Brain death and brain life: rethinking the connection

The connection between brain life and brain death is neither as simple nor as defensible as it might at first appear. The problem rests with the two dominant competing definitions of death:...the loss of that which is necessary for the organism to continue to function as a whole;....the loss of that which is essentially significant to the nature of the organism... If death is understood as the loss of that which is necessary for the continued functioning of the organism as whole, then the apparent symmetry breaks down. If...death could be understood as the loss of that which is essentially significant to the nature of the organism....consciousness, then the symmetry would hold. However, that definition of death is indefensible. Therefore...statements about the status of anencephalic infants and early human embryos based upon a connection between brain death and brain life are unfounded.     

DEADLY PLURALISM? WHY DEATH‐CONCEPT,DEATH‐DEFINITION,DEATH‐CRITERION AND DEATH‐TEST PLURALISM SHOULD BE ALLOWED,EVEN THOUGH IT CREATES SOME PROBLEMS

Death concept, death definition, death criterion and death test pluralism has been described by some as a problematic approach. Others have claimed it to be a promising way forward within modern pluralistic societies. This article describes the New Jersey Death Definition Law and the Japanese Transplantation Law. Both of these laws allow for more than one death concept within a single legal system. The article discusses a philosophical basis for these laws starting from John Rawls' understanding of comprehensive doctrines, reasonable pluralism and overlapping consensus. It argues for the view that a certain legal pluralism in areas of disputed metaphysical, philosophical and/or religious questions should be allowed, as long as the disputed questions concern the individual and the resulting policy, law or acts based on the policy/law, do not harm the lives of other individuals to an intolerable extent. However, while this death concept, death definition, death criterion and death test pluralism solves some problems, it creates others.     

Reviving Brain Death: A Functionalist View

Recently both whole brain death (WBD) and higher brain death (HBD) have come under attack. These attacks, we argue, are successful, leaving supporters of both views without a firm foundation. This state of affairs has been described as “the death of brain death.” Returning to a cardiopulmonary definition presents problems we also find unacceptable. Instead, we attempt to revive brain death by offering a novel and more coherent standard of death based on the permanent cessation of mental processing. This approach works, we claim, by being functionalist instead of being based in biology, consciousness, or personhood. We begin by explaining why an objective biological determination of death fails. We continue by similarly rejecting current arguments offered in support of HBD, which rely on consciousness and/or personhood. In the final section, we explain and defend our functionalist view of death. Our definition centers on mental processing, both conscious and preconscious or unconscious. This view provides the philosophical basis of a functional definition that most accurately reflects the original spirit of brain death when first proposed in the Harvard criteria of 1968.     

Morphogens and cell survival during development

The notion of "morphogens" is an important one in developmental biology. By definition, a morphogen is a molecule that emanates from a specific set of cells that is present in a concentration gradient and that specifies the fate of each cell along this gradient. The strongest candidate morphogens are members of the transforming growth factor-beta (TGF-beta), Hedgehog (Hh), and Wnt families. While these morphogens have been extensively described as differentiation inducers, some reports also suggest their possible involvement in cell death and cell survival. It is frequently speculated that the cell death induction that is found associated with experimental removal of morphogens is the manifestation of abnormal differentiation signals. However, several recent reports have raised controversy about this death by default, suggesting that cell death regulation is an active process for shaping tissues and organs. In this review, we will present morphogens, with a specific emphasis on Sonic Hedgehog, a mammalian member of the Hh family, not as a positive regulators of cell differentiation but as key regulators of cell survival.     

COPD exacerbation: Lost in translation

The introduction and acceptance of a standard definition for exacerbations of COPD can be helpful in prompt diagnosis and management of these events. The latest GOLD executive committee recognised this necessity and it has now included a definition of exacerbation in the guidelines for COPD which is an important step forward in the management of the disease. This definition is pragmatic and compromises the different approaches for exacerbation. However, the inclusion of the "healthcare utilisation" approach (".. may warrant a change in regular medication") in the definition may introduce in the diagnosis of exacerbation factors related to the access to health care services which may not be related to the underlying pathophysiologal process which characterizes exacerbations. It should be also noted that the aetiology of COPD exacerbations has not yet been included in the current definition. In this respect, the definition does not acknowledge the fact that many patients with COPD may suffer from additional conditions (i.e. congestive cardiac failure or pulmonary embolism) that can masquerade as exacerbations but they should not be considered as causes of them. The authors therefore suggest that an inclusion of the etiologic factors of COPD exacerbations in the definition. Moreover, COPD exacerbations are characterized by increased airway and systemic inflammation and significant deterioration in lung fuction. These fundamental aspects should be accounted in diagnosis/definition of exacerbations. This could be done by the introduction of a "laboratory" marker in the diagnosis of these acute events. The authors acknowledge that the use of a test or a biomarker in the diagnosis of exacerbations meets certain difficulties related to performing lung function tests or to sampling during exacerbations. However, the introduction of a test that reflects airway or systemic inflammation in the diagnosis of exacerbations might be another step forward in the management of COPD.     

Death and transplantation: let's try to get things methodologically straight

The purpose of this paper is methodological. I begin by showing the methodological frailties of both the heart and brain approach to the criteria of death used in connection with organ transplantation. I then clarify what a definition is. Finally, I propose to abandon the definition of death, and suggest a pragmatic definition of ‘explantability window’.     

Autophagic cell death: Loch Ness monster or endangered species?

The concept of autophagic cell death was first established based on observations of increased autophagic markers in dying cells. The major limitation of such a morphology-based definition of autophagic cell death is that it fails to establish the functional role of autophagy in the cell death process, and thus contributes to the confusion in the literature regarding the role of autophagy in cell death and cell survival. Here we propose to define autophagic cell death as a modality of non-apoptotic or necrotic programmed cell death in which autophagy serves as a cell death mechanism, upon meeting the following set of criteria: (i) cell death occurs without the involvement of apoptosis; (ii) there is an increase of autophagic flux, and not just an increase of the autophagic markers, in the dying cells; and (iii) suppression of autophagy via both pharmacological inhibitors and genetic approaches is able to rescue or prevent cell death. In light of this new definition, we will discuss some of the common problems and difficulties in the study of autophagic cell death and also revisit some well-reported cases of autophagic cell death, aiming to achieve a better understanding of whether autophagy is a real killer, an accomplice or just an innocent bystander in the course of cell death. At present, the physiological relevance of autophagic cell death is mainly observed in lower eukaryotes and invertebrates

such as Dictyostelium discoideum and Drosophila melanogaster. We believe that such a clear definition of autophagic cell death will help us study and understand the physiological or pathological relevance of autophagic cell death in mammals.     

Autophagic cell death: Loch Ness monster or endangered species?

The concept of autophagic cell death was first established based on observations of increased autophagic markers in dying cells. The major limitation of such a morphology-based definition of autophagic cell death is that it fails to establish the functional role of autophagy in the cell death process, and thus contributes to the confusion in the literature regarding the role of autophagy in cell death and cell survival. Here we propose to define autophagic cell death as a modality of non-apoptotic or necrotic programmed cell death in which autophagy serves as a cell death mechanism, upon meeting the following set of criteria: (i) cell death occurs without the involvement of apoptosis; (ii) there is an increase of autophagic flux, and not just an increase of the autophagic markers, in the dying cells; and (iii) suppression of autophagy via both pharmacological inhibitors and genetic approaches is able to rescue or prevent cell death. In light of this new definition, we will discuss some of the common problems and difficulties in the study of autophagic cell death and also revisit some well-reported cases of autophagic cell death, aiming to achieve a better understanding of whether autophagy is a real killer, an accomplice or just an innocent bystander in the course of cell death. At present, the physiological relevance of autophagic cell death is mainly observed in lower eukaryotes and invertebrates such as Dictyostelium discoideum and Drosophila melanogaster. We believe that such a clear definition of autophagic cell death will help us study and understand the physiological or pathological relevance of autophagic cell death in mammals.     

Necrosis in yeast

Necrosis was long regarded as an accidental cell death process resulting from overwhelming cellular injury such as chemical or physical disruption of the plasma membrane. Such a definition, however, proved to be inapplicable to many necrotic scenarios. The discovery that genetic manipulation of several proteins either protected or enhanced necrotic cell death argued in favor of a regulated and hence programmed process, as it is the case for apoptosis. For more than a decade, yeast has served as a model for apoptosis research; recently, evidence accumulated that it also harbors a necrotic program. Here, we summarize the current knowledge about factors that control necrotic cell death in yeast. Mitochondria, aging and a low pH are positive regulators of this process while cellular polyamines (e.g. spermidine) and endonuclease G as well as homeostatic organelles like the vacuole or peroxisomes are potent inhibitors of necrosis. Physiological necrosis may stimulate intercellular signaling via the release of necrotic factors that promote viability of healthy cells and, thus, assure survival of the clone. Together, the data obtained in yeast argue for the existence of a necrotic program, which controls longevity and whose physiological function may thus be aging.     

Causality and methodology. Notes on thanatochronological estimations

The authors propose some methodological considerations on thanatochronological estimations. They first consider the problem of the definition of death, and then they deal with the issue of the estimations of death time, that is, with the Post-Mortem Interval (PMI). As regards the first question, they note that it does not concern only the definition of death, but also the choice of a particular kind of definition of 'definition'. With reference to the second question, the authors suggest a causal model showing that the presence of many causal chains must be taken into consideration. Finally they discuss what 'most convenient and reliable causal chain' means for a thanatochronologist.     

Defining life from death: Problems with the somatic integration definition of life

To determine when the life of a human organism begins, Mark T. Brown has developed the somatic integration definition of life. Derived from diagnostic criteria for human death, Brown’s account requires the presence of a life-regulation internal control system for an entity to be considered a living organism. According to Brown, the earliest point at which a developing human could satisfy this requirement is at the beginning of the fetal stage, and so the embryo is not regarded as a living human organism. This, Brown claims, has significant bioethical implications for both abortion and embryo experimentation. Here, we dispute the cogency of Brown’s derivation. Diagnostic criteria for death are used to determine when an organism irreversibly ceases functioning as an integrated whole, and may vary significantly depending on how developed the organism is. Brown’s definition is derived from a specific definition of death applicable to postnatal human beings, which is insufficient for generating a general definition for human organismal life. We have also examined the bioethical implications of Brown’s view, and have concluded that they are not as significant as he believes. Whether the embryo is classified as a human organism is of peripheral interest—a far more morally relevant question is whether the embryo is a biological individual with an identity that is capable of persisting during development.     

Understanding Death in Custody: A Case for a Comprehensive Definition

Prisoners sometimes die in prison, either due to natural illness, violence, suicide, or a result of imprisonment. The purpose of this study is to understand deaths in custody using qualitative methodology and to argue for a comprehensive definition of death in custody that acknowledges deaths related to the prison environment. Interviews were conducted with 33 experts, who primarily work as lawyers or forensic doctors with national and/or international organisations. Responses were coded and analysed qualitatively. Defining deaths in custody according to the place of death was deemed problematic. Experts favoured a dynamic approach emphasising the link between the detention environment and occurrence of death rather than the actual place of death. Causes of deaths and different patterns of deaths were discussed, indicating that many of these deaths are preventable. Lack of an internationally recognised standard definition of death in custody is a major concern. Key aspects such as place, time, and causes of death as well as relation to the prison environment should be debated and incorporated into the definition. Systematic identification of violence within prison institutions is critical and efforts are needed to prevent unnecessary deaths in prison and to protect vulnerable prisoners.     

Postmodern Personhood: A Matter of Consciousness

The concept of person is integral to bioethical discourse because persons are the proper subject of the moral domain. Nevertheless, the concept of person has played no role in the prevailing formulation of human death because of a purported lack of consensus concerning the essential attributes of a person. Beginning with John Locke's fundamental proposition that person is a 'forensic term', I argue that in Western society we do have a consensus on at least one necessary condition for personhood, and that is the capacity for conscious experience. When we consider the whole brain formulation of death, and the most prominent defense of it by the President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research, we can readily identify the flaws that grow out of the failure to define human death as the permanent loss of the capacity for conscious experience. Most fundamental among these flaws is a definition of human death that reduces persons to the capacity of the brain to regulate purely physiological functioning. Such a formulation would, in theory, apply to any member of the animal kingdom. I suggest that an appropriate concept of death should capture what it is about a particular living being that is so essential to it that the permanent loss of that thing constitutes death. What is essential to being a human being is living the life of a person, which derives from the capacity for conscious experience.     

Postmodern personhood: a matter of consciousness

The concept of person is integral to bioethical discourse because persons are the proper subject of the moral domain. Nevertheless, the concept of person has played no role in the prevailing formulation of human death because of a purported lack of consensus concerning the essential attributes of a person. Beginning with John Locke's fundamental proposition that person is a 'forensic term', I argue that in Western society we do have a consensus on at least one necessary condition for personhood, and that is the capacity for conscious experience. When we consider the whole brain formulation of death, and the most prominent defense of it by the President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research, we can readily identify the flaws that grow out of the failure to define human death as the permanent loss of the capacity for conscious experience. Most fundamental among these flaws is a definition of human death that reduces persons to the capacity of the brain to regulate purely physiological functioning. Such a formulation would, in theory, apply to any member of the animal kingdom. I suggest that an appropriate concept of death should capture what it is about a particular living being that is so essential to it that the permanent loss of that thing constitutes death. What is essential to being a human being is living the life of a person, which derives from the capacity for conscious experience.     

Identifying skeletal-related events for prostate cancer patients in routinely collected hospital data

BackgroundNon-osteoporotic skeletal-related events (SREs) are clinically important markers of disease progression in prostate cancer. We developed and validated an approach to identify SREs in men with prostate cancer using routinely-collected data.MethodsPatients diagnosed with prostate cancer between January 2010 and December 2013 were identified in the National Prostate Cancer Audit, based on English cancer registry data. A coding framework was developed based on diagnostic and procedure codes in linked national administrative hospital and routinely-collected radiotherapy data to identify SREs occurring before December 2015. Two coding definitions of SREs were assessed based on whether the SRE codes were paired with a bone metastasis code (‘specific definition’) or used in isolation (‘sensitive definition’). We explored the validity of both definitions by comparing the cumulative incidence of SREs from time of diagnosis according to prostate cancer stage at diagnosis with death as a competing risk.ResultsWe identified 40,063, 25,234 and 13,968 patients diagnosed with localised, locally advanced and metastatic disease, respectively. Using the specific definition, we found that the 5-year cumulative incidence of SREs was 1.0 % in patients with localised disease, 6.0 % in patients with locally advanced disease, and 42.3 % in patients with metastatic disease. Using the sensitive definition, the corresponding cumulative incidence figures were 9.0 %, 14.9 %, and 44.4 %, respectively.ConclusionThe comparison of the cumulative incidence of SREs identified in routinely collected hospital data, based on a specific coding definition in patients diagnosed with different prostate cancer stage, supports their validity as a clinically important marker of cancer progression.     

猪繁殖与呼吸综合征病毒分子生物学研究进展

猪繁殖与呼吸综合征是由猪繁殖与呼吸综合征病毒(PRRSV)诱发的一种接触性传染病,其症状主要表现为怀孕母猪流产、早产、产死胎、木乃伊胎及成年猪的呼吸道症状。本病自1987年在美国爆发后,给世界养猪业造成巨大损失。近年来,由于其危害性大而引起专家学者的关注,PRRS在分子生物学方面研究者较多。就其病原特性,基因结构,病毒蛋白,分子生物学诊断以及PRRS基因工程疫苗的研究等方面进行论述。     

上消化道出血在ICU的诊治近况

近年来,ICU在急重症上消化道出血救治中的作用越来越受到重视。上消化道出血是重症监护病房(ICU)内常见的危重病症 之一,与多器官功能不全密切相关,是多种危重病引起的常见并发症,病情严重者甚至危及生命。引起上消化道出血的病因很多, 其中非特异性粘膜异常、非甾体类抗炎药和抗血小板药物的不合理使用逐渐引起临床的重视。本文对国内外临床诊断和治疗上 消化道出血的近况进行了回顾分析,进一步阐述上消化道出血与多器官功能不全之间的联系,为多学科联合诊断提供参考。     

Impact of the Brain Death Ruling in Washington State

In a 1980 Washington State Supreme Court decision, brain death was recognized as a means of determining death, but the court declined to specify a procedural mechanism to be followed. According to a survey of hospitals in Washington, the decision has had little impact in the state, apparently due to the medical profession''s unfamiliarity with it. As a result of the survey, we have identified problems of procedure and interaction with the legal system. A consensus of those contacted was that no formal, hospital-mandated definition of brain death is needed.     

The "cytokine profile": a code for sepsis

Sepsis--the most common cause of death in hospitalized patients--affects over 18 million people worldwide and has an expected 1% increase of incidence per year. Recent clinical trials indicate that therapeutic approaches effective in diseases with similar pathogenesis have a modest effect against sepsis. Although the reason for this failure remains controversial, recent studies provide new insights and promising experimental strategies. We propose that the current definition of sepsis is too broad and encompasses heterogeneous groups of patients suffering similar, but different, syndromes that are historically grouped under the general diagnosis of sepsis. Future clinical trials might define patient populations and therapeutic strategies according to the profile of expression of cytokines.     

Problems and possibilities in the differential diagnosis of Syndrome Spinocerebellar Ataxia

Differential diagnosis in neurologic patients with spinocerebellar syndrome is complex as a result of the great degree of variability in phenotypic and genetic aspects of more than 200 nosological entities. In the past decade, genetic etiology has been discovered in part of the diseases and the term 'spinocerebellar ataxia' has become, from a neurologic point of view, a loose definition applied to a group of autosomal dominant diseases. Topical extensive literature about differential diagnoses of ataxias usually refers to genetics classification or is produced by a group of radiologists, elektrophysiologists and biologists as well as others in the field. A further problem is that the majority of studies do not take into account other acquired illnesses and diseases which may fundamentally alter the symptomology and course of a primary disease, not to mention the possibility of concomitancy in hereditary diseases. The following article was prompted by daily contact with ataxic patients and related issues raised by colleagues; its goal is to clarify problems faced by child neurologists and neurologists in clinical practice.