The N‐end rule denotes the relationship between the identity of the amino‐terminal residue of a protein and its in vivo half‐life. Since its discovery in 1986, the N‐end rule has generally been described by a defined set of rules for determining whether an amino‐terminal residue is stabilizing or not. However, recent studies are revealing that this N‐end rule (or N‐degron concept) is less straightforward than previously appreciated. For instance, it is unveiled that N‐terminal acetylation of N‐terminal residues (...) may create a degradation signal (Ac‐degron) that promotes the degradation of target proteins. A recent high‐throughput dissection of degrons in yeast proteins amino termini intriguingly suggested that the hydrophobicity of amino‐terminal residues—but not the N‐terminal acetylation status—may be the indispensable feature of amino‐terminal degrons. Herein, these recent advances in N‐terminal acetylation and the complexity of N‐terminal degradation signals in the context of the N‐degron pathway are analyzed. (shrink)

The N‐terminal domain of histone H4 has been implicated in various nuclear functions, including gene silencing and activation and replication‐linked chromatin assembly. Many of these have been identified by using H4 mutants in the yeast S. cerevisiae. In a recent paper, Megee et al.(1) use this approach to show that mutants in which all four N‐terminal H4 lysines are substituted with glutamines accumulate increased levels of DNA damage. A single lysine, but not an arginine, anywhere in the (...) class='Hi'>N‐terminal domain suppresses this phenotype. It is suggested that histone H4 plays a role in maintaining genome integrity through the cell cycle, possibly by a mechanism involving lysine acetylation. (shrink)

The ring‐shaped ATPase machine, cohesin, regulates sister chromatid cohesion, transcription, and DNA repair by topologically entrapping DNA. Here, we propose a rigid scaffold model to explain how the cohesin regulators Pds5 and Wapl release cohesin from chromosomes. Recent studies have established the Smc3‐Scc1 interface as the DNA exit gate of cohesin, revealed a requirement for ATP hydrolysis in ring opening, suggested regulation of the cohesin ATPase activity by DNA and Smc3 acetylation, and provided insights into how Pds5 and Wapl (...) open this exit gate. We hypothesize that Pds5, Wapl, and SA1/2 form a rigid scaffold that docks on Scc1 and anchors the N‐terminal domain of Scc1 (Scc1N) to the Smc1 ATPase head. Relative movements between the Smc1‐3 ATPase heads driven by ATP and Wapl disrupt the Smc3‐Scc1 interface. Pds5 binds the dissociated Scc1N and prolongs this open state of cohesin, releasing DNA. We review the evidence supporting this model and suggest experiments that can further test its key principles. (shrink)

Acetylation of internal lysine residues of core histone N-terminal domains has been found correlatively associated with transcriptional activation in eukaryotes for more than three decades. Recent discoveries showing that several transcriptional regulators possess intrinsic histone acetyltransferase (HAT) and deacetylase (HDAC) activities strongly suggest that histone acetylation and deacetylation each plays a causative role in regulating transcription. Intriguingly, several HATs have been shown an ability to acetylate nonhistone protein substrates (e.g., transcription factors) in vitro as well, suggesting the possibility (...) that internal lysine acetylation of multiple proteins exists as a rapid and reversible regulatory mechanism much like protein phosphorylation. This article reviews recent developments in histone acetylation and transcriptional regulation. We also discuss several important, yet unanswered, questions. BioEssays 20:615–626, 1998. © 1998 John Wiley & Sons Inc. (shrink)

_The purpose _of this article is to find out whether philosophical and anthropological studies of human nature affect the legitimization of decisions about human life and death, using the example of a philosophical analysis of the problem of euthanasia. _Theoretical__ basis._ Philosophically and anthropologically based situational analysis in bioethics is chosen as the research methodology, which reveals the legitimation of euthanasia as a complex and highly responsible moral decision, which should be based on both the consideration of all the patient’s (...) special circumstances and the competent and adequate application of fundamental knowledge about the human being. _Originality._ From a philosophical point of view, it would be correct to legalize euthanasia, but under the condition of significantly limiting the cases of its application, clearly defining the conditions for its provision and strict control over its implementation. It is morally unacceptable to justify either murder or torture, so euthanasia appears as an attempt to avoid both at the same time. _Conclusions._ Specific solutions to practical problems often indicate the necessary direction for solving theoretical difficulties. Thus, making proper moral decisions about euthanasia requires reliance on fundamental knowledge about human beings, but at the same time it provides arguments "for" and "against" artificial termination of life. The basic principles of bioethics – autonomy, nonmaleficence, beneficence and respect for the dignity of human life – serve as criteria for making balanced ethical decisions both in theory and in practice. These principles should be complemented by a coherent ethical, legal and philosophical position on euthanasia, which is achieved through legitimation procedures. Decisive for making a decision on euthanasia should be the strong desire of the patient himself. (shrink)

Objectives To explore attitudes and reasoning among Swedish physicians and the general public regarding the withdrawal of life-sustaining treatment at a competent patient's request. Design A vignette-based postal questionnaire including 1202 randomly selected individuals in the county of Stockholm and 1200 randomly selected Swedish physicians with various specialities. The vignettes described patients requesting withdrawal of their life-sustaining treatment: (1) a 77-year-old woman on dialysis; (2) a 36-year-old man on dialysis; (3) a 34-year-old ventilator-dependent tetraplegic man. Responders were asked to classify (...) the act of terminating treatment and to prioritise arguments for/against. Results A majority in both groups prioritised arguments in favour of terminating treatment and classified the act as defensible in all vignettes. However, among the general public, 16% classified the act as euthanasia in all vignettes; among physicians this view was most expressed regarding ventilator treatment (26%). Some who classified the act as euthanasia prioritised arguments in favour of terminating treatment: among physicians 18% in vignette 1, 19% in vignette 2 and 34% in vignette 3; among the general public 35% in vignette 1, 20% in vignette 2 and 48% in vignette 3. Conclusion There is a widespread consensus regarding competent patients' right to abstain from life-sustaining treatment. An association between the hastening of death, caused by the withdrawal of life-sustaining treatment and the concept of euthanasia is proposed. The results also suggest that classifying the withdrawal of life-sustaining treatment as ‘euthanasia’ does not necessarily mean that the act is interpreted as ethically unacceptable. (shrink)

Mutations in the CEBPA gene are present in 10–15% of acute myeloid leukemia (AML) patients. The most frequent type of mutations leads to the expression of an N‐terminally truncated variant of the transcription factor CCAAT/enhancer‐binding protein alpha (C/EBPα), termed p30. While initial reports proposed that p30 represents a dominant‐negative version of the wild‐type C/EBPα protein, other studies show that p30 retains the capacity to actively regulate gene expression. Recent global transcriptomic and epigenomic analyses have advanced the understanding of the distinct (...) roles of the p30 isoform in leukemogenesis. This review outlines direct and indirect effects of the C/EBPα p30 variant on oncogenic transformation of hematopoietic progenitor cells and discusses how studies of N‐terminal CEBPA mutations in AML can be extrapolated to identify novel gain‐of‐function features in oncoproteins that arise from recurrent truncating mutations in transcription factors. (shrink)

The c‐Jun N‐terminal kinases (JNKs) are members of the mitogen‐activated protein kinase (MAPK) family. In mammalian genomes, three genes encode the JNK family. To evaluate JNK function, mice have been created with deletions in one or more of three Jnk genes. Initial studies on jnk1−/− or jnk2−/− mice have shown roles for these JNKs in the immune system whereas studies on jnk3−/− mice have highlighted roles for JNK3 in the nervous system. Further studies have highlighted the contributions of JNK1 (...) and/or JNK2 to a range of biological and pathological processes. These include bone remodelling and joint disease, inflammatory and autoimmune diseases, obesity, diabetes, cardiovascular disease, liver disease and tumorigenesis in addition to effects in neurons. These results emphasise the differences in the roles played by JNK isoforms in vivo and suggest that the design of JNK inhibitors for subsequent therapeutic uses may benefit from selective inhibition of individual JNK isoforms. BioEssays 28: 923–934, 2006. © 2006 Wiley periodicals, Inc. (shrink)

During the eukaryotic cell cycle, chromosomes undergo large structural transitions and spatial rearrangements that are associated with the major cell functions of genome replication, transcription and chromosome condensation to metaphase chromosomes. Eukaryotic cells have evolved cell cycle dependent processes that modulate histone:DNA interactions in chromosomes. These are; (i) acetylations of lysines; (ii) phosphorylations of serines and threonines and (iii) ubiquitinations of lysines. All of these reversible modifications are contained in the well‐defined very basic N‐ and C‐ terminal domains of histones. (...) Acetylations and phosphorylations markedly affect the charge densities of these domains whereas ubiquitination adds a bulky globular protein, ubiquitin, to lysines in the C‐terminal tails of H2A and H2B. Histone acetylations are strictly associated with genome replication and transcription; histone H1 and H3 phosphorylations correlate with the process of chromosome condensation. The subunits of histone H1 kinase have now been shown to be cyclins and the p34CDC2 kinase product of the cell cycle control gene CDC2. It is probable that all of the processes that control chromosome structure:function relationships are also involved in the control of the cell cycle. (shrink)

It has long been believed that membrane proteins present in degradative compartments such as endolysosomes or vacuoles would be destined for destruction. Now however, it appears that mechanisms and machinery exist in simple eukaryotes such as yeast and more complex organisms such as mammals that can rescue potentially “doomed” membrane proteins by retrieving them from these “late” compartments and recycling them back to the Golgi complex. In yeast, a sorting nexin dimer containing Snx4p can recognize and retrieve the Atg27p membrane (...) protein while in mammals, the AP5 complex (with SPG11 and SPG15) directs the recycling of Golgi‐localized proteins along with the cation‐independent mannose 6‐phosphate receptor (CIMPR). Although the respective machinery is different, there is much commonality between yeast and mammals regarding the mechanisms of retrieval and the physiological importance of these late recycling pathways. (shrink)

Ravelingien et al1 argue that, given the restrictions that must be imposed on recipients of xenotransplanted organs, we should conduct clinical trials of xenotransplantation only on patients in a persistent vegetative state. I argue that there is no ethical barrier to using terminally ill patients instead. Such patients can choose to waive their rights to the liberties that xenotransplantation would probably restrict; it is surely rational to prefer to waive your rights rather than to die, and permissible to allow patients (...) to make this choice.Perhaps the single most important advance in the history of moral thought occurred when it came to be generally recognised that all people are protected by rights that are inviolable, at least without their consent. The precise nature and content of these rights is controversial, but there is a consensus among reasonable people over their core. We all have a right to life, to liberty, to security of person and to equality before the law. Other rights—so-called positive rights, such as the right to economic security, or cultural rights, for instance—may be controversial, but we all agree at least on these.Ravelingien et al1 therefore seem to be on solid ground when they conclude that it would not be permissible to use living persons as subjects in clinical trials of xenotransplantation, as such trials, potentially or actually, result in the violation of the core human rights of the subjects. Their argument is as follows:" Xenotransplantation carries with it a currently unquantifiable risk of the transmission of viruses, from the animal that is the source of the organ transplanted, to the human recipient. Such viruses could have potentially catastrophic consequences, up to and including triggering a global and devastating pandemic. Therefore, it would be necessary to monitor the health status of recipients of … ". (shrink)

In The Concept of Mind, Ryle's official position seems to be that mental acts cannot be intrinsically private. In The Concept of Mind as well as his later work on thinking, Ryle views thinking as an activity that terminates in a thought, which is a state of being prepared for a performance. Thinking is characterised by what Ryle calls intention-parasitism; for it is, insofar as its underlying motive is concerned, parasitic on the final performance which will take place later. Ryle (...) shows that acts of thinking, owing to their intention-parasitism, can be described in a tactical idiom, with reference to the final performance for which it was intended. However, this framework of intention-parasitism is not adequate to describe all instances of thinking in all their aspects, which therefore remain inextricably private. The task of this paper is to accommodate such privacy within the theoretical framework suggested in The Concept of Mind. (shrink)

Dès le moment de la Réforme, l'Église protestante s'est constituée en une communauté plurielle, marquée par des sensibilités diverses. Cette diversité paraît justifier le constat de tendances plus libérales marquant une confiance plus optimiste dans les capacités d'action des hommes, tandis que des tendances plus doctrinales soulignent plus volontiers le poids du mal. Après le rappel des caractéristiques et développements d'une tradition libérale moderne au XIX° siècle, avec l'évocation de la figure d'Harnack, l'auteur soulève la question des rapports de cette (...) tradition avec le mouvement oecuménique, rapports marqués par les événements liés aux deux Guerres mondiales, ce qui lui fait évoquer en terminant la figure de Karl Barth.From the moment of the Reformation the Protestant Church constituted itself into a plural community, marked by diverse sensibilities. This diversity appears to justify the appearance of more liberal tendencies, which indicate a more optimistic confi­dence in the capacities of men's actions, while the more doctrinal tendencies readily underline the weight of evil. After recalling the characteristics and developments of the modern liberal tradition in the 19th century, evoking the personage of Harnack, the author raises the question of the relationships of this tradition with the ecumenical movement. These relationships were effected by the events related to the two World Wars, which leads the author to refer, at the end, to Karl Barth. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:Criminal Law, Pain Relief, and Physician Aid in DyingFaye Girsh, Ed.D., Executive DirectorMadam:The article by Cantor and Thomas on “Pain Relief, Acceleration of Death, and Criminal Law” (KIEJ, June 1996) was a tortured attempt to develop criteria for the humane and compassionate physician who tries to serve the needs of a patient in unremitting pain. There are three areas that merit comment.The authors dealt with pain medications that might (...) have the undesirable side effect of causing death. They did not mention tolerance, which usually occurs in a patient with chronic pain and which would require exceedingly high doses to be effective. They did not mention barbiturates, which are preferable to opiates in causing death and which are used increasingly by compassionate physicians to answer the pleas of their suffering patients, but for which there is no excuse about alleviating pain. Would the criminal law just call the prescription of a lethal dose of barbiturates a reckless act and require conviction? Fortunately, juries, as the authors point out, do not balance these formulas on the head of a pin. When they see the circumstances under which these doctors do help their patients, they choose to nullify the law and would ignore the suggestions made in this article.The authors refer to the “consent” of the patient. They do not mention that these doctors are operating with more than consent; they are administering these medications because suffering patients are begging them to put them out of their pain and the indignities of the dying process. The article discusses the process as though it were the same as consent to elective surgery. These patients—with AIDS, cancer, and hopeless neurological degeneration—are not simply agreeing to a procedure; they are desperately seeking a way out. If the criminal law were to develop criteria for physician aid in dying, certainly one of them should be the active, witnessed, repeated request of such a patient for a certain, quick, painless, gentle death.The third point is that physicians do not face prosecution when administering no treatment to a patient whose life could be saved with treatment but who chooses not to receive it. This has been upheld by the U.S. Supreme Court; no criteria for suffering, alternatives, terminality, justifiability, or unbearability are required. The doctor can stand by while the patient dies what may be a protracted, difficult death, but it is within the law. What matters in this situation is the decision of the patient to refuse treatment, and that is absolute. How ironic that the patient who cannot refuse treatment must, with his or her doctor, jump through all these hoops to achieve a peaceful death.One worries that the physician who must balance the risk of “risky pain relief” against the accusation of recklessness will err in the direction of allowing [End Page 103] the patient to bear the pain rather than help with a dose of analgesics that might be considered beyond the stipulated “risk.”Why don’t we just be honest about it? Allow dying or hopelessly ill patients to make the decision about what they want by passing a carefully defined law allowing euthanasia rather than balancing the risk and trying to determine the “purpose” of the physician’s ministrations. We protect some patients from themselves while allowing others almost complete autonomy to make the choice of ending their lives. The authors were right in saying that proponents of rational laws consider this sheer hypocrisy.Faye Girsh, Executive DirectorHemlock Society U.S.A. Denver, COFaye Girsh misconceives our article’s objective as an “attempt to develop criteria” for the humane physician. Our goal in writing the paper was to analyze the current criminal law framework in the hope of sharpening debate and engendering normative critiques. We readily acknowledge tensions in the current legal framework and would support changes in that framework.Copyright © 1997 The Johns Hopkins University Press... (shrink)

Processing the motivational relevance of a visual scene and reacting accordingly is crucial for survival. Previous work suggests the emotional content of naturalistic scenes affects response speed, such that unpleasant content slows responses whereas pleasant content accelerates responses. It is unclear whether these effects reflect motor-cognitive processes, such as attentional orienting, or vary with the function/outcome of the motor response itself. Four experiments manipulated participants’ ability to terminate the picture and, thereby, the response’s function and motivational value. Attentive orienting was (...) manipulated via picture repetition, which diminishes orienting. A total of N = 81 participants completed versions of a go/no-go task, discriminating between distorted versus intact pictures drawn from six content categories varying in positive, negative, or neutral valence. While all participants responded faster with repetition, only participants without offset control exhibited slower responses to unpleasant and accelerated responses to pleasant content. Emotional engagement, measured by the late positive potential, was not modulated by attentional orienting, suggesting that the interaction between repetition and offset control is not due to altered emotional engagement. Together, results suggest that response time changes as a function of emotional content and sensitivity to attention orienting depends on the motivational function of the motor response. (shrink)

When testing primates with cognitive tasks, it is usually not considered that subjects differ markedly in terms of emotional reactivity toward the experimenter, which potentially affects a subject’s cognitive performance. We addressed this issue in common marmosets (Callithrix jacchus), a monkey species in which males tend to show stronger emotional reactivity in testing situations, whereas females have been reported to outperform males in cognitive tasks. In a two-phase experiment, we first quantified the emotional reactivity of 14 subjects toward four different (...) experimenters performing a standardized behavioral action sequence and then assessed whether and how it affected the subjects’ participation and performance in a subsequent object permanence task. A test session was terminated if a subject refused to make a choice in four consecutive trials. Highly emotionally aroused individuals, particularly males, were less likely to participate in the cognitive task and completed fewer trials. However, whenever they did participate and were attentive to the task, their performance was not affected. Our results suggest that differences in emotional reactivity toward an experimenter have no major impact on cognitive performance if strict criteria are applied on when to abandon a test session and if performance is corrected for attention to the test procedure. Furthermore, they suggest that the reported sex differences in cognitive performance in marmosets may be owing to motivational and attentional factors, rather than a difference in cognitive ability per se. (shrink)

Recent studies have provided evidence of associations between neurochemistry and reading (dis)ability (Pugh et al., 2014). Based on a long history of studies indicating that fluent reading entails the automatic convergence of the written and spoken forms of language and our recently proposed Neural Noise Hypothesis (Hancock et al., 2017), we hypothesized that individual differences in cross-modal integration would mediate, at least partially, the relationship between neurochemical concentrations and reading. Cross-modal integration was measured in 231 children using a two-alternative forced (...) choice cross-modal matching task with three language conditions (letters, words, and pseudowords) and two levels of difficulty within each language condition. Neurometabolite concentrations of Choline (Cho), Glutamate (Glu), gamma-Aminobutyric (GABA), and N- acetyl-aspartate (NAA) were then measured in a subset of this sample (n = 70) with Magnetic Resonance Spectroscopy (MRS). A structural equation mediation model revealed that the effect of cross-modal word matching mediated the relationship between increased Glu (which has been proposed to be an index of neural noise) and poorer reading ability. In addition, the effect of cross-modal word matching fully mediated a relationship between increased Cho and poorer reading ability. Multilevel mixed effects models confirmed that lower Cho predicted faster cross-modal matching reaction time, specifically in the hard word condition. These Cho... (shrink)

Patients who are dying of cancer usually give up eating and then stop drinking. This raises ethical dilemmas about providing nutritional support and fluid replacement. The decision-making process should be based on a knowledge of the risks and benefits of giving or withholding treatments. There is no clear evidence that increased nutritional support or fluid therapy alters comfort, mental status or survival of patients who are dying. Rarely, subcutaneous fluid administration in the dying patient may be justified if the family (...) remain distressed despite due consideration of the lack of medical benefit versus the risks. Some cancer patients who are not imminently dying become dehydrated from reversible conditions such as hypercalcaemia. This may mimic the effects of advanced cancer. These conditions should be sought and fluid replacement therapy should be given along with the specific treatments for the condition. (shrink)

In 2004, twelve capuchin monkeys were moved from the labs of the Danish psychiatric hospital of Sankt Hans to a small private-owned zoo in another part of Denmark in order to be rehabilitated. These monkeys were the last nonhuman primates to be used as research animals in Danish biomedical laboratories. The normal procedure would be to kill research animals after the termination of an experiment; in this case, however, a decision was reached to close down the lab. The moral landscape (...) had changed, and it was no longer considered acceptable to use nonhuman primates in Danish biomedicine. From being considered a biological resource serving as a model of man, the monkeys had become moral subjects with a claim to a life suiting their natural needs. Simultaneously, the monkeys became instrumental in creating moral legitimacy for the actors involved in their rescue. What we see is an instance of pathfinding in a changing moral landscape where actors negotiate nonhuman primate nature as they create new moral positions for themselves. (shrink)

La fiction historique dont nous parlons ici a vu le jour par rapport à la pensée de l'écriture, ou de l'inscription, telle qu'elle a eu lieu dans le travail de Jacques Derrida des années 60. Au coeur de ce travail, il y a trois textes publiés en 1967 : La voix et le phénomène, De la grammatologie, L'écriture et la différence. Traverser ces travaux revient à traverser : premièrement, l'imagination du mot, qui n'était pour Husserl que pure fiction ; deuxièmement, (...) l'imagination comme séparation de la nature dans la nature chez Rousseau ; et troisièmement, la fiction comme imaginaire dans le cas du structuralisme littéraire, au-delà duquel a lieu la fiction sans imaginaire de Mallarmé. Juste avant ces travaux il y a, dans l'oeuvre publiée, le moment où la fiction historique commence à percer ; juste après, le moment où ses fondements ont déjà été établis : l''Introduction' à L'Origine de la géométrie de Husserl et 'La double séance' dans La dissémination, respectivement. C'est également l'espace compris entre le problème de l'historicité et celui d'une littérature sans condition. À cet espace appartient la possibilité de 'devenir une chose littéraire' de tout texte 'confié à l'espace public [...] dont le contenu, le sens, le référent, le signataire et le destinataire ne sont pas des réalités pleinement déterminables, des réalités à la fois non-fictives ou pures de toute fiction...' (Donner la mort)."--Page 4 of cover. (shrink)

LANGUAGE NOTE | Document text in Chinese; abstract also in English. 傳統意義下的臨終關懷，以全面的身心照料為中心，為瀕臨離世的病患及其家屬提供涵蓋生理、社會及心靈方面的支援及照護服務，使其消除焦慮和對死亡的恐懼，最終幫助病人有尊嚴地、舒緩平和地抵達人生盡頭，也慰藉患者 家屬走出失去至親的傷痛。然而，在「新冠」疫情的影響下，臨終關懷面臨著倫理困境，善終的意義也一度受到挑戰。本文以香港疫情下受限的探訪和殯葬安排為例，通過儒家思想中的以人文本、家庭主義和臨終禮儀，分析防疫 政策對臨終關懷和善終的影響並探究其倫理正當性，為今後突發公共衛生事件下臨終關懷必要性、執行過程和發展提供思考。 End-of-life care aims to provide supportive physical, social, mental, and spiritual care for terminally ill patients and their family members. Not only does it help patients approach the end of their lives with dignity and peace, but it also helps family members overcome the grief of losing a loved one. In the context of the COVID-19 pandemic, ethical dilemmas have emerged within the field of end-of-life care, and it (...) has been challenging to help people experience a good death. This article takes the example of the pandemic-related restrictions in Hong Kong that affected visiting and funeral arrangements. It analyzes the impact of anti-pandemic measures on end-of-life care and the provision of a good death. It examines the ethical justifications of these measures through the Confucian themes of human-orientedness, familism, and death rituals, and it outlines practical implications for end-of-life care under similar circumstances. (shrink)

This manual presents a carefully researched, detailed psychodynamic treatment program for the alleviation of a transdiagnostic range of primary Axis I anxiety disorders, including panic disorder, generalized anxiety disorder, social anxiety disorder, post-traumatic stress disorder, and related psychological problems. First exploring the principles of psychodynamic theory and formulation, the authors then present a three-phased process of Panic Focused Psychodynamic Psychotherapy-Extended Range : initial evaluation, interpretation of central conflicts and defense mechanisms, and termination. Each phase is discussed in depth and relies (...) on central case illustrations to demonstrate techniques and results. A subsequent chapter explores how to address complex issues that may arise during the course of treatment. Altogether, this manual not only provides a demonstrated, adaptable approach for anxiety disorders, but also clearly embodies a spirit of research and empiricism heretofore rare in psychodynamic psychotherapies, with an eye toward future development. (shrink)

The management of children born with trisomy 18 is controversial, and both providers and parents often have differing opinions. Many parents choose to terminate the pregnancy while others go forward, making decisions based on their beliefs, understanding, and physician recommendations. Physicians are similarly divided regarding treatment of these children, as some feel that aggressive treatments are futile while others defer to the parents' wishes.Interrupted aortic arch with ventricular septal defect in children with trisomy 18 presents an ethical dilemma that highlights (...) the kinds of controversies in medical decision making facing physicians on a daily basis. Repair of interrupted aortic arch with ventricular septal defect poses a high risk to newborns with or without trisomy 18. Therefore, the option for surgery should be treated as with any routine informed consent process. Parents should be counseled about the risks, benefits, alternatives, and the likelihood of success both short and long term and be should offered a choice between surgery and palliative care. (shrink)

Western scholarly literature suggests that (1) weaning is initiated by mothers; (2) weaning takes place within a few days once mothers decide to stop nursing; (3) mothers employ specific techniques to terminate nursing; (4) semi-solid foods (gruels and mashed foods) are essential when weaning; (5) weaning is traumatic for children (it leads to temper tantrums, aggression, etc.); (6) developmental stages in relationships with mothers and others can be demarcated by weaning; and (7) weaning is a process that involves mothers and (...) children exclusively, with weaned children moving from close relationships with their mothers to strengthened relationships with other children. In many respects, these presumptions are consistent with contemporary Euroamerican practices: nursing stops early (usually before six months) relative to other cultures and takes place over a few days or weeks with the help of bottles and baby foods. Because bottles are available, weaning seldom appears traumatic, but it is seen as an important step in the establishment of independence between mothers and infants. By contrast, weaning from the bottle is often perceived as traumatic. Despite considerable academic and popular interest, weaning has seldom been studied systematically, especially in small-scale cultures. Qualitative and quantitative data from a study of Bofi foragers in Central Africa are used here to evaluate the cross-cultural applicability of the assumptions summarized above. (shrink)

This book, called "Hindu Philosophy of Life: Meaning of Life in Hinduism," stands out in multiple ways from the usual introductions to Hindu thought. Its salient four-point definition of Hinduism is just the start. It shows that the Hindu philosophy of life envisages a rounded and balanced life of physical, social, moral and spiritual fulfillment for all who would claim to benefit by what it offers. Accordingly, meaning of life in Hinduism consists of achieving diversified fulfillment arranged to move progressively (...) toward increasingly more challenging and more fulfilling levels. It culminates in terminally fulfilling level called moksha or spiritual freedom. Nine outstanding features of Hinduism are related at the outset, showing how Hinduism stands out rather than fits in the received prevalent religious schemes. What attributes an ideal or model religion should have? A modern Hindu is asked that question to elicit a list of desired attributes. Nine-item wish list is developed. Noting that even those who say they are proud of being Hindu have a hard time saying what they are proud of and observing that even scholars of Hinduism have that problem, the great importance of defining Hinduism is demonstrated. An unusual but accurate definition of Hinduism is developed in four points. This is further enriched and expanded into sixteen elements or foundations of Hinduism to incorporate a full-fledged philosophy of life as typically offered by Hindu spiritual thought. It is shown how it fulfills the Hindu’s wish list. Its great strength, tenacity and resilience are made obvious, which helped it to survive impossible odds it faced through its long history. Its humanity, flexibility, wide coverage and applicability to all aspects of human life in general are shown for its potential to heal a polarized and conflicting society’s ills at this and all times. In sum, the book "Hindu Philosophy of Life: Meaning of Life in Hinduism" more than fulfills the promise its title offers. (shrink)

" Journal of the American Medical Association "Walton has made a successful attempt to write about medical concerns without ever leaving the layperson to ...

This article will explore pediatric consent through the analysis of a clinical case study using the principles of biomedical ethics approach. Application of the principles of autonomy, nonmaleficence, beneficence, and justice will be dissected in order to attempt to establish resolution of the ethical dilemma. The main conflict in this case study deals with whether the wishes of an adolescent for end-of-life care should be followed or should the desire of his parents outweigh this request. In terminal cancer, the hope (...) of early palliative care and dignity in dying serve as priorities in therapy. Application of the moral principles to both sides of the dilemma aided in providing an objective resolution to uphold pediatric consent. (shrink)

This article discusses the representation of AIDS in Guibert's posthumously published novel Le Paradis. The novel is situated in relation to Guibert's better known previous AIDS writings. The article proposes that Guibert's AIDS works fall in to three related categories: writings about other peoples' AIDS; autobiographical writings about AIDS, and, in the third, terminal stage in which Le Paradis fits, writing AIDS. As such the article suggests that Le Paradis manages to reflect and communicate some of the trauma of living (...) with AIDS by specifically trying not to write about it. The article raises issues related to constructions of sexualized and AIDS identities in fiction, and presents the novel as a form which represents a loss of self. The novel, it is argued, becomes a self-mourning for a healthy past which is memorialized in a fictional present, itself always-already haunted by the nostalgia for a lost future. (shrink)

At a time when even a brief hospital stay means becoming terrifyingly dependent on the kindness of strangers, this compassionate and practical book by a prominent medical ethicist gives power back to patients while providing invaluable guidance to their friends and families. "A cutting-edge book about cutting-edge issues (that) every American must know. . . ".--Alan Dershowitz.

The structure of traditional fiction is essentially linear or serial. No matter how complex a given work may be, it presents information to its reader successively, one element at a time, in a sequence determined by its author. By contrast, interactive fiction is parallel in structure or, more accurately, dendritic or tree-shaped. Not one, but several possible courses of action are open to the reader. Further, which one actually happens depends largely, though not exclusively, upon the reader’s own choices. To (...) be sure, the author is still in overall control, since it is she who has set up the particular nexus of events, but the route up the narrative tree, the actual sequence of events, is generally affected, if not completely determined, by the reader’s responses to that particular reader’s specific situation. In an adventure, the sequence of action frequently depends upon the reader’s decision to go in one geographical direction rather than another. In the eliza sample, the content of the “story” depends on such particulars as whether this reader has a brother or not, whether she fears her father, and why she has consulted the terminal. In general, the text presented to the eliza-reader depends on what that reader has already said and how the computer has interpreted and stored it, and this is generally true of interactive fiction.Further, interactive fiction is, in principle , open-ended—infinite. A conversation with eliza could go on for as long as one with Woody Allen’s psychoanalyst—in principle, forever. It has no necessary terminus. The program will go one writing texts and answers on the screen as long as the reader or player chooses to supply responses. Further, the computer can act as a metafictional narrator like John Barth or Thomas Pynchon who can create a story within a story or a story that generates another story within itself which generates another story within itself and so on, fictions dizzying and dazzling. One senses one’s essential humanity wobbling in the midst of the infinite paradoxes of existence and meaning. Anthony J. Niesz, assistant professor of German at Yale University, is the author of Dramaturgy in German Drama: From Gryphius to Goethe . He is interested in the phenomenon of the meta-theater, especially in seventeenth- and eighteenth-century German drama, as well as in the literature and cultural policies of the German Democratic Republic. Norman N. Holland is Milbauer Eminent Scholar at the University of Florida. He is the author of Laughing and The I. (shrink)

In “Avoiding a Death Panel Redux,” Nicole Piemonte and Laura Hermer make the argument that the advance care planning consultation provision during the health care reform debate collapsed both because the language in the provision was deliberately misread and because some features of the language could in fact be misleading. We agree on both counts. We add that the cost‐effectiveness provisions of the bill make us face difficult decisions we as a nation would rather avoid, but can and must face (...) squarely and together. It is time for an honest national conversation about at least two issues concerning medical care near the end of life. First, talking about or planning a good death with your doctor or nurse will not make death happen sooner. The data show that better planning for a well‐managed terminal illness leads to longer life as well as better symptom control and less distress. Second, we need to quickly and directly confront the cost of end of life care in the United State, recognize the political consequences, and work with the broad middle to advance the common good. (shrink)

Phosphatidylinositol‐3‐kinases (PI3Ks) are lipid kinases that produce 3‐phosphorylated derivatives of phosphatidylinositol upon activation by various cues. These 3‐phosphorylated lipids bind to various protein effectors to control many cellular functions. Lipid phosphatases such as phosphatase and tensin homolog (PTEN) terminate PI3K‐derived signals and are critical to ensure appropriate signaling outcomes. Many lines of evidence indicate that PI3Ks and PTEN, as well as some specific lipid effectors are highly compartmentalized, either in plasma membrane nanodomains or in endosomal compartments. We examine the evidence (...) for specific recruitment of PI3Ks, PTEN, and other related enzymes to membrane nanodomains and endocytic compartments. We then examine the hypothesis that scaffolding of the sources (PI3Ks), terminators (PTEN), and effectors of these lipid signals with a common plasma membrane nanodomain may achieve highly localized lipid signaling and ensure selective activation of specific effectors. This highlights the importance of spatial regulation of PI3K signaling in various physiological and disease contexts. (shrink)

The brain and body need to adapt constantly to changing social and physical environments. A key mechanism for this adaptation is the ‘stress response’, which is necessary and not negative in and of itself. The term ‘stress’, however, is ambiguous and has acquired negative connotations. We argue that the concept of allostasis can be used instead to describe the mechanisms employed to achieve stability of homeostatic systems through active intervention (adaptive plasticity). In the context of allostasis, resilience denotes the ability (...) of an organism to respond to stressors in the environment by means of the appropriate engagement and efficient termination of allostatic responses. In this review, we discuss the neurobiological and organismal factors that modulate resilience, such as growth factors, chaperone molecules and circadian rhythms, and highlight its consequences for cognition and behavior. (shrink)

OBJECTIVES: Life-sustaining treatment at the end of life gives rise to many ethical problems in Japan. Recent surveys of Japanese physicians suggested that they tend to treat terminally ill patients aggressively. We studied why Japanese physicians were reluctant to withhold or withdraw life-support from terminally ill patients and what affected their decisions. DESIGN AND PARTICIPANTS: A qualitative study design was employed, using a focus group interview with seven physicians, to gain an in-depth understanding of attitudes and rationales in Japan regarding (...) medical care at the end of life. RESULTS: Analysis revealed that physicians and patients' family members usually make decisions about life-sustaining treatment, while the patients' wishes are unavailable or not taken into account. Both physicians and family members tend to consider withholding or withdrawing life-sustaining treatment as abandonment or even killing. The strongest reason to start cardiopulmonary resuscitation- and to continue it until patients' family members arrive-seems to be the family members' desire to be at the bedside at the time of death. All physicians participating in our study regarded advance directives that provide information as to patients' wishes about life-sustaining treatment desirable. All expressed concern, however, that it would be difficult to forego or discontinue life-support based on a patient's advance directive, particularly when the patient's family opposed the directive. CONCLUSION: Our group interview suggested several possible barriers to death with dignity and the appropriate use of advance directives in Japan. Further qualitative and quantitative research in this regard is needed. (shrink)

OBJECTIVE: To report and analyse the pattern of end-of-life decision making for terminal Chinese cancer patients. DESIGN: Retrospective descriptive study. SETTING: A cancer clinical trials unit in a large teaching hospital. PATIENTS: From April 1992 to August 1997, 177 consecutive deaths of cancer clinical trial patients were studied. MAIN MEASUREMENT: Basic demographic data, patient status at the time of signing a DNR consent, or at the moment of returning home to die are documented, and circumstances surrounding these events evaluated. RESULTS: (...) DNR orders were written for 64.4% of patients. Patients in pain (odds ratio 0.45, 95% CI 0.22-0.89), especially if requiring opioid analgesia (odds ratio 0.40, 95% CI 0.21-0.77), were factors associated with a higher probability of such an order. Thirty-five patients were taken home to die, a more likely occurrence if the patient was over 75 years (odds ratio 0.12, 95% CI 0.04-0.34), had children (odds ratio 0.14, 95% CI 0.02-0.79), had Taiwanese as a first language (odds ratio 6.74, 95% CI 3.04-14.93), or was unable to intake orally (odds ratio 2.73, 95% CI 1.26-5.92). CPR was performed in 30 patients, none survived to discharge. CONCLUSIONS: DNR orders are instituted in a large proportion of dying Chinese cancer patients in a cancer centre, however, the order is seldom signed by the patient personally. This study also illustrates that as many as 20% of dying patients are taken home to die, in accordance with local custom. (shrink)

The high prevalence of cardiovascular diseases demands a reliable and sensitive risk assessment technique. In order to develop a fast and label-free immunosensor for C-reactive protein, a risk factor for this condition, anti-CRP antibodies were physically adsorbed to the hydrogen -terminated surface of nanocrystalline diamond. An Enzyme-Linked ImmunoSorbent Assay reference technique showed that this was a suitable substrate for antibody-antigen recognition reactions. Electrochemical Impedance Spectroscopy was used to electronically detect CRP recognition. The specificity of the immunosensor was demonstrated by incubation (...) with CRP and plasminogen as reference molecule. A different impedance behavior was observed in real-time after CRP addition as compared to plasminogen addition: the impedance increased only during CRP incubation. Fitting the data showed that this corresponded with a decrease in capacitance of the molecular layer due to its increased thickness by specific CRP recognition. Sensitivity experiments in real-time showed a clear discrimination between 1 μM, 100 nM, and 10 nM of CRP after 10 min at 100 Hz. Since, 10 nM of CRP was still clearly distinguishable from buffer solution, our CRP-directed immunosensor prototype reaches a sensitivity that is within the physiologically relevant concentration range of this biomarker in healthy controls and CVD patients. Moreover, this prototype displayed real-time discriminating power between spiked and unspiked serum, and thus also shows its applicability in this biological matrix. © 2011 Elsevier B.V. All rights reserved. (shrink)

Objectives: To investigate the current situation of completing the informed consent for do-not-resuscitate (DNR) orders among the competent patients with terminal illness and the ethical dilemmas related to it. Participants: This study enrolled 152 competent patients with terminal cancer, who were involved in the initial consultations for hospice care. Analysis: Comparisons of means, analyses of variance, Student’s t test, χ2 test and multiple logistic regression models. Results: After the consultations, 117 (77.0%) of the 152 patients provided informed consent for hospice (...) care and DNR orders. These included 21 patients (17.9%) who signed the consent by themselves, and 96 (82.1%) whose consent sheet was signed only by family members. The reasons why patients were not involved in the discussions toward the consent (n = 82) included poor physical or psychological condition (44.9%), concerns of the consultant hospice team (37.2%), and the family’s refusal (28.2%). On a multivariate analysis, patients’ awareness of their poor prognosis (odds ratio = 4.07, 95% confidence interval = 2.05 to 8.07) and their understanding of hospice care (2.27, 1.33 to 3.89) were two independent factors (p<0.01) that influenced their participation in the discussions or their personal signature in the informed consent. Conclusion: The family-oriented culture in Asian countries may violate the principles of the Patient Self-Determination Act and the requirements of the Hospice Care Law in Taiwan, which inevitably poses an ethical dilemma. Earlier truth-telling and continuing education of the public by hospice care workers will be helpful in solving such ethical dilemmas. (shrink)

Background: Due to recent legislations on euthanasia and its current practice in the Netherlands and Belgium, issues of end-of-life medicine have become very vital in many European countries. In 2002, the Ethics Working Group of the German Association for Palliative Medicine (DGP) has conducted a survey among its physician members in order to evaluate their attitudes towards different end-of-life medical practices, such as euthanasia (EUT), physician-assisted suicide (PAS), and terminal sedation (TS). Methods: An anonymous questionnaire was sent to the 411 (...) DGP physicians, consisting of 14 multiple choice questions on positions that might be adopted in different hypothetical scenarios on situations of “intolerable suffering” in end-of-life care. For the sake of clarification, several definitions and legal judgements of different terms used in the German debate on premature termination of life were included. For statistical analysis t-tests and Pearson-correlations were used. Results: The response rate was 61% (n=251). The proportions of the respondents who were opposed to legalizing different forms of premature termination of life were: 90% opposed to EUT, 75% to PAS, 94% to PAS for psychiatric patients. Terminal sedation was accepted by 94% of the members. The main decisional bases drawn on for the answers were personal ethical values, professional experience with palliative care, knowledge of alternative approaches, knowledge of ethical guidelines and of the national legal frame. Conclusions: In sharp contrast to similar surveys conducted in other countries, only a minority of 9.6% of the DGP physicians supported the legalization of EUT. The misuse of medical knowledge for inhumane killing in the Nazi period did not play a relevant role for the respondents’ negative attitude towards EUT. Palliative care needs to be stronger established and promoted within the German health care system in order to improve the quality of end-of-life situations which subsequently is expected to lead to decreasing requests for EUT by terminally ill patients. (shrink)

Respecting and encouraging autonomy in the elderly is basic to the practice of geriatrics. In this paper, we examine the practice of cardiopulmonary resuscitation (CPR) and "artificial" feeding in a geriatric unit in a general hospital subscribing to jewish orthodox religious principles, in which the sanctity of life is a fundamental ethical guideline. The literature on the administration of food and water in terminal stages of illness, including dementia, still shows division of opinion on the morality of withdrawing nutrition. We (...) uphold the principle that as long as feeding by naso-gastric (N-G) or percutaneous endoscopic gastrostomy (PEG) does not constitute undue danger or arouse serious opposition it should be given, without causing suffering to the patient. This is part of basic care, and the doctor has no mandate to withdraw this. The question of CPR still shows much discrepancy regarding elderly patients' wishes, and doctors' opinions about its worthwhileness, although up to 10 percent survive. Our geriatric patients rarely discuss the subject, but it is openly ventilated with families who ask about it, who are then involved in the decision-making, and the decision about CPR or "do-not-resuscitate" (DNR) is based on clinical and prognostic considerations. (shrink)

Cette étude examine comment Etre et temps interprète son inachèvement à partir de sa structure, cʹest-à-dire à partir dʹun projet méréologique de détermination qui, parce quʹil culmine dans la découverte dʹune indétermination constitutive, nʹautorise plus aucune articulation du tout et des parties, et qui, pourtant, ne peut ou ne veut abandonner la structure de traité initialement adoptée.

We consider total well-founded orderings on monadic terms satisfying the replacement and full invariance properties. We show that any such ordering on monadic terms in one variable and two unary function symbols must have order typeω,ω2orωω. We show that a familiar construction gives rise to continuum many such orderings of order typeω. We construct a new family of such orderings of order typeω2, and show that there are continuum many of these. We show that there are only four such orderings (...) of order typeωω, the two familiar recursive path orderings and two closely related orderings. We consider also total well-founded orderings onNnwhich are preserved under vector addition. We show that any such ordering must have order typeωkfor some 1 ≤k≤n. We show that ifkshrink)