Less death in the dying

Diseases associated with aging are now the primary causes of death in developed countries. This is in part due to the long recognized exponential association of cancer with age and perhaps to a deterioration of the immune system with advanced age. Both prevention of tumorigenesis and immune function are critically dependent on apoptosis. In this study we examined apoptosis in mice of various age following gamma irradiation. We found a striking age-dependent decrease in radiation-induced apoptosis in splenic lymphocytes but not in colorectal epithelial cells. These observations may therefore provide a clue to the decline of immune function with age.     

Spiritual aspects of death and dying.

Dying is an event beyond our comprehension, an experience that can only be imagined. Patients with cancer have a gift denied many others: some time to prepare for the approaching end of life. This time can be used to bring old conflicts to a close, to say goodbye and seek forgiveness from others, to express love and gratitude for the gifts of a life. Physicians can help patients by being aware of the spiritual dimensions to life that many patients have. In major religious traditions, death is accepted as the natural end of the gift of life and as a point of transition to another, yet unknown, existence. For many patients, it is not death that is feared, but abandonment. The physician's awareness of the spiritual needs of patients can make care of the dying more rewarding and fulfilling for all concerned.     

Neuronal necrosis and spreading death in a Drosophila genetic model

Brain ischemia often results in neuronal necrosis, which may spread death to neighboring cells. However, the molecular events of neuronal necrosis and the mechanisms of this spreading death are poorly understood due to the limited genetic tools available for deciphering complicated responses in mammalian brains. Here, we engineered a Drosophila model of necrosis in a sub-population of neurons by expressing a leaky cation channel in the Drosophila eye. Expression of this channel caused necrosis in defined neurons as well as extensive spreading of cell death. Jun N-terminal kinase (JNK)-mediated, caspase-independent apoptosis was the primary mechanism of cell death in neurons, while caspase-dependent apoptosis was primarily involved in non-neuronal cell death. Furthermore, the JNK activation in surrounding neurons was triggered by reactive oxygen species (ROS) and Eiger (Drosophila tumor necrosis factor α (TNFα)) released from necrotic neurons. Because the Eiger/ROS/JNK signaling was also required for cell death induced by hypoxia and oxidative stress, our fly model of spreading death may be similar to brain ischemia in mammals. We performed large-scale genetic screens to search for novel genes functioning in necrosis and/or spreading death, from which we identified several classes of genes. Among them, Rho-associated kinase (ROCK) had been reported as a promising drug target for stroke treatment with undefined mechanisms. Our data indicate that ROCK and the related trafficking pathway genes regulate neuronal necrosis. We propose the suppression of the function of the trafficking system, ROS and cytokines, such as TNFα, as translational applications targeting necrosis and spreading death.     

Sharing death and dying: advance directives, autonomy and the family

This paper critically examines the liberal model of decision making for the terminally ill and contrasts it with the familial model that can be found in some Asian cultures. The contrast between the two models shows that the liberal model is excessively patient-centered, and misconceives and marginalises the role of the family in the decision making process. The paper argues that the familial model is correct in conceiving the last journey of one's life as a sharing process rather than a process of exercising one's prior or counterfactual choice, and concludes by suggesting a policy framework for the practice of familialism that can answer the liberal challenge that familialism cannot safeguard the patient from abuse and neglect.     

Early neural cell death: dying to become neurons

The importance of programmed cell death (PCD) during vertebrate development has been well established. During the development of the nervous system in particular, neurotrophic cell death in innervating neurons matches the number of neurons to the size of their target field. However, PCD also occurs during earlier stages of neural development, within populations of proliferating neural precursors and newly postmitotic neuroblasts, all of which are not yet fully differentiated. This review addresses early neural PCD, which is distinct from neurotrophic death in differentiated neurons. Although early neural PCD is observed in a range of organisms, from Caenorhabditis elegans to mouse, the role and the regulation of early neural PCD are not well understood. The regulation of early neural PCD can be inferred from the function of factors such as bone morphogenetic proteins (BMPs), Wnts, fibroblast growth factors (FGFs), and Sonic Hedgehog (Shh), which regulate both early neural development and PCD occurring in other developmental processes. Cell number control, removal of damaged or misspecified cells (spatially or temporally), and selection are the proposed roles early neural PCDs play during neural development. Data from developmental PCD in C. elegans and Drosophila provide insights into the possible signaling pathways integrating PCD with other processes during early neural development and the roles they might play.     

Programmed cell death via mitochondria: Different modes of dying

Programmed cell death (PCD)is a major component of normal development, preservation of tissue homeostasis, and elimination of damaged cells. Many studies have subdivided PCD into the three categories of apoptosis, autophagy, and necrosis based on criteria such as morphological alterations, initiating death signal, or the implication of caspases. However, these classifications fail to address the interplay between the three types of PCD. In this review, we will discuss the central role of the mitochondrion in the integration of the cell death pathways. Mitochondrial alterations such as the release of sequestered apoptogenic proteins, loss of transmembrane potential, production of reactive oxygen species (ROS), disruption of the electron transport chain, and decreases in ATP synthesis have been shown to be involved in, and possibly responsible for, the different manifestations of cell death. Thus, the mitochondria can be viewed as a central regulator of the decision between cellular survival and demise.Translated from Biokhimiya, Vol. 70, No. 2, 2005, pp. 284 293.Original Russian Text Copyright ¢ 2005 by Bras, Queenan, Susin.This revised version was published online in April 2005 with corrections to the post codes.     

Neuronal cell death during metamorphosis of Hydractina echinata (Cnidaria, Hydrozoa)

In planula larvae of the invertebrate Hydractinia echinata (Cnidaria, Hydrozoa), peptides of the GLWamide and the RFamide families are expressed in distinct subpopulations of neurons, distributed in a typical spatial pattern through the larval body. However, in the adult polyp GLWamide or RFamide-expressing cells are located at body parts that do not correspond to the prior larval regions. Since we had shown previously that during metamorphosis a large number of cells are removed by programmed cell death (PCD), we aimed to analyze whether cells of the neuropeptide-expressing larval nerve net are among those sacrificed. By immunohistochemical staining and in situ hybridization, we labeled GLWamide- and RFamide-expressing cells. Double staining of neuropeptides and degraded DNA (TUNEL analysis) identified some neurosensory cells as being apoptotic. Derangement of the cytoplasm and rapid destruction of neuropeptide precursor RNA indicated complete death of these particular sensory cells in the course of metamorphosis. Additionally, a small group of RFamide-positive sensory cells in the developing mouth region of the primary polyp could be shown to emerge by proliferation. Our results support the idea that during metamorphosis, specific parts of the larval neuronal network are subject to neurodegeneration and therefore not used for construction of the adult nerve net. Most neuronal cells of the primary polyp arise by de novo differentiation of stem cells commited to neural differentiation in embryogenesis. At least some nerve cells derive from proliferation of progenitor cells. Clarification of how the nerve net of these basal eumetazoans degenerates may add information to the understanding of neurodegeneration by apoptosis as a whole in the animal kingdom.     

Neuronal death is an active, caspase-dependent process after moderate but not severe DNA damage

Mild insults to neurons caused by ischemia or glutamate induce apoptosis, whereas severe insults induce non apoptotic death, such as necrosis. The molecular targets that are damaged by these insults and ultimately induce cell death are not fully established. To determine if DNA damage can induce apoptotic or non apoptotic death depending on the severity, neurons were treated with up to 128 Gy of ionizing radiation. Such treatment induced a dose-related increase in DNA single-strand breaks but no immediate membrane disruption or lipid peroxidation. Following moderate doses of < or = 32 Gy, neuronal death had many characteristics of apoptosis including nuclear fragmentation and DNA laddering. Nuclear fragmentation and membrane breakdown after moderate DNA damage could be blocked by inhibition of active protein synthesis with cycloheximide and by inhibition of caspases. In contrast, cell death after doses of > 32 Gy was not blocked by cycloheximide or caspase inhibitors, and membrane breakdown occurred relatively early in the cell death process. These data suggest that cell death after high dose irradiation and severe DNA damage can occur by non apoptotic mechanisms and that blocking apoptotic pathways may not prevent death after severe damage.