences together with DNA repair maintain a steady-state level of damage representing minimal risk to cell or organism. BioEssays 21:238–246, 1999. © 1999 John Wiley & Sons, Inc. (shrink)

Oxidised bases, such as 8-oxo-guanine, occur in cellular DNA as a result of attack by oxygen free radicals. The cancer-protective effect of vegetables and fruit is attributed to the ability of antioxidants in them to scavenge free radicals, preventing DNA damage and subsequent mutation. Antioxidant supplements (e.g., β-carotene, vitamin C) increase the resistance of lymphocytes to oxidative damage, and a negative correlation is seen between antioxidant concentrations in tissues and oxidised bases in DNA. Large-scale intervention trials with β-carotene (...) have, however, led to increases in cancer. Recent measurements of the frequency of oxidised DNA bases indicate that earlier estimates were greatly exaggerated; there may be only a few thousand 8-oxo-guanines per cell. Convincing evidence for mutations resulting from oxidative damage, in tumours or cultured cells, is lacking. It seems that efficient antioxidant defences together with DNA repair maintain a steady-state level of damage representing minimal risk to cell or organism. BioEssays 21:238–246, 1999. © 1999 John Wiley & Sons, Inc. (shrink)

Polyploid cells contain multiple copies of all chromosomes. Polyploidization can be developmentally programmed to sustain tissue barrier function or to increase metabolic potential and cell size. Programmed polyploidy is normally associated with terminal differentiation and poor proliferation capacity. Conversely, non‐programmed polyploidy can give rise to cells that retain the ability to proliferate. This can fuel rapid genome rearrangements and lead to diseases like cancer. Here, the mechanisms that generate polyploidy are reviewed and the possible challenges upon polyploid cell division (...) are discussed. The discussion is framed around a recent study showing that asynchronous cell cycle progression (an event that is named “chronocrisis”) of different nuclei from a polyploid cell can generate DNA damage at mitotic entry. The potential mechanisms explaining how mitosis in non‐programmed polyploid cells can generate abnormal karyotypes and genetic instability are highlighted. (shrink)

Caffeine, a known CNS stimulant is given as an adjunct component in most abused drugs which could be fatal with repeated administration in many circumstances. This paper presents a study to investigate the effect of repeated administration of caffeine at high dose on rat liver, and discusses ethical and policy issues of caffeine use. Long Evans rats were treated with pure caffeine solution in distilled water through intragastric route once daily for consecutive 56 days. Three groups of rats recognized as (...) low dose, high dose and control group received 6mg caffeine / kg BW, 12mg caffeine / kg BW and distilled water, respectively. Rat plasma was examined for liver transaminases and alkaline phosphatases concentrations which were significantly increased in plasma as compared to the control. Both rat plasma and liver homogenate were subjected to estimate malondialdehyde, advanced oxidation protein product, nitric oxide, antioxidant enzyme catalase, glutathione and superoxide dismutase activity. MDA, AOPP, NO levels increased and SOD activity decreased significantly in both plasma and liver as compared to those of control where as CAT and GSH activity remain unchanged. Rat liver tissues were studied histochemically with Hematoxylin and Eosin, and Picro Sirius Red staining. Significantly increased infiltration of inflammatory cells and progressive deposition of collagen fibre were visible in liver tissue of caffeine treated both dose groups as compared to the control. Long term administration of caffeine at higher dose, significantly contributes to liver inflammation and consequent fibrogenesis. This raises significant ethical and policy issues. (shrink)

Bodily sensations, such as pain, hunger, itches, or sexual feelings, are commonly characterized in terms of their phenomenal character. In order to account for this phenomenal character, many philosophers adopt strong representationalism. According to this view, bodily sensations are essentially and entirely determined by an intentional content related to particular conditions of the body. For example, pain would be nothing more than the representation of actual or potential tissue damage. In order to motivate and justify their view, strong (...) representationalists often appeal to the reliable causal covariance between bodily sensations and certain kinds of bodily conditions or to the corresponding biological function that these bodily sensations are supposed to fulfill. In this paper, I argue on the basis of recent empirical research that arguments from reliable causal covariance and biological function cannot motivate the introduction of corresponding intentional content. In particular, I argue that bodily sensations are caused by a heterogeneous class of physiological and psychological factors and their biological functions are too diverse to be reduced to the representation of a particular bodily condition. Responses are available to strong representationalists, but they either require substantial alterations to their core assumptions or incur a significant empirical burden. (shrink)

According to the increasingly popular perceptual/representational accounts of pain (and other bodily sensations such as itches, tickles, orgasms, etc.), feeling pain in a body region is perceiving a non-mental property or some objective condition of that region, typically equated with some sort of (actual or potential) tissue damage. In what follows I argue that given a natural understanding of what sensory perception requires and how it is integrated with (dedicated) conceptual systems, these accounts are mistaken. I will also (...) examine the relationship between perceptual views and two (weak and strong) forms of representationalism about experience. I will argue that pains pose very serious problems for strong representationalism as well. (shrink)

The IASP definition of 'pain' defines pain as a subjective experience. The Note accompanying the definition emphasizes that as such pains are not to be identified with objective conditions of body parts (such as actual or potential tissue damage). Nevertheless, it goes on to state that a pain "is unquestionably a sensation in a part or parts of the body, but it is also always unpleasant and therefore also an emotional experience." This generates a puzzle that philosophers have (...) been well familiar with: how to understand our utterances and judgments attributing pain to body parts. (The puzzle is of course general extending to all sensations routinely located in body parts.) The present work tackles this puzzle. I go over various options specifying the truth-conditions for pain attributing judgments, and at the end make my own recommendation which is an adverbialist, qualia-friendly proposal with completely naturalistic credentials that is also compatible with forms of weak intentionalism. The results are generalizable to other bodily sensations and can be used to illustrate, quite generally, the viability of a qualia-friendly adverbialist (but naturalist and weakly intentionalist) account of perception. (shrink)

The subject of biomaterials science concerns artificial materials used in medical devices to repair or reconstruct natural human tissue damaged by disease or trauma. It embraces the emerging field of tissue engineering, where artificial materials are used as scaffolds to provide the architecture for replacement organs. As such, the field raises numerous ethical issues, which are reviewed in this paper. These include the use of animal models, the testing materials and devices in patients, and what may be viewed (...) as potential abuses, where augmentation and repair are carried out for cosmetic as opposed to clinical reasons. The paper gives detailed consideration of the recent problems of metal-on-metal hip replacements as an exemplar of some of the key ethical issues that arise in this field. (shrink)

A scientific understanding of pain requires an experiential‐phenomenological approach and method, one that precedes mechanistic explanations provided by neuroscience, molecular neurobiology, and even the rest of psychology. A key challenge in this approach is to find ways to observe and characterize the experience of pain. An experiential method applied to both clinical and experimental pain has found three common factors in all instances of pain: a somatic or visceral experience that is comprised of 1) unique sensory qualities that are like (...) those which occur during tissue damaging stimulation, 2) a closely related meaning of intrusion and/or threat, and 3) a feeling of unpleasantness and/or other possible negative emotion(s) in response to 1 and 2. These three factors comprise an experiential definition of pain and they are each correlated with brain activities and functional connections that serve them. Much more is to be learned about the factors and their neural basis. (shrink)

In a recent paper, Reuter, Seinhold and Sytsma put forward an implicature account to explain the intuitive failure of the pain-in-mouth argument. They argue that utterances such as ‘There is tissue damage / a pain / an inflammation in my mouth’ carry the conversational implicature that there is something wrong with the speaker’s mouth. Appealing to new empirical data, this paper argues against the implicature account and for the entailment account, according to which pain reports using locative locutions, (...) such as ‘There is a pain in my mouth’, are intuitively understood as entailing corresponding predicative locutions, such as ‘My mouth hurts.’ On this latter account, the pain-in-mouth argument seems invalid because the conclusion is naturally understood as entailing something which cannot be inferred from the premisses. Implications for the philosophical debate about pain are also drawn. (shrink)

We present an ontology of pain and of other pain-related phenomena, building on the definition of pain provided by the International Association for the Study of Pain (IASP). Our strategy is to identify an evolutionarily basic canonical pain phenomenon, involving unpleasant sensory and emotional experience based causally in localized tissue damage that is concordant with that experience. We then show how different variant cases of this canonical pain phenomenon can be distinguished, including pain that is elevated relative to (...) peripheral trauma, pain that is caused neuropathically (thus with no necessary peripheral stimulus), and pain reports arising through deception either of self or of others. We describe how our approach can answer some of the objections raised against the IASP definition, and sketch how it can be used to support more sophisticated discrimination of different types of pain resulting in improved data analysis that can help in advancing pain research. (shrink)

Pain assessment in fish is particularly challenging due toBioscience Building, Liverpool, L69 7ZB their evolutionary distance from humans, their lack of audible vocalization, and apparently expressionless demeanour. However, there are criteria that can be used to gauge whether pain perception occurs using carefully executed scientific approaches. Here, the standards for pain in fish are discussed and can be considered in three ways: neural detection and processing of pain; adverse responses to pain; and consciously experiencing pain. Many procedures that we subject (...) fish to cause tissue damage and may give rise to the sensation of pain. Fish are popular as pets, in animal exhibits, and as experimental models, but are also cultured or caught for food. There is little legislation for the protection of fish welfare. Many countries are now exploring the welfare cost to fish, and current practices may need to be reviewed with respect to the current evidence for fish perceiving pain. (shrink)

Pain is most often an unpleasant experience that alerts us to actual or possible tissue damage. However, insisting that pain is always bad news may hinder understanding of pain’s many facets. Despite its unpleasantness – or perhaps because of it – pain is known to enhance the perceived value of certain activities, such as punishment or endurance sports. Here, we review evidence for a series of mechanisms involved in putative benefits of pain. A byproduct of pain’s attention-grabbing quality (...) can be enhanced perception of concurrent pleasurable stimuli. This is thought to explain why pain may augment the pleasure of spicy foods. By providing an aversive contrast, pain can also improve the experience of events that follow pain’s offset and lead to pleasant relief. Other potential benefits of pain derive from its ability to inhibit other unpleasant experiences and to elicit empathy and social support. The experience of pain can benefit our defence systems, since pain can enhance motivation to accumulate resources such as social support and calorie-rich foods. It can also reduce the guilt we feel after self-indulgence or moral transgressions. In sum, we highlight a series of potentially positive effects linked to pain. This framework can aid the understanding of why people sometimes seek out, enjoy, and gain rewards from pain as well as pleasure. (shrink)

In eukaryotes, small amounts of nitrite confer cytoprotection against ischemia/reperfusion‐related tissue damage in vivo, possibly via reduction to nitric oxide (NO) and inhibition of mitochondrial function. Several hemeproteins are involved in this protective mechanism, starting with deoxyhemoglobin, which is capable of reducing nitrite. In facultative aerobic bacteria, such as Pseudomonas aeruginosa, nitrite is reduced to NO by specialized heme‐containing enzymes called cd1 nitrite reductases. The details of their catalytic mechanism are summarized below, together with a hypothesis on the (...) biological role of the unusual d1‐heme, which, in the reduced state, shows unique properties (very high affinity for nitrite and exceptionally fast dissociation of NO). Our results support the idea that the nitrite‐based reactions of contemporary eukaryotes are a vestige of earlier bacterial biochemical pathways. The evidence that nitrite reductase activities of enzymes with different cellular roles and biochemical features still exist today highlights the importance of nitrite in cellular homeostasis. (shrink)

My account of the causal role of consciousness in a physical world is modeled on Dretske’s celebrated explanation of the causal role of beliefs (something that Dretske himself never offered). First, behavior must be understood as a (broadly individuated) process that begins with some external stimulus causing some neurological event C, and ends with causing a bodily movement M (e.g., the Kennedy assassination is a process that begins with Oswald pulling the trigger at 12:30pm CST on November 23 in 1963 (...) in Dallas, Texas, but only ends half an hour later when Kennedy is pronounced dead at 1 pm CST). The internal neurological event C causes bodily movement M, but only by virtue of being recruited by natural selection to represent the instantiation of some external property F when properly stimulated under normal circumstances. But the reason why C causes M lies in the fact that C represents the instantiation of the external property F. I withdraw my hand from a hot surface because the activation of nociceptive specific neurons in my parietal lobe (together with the activation of neuronal patterns in my motor cortices) was recruited by natural selection to represent the tissue damage in my hand. The activation of nociceptive specific neurons causes my hand to withdraw but for the reason that it represents tissue data at the time that I felt pain in my hand. (shrink)

Radioactivity accompanied by ionizing radiation has always existed on the Earth, as well as in space, and so in every living tissue there are traces of radioactivity. With the discovery of the said radiation and identifying its effects on the human body, the fear of this phenomenon appeared. At high doses radiation causes serious tissue damages, while at small doses it can cause cancer and induce genetic defects. The best antidote for fear is knowledge. It is important to (...) know the margins safety of radiation for human life. As a result, the topic of radioactive contamination of the environment has now become one of the most significant. In recent years the radon problem is a subject of a wide debate of geologists, geophysicists, ecologists, physicians, specialists in radiometry, and, of course, philosophers and sociologists, since the need for assessing the potential radon danger concerns human lives, human functions in society, and human future. (shrink)

Sickle cell disease is an autosomal recessive hemoglobinopathy found mainly in populations of African and Mediterranean descent, including approximately 100,000 Americans. It is also very common in Spanish-speaking regions of Central America, South America, and parts of the Caribbean, in Saudi Arabia, and in India and Sri Lanka. The disorder is characterized most commonly by lifelong recurrent unpredictable vaso-occlusive pain that may be disabling, and by chronic tissue damage and organ dysfunction. There are several genotypes of the disease. (...) Although SCD pain frequency generally varies between genotypes, it also varies between subjects even within genotype. It may worsen from childhood to adulthood. It may vary by gender. Its location, timing, and severity may be unpredictable.Until recently, pain in SCD had been characterized as episodes that were acute, periodic, and relatively rare. Crises were viewed as usually associated with hospitalization. Many patients utilized hospital or emergency care for pain once per year or less, so painful episodes in SCD were called vaso-occlusive “crises.”. (shrink)

The paradox of pain is that pain is in some ways like a bodily state and in other ways like a mental state. You can have a pain in your shin, but there is no denying that you are in pain if it feels like you are. How can a state be both in your shin and in your mind? Evaluativism is a promising answer. According to evaluativism, an experience of pain in your shin represents that there is a disturbance (...) in your shin, and that it is bad that this disturbance is there. Thus, the experience brings you to tend to your shin by telling you something about the state of your shin. But the paradox of pain still confronts evaluativism in the form of the killing the messenger objection: The evaluativist has a nice story about our body‐directed responses to pain, like tending to wounds, but this story does not explain responses to pain, like taking painkillers, that seem to be experience‐directed. Evaluativists have offered accounts of experience‐directed responses to pain, but I will argue that these accounts conflict with the Transparency thesis—the claim that we can only access our experiences inferentially. Evaluativism and Transparency are natural bedfellows, so this is a problem for evaluativists. Having argued as much, I will go on to develop a new evaluativist account of taking painkillers, which does not conflict with Transparency. I call it naïve evaluativism. According to naïve evaluativism, we experience painkillers as making tissue damage or disruption less bad, and absent further reflection, that is, why we take them. (shrink)

Different ethical principles conflict in research conducted in emergency research. Clinical care and its development should be based on research. Patients in critical clinical condition are in the greatest need of better medicines. The critical condition of the patient and the absence of a patient representative at the critical time period make it difficult and sometimes impossible to request an informed consent before the beginning of the trial. In an emergency, care decisions must be made in a short period of (...) time, and the more time is wasted, the more the risk of death or severe tissue damage and incapacity increases. Consent requests take time, and so the time period before treatment might put the patient’s life in jeopardy. Not requesting consent before a trial is also contradictory. A person should not be forced to participate in a trial against his or her will. Due to the dark history of medical research previously, international declarations and conventions have set up ethical principles for medical research. They emphasize the autonomy of the research participant—or his or her legal representative—to give a free and informed consent prior to the initiation of research. In the case of a critical emergency, the unconscious state of the patient, the emotional stress of family members or the lack of time to start life-sustaining measures may often restrict the possibilities of communicating with the patient or his/her representative. Therefore, written informed consent is difficult to achieve, and its voluntariness in emergency situations is, at best, open to question. The mortality of patients is high without clinical interventions in emergency research. Random selection of patients is difficult and requires extra work from personnel in the emergency rooms. Recruitment, information and asking for consent may also take time, postpone the initiation of treatment and increase the risk of death and irreversible tissue and organ damage, and therefore be risky for the patient. It is therefore essential that the health care professionals recruiting suitable research participants are well motivated and well trained. Medical research in an emergency setting should always be regarded as an exceptional situation requiring special provisions. Only such research should be done as cannot be done in other conditions. An independent body must approve the research protocol and the ways in which the consent of the participant or proxy are to be sought. In addition, the trial must be expected to result in direct and significant benefit for the research participants. If research without prior consent is not approved, the development of emergency care is threatened. On the other hand, if prior consent is not required, a person could be recruited into a clinical trial against his or her will. Doing good and avoiding harm, and respecting the autonomy of the patient are in conflict in the context of emergency medical research. To develop better medicines for patients experiencing acute medical emergencies, research into such conditions should be allowed. Research participants should have the possibility to participate or refuse to participate in research that may benefit them and other patients. The risk of irreversible damage occurring as the consequence of time delays for seeking consent is unacceptable. A prior wish about participation in clinical trials should be respected, if known. The conditions under which medical research in emergencies can be considered acceptable can be determined and agreed upon nationally and internationally. (shrink)

Pain is not a single entity but is instead a collection of sensory experiences commonly associated with tissue damage. There is growing recognition that not all pains are equivalent, that pains and pathologies are not related in a simple manner, and that acute pains differ in many respects from persistent pains. Great strides have been made in improving our understanding of the neuronal mechanisms responsible for acute pain, but the studies leading to these advances have also led to (...) the realization that a bewildering array of processes are interposed between tissue damage and sensations of pain, especially in persistent pains. Persistent pains often seem unrelated or disproportionate to identifiable pathology, and they are modulated by a multitude of factors. This complexity in such a vital function serves as a challenge both to scientists seeking fundamental understanding and to clinicians faced with the immediate need to treat patients with painful disorders. (shrink)

A distinguishing characteristic of the biomedical model is its compartmentalized view of man. This way of seeing human beings has its origin in Greek thought; it was stated by Descartes and to this day it still considers humans as beings composed of distinct entities combined into a certain form. Because of this observation, one began to believe that the focus of a health treatment could be exclusively on the affected area of the body, without the need to pay attention to (...) patient’s subjectivity. By seeing pain as a merely sensory response, this model was not capable of encompassing chronic pain, since the latter is a complex process that can occur independently of tissue damage. As of the second half of the twentieth century, when it became impossible to deny the relationship between psyche and soma, the current understanding of chronic pain emerges: that of chronic pain as an individual experience, the result of a sum of physical, psychological, and social factors that, for this reason, cannot be approached separately from the individual who expresses pain. This understanding has allowed a significant improvement in perspective, emphasizing the characteristic of pain as an individual experience. However, the understanding of chronic pain as a sum of factors corresponds to the current way of seeing the process of falling ill, for its conception holds a Cartesian duality and the positivist premise of a single reality. For phenomenology, on the other hand, the individual in his/her unity is more than a simple sum of parts. Phenomenology sees a human being as an intending entity, in which body, mind, and the world are intertwined and constitute each other mutually, thus establishing the human being’s integral functioning. Therefore, a real understanding of the chronic pain process would only be possible from a phenomenological point of view at the experience lived by the individual who expresses and communicates pain. (shrink)

Like other fundamental experiences, the phenomenal qualities of pain seem to defy description. But, unlike these experiences, it is difficult to define pain in terms of a consistent relationship with the extra-mental world. The IASP's solution is to qualify an imprecise characterization of pain's phenomenal qualities through an association with tissue damage and an ability to recognize pain sensation. In this paper I will argue that the IASP's definition lacks the clarity and coherence necessary to provide an adequate (...) definition of pain. I begin by setting out the difficulties of defining pain. I then describe the IASP's solution and provide a detailed criticism of their approach. I also discuss inconsistencies evident in their wider taxonomy. In the final section I argue that pain can be objectively grounded by reference to pain's evolutionary role and suggest an alternative definition. (shrink)

Feelings associated with grief are regularly described as painful, but in what respect are they to be understood as pain? The acute pain of easily located tissue damage has long been the paradigm of pain in scientific and philosophical analysis, a dominance serving to obscure features the pain of grief might share not only with chronic pain but with some depressive suffering. Two examples of such commonalities are explored (ways pain feelings are experienced as in and of the (...) body; and are often recessed to the background of consciousness). These features are introduced to illustrate how a preliminary search for additional pain paradigms might proceed, and in so doing to offer some support for the proposal that pain endured as part of grieving may be real pain, not merely 'pain'. (shrink)

: Extreme pain and suffering are associated with depression as well as tissue damage. The impossibility of imagining any feelings of pain and suffering intersect with two matters: the kind of imagining involved, and the nature of delusions. These two correspond to the sequence of the following discussion, in which it is contended first that feelings of pain and suffering resist being imagined in a certain, key way, and second that, given a certain analysis of delusional thought, this (...) precludes the possibility of delusional affections while allowing delusions about affections. Keywords: Pain; Imagination; Delusion; Affection; Feelings Dolore immaginato e dolore illusorio Riassunto: Dolore estremo e sofferenza sono solitamente associati a depressione e danni tissutali. L’impossibilità di immaginare il provare dolore e sofferenza dipende da due fattori: il tipo di immaginazione coinvolta e la natura dell’illusione. Questi due fattori saranno trattati in parallelo nell’analisi che qui si propone, in cui si discuterà in primo luogo come il provare dolore e sofferenza oppongano resistenza all’essere immaginati in un certo modo e in secondo luogo come, secondo una certa analisi del pensiero illusorio, questo preclude la possibilità di affezioni illusorie mentre consente illusioni circa le affezioni. Parole chiave: Dolore; Immaginazione; Illusioni; Affezione; Sensazioni. (shrink)

If martin and rosenberg were right, It ought to have been possible for higher animals to evolve neural mechanisms that evoke complex avoidance-Of-Tissue-Damage behavior "without" their experiencing pain. The alleged identity of mental event types like pain with unspecified brain state types thus can have no evolutionary explanation. It will not do to say that these brain state types may be discovered some day to have a distinguishing property x, Since x would still be a physical property and (...) one could always ask why pain-Experience necessarily accompanies x-Propertied brain states, This being causally gratuitous to the behavior they would evoke without it "if" physicalism is true. (shrink)

I argue that an analogy between pains and sounds suggests a way to give an objective account of pain which fits well with a naïve perceptualist account of feeling pain. According to the proposed metaphysical account, pains are relational physical events with shared qualitative nature, each of which is constituted by tissue damage and the activation of nociceptors. I proceed to show that the metaphysical proposal is compatible with platitudes about pains being animate, private, and self-intimating states.

To enable microbial colonisation of the gut mucosa, the intestinal immune system must not only react to danger signals but also recognize cues that indicate safety. Safety recognition, paradoxically, is mediated by the same environmental sensors that are involved in signalling danger. Indeed, in addition to their well established role in inducing inflammation in response to stress signals, pattern recognition receptors (PRRs) and a variety of metabolic sensors also promote gut-microbiota symbiosis by responding to "microbial symbiosis factors", "resolution-associated molecular patterns", (...) markers of energy extraction and other signals indicating the absence of pathogenic infection and tissue damage. Here we focus on how the paradoxical role of immune receptors and other environmental sensors define the microbiota signature of the individual. (shrink)

To ensure their survival in natural habitats, plants must recognize and respond to a wide variety of insect herbivores. Aphids and other Hemiptera pose a particular challenge, because they cause relatively little direct tissue damage when inserting their slender stylets intercellularly to feed from the phloem sieve elements. Plant responses to this unusual feeding strategy almost certainly include recognition of aphid salivary components and the induction of phloem‐specific defenses. Due to the excellent genetic and genomic resources that are (...) available for Arabidopsis thaliana (Arabidopsis), this plant was chosen as a model system to study the metabolic and transcriptional responses to infestation by two aphids, Myzus persicae (green peach aphid, a broad generalist) and Brevicoryne brassicae (cabbage aphid, a crucifer‐feeding specialist). Future research on Arabidopsis–aphid interactions will lead to the identification of aphid‐specific elicitors, components of the defense‐signaling pathway, and additional metabolic responses that are induced by aphid infestation. BioEssays 29:871–883, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

The mammary gland is a skin gland unique to the class Mammalia. Despite a growing molecular and histological understanding of the development and physiology of the mammary gland, its functional and morphological origins have remained speculative. Numerous theories on the origin of the mammary gland and lactation exist. The purpose of the mammary gland is to provide the newborn with copious amounts of milk, a unique body fluid that has a dual role of nutrition and immunological protection. Interestingly, antimicrobial enzymes, (...) such as xanthine oxidoreductase or lysozyme, are directly involved in the evolution of the nutritional aspect of milk. We outline that xanthine oxidoreductase evolved a dual role in the mammary gland and hence provide new evidence supporting the hypothesis that the nutritional function of the milk evolved subsequent to its protective function. Therefore, we postulate that the mammary gland evolved from the innate immune system. In addition, we suggest that lactation partly evolved as an inflammatory response to tissue damage and infection, and discuss the observation that the two signaling pathways, NF‐kB and Jak/Stat, play central roles in inflammation as well as in lactation. BioEssays 28: 606–616, 2006. © 2006 Wiley Periodicals, Inc. (shrink)

Cellular mechanisms whereby quiescent stem cells sense tissue injury and transition to an activated state are largely unknown. Quiescent skeletal muscle stem cells (MuSCs, also called satellite cells) have elaborate, heterogeneous projections that rapidly retract in response to muscle injury. They may therefore act as direct sensors of their niche environment. Retraction is driven by a Rac‐to‐Rho GTPase activity switch that promotes downstream MuSC activation events. These and other observations lead to several hypotheses: (1) projections are morphologically dynamic at (...) quiescence, providing a surveillance function for muscle damage; (2) quiescent projection dynamics are regulated by the relative balance of Rac and Rho activities promoted by niche‐derived cues; (3) projections, particularly their associated filopodia, sense tissue damage via changes to the biomechanical properties of the niche and/or detection of signaling cues released by damaged myofibers; and (4) the dynamic nature of projections results in a population of MuSCs with heterogeneous functional properties. These concepts may extend to other types of quiescent stem cells, as well as prove useful in translational research settings. (shrink)

BackgroundThe evaluation of pain remains one of the most difficult challenges that healthcare practitioners face. Chronic pain appears to affect more than 35% of the population in the West, and indeed, pain is the most common reason patients seek medical care. Despite its ubiquity, studies in the last decades reveal that many patients feel their pain is dismissed by healthcare practitioners and that, as a result, they are denied proper medical care. Buchman, Ho, and Goldberg (J Bioethic Inq 14:31-42, 2017) (...) point to this phenomenon as a form of “epistemic injustice”: an unfair and harmful downgrading of credibility affecting some individuals and groups, which prevents them from receiving appropriate and beneficial medical care.MethodsBy exploring the existing literature on this downgrading of patients’ credibility written by healthcare professionals and scholars in medical humanities, I identify and examine the reasons patients are often not believed about their pain and why healthcare is too-often unhelpful or hurtful to people presenting with chronic pain. I also explore to what extent it is possible to forge an alternative epistemological model.ResultsI suggest that most of the causes of this downgrading of patient’s credibility result from either the difficulty in communicating pain or the widespread belief that pathology is always the result of objective tissue damage. I examine whether pain has to be effectively communicated and have an objective cause in order for it to be deemed credible. In the end, I argue that in the case of pain, both communication and objectivity are highly problematic.ConclusionsI conclude by suggesting that, although alternative epistemological models might be impossible to build, believing patients has both moral and clinical benefits, and this warrants further research. (shrink)

Receptor‐mediated stimulation induces massive actin polymerization and cyto‐skeletal reorganization. The activity of a potent actin‐modulating protein, gelsolin, is regulated both by Ca2+ and polyphos‐phoinositides, and it may have a pivotal role in restructuring the actin cytoskeleton in response to agonist stimulation. Structure‐function analysis of gelsolin has (1) indicated that its NH2‐terminal half is primarily responsible for modulating actin filament length and polymerization; and (2) elucidated mechanisms by which Ca2+ and phospholipids may regulate such functions. Gelsolin is functionally and structurally similar (...) to villin, another Ca2+‐activated actin‐severing protein found in microvilli, suggesting that gelsolin may be a prototype of this family of actin‐modulating proteins. A molecular variant of gelsolin is secreted and may be involved in the clearance of actin filaments released during tissue damage. The two forms of gelsolin are encoded by a single gene, and distinct messages are derived by alternative message splicing. (shrink)

As the prevalence of self-harm among adolescents in Chinese escalates, finding out the potential risk factors associated with self-harm behaviors has aroused much attention. This study aims to explore the association between parent-child separation and series of self-harm subtypes among Chinese adolescents. We survey a total of 4,928 middle school students aged from 12 to 18 years at school. Parent-child separation was investigated from four dimensions—occurrence of parental separation, separation status, age at first separation and duration of separation. Self-harm series (...) are deemed as five subtypes—highly lethal self-harm, less lethal self-harm with visible tissue damage, self-harm without visible tissue damage, self-harmful behaviors with latent damage and psychological self-harm. Multivariate logistic regression is used to explore the associations between parent-child separation and different subtypes of self-harm among adolescents. Paternal separation is associated with each type of self-harm whilst maternal separation is not correlated with highly lethal self-harm. Except for highly lethal self-harm, the other four subtypes of self-harm demonstrate a relation with both length of paternal separation and maternal separation with aOR ranging from 1.02 to 1.06. Individuals who suffer parental separation prior to the age of three were at a higher risk for four types of less-lethal self-harm. The association of parent-child separation with self-harm deserves our attention, and future research is needed to identify the underlying mechanisms. (shrink)

Michael Tye argues for two crucial theses: (1) that experiences of pain have representational content (essentially); (2) that the representational content can be specified in terms of something like damage in parts of the body. (Different types of pain are connected with different types of damage.) I reject both of these theses. In my view experiences of pain carry nonconceptual content, but do not represent essentially. Rather they are apt to represent when the subject attends to them. The (...) experiences carry nonconceptual content not only about tissue damage, but about many other qualities as well, including dispositional qualities. (shrink)

There are some conspicuous differences between the sensibilities of cutaneous and visceral tissues: (1) Direct trauma, which readily produces pain when applied to the skin, is mostly without effect in healthy visceral tissue. (2) Pain that arises from visceral tissues is initially often poorly localised and diffuse. (3) With time, visceral pains are often referred to more superficial structures. (4) The site of referred pain may also show hyperalgesia. (5) In disease states, the afflicted viscera may also become hyperalgesic. (...) In this target article, I consider to what extent differences in the physiology, anatomy, and chemistry of peripheral processing systems explain these different sensibilities. In almost every aspect, there are subtle differences in the properties of the processing mechanisms for cutaneous and visceral information. These may arise because of distinct developmental cues operating in the two domains. Many of the differences between visceral and cutaneous afferents are quantitative rather than qualitative. The quantitative differences, for example in the density of afferent innervation, can be large. The quantitative differences in the numbers of afferents alone may be a sufficient explanation for some aspects of the differential sensibility, for example, the poor localisation of sensation and the apparent insensitivity to focal yet tissue- damaging stimuli. In addition, the few clear qualitative differences apparent in the innervations of the two tissue types may be of special importance. That the encoding of visceral nociceptive events may occur by an intensity mechanism rather than a specificity mechanism could be the key difference in viscerosensory and somatosensory processing. (shrink)

As the spread of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) continues to surge worldwide, our knowledge of coronavirus disease 2019 (COVID‐19) is rapidly expanding. Although most COVID‐19 patients recover within weeks of symptom onset, some experience lingering symptoms that last for months (“long COVID‐19”). Early reports of COVID‐19 sequelae, including cardiovascular, pulmonary, and neurological conditions, have raised concerns about the long‐term effects of COVID‐19, especially in hard‐hit communities. It is becoming increasingly evident that cancer patients are more susceptible to (...) SARS‐CoV‐2 infection and are at a higher risk of severe COVID‐19 than the general population. Nevertheless, whether long COVID‐19 increases the risk of cancer in those with no prior malignancies, remains unclear. Given, the disproportionate impact of the disease on the African American community, yet another unanswered question is whether racial disparities are to be expected in COVID‐19 sequelae. Herein, we propose that long COVID‐19 may predispose recovered patients to cancer development and accelerate cancer progression. This hypothesis is based on growing evidence of the ability of SARS‐CoV‐2 to modulate oncogenic pathways, promote chronic low‐grade inflammation, and cause tissue damage. Comprehensive studies are urgently required to elucidate the effects of long COVID‐19 on cancer susceptibility. (shrink)

Genomes are inherently unstable because of the need for DNA sequence variation as a substrate for evolution through natural selection. However, most multicellular organisms have postmitotic tissues, with limited opportunity for selective removal of cells harboring persistent damage and deleterious mutations, which can therefore contribute to functional decline, disease, and death. Key in this process is the role of genome maintenance, the network of protein products that repair DNA damage and signal DNA damage response pathways. Genome maintenance (...) is beneficial early in life by swiftly eliminating DNA damage or damaged cells, facilitating rapid cell proliferation. However, at later ages accumulation of unrepaired damage and mutations, as well as ongoing cell depletion, promotes cancer, atrophy, and other deleterious effects associated with aging. As such, genome maintenance and its phenotypic sequelae provide yet another example of antagonistic pleiotropy in aging and longevity. (shrink)

Cognitive deficits were produced in rats by different methods of damaging the brain: chronic ingestion of alcohol, causing widespread damage to diffuse cholinergic and aminergic projection systems; lesions (by local injection of the excitotoxins, ibotenate, quisqualate, and AMPA) of the nuclei of origin of the forebrain cholinergic projection system (FCPS), which innervates the neocortex and hippocampal formation; transient cerebral ischaemia, producing focal damage especially in the CA1 pyramidal cells of the dorsal hippocampus; and lesions (by local injection of (...) the neurotoxin, colchicine) of the granule cells of the dentate gyrus. Following chronic alcohol or lesions of the FCPS, transplants of cholinergically rich fetal brain tissue into the terminal areas (neocortex and/or hippocampus) restored performance almost to control levels, with a time course consistent with growth of the transplants and integration with host tissue; transplants of cholinergically poor fetal tissue (hippocampus) were without effect, as were transplants of cholinergically rich tissue into the region containing the nuclei of origin of the FCPS. Grafts of primary cells enriched in glia and cultured neuroblastoma cells into the terminal areas of the FCPS were equally effective, suggesting that there are multiple mechanisms by which neural transplants can restore cognitive function following diffuse cholinergic damage. In contrast, after ischaemia- or neurotoxin-induced damage to CA1 or dentate granule cells respectively, cholinergically rich fetal transplants into the damaged hippocampal formation were ineffective in restoring performance. After ischaemic damage, however, performance was restored by suspension grafts of CA1 cells but not by transplants containing CA3 pyramidal cells or granule cells; and after colchicine damage it was restored by solid grafts containing granule but not CA1 pyramidal cells. Furthermore, electrophysiological evidence has demonstrated functional, graft type-specific host-graft functional neuronal connectivity. Thus, restoration of cognitive function by neural transplants is possible after damage to either diffuse (cholinergic) or point-to-point (intrahippocampal) forebrain systems, but the transplant must be appropriate to the damage to be repaired. Because the different types of brain damage studied provide analogues of human alcoholic dementia, Alzheimer's disease, and heart attack, these results are encouraging with regard to the eventual application of neural transplant surgery to the treatment of cognitive deficits in humans. (shrink)