The degree of certainty in brain death: probability in clinical and Islamic legal discourse.

PubMed

Qazi, Faisal; Ewell, Joshua C; Munawar, Ayla; Asrar, Usman; Khan, Nadir

2013-04-01

The University of Michigan conference "Where Religion, Policy, and Bioethics Meet: An Interdisciplinary Conference on Islamic Bioethics and End-of-Life Care" in April 2011 addressed the issue of brain death as the prototype for a discourse that would reflect the emergence of Islamic bioethics as a formal field of study. In considering the issue of brain death, various Muslim legal experts have raised concerns over the lack of certainty in the scientific criteria as applied to the definition and diagnosis of brain death by the medical community. In contrast, the medical community at large has not required absolute certainty in its process, but has sought to eliminate doubt through cumulative diagnostic modalities and supportive scientific evidence. This has recently become a principal model, with increased interest in data analysis and evidence-based medicine with the intent to analyze and ultimately improve outcomes. Islamic law has also long employed a systematic methodology with the goal of eliminating doubt from rulings regarding the question of certainty. While ample criticism of the scientific criteria of brain death (Harvard criteria) by traditional legal sources now exists, an analysis of the legal process in assessing brain death, geared toward informing the clinician's perspective on the issue, is lacking. In this article, we explore the role of certainty in the diagnostic modalities used to establish diagnoses of brain death in current medical practice. We further examine the Islamic jurisprudential approach vis-à-vis the concept of certainty (yaqīn). Finally, we contrast the two at times divergent philosophies and consider what each perspective may contribute to the global discourse on brain death, understanding that the interdependence that exists between the theological, juridical, ethical, and medical/scientific fields necessitates an open discussion and active collaboration between all parties. We hope that this article serves to continue the discourse that was successfully begun by this initial interdisciplinary endeavor at the University of Michigan.

Naked mole-rat cortical neurons are resistant to acid-induced cell death.

PubMed

Husson, Zoé; Smith, Ewan St John

2018-05-09

Regulation of brain pH is a critical homeostatic process and changes in brain pH modulate various ion channels and receptors and thus neuronal excitability. Tissue acidosis, resulting from hypoxia or hypercapnia, can activate various proteins and ion channels, among which acid-sensing ion channels (ASICs) a family of primarily Na + permeable ion channels, which alongside classical excitotoxicity causes neuronal death. Naked mole-rats (NMRs, Heterocephalus glaber) are long-lived, fossorial, eusocial rodents that display remarkable behavioral/cellular hypoxia and hypercapnia resistance. In the central nervous system, ASIC subunit expression is similar between mouse and NMR with the exception of much lower expression of ASIC4 throughout the NMR brain. However, ASIC function and neuronal sensitivity to sustained acidosis has not been examined in the NMR brain. Here, we show with whole-cell patch-clamp electrophysiology of cultured NMR and mouse cortical and hippocampal neurons that NMR neurons have smaller voltage-gated Na + channel currents and more hyperpolarized resting membrane potentials. We further demonstrate that acid-mediated currents in NMR neurons are of smaller magnitude than in mouse, and that all currents in both species are reversibly blocked by the ASIC antagonist benzamil. We further demonstrate that NMR neurons show greater resistance to acid-induced cell death than mouse neurons. In summary, NMR neurons show significant cellular resistance to acidotoxicity compared to mouse neurons, contributing factors likely to be smaller ASIC-mediated currents and reduced NaV activity.

Control of adult neurogenesis by programmed cell death in the mammalian brain.

PubMed

Ryu, Jae Ryun; Hong, Caroline Jeeyeon; Kim, Joo Yeon; Kim, Eun-Kyoung; Sun, Woong; Yu, Seong-Woon

2016-04-21

The presence of neural stem cells (NSCs) and the production of new neurons in the adult brain have received great attention from scientists and the public because of implications to brain plasticity and their potential use for treating currently incurable brain diseases. Adult neurogenesis is controlled at multiple levels, including proliferation, differentiation, migration, and programmed cell death (PCD). Among these, PCD is the last and most prominent process for regulating the final number of mature neurons integrated into neural circuits. PCD can be classified into apoptosis, necrosis, and autophagic cell death and emerging evidence suggests that all three may be important modes of cell death in neural stem/progenitor cells. However, the molecular mechanisms that regulate PCD and thereby impact the intricate balance between self-renewal, proliferation, and differentiation during adult neurogenesis are not well understood. In this comprehensive review, we focus on the extent, mechanism, and biological significance of PCD for the control of adult neurogenesis in the mammalian brain. The role of intrinsic and extrinsic factors in the regulation of PCD at the molecular and systems levels is also discussed. Adult neurogenesis is a dynamic process, and the signals for differentiation, proliferation, and death of neural progenitor/stem cells are closely interrelated. A better understanding of how adult neurogenesis is influenced by PCD will help lead to important insights relevant to brain health and diseases.

Killing by organ procurement: brain-based death and legal fictions.

PubMed

Veatch, Robert M

2015-06-01

The dead donor rule (DDR) governs procuring life-prolonging organs. They should be taken only from deceased donors. Miller and Truog have proposed abandoning the rule when patients have decided to forgo life-sustaining treatment and have consented to procurement. Organs could then be procured from living patients, thus killing them by organ procurement. This proposal warrants careful examination. They convincingly argue that current brain or circulatory death pronouncement misidentifies the biologically dead. After arguing convincingly that physicians already cause death by withdrawing treatment, they claim no bright-line differences preclude organ removal from the living. The argument fails for those who accept the double effect doctrine or other grounds for distinguishing forgoing life support from active, intentional killing. If the goal is determining irreversible loss of somatic function, they correctly label current death pronouncement a "legal fiction." Recognizing a second, public policy meaning of the term death provides grounds for maintaining the DDR without jeopardizing procurement. © The Author 2015. Published by Oxford University Press, on behalf of the Journal of Medicine and Philosophy Inc. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Brainstem death: A comprehensive review in Indian perspective

PubMed Central

Dhanwate, Anant Dattatray

2014-01-01

With the advent of cardiopulmonary resuscitation techniques, the cardiopulmonary definition of death lost its significance in favor of brain death. Brain death is a permanent cessation of all functions of the brain in which though individual organs may function but lack of integrating function of the brain, lack of respiratory drive, consciousness, and cognition confirms to the definition that death is an irreversible cessation of functioning of the organism as a whole. In spite of medical and legal acceptance globally, the concept of brain death and brain-stem death is still unclear to many. Brain death is not promptly declared due to lack of awareness and doubts about the legal procedure of certification. Many brain dead patients are kept on life supporting systems needlessly. In this comprehensive review, an attempt has been made to highlight the history and concept of brain death and brain-stem death; the anatomical and physiological basis of brain-stem death, and criteria to diagnose brain-stem death in India. PMID:25249744

Severe neurological impairment: legal aspects of decisions to reduce care.

PubMed

Beresford, H R

1984-05-01

Decisions to reduce care for patients with severe neurological impairment may raise legal questions. The laws of most states now authorize physicians to stop care for those who have suffered irreversible cessation of all functions of the brain ("brain death"). Where state law is not explicit, it is nevertheless probably lawful to regard brain death as death for legal purposes so long as currently accepted criteria are satisfied. Several courts have ruled that it is lawful to reduce care for patients in vegetative states, but have prescribed differing standards and procedures for implementing such decisions. The issue of whether parents can authorize physicians to reduce care for neurologically impaired children is the focus of current litigation. Implicit in this litigation is the question of how severe neurological impairment must be before parents and physicians may lawfully agree to reduce care. For severely impaired but not vegetative adults, there is some legal authority to justify certain decisions to reduce care. The issue of whether withholding feeding from a severely demented patient with life-threatening medical problems constitutes criminal behavior is now being considered by a state supreme court.

A Response to the Legitimacy of Brain Death in Islam.

PubMed

Rady, Mohamed Y; Verheijde, Joseph L

2016-08-01

Brain death is a novel construct of death for the procurement of transplantable organs. Many authoritative Islamic organizations and governments have endorsed brain death as true death for organ donation. Many commentators have reiterated the misconception that the Quranic text does not define death. We respond by clarifying: (1) the Quran does define death as biologic disintegration and clearly distinguishes it from the dying process, (2) brain death belongs scientifically within the spectrum of neurologic disorders of consciousness and should not be confused with death, and (3) religious and legal discord about brain death has grown in jurisdictions worldwide. We urge for public transparency and truthfulness about brain death and the accommodation and respect of religious objection to the determination of death by neurologic criteria.

Using the brain criterion in organ donation after the circulatory determination of death.

PubMed

Dalle Ave, Anne L; Bernat, James L

2016-06-01

The UK, France, and Switzerland determine death using the brain criterion even in organ donation after the circulatory determination of death (DCDD), in which the United States and Canada use the circulatory-respiratory criterion. In our analysis of the scientific validity of the brain criterion in DCDD, we concluded that although it may be attractive in theory because it conceptualizes death as a unitary phenomenon, its use in practice is invalid. The preconditions (ie, the absence of reversible causes, such as toxic or metabolic disorders) for determining brain death cannot be met in DCDD. Thus, although brain death tests prove the cessation of tested brain functions, they do not prove that their cessation is irreversible. A stand-off period of 5 to 10 minutes is insufficient to achieve the irreversibility requirement of brain death. Because circulatory cessation inevitably leads to cessation of brain functions, first permanently and then irreversibly, the use of brain criterion is unnecessary to determine death in DCDD. Expanding brain death to permit it to be satisfied by permanent cessation of brain functions is controversial but has been considered as a possible means to declare death in uncontrolled DCDD. Copyright © 2016 Elsevier Inc. All rights reserved.

An educational initiative to improve medical student awareness about brain death.

PubMed

Lewis, Ariane; Howard, Jonathan; Watsula-Morley, Amanda; Gillespie, Colleen

2018-04-01

Medical student knowledge about brain death determination is limited. We describe an educational initiative to improve medical student awareness about brain death and assess the impact of this initiative. Beginning in July 2016, students at our medical school were required to attend a 90-min brain death didactic and simulation session during their neurology clerkship. Students completed a test immediately before and after participating in the initiative. Of the 145 students who participated in this educational initiative between July 2016 and June 2017, 124 (86%) consented to have their data used for research purposes as part of a medical education registry. Students correctly answered a median of 53% of questions (IQR 47-58%) on the pretest and 86% of questions (IQR 78-89%) on the posttest (p < .001). Comfort with both performing a brain death evaluation and talking to a family about brain death improved significantly after this initiative (18% of students were comfortable performing a brain death evaluation before the initiative and 86% were comfortable doing so after the initiative, p < .001; 18% were comfortable talking to a family about brain death before the initiative and 76% were comfortable doing so after the initiative, p < .001). Incorporation of simulation in undergraduate medical education is high-yield. At our medical school, knowledge about brain death and comfort performing a brain death exam or talking to a family about brain death was limited prior to development of this initiative, but awareness and comfort dealing with brain death improved significantly after this initiative. Copyright © 2018 Elsevier B.V. All rights reserved.

Traumatic Brain Injury and Personality Change

ERIC Educational Resources Information Center

Fowler, Marc; McCabe, Paul C.

2011-01-01

Traumatic brain injury (TBI) is the leading cause of death and lifelong disability in the United States for individuals below the age of 45. Current estimates from the Center for Disease Control (CDC) indicate that at least 1.4 million Americans sustain a TBI annually. TBI affects 475,000 children under age 14 each year in the United States alone.…

The influence of sociocultural factors on organ donation and transplantation in Korea: findings from key informant interviews.

PubMed

Kim, Jung Ran; Elliott, Doug; Hyde, Cheryl

2004-04-01

Although brain death was formally recognized in Korea in 2000 for the purpose of organ donation, traditional Confucian-based thought still prevails. The aim of this study was to explore sociocultural perspectives that influence health professionals' attitudes and perceptions regarding organ donation. Semistructured interviews were conducted with nine key informants from three major hospitals providing transplant services in South Korea. Several themes were identified as barriers to organ donation: Confucianism, misunderstandings and myths, organs as spare for selling, lack of clarity in the definition of death in the new legislation, and limited medical insurance coverage. It remains difficult for brain death to be accepted as true death, and there is currently a poor rate of organ procurement. Findings of the study will help identify socioculturally appropriate strategies to promote acceptance and accessibility of organ transplantation among South Koreans.

Brain death in the pediatric patient: historical, sociological, medical, religious, cultural, legal, and ethical considerations.

PubMed

Farrell, M M; Levin, D L

1993-12-01

To detail the origins of the definition of death, the development of the criterion of whole brain death as fulfilling the definition of death, and the tests used to fulfill that criterion. A review of the literature was performed. No Institutional Review Board approval was necessary. In 1959, patients were described as being in "coma dépassé" or beyond coma. In 1967, the first successful heart transplantation took place, with the organ coming from a brain-dead, beating-heart donor. However, anxiety over the definitions of death did not begin with the modern, technological era, and death itself has never been definable in objective terms. It has always been a subjective and value-based construct. During ancient times, most people agreed that death occurred when a person's heartbeat and breathing stopped. For the Greeks, the heart was the center of life; for the ancient Hebrews and Christians, the breath was the center of life. In the 12th century, Maimonides pointed toward the head, and the loss thereof, as the reason for lack of central guidance of the soul. Physicians neither diagnosed nor certified death. During the Enlightenment, the necessity of heartbeat, breath, and consciousness for the definition of life was questioned, leading to questioning regarding the definition of death. Tests to fulfill the criteria of death, and tests to determine the absence of integration between functions of respiration, circulation, and neurology were introduced. Sensorimotor potential was becoming recognized as defining life, rather than heartbeat and respiration. As new tests were devised to fulfill criteria of death, the physician developed a professional monopoly on meeting the criteria of brain death. In the modern era, the boundary between life and death has been blurred, but the intensive care unit straddles this boundary. We may have situations where the patient is alive but in a coma, without functioning heart, lungs, kidneys, or gastrointestinal tract, with a transplanted liver, a reversed coagulation system, a blocked immune system, and a paralyzed musculoskeletal system. A human being is a man, woman, or child who is a composite of two intricately related but conceptually distinguishable components: the biological entity and the person. Therefore, human beings can suffer more than one death: a biological death and decay, and another death. Biological death is a cessation of processes of biological synthesis and replication, and is an irreversible loss of integration of the biological units. The reasons for having criteria for death are to diagnose death and pronounce a person dead. Society can then begin to engage in grief, religious rites, funerals, and burials, and accept biological death. Wills can be read, property distributed, insurance claimed, individuals can remarry, succession can take place, and legal proceedings can begin. Also, organ donation can take place, which entails difficult ethical decisions. The Harvard criteria of 1968 were devised to set forth brain-death criteria with whole brain death in mind. Currently, there are several controversies regarding these criteria: a) whether they apply to infants and children; b) whether ancillary tests are necessary; c) what the intervals of observation and testing are; and d) are there exceptions to the whole brain death criteria. Concerning the use of the adult criteria for infants and children, most researchers now agree that the adult criteria apply to infants and children who are full term and > 7 days of age. Concerning ancillary tests, there has been, in our machine- and technology-oriented profession, a great deal of emphasis on the different tests and their ability to fulfill the criteria of whole brain death. However, clinical examination and the apnea test are usually sufficient to fulfill the criteria. Ancillary tests may be desired in some cases, and a variety of these tests is available. (ABSTRACT TR

Neuroscience and Brain Death Controversies: The Elephant in the Room.

PubMed

Verheijde, Joseph L; Rady, Mohamed Y; Potts, Michael

2018-06-21

The conception and the determination of brain death continue to raise scientific, legal, philosophical, and religious controversies. While both the President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research in 1981 and the President's Council on Bioethics in 2008 committed to a biological definition of death as the basis for the whole-brain death criteria, contemporary neuroscientific findings augment the concerns about the validity of this biological definition. Neuroscientific evidentiary findings, however, have not yet permeated discussions about brain death. These findings have critical relevance (scientifically, medically, legally, morally, and religiously) because they indicate that some core assumptions about brain death are demonstrably incorrect, while others lack sufficient evidential support. If behavioral unresponsiveness does not equate to unconsciousness, then the philosophical underpinning of the definition based on loss of capacity for consciousness as well as the criteria, and tests in brain death determination are incongruent with empirical evidence. Thus, the primary claim that brain death equates to biological death has then been de facto falsified. This conclusion has profound philosophical, religious, and legal implications that should compel respective authorities to (1) reassess the philosophical rationale for the definition of death, (2) initiate a critical reappraisal of the presumed alignment of brain death with the theological definition of death in Abrahamic faith traditions, and (3) enact new legislation ratifying religious exemption to death determination by neurologic criteria.

Total Brain Death and the Integration of the Body Required of a Human Being

PubMed Central

Lee, Patrick

2016-01-01

I develop and refine an argument for the total brain death criterion of death previously advanced by Germain Grisez and me: A human being is essentially a rational animal, and so must have a radical capacity for rational operations. For rational animals, conscious sensation is a pre-requisite for rational operation. But total brain death results in the loss of the radical capacity for conscious sensation, and so also for rational operations. Hence, total brain death constitutes a substantial change—the ceasing to be of the human being. Objections are considered, including the objection that total brain death need not result in the loss of capacity for sensation, and that damage to the brain less than total brain death can result in loss of capacity for rational operations. PMID:27097647

Questionnaire on Brain Death and Organ Procurement.

PubMed

Hammad, Saleh; Alnammourah, Manal; Almahmoud, Farah; Fawzi, Mais; Breizat, Abdel-Hadi

2017-02-01

The subject of organs for transplant after brain death raises many concerns, including definition and timing of death, how to permit human organ transplant, and the idea of paying for organs. Many ethical concerns are raised regarding regulations and procedures for organ transplant in developing countries. These include where and how to obtain organs and the concept of justice in organ distribution. We administered 2682 questionnaires to 628 men and 2054 women over 24 months (range, 18 to 70 years old). We included people from universities, colleges, and the general public and asked questions on the circumstances of death, the conditions of conversations around organ donation, and reasons for acceptance or refusal of donation. The identical questionnaire, consisting of 8 questions, was administered twice: before and after a teaching session on brain death and organ procurement. The study was approved by our Ethical Review Committee and in accordance with the ethical guidelines of the 1975 Helsinki Declaration. Written informed consent was obtained from all participants. We found that 72.1% understood brain death in the prequestionnaire and 88% understood brain death in the postquestionnaire, with 63.8% versus 68% accepting the concept of brain death, 50.6% versus 58.3% thinking that their religion is against brain death, 11.3% versus 11.3% carrying a donor card, 50.7% versus 58.9% wanting to carry a donor card, 46.4% versus 56.4% agreeing to give consent for organ donation if a relative was diagnosed with brain death, 28.3% versus 50% aware of the laws and regulations concerning brain death and organ donation and transplant in Jordan, and 35.4% versus 40% in agreement with the Presumed Consent Law, respectively. In Jordan, along with legal requirements concerning brain death and organ donation and transplant, there is a lack of acceptance of organ donation after brain death, necessitating further work and activities to achieve self-sufficiency from donated organs.

A Brief Overview of Tauopathy: Causes, Consequences, and Therapeutic Strategies.

PubMed

Orr, Miranda E; Sullivan, A Campbell; Frost, Bess

2017-07-01

There are currently no disease-modifying therapies for the treatment of tauopathies, a group of progressive neurodegenerative disorders that are pathologically defined by the presence of tau protein aggregates in the brain. Current challenges for the treatment of tauopathies include the inability to diagnose early and to confidently discriminate between distinct tauopathies in patients, alongside an incomplete understanding of the cellular mechanisms involved in pathogenic tau-induced neuronal death and dysfunction. In this review, we describe current diagnostic and therapeutic strategies, known drivers of pathogenic tau formation, recent contributions to our current mechanistic understanding of how pathogenic tau induces neuronal death, and potential diagnostic and therapeutic approaches. Copyright © 2017 Elsevier Ltd. All rights reserved.

Genistein inhibition of OGD-induced brain neuron death correlates with its modulation of apoptosis, voltage-gated potassium and sodium currents and glutamate signal pathway.

PubMed

Ma, Xue-Ling; Zhang, Feng; Wang, Yu-Xiang; He, Cong-Cong; Tian, Kun; Wang, Hong-Gang; An, Di; Heng, Bin; Liu, Yan-Qiang

2016-07-25

In the present study, we established an in vitro model of hypoxic-ischemia via exposing primary neurons of newborn rats to oxygen-glucose deprivation (OGD) and observing the effects of genistein, a soybean isoflavone, on hypoxic-ischemic neuron viability, apoptosis, voltage-activated potassium (Kv) and sodium (Nav) currents, and glutamate receptor subunits. The results indicated that OGD exposure reduced the viability and increased the apoptosis of brain neurons. Meanwhile, OGD exposure caused changes in the current-voltage curves and current amplitude values of voltage-activated potassium and sodium currents; OGD exposure also decreased GluR2 expression and increased NR2 expression. However, genistein at least partially reversed the effects caused by OGD. The results suggest that hypoxic-ischemia-caused neuronal apoptosis/death is related to an increase in K(+) efflux, a decrease in Na(+) influx, a down-regulation of GluR2, and an up-regulation of NR2. Genistein may exert some neuroprotective effects via the modulation of Kv and Nav currents and the glutamate signal pathway, mediated by GluR2 and NR2. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

A change of heart and a change of mind? Technology and the redefinition of death in 1968.

PubMed

Giacomini, M

1997-05-01

In 1968, an ad hoc committee of Harvard faculty publicly redefined death as "brain death". What interests and issues compelled the redefinition of death, and formed the "spirit" of this precedent-setting policy? This paper reports on an historical study of the files of the Harvard ad hoc committee, the proceedings of an international conference on ethical issues in organ transplantation, and a review of the medical literature and media in the decades preceding the redefinition of death. This analysis of the technological and professional forces involved in the redefinition of death in 1968 questions two common theses: that technological "progress", primarily in the areas of life support and electroencephalography, literally created brain-dead bodies and dictated their defining features (respectively), and that Harvard's definition of brain death by committee constituted a net loss of autonomy for medicine. In fact, medical researchers through the 1960s disputed and negotiated many features of the brain death syndrome, and transplantation interests-perhaps more kidney than heart-played a particularly influential role in tailoring the final criteria put forth by Harvard in 1968. It is also doubtful whether Harvard's definition of brain death by multidisciplinary committee undermined medical privilege and autonomy. The Harvard Ad Hoc Committee may not have succeeded in establishing definitive, indisputable brain death criteria and ensuring their consistent application to all clinical cases of brain death. However, it did gain significant ground for transplant and other medical interests by (1) establishing brain death as a technical "fact" and the definition of brain death as an exercise for medical theorists, (2) involving non-medical ethics and humanities experts in supporting the technical redefinition of death, and, (3) successfully involving transplant surgeons in the redefinition of death and attempting (albeit unsuccessfully) not to exclude them from the actual diagnosis of death in individual cases.

Deconstructing the Brain Disconnection–Brain Death Analogy and Clarifying the Rationale for the Neurological Criterion of Death

PubMed Central

Moschella, Melissa

2016-01-01

This article explains the problems with Alan Shewmon’s critique of brain death as a valid sign of human death, beginning with a critical examination of his analogy between brain death and severe spinal cord injury. The article then goes on to assess his broader argument against the necessity of the brain for adult human organismal integration, arguing that he fails to translate correctly from biological to metaphysical claims. Finally, on the basis of a deeper metaphysical analysis, I offer a revised rationale for the validity of the neurological criterion of human death. PMID:27095749

Mitochondrial mechanisms of neuronal rescue by F-68, a hydrophilic Pluronic block co-polymer, following acute substrate deprivation.

PubMed

Wang, Janice C; Bindokas, Vytautas P; Skinner, Matthew; Emrick, Todd; Marks, Jeremy D

2017-10-01

Global brain ischemia can lead to widespread neuronal death and poor neurologic outcomes in patients. Despite detailed understanding of the cellular and molecular mechanisms mediating neuronal death following focal and global brain hypoxia-ischemia, treatments to reduce ischemia-induced brain injury remain elusive. One pathway central to neuronal death following global brain ischemia is mitochondrial dysfunction, one consequence of which is the cascade of intracellular events leading to mitochondrial outer membrane permeabilization. A novel approach to rescuing injured neurons from death involves targeting cellular membranes using a class of synthetic molecules called Pluronics. Pluronics are triblock copolymers of hydrophilic poly[ethylene oxide] (PEO) and hydrophobic poly[propylene oxide] (PPO). Evidence is accumulating to suggest that hydrophilic Pluronics rescue injured neurons from death following substrate deprivation by preventing mitochondrial dysfunction. Here, we will review current understanding of the nature of interaction of Pluronic molecules with biological membranes and the efficacy of F-68, an 80% hydrophilic Pluronic, in rescuing neurons from injury. We will review data indicating that F-68 reduces mitochondrial dysfunction and mitochondria-dependent death pathways in a model of neuronal injury in vitro, and present new evidence that F-68 acts directly on mitochondria to inhibit mitochondrial outer membrane permeabilization. Finally, we will present results of a pilot, proof-of-principle study suggesting that F-68 is effective in reducing hippocampal injury induced by transient global ischemia in vivo. By targeting mitochondrial dysfunction, F-68 and other Pluronic molecules constitute an exciting new approach to rescuing neurons from acute injury. Copyright © 2017 Elsevier Ltd. All rights reserved.

Total brain death: a reply to Alan Shewmon.

PubMed

Lee, Patrick; GriseZ, Germain

2012-06-01

D. Alan Shewmon has advanced a well-documented challenge to the widely accepted total brain death criterion for death of the human being. We show that Shewmon’s argument against this criterion is unsound, though he does refute the standard argument for that criterion. We advance a distinct argument for the total brain death criterion and answer likely objections. Since human beings are rational animals--sentient organisms of a specific type--the loss of the radical capacity for sentience (the capacity to sense or to develop the capacity to sense) involves a substantial change, the passing away of the human organism. In human beings total brain death involves the complete loss of the radical capacity for sentience, and so in human beings total brain death is death.

Total Brain Death and the Integration of the Body Required of a Human Being.

PubMed

Lee, Patrick

2016-06-01

I develop and refine an argument for the total brain death criterion of death previously advanced by Germain Grisez and me: A human being is essentially a rational animal, and so must have a radical capacity for rational operations. For rational animals, conscious sensation is a pre-requisite for rational operation. But total brain death results in the loss of the radical capacity for conscious sensation, and so also for rational operations. Hence, total brain death constitutes a substantial change-the ceasing to be of the human being. Objections are considered, including the objection that total brain death need not result in the loss of capacity for sensation, and that damage to the brain less than total brain death can result in loss of capacity for rational operations. © The Author 2016. Published by Oxford University Press, on behalf of the Journal of Medicine and Philosophy Inc. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Increased reduction in exsanguination rates leaves brain injury as the only major cause of death in blunt trauma.

PubMed

Jochems, D; Leenen, L P H; Hietbrink, F; Houwert, R M; van Wessem, K J P

2018-05-23

Central nervous system (CNS) related injuries and exsanguination have been the most common causes of death in trauma for decades. Despite improvements in haemorrhage control in recent years exsanguination is still a major cause of death. We conducted a prospective database study to investigate the current incidence of haemorrhage related mortality. A prospective database study of all trauma patients admitted to an urban major trauma centre between January 2007 and December 2016 was conducted. All in-hospital trauma deaths were included. Cause of death was reviewed by a panel of trauma surgeons. Patients who were dead on arrival were excluded. Trends in demographics and outcome were analysed per year. Further, 2 time periods (2007-2012 and 2013-2016) were selected representing periods before and after implementation of haemostatic resuscitation and damage control procedures in our hospital to analyse cause of death into detail. 11,553 trauma patients were admitted, 596 patients (5.2%) died. Mean age of deceased patients was 61 years and 61% were male. Mechanism of injury (MOI) was blunt in 98% of cases. Mean ISS was 28 with head injury the most predominant injury (mean AIS head 3.4). There was no statistically significant difference in sex and MOI over time. Even though deceased patients were older in 2016 compared to 2007 (67 vs. 46 years, p < 0.001), mortality was lower in later years (p = 0.02). CNS related injury was the main cause of death in the whole decade; 58% of patients died of CNS in 2007-2012 compared to 76% of patients in 2013-2016 (p = 0.001). In 2007-2012 9% died of exsanguination compared to 3% in 2013-2016 (p = 0.001). In this cohort in a major trauma centre death by exsanguination has decreased to 3% of trauma deaths. The proportion of traumatic brain injury has increased over time and has become the most common cause of death in blunt trauma. Besides on-going prevention of brain injury future studies should focus on treatment strategies preventing secondary damage of the brain once the injury has occurred. Copyright © 2018 Elsevier Ltd. All rights reserved.

Role of Caspase-8 and Fas in Cell Death After Spinal Cord Injury

PubMed Central

Sobrido-Cameán, Daniel; Barreiro-Iglesias, Antón

2018-01-01

Spinal cord injury (SCI) causes the death of neurons and glial cells due to the initial mechanical forces (i.e., primary injury) and through a cascade of secondary molecular events (e.g., inflammation or excitotoxicity) that exacerbate cell death. The loss of neurons and glial cells that are not replaced after the injury is one of the main causes of disability after SCI. Evidence accumulated in last decades has shown that the activation of apoptotic mechanisms is one of the factors causing the death of intrinsic spinal cord (SC) cells following SCI. Although this is not as clear for brain descending neurons, some studies have also shown that apoptosis can be activated in the brain following SCI. There are two main apoptotic pathways, the extrinsic and the intrinsic pathways. Activation of caspase-8 is an important step in the initiation of the extrinsic pathway. Studies in rodents have shown that caspase-8 is activated in SC glial cells and neurons and that the Fas receptor plays a key role in its activation following a traumatic SCI. Recent work in the lamprey model of SCI has also shown the retrograde activation of caspase-8 in brain descending neurons following SCI. Here, we review our current knowledge on the role of caspase-8 and the Fas pathway in cell death following SCI. We also provide a perspective for future work on this process, like the importance of studying the possible contribution of Fas/caspase-8 signaling in the degeneration of brain neurons after SCI in mammals. PMID:29666570

Confounding factors in diagnosing brain death: a case report.

PubMed

Burns, Jeffrey M; Login, Ivan S

2002-06-26

Brain death is strictly defined medically and legally. This diagnosis depends on three cardinal neurological features: coma, absent brainstem reflexes, and apnea. The diagnosis can only be made, however, in the absence of intoxication, hypothermia, or certain medical illnesses. A patient with severe hypoxic-ischemic brain injury met the three cardinal neurological features of brain death but concurrent profound hypothyroidism precluded the diagnosis. Our clinical and ethical decisions were further challenged by another facet of this complex case. Although her brain damage indicated a hopeless prognosis, we could not discontinue care based on futility because the only known surrogate was mentally retarded and unable to participate in medical planning. The presence of certain medical conditions prohibits a diagnosis of brain death, which is a medicolegal diagnosis of death, not a prediction or forecast of future outcome. While prognostication is important in deciding to withdraw care, it is not a component in diagnosing brain death.

Brain death: the challenges of translating medical science into Islamic bioethical discourse.

PubMed

Padela, Aasim I; Basser, Taha A

2012-09-01

Islamic ethico-legal assessments of brain death are varied and controversial. Some Islamic ethico-legal bodies have concluded that brain death is equivalent to cardiopulmonary death; others regard it as an intermediate state between life and death, and a few opine that it does not meet the standards for legal death according to Islamic law. Yet this translation of the concept of brain death into the Islamic ethico-legal domain has generated multiple ethical complexities that receive insufficient attention within the extant medical and fiqh literature. How do Islamic legists understand brain death as a clinical phenomenon? How does the Islamic ethico-legal system treat medical uncertainty? What Islamic ethico-legal principles should apply to bioethical questions about life and death? In this paper, we analyze the arguments for, and against, the acceptance of brain death within the context of the deliberation of a representative juridical council. In our discussion we focus on areas in which the legists' ethico-legal reasoning hinges upon clinical conceptions of the state of the individual when diagnosed as brain dead. As Islamic ethics continues to engage scientific and technological advancements in these areas, such exploration of internal workings is necessary if we wish to better understand how Islamic ethical principles can contribute to bioethical deliberation.

The Case for Reasonable Accommodation of Conscientious Objections to Declarations of Brain Death.

PubMed

Johnson, L Syd M

2016-03-01

Since its inception in 1968, the concept of whole-brain death has been contentious, and four decades on, controversy concerning the validity and coherence of whole-brain death continues unabated. Although whole-brain death is legally recognized and medically entrenched in the United States and elsewhere, there is reasonable disagreement among physicians, philosophers, and the public concerning whether brain death is really equivalent to death as it has been traditionally understood. A handful of states have acknowledged this plurality of viewpoints and enacted "conscience clauses" that require "reasonable accommodation" of religious and moral objections to the determination of death by neurological criteria. This paper argues for the universal adoption of "reasonable accommodation" policies using the New Jersey statute as a model, in light of both the ongoing controversy and the recent case of Jahi McMath, a child whose family raised religious objections to a declaration of brain death. Public policies that accommodate reasonable, divergent viewpoints concerning death provide a practical and compassionate way to resolve those conflicts that are the most urgent, painful, and difficult to reconcile.

Demyelination as a rational therapeutic target for ischemic or traumatic brain injury.

PubMed

Shi, Hong; Hu, Xiaoming; Leak, Rehana K; Shi, Yejie; An, Chengrui; Suenaga, Jun; Chen, Jun; Gao, Yanqin

2015-10-01

Previous research on stroke and traumatic brain injury (TBI) heavily emphasized pathological alterations in neuronal cells within gray matter. However, recent studies have highlighted the equal importance of white matter integrity in long-term recovery from these conditions. Demyelination is a major component of white matter injury and is characterized by loss of the myelin sheath and oligodendrocyte cell death. Demyelination contributes significantly to long-term sensorimotor and cognitive deficits because the adult brain only has limited capacity for oligodendrocyte regeneration and axonal remyelination. In the current review, we will provide an overview of the major causes of demyelination and oligodendrocyte cell death following acute brain injuries, and discuss the crosstalk between myelin, axons, microglia, and astrocytes during the process of demyelination. Recent discoveries of molecules that regulate the processes of remyelination may provide novel therapeutic targets to restore white matter integrity and improve long-term neurological recovery in stroke or TBI patients. Copyright © 2015 Elsevier Inc. All rights reserved.

Brain death in Islamic ethico-legal deliberation: challenges for applied Islamic bioethics.

PubMed

Padela, Aasim I; Arozullah, Ahsan; Moosa, Ebrahim

2013-03-01

Since the 1980s, Islamic scholars and medical experts have used the tools of Islamic law to formulate ethico-legal opinions on brain death. These assessments have varied in their determinations and remain controversial. Some juridical councils such as the Organization of Islamic Conferences' Islamic Fiqh Academy (OIC-IFA) equate brain death with cardiopulmonary death, while others such as the Islamic Organization of Medical Sciences (IOMS) analogize brain death to an intermediate state between life and death. Still other councils have repudiated the notion entirely. Similarly, the ethico-legal assessments are not uniform in their acceptance of brain-stem or whole-brain criteria for death, and consequently their conceptualizations of, brain death. Within the medical literature, and in the statements of Muslim medical professional societies, brain death has been viewed as sanctioned by Islamic law with experts citing the aforementioned rulings. Furthermore, health policies around organ transplantation and end-of-life care within the Muslim world have been crafted with consideration of these representative religious determinations made by transnational, legally-inclusive, and multidisciplinary councils. The determinations of these councils also have bearing upon Muslim clinicians and patients who encounter the challenges of brain death at the bedside. For those searching for 'Islamically-sanctioned' responses that can inform their practice, both the OIC-IFA and IOMS verdicts have palpable gaps in their assessments and remain clinically ambiguous. In this paper we analyze these verdicts from the perspective of applied Islamic bioethics and raise several questions that, if answered by future juridical councils, will better meet the needs of clinicians and bioethicists. © 2011 Blackwell Publishing Ltd.

Which experimental model can sensitively indicate brain death by functional near-infrared spectroscopy?

NASA Astrophysics Data System (ADS)

Pan, Boan; Liu, Weichao; Fang, Xiang; Huang, Xiaobo; Li, Ting

2018-02-01

Brain death is defined as permanent loss of the brain functions. The evaluation of it has many meanings, such as the relief of organ transplantation stress and family burden. However, it is hard to be judged precisely. The standard clinical tests are expensive, time consuming and even dangerous, and some auxiliary methods have limitations. Functional near infrared spectroscopy (fNIRS), monitoring cerebral hemodynamic responses noninvasively, evaluate brain death in some papers published, but there is no discussion about which experimental mode can monitor brain death patient more sensitively. Here, we attempt to use our fNIRS to evaluate brain death and find which experimental mode is effective. In order to discuss the problem, we detected eleven brain death patients and twenty normal patients under natural state. They were provided different fraction of inspiration O2 (FIO2) in different phase. We found that the ratio of Δ[HbO2] (the concentration changes in oxyhemoglobin) to Δ[Hb] (the concentration changes in deoxyhemoglobin) in brain death patients is significantly higher than normal patients in FIO2 experiment. Combined with the data analysis result, restore oxygen change process and low-high-low paradigm is more sensitively.

Evaluation and diagnosis of brain death by functional near-infrared spectroscopy

NASA Astrophysics Data System (ADS)

Pan, Boan; Zhong, Fulin; Huang, Xiaobo; Pan, Lingai; Lu, Sen; Li, Ting

2017-02-01

Brain death, the irreversible and permanent loss of the brain and brainstem functions, is hard to be judged precisely for some clinical reasons. The traditional diagnostic methods are time consuming, expensive and some are even dangerous. Functional near infrared spectroscopy (FNIRS), using the good scattering properties of major component of blood to NIR, is capable of noninvasive monitoring cerebral hemodynamic responses. Here, we attempt to use portable FNIRS under patients' natural state for brain death diagnosis. Ten brain death patients and seven normal subjects participated in FNIRS measurements. All of them were provided different fractional concentration of inspired oxygen (FIO2) in different time periods. We found that the concentration variation of deoxyhemoglobin concentration (Δ[Hb]) presents the trend of decrease in the both brain death patients and normal subjects with the raise of the FIO2, however, the data in the normal subjects is more significant. And the concentration variation of oxyhemoglobins concentration (Δ[HbO2]) emerges the opposite trends. Thus Δ[HbO2]/Δ[Hb] in brain death patients is significantly higher than normal subjects, and emerges the rising trend as time went on. The findings indicated the potential of FNIRS-measured hemodynamic index in diagnosing brain death.

Serum S100B protein concentration in brain-dead organ donors: a pilot study.

PubMed

Krzych, Łukasz J; Czempik, Piotr Filip; Saucha, Wojciech; Kokocińska, Danuta; Knapik, Piotr

2015-01-01

Protein S100B is considered to be a marker of brain damage, but there is a paucity of data regarding the utility of its assessment in brain-dead organ donors. The aim of the study was to compare serum protein S100B concentrations between brain-dead organ donors and patients with a confirmed permanent neurological deficit but without signs of brain death. The concentration of serum S100B protein was measured in 12 brain-dead organ donors (including 7 males with a median age of 40 years). All measurements were taken when brain death was confirmed by the commission. Twenty-nine patients (including 13 males with a median age of 63 years) who died in the medical ICU with confirmed permanent brain injury without signs of brain death acted as controls. In these patients, S-100B protein measurements were performed upon ICU admission. In brain-dead organ donors, the median values of serum S100B protein were much higher in comparison to the control group (median and IQR, respectively: 5.04 μg L⁻¹; 1.775-6.765 vs 0.897 μg L⁻¹; 0.324-1.880, P < 0.001). S100B serum values > 1.81 μg L⁻¹ predicted brain death with the highest accuracy (AUROC = 0.83; 95% CI 0.68-0.93; P < 0.001). Concentrations of serum S100B protein in brain-dead organ donors are extremely high and may support the diagnosis of brain death. This fact may be of value when the presence of reflex movements (frequently reported despite brain death) might delay determination of brain death and result in the failure of organ donation.

Dementia resulting from traumatic brain injury

PubMed Central

Ramalho, Joana; Castillo, Mauricio

2015-01-01

Traumatic brain injury (TBI) represents a significant public health problem in modern societies. It is primarily a consequence of traffic-related accidents and falls. Other recently recognized causes include sports injuries and indirect forces such as shock waves from battlefield explosions. TBI is an important cause of death and lifelong disability and represents the most well-established environmental risk factor for dementia. With the growing recognition that even mild head injury can lead to neurocognitive deficits, imaging of brain injury has assumed greater importance. However, there is no single imaging modality capable of characterizing TBI. Current advances, particularly in MR imaging, enable visualization and quantification of structural and functional brain changes not hitherto possible. In this review, we summarize data linking TBI with dementia, emphasizing the imaging techniques currently available in clinical practice along with some advances in medical knowledge. PMID:29213985

Successful multiple organ donation after donor brain death due to Actinomyces israelii meningitis.

PubMed

Lagunes, Leonel; Len, Oscar; Sandiumenge, Alberto; Martínez-Saez, Elena; Pumarola, Tomás; Bodro, Marta; Macías, Antonio; Silva, Jose T; Nuvials, F Xavier; Charco, Ramon; Moreso, Francesc; Pont, Teresa

2017-08-01

The increasing gap between availability of solid organs for transplantation and the demand has led to the inclusion of donor organs that, according to current guidelines, may be discarded, some of them because of the possibility for transmission of infection to the recipients. We present the first report, to the best of our knowledge, of a case of a brain-dead donor with a localized and treated Actinomyces israelii central nervous system infection who, after a thorough evaluation, provided organs for successful transplant procedures in four recipients. There was no evidence of transmission of infection within a 6-month follow-up. Relative contraindications must be individualized in order to expand the number of real organ donors, emphasizing caution in rare causes for brain death in which patients should be thoroughly evaluated for possible donation. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Methamphetamine-induced neuronal necrosis: the role of electrographic seizure discharges

PubMed Central

Fujikawa, Denson G.; Pais, Emil S.; Aviles, Ernesto R.; Hsieh, Kung-Chiao; Bashir, Muhammad Tariq

2016-01-01

We have evidence that methamphetamine (METH)-induced neuronal death is morphologically necrotic, not apoptotic, as is currently believed, and that electrographic seizures may be responsible. We administered 40 mg/kg i.p. to 12 male C57BL/6 mice and monitored EEGs continuously and rectal temperatures every 15 min, keeping rectal temperatures <41.0 °C. Seven of the 12 mice had repetitive electrographic seizure discharges (RESDs) and 5 did not. The RESDs were often not accompanied by behavioral signs of seizures–i.e., they were often not accompanied by clonic forelimb movements. The 7 mice with RESDs had acidophilic neurons (the H&E light-microscopic equivalent of necrotic neurons by ultrastructural examination) in all of 7 brain regions (hippocampal CA1, CA2, CA3 and hilus, amygdala, piriform cortex and entorhinal cortex), the same brain regions damaged following generalized seizures, 24 h after METH administration. The 5 mice without RESDs had a few acidophilic neurons in 4 of the 7 brain regions, but those with RESDs had significantly more in 6 of the 7 brain regions. Maximum rectal temperatures were comparable in mice with and without RESDs, so that cannot explain the difference between the two groups with respect to METH-induced neuronal death. Our data show that METH-induced neuronal death is morphologically necrotic, that EEGs must be recorded to detect electrographic seizure activity in rodents without behavioral evidence of seizures, and that RESDs may be responsible for METH-induced neuronal death. PMID:26562800

Confounding factors in diagnosing brain death: a case report

PubMed Central

Burns, Jeffrey M; Login, Ivan S

2002-01-01

Background Brain death is strictly defined medically and legally. This diagnosis depends on three cardinal neurological features: coma, absent brainstem reflexes, and apnea. The diagnosis can only be made, however, in the absence of intoxication, hypothermia, or certain medical illnesses. Case presentation A patient with severe hypoxic-ischemic brain injury met the three cardinal neurological features of brain death but concurrent profound hypothyroidism precluded the diagnosis. Our clinical and ethical decisions were further challenged by another facet of this complex case. Although her brain damage indicated a hopeless prognosis, we could not discontinue care based on futility because the only known surrogate was mentally retarded and unable to participate in medical planning. Conclusion The presence of certain medical conditions prohibits a diagnosis of brain death, which is a medicolegal diagnosis of death, not a prediction or forecast of future outcome. While prognostication is important in deciding to withdraw care, it is not a component in diagnosing brain death. PMID:12097152

"Brain Death" and dead donor rule. Discussion and proposals on the thesis of Truog.

PubMed

Bruzzone, Paolo

2015-01-01

The introduction in 1968 by the "ad hoc" Harvard committee of the concept of "Brain Death" gave birth to the worldwide diffusion of organ transplantation. Recently "Total Brain Failure" has been proposed as preferred term, instead of "Brain Death", by the President's Council on Bioethics. The concepts of "brain death" and of "dead donor rule" remain the ethical and moral support of organ transplantation. However both criteria has been questioned , either separately or all together , by many authors and particularly by Dr. Robert D. Truog.

Predictors of neurologic and nonneurologic death in patients with brain metastasis initially treated with upfront stereotactic radiosurgery without whole-brain radiation therapy

PubMed Central

Johnson, Adam G.; Ruiz, Jimmy; Isom, Scott; Lucas, John T.; Hinson, William H.; Watabe, Kounosuke; Laxton, Adrian W.; Tatter, Stephen B.; Chan, Michael D.

2017-01-01

Abstract Background. In this study we attempted to discern the factors predictive of neurologic death in patients with brain metastasis treated with upfront stereotactic radiosurgery (SRS) without whole brain radiation therapy (WBRT) while accounting for the competing risk of nonneurologic death. Methods. We performed a retrospective single-institution analysis of patients with brain metastasis treated with upfront SRS without WBRT. Competing risks analysis was performed to estimate the subdistribution hazard ratios (HRs) for neurologic and nonneurologic death for predictor variables of interest. Results. Of 738 patients treated with upfront SRS alone, neurologic death occurred in 226 (30.6%), while nonneurologic death occurred in 309 (41.9%). Multivariate competing risks analysis identified an increased hazard of neurologic death associated with diagnosis-specific graded prognostic assessment (DS-GPA) ≤ 2 (P = .005), melanoma histology (P = .009), and increased number of brain metastases (P<.001), while there was a decreased hazard associated with higher SRS dose (P = .004). Targeted agents were associated with a decreased HR of neurologic death in the first 1.5 years (P = .04) but not afterwards. An increased hazard of nonneurologic death was seen with increasing age (P =.03), nonmelanoma histology (P<.001), presence of extracranial disease (P<.001), and progressive systemic disease (P =.004). Conclusions. Melanoma, DS-GPA, number of brain metastases, and SRS dose are predictive of neurologic death, while age, nonmelanoma histology, and more advanced systemic disease are predictive of nonneurologic death. Targeted agents appear to delay neurologic death. PMID:27571883

Deconstructing the Brain Disconnection-Brain Death Analogy and Clarifying the Rationale for the Neurological Criterion of Death.

PubMed

Moschella, Melissa

2016-06-01

This article explains the problems with Alan Shewmon's critique of brain death as a valid sign of human death, beginning with a critical examination of his analogy between brain death and severe spinal cord injury. The article then goes on to assess his broader argument against the necessity of the brain for adult human organismal integration, arguing that he fails to translate correctly from biological to metaphysical claims. Finally, on the basis of a deeper metaphysical analysis, I offer a revised rationale for the validity of the neurological criterion of human death. © The Author 2016. Published by Oxford University Press, on behalf of the Journal of Medicine and Philosophy Inc. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Is slack an intrinsic seizure terminator?

PubMed

Igelström, Kajsa M

2013-06-01

Understanding how epileptic seizures are initiated and propagated across large brain networks is difficult, but an even greater mystery is what makes them stop. Failure of spontaneous seizure termination leads to status epilepticus-a state of uninterrupted seizure activity that can cause death or permanent brain damage. Global factors, like changes in neuromodulators and ion concentrations, are likely to play major roles in spontaneous seizure cessation, but individual neurons also have intrinsic active ion currents that may contribute. The recently discovered gene Slack encodes a sodium-activated potassium channel that mediates a major proportion of the outward current in many neurons. Although given little attention, the current flowing through this channel may have properties consistent with a role in seizure termination.

Of wholes and parts: A Thomistic refutation of "Brain Death".

PubMed

Accad, Michel

2015-08-01

I propose a refutation of the two major arguments that support the concept of "brain death" as an ontological equivalent to death of the human organism. I begin with a critique of the notion that a body part, such as the brain, could act as "integrator" of a whole body. I then proceed with a rebuttal of the argument that destruction of a body part essential for rational operations-such as the brain-necessarily entails that the remaining whole is indisposed to accrue a rational soul. Next, I point to the equivocal use of the terms "alive" or "living" as being at the root of conceptual errors about brain death. I appeal to the Thomistic definition of life and to the hylomorphic concept of "virtual presence" to clarify this confusion. Finally, I show how the Thomistic definition of life supports the traditional criterion for the determination of death. Lay summary: By the mid-1960s, medical technology became available that could keep "alive" the bodies of patients who had sustained complete and irreversible brain injury. The concept of "brain death" emerged to describe such states. Physicians, philosophers, and ethicists then proposed that the state of brain death is equivalent to the state of death traditionally identified by the absence of spontaneous pulse and respiration. This article challenges the major philosophical arguments that have been advanced to draw this equivalence.

Lived Experiences of Iranian Nurses Caring for Brain Death Organ Donor Patients: Caring as “Halo of Ambiguity and Doubt”

PubMed Central

Keshtkaran, Zahra; Sharif, Farkhondeh; Navab, Elham; Gholamzadeh, Sakineh

2016-01-01

Background: Brain death is a concept in which its criteria have been expressed as documentations in Harvard Committee of Brain Death. The various perceptions of caregiver nurses for brain death patients may have effect on the chance of converting potential donors into actual organ donors. Objective: The present study has been conducted in order to perceive the experiences of nurses in care-giving to the brain death of organ donor patients. Methods: This qualitative study was carried out by means of Heidegger’s hermeneutic phenomenology. Eight nurses who have been working in ICU were interviewed. The semi-structured interviews were recorded by a tape-recorder and the given texts were transcribed and the analyses were done by Van-Mannen methodology and (thematic) analysis. Results: One of the foremost themes extracted from this study included ‘Halo of ambiguity and doubt’ that comprised of two sub-themes of ‘having unreasonable hope’ and ‘Conservative acceptance of brain death’. The unreasonable hope included lack of trust (uncertainty) in diagnosis and verification of brain death, passing through denial wall, and avoidance from explicit and direct disclosure of brain death in patients’ family. In this investigation, the nurses were involved in a type of ambiguity and doubt in care-giving to the potentially brain death of organ donor patients, which were also evident in their interaction with patients’ family and for this reason, they did not definitely announce the brain death and so far they hoped for treatment of the given patient. Such confusion and hesitance both caused annoyance of nurses and strengthening the denial of patients’ family to be exposed to death. Conclusion: The results of this study reveal the fundamental perceived care-giving of brain death in organ donor patients and led to developing some strategies to improve care-giving and achievement in donation of the given organ and necessity for presentation of educational and supportive services for nurses might become more evident than ever. PMID:26925919

Knowledge of the Brain Death Concept Among the Population of Havana, Cuba.

PubMed

Ríos, A; López-Navas, A I; Sánchez, Á; Martinez-Alarcon, L; Ayala, M A; Garrido, G; Sebastián, M J; Ramis, G; Abdo-Cuza, A; Hernández, A; Ramírez, P; Parrilla, P

2018-03-01

One of the main reasons against organ donation is the fear of apparent death due to ignorance of the brain death concept. Our aim was to assess knowledge about and acceptance of the brain death concept among the population of Havana, Cuba. The population screened, stratified by gender and age, included those >15 years old and living in Havana, Cuba. The appraisal tool utilized was a questionnaire on attitude toward organ donation ("PCID-DTO Ríos"). A random selection of individuals were surveyed according to the stratification. Cuba's census data were used. The participation was anonymized and self-administered. The verbal consent of participants was provided. There were 920 respondents: 31% (n = 282) knew the concept of brain death and accepted it; 57% (n = 529) did not; and 12% (n = 109) had a misperception, or did not accept brain death as a person's death. Those who knew and accepted the concept had a more favorable attitude toward their own organ donation after death (85% vs 61%; P < .001). The psychosocial factors related to the knowledge of brain death concept were: the gender (P = .002), to make up for speaking at a family level about the organ transplant (P < .001), the couple's opinion about the organ donation (P < .001) and the religion (P < .001). The brain death concept is not well understood in the population of Havana, Cuba. Copyright © 2017 Elsevier Inc. All rights reserved.

Public education and misinformation on brain death in mainstream media.

PubMed

Lewis, Ariane; Lord, Aaron S; Czeisler, Barry M; Caplan, Arthur

2016-09-01

We sought to evaluate the caliber of education mainstream media provides the public about brain death. We reviewed articles published prior to July 31, 2015, on the most shared/heavily trafficked mainstream media websites of 2014 using the names of patients from two highly publicized brain death cases, "Jahi McMath" and "Marlise Muñoz." We reviewed 208 unique articles. The subject was referred to as being "alive" or on "life support" in 72% (149) of the articles, 97% (144) of which also described the subject as being brain dead. A definition of brain death was provided in 4% (9) of the articles. Only 7% (14) of the articles noted that organ support should be discontinued after brain death declaration unless a family has agreed to organ donation. Reference was made to well-known cases of patients in persistent vegetative states in 16% (34) of articles and 47% (16) of these implied both patients were in the same clinical state. Mainstream media provides poor education to the public on brain death. Because public understanding of brain death impacts organ and tissue donation, it is important for physicians, organ procurement organizations, and transplant coordinators to improve public education on this topic. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Predictors of neurologic and nonneurologic death in patients with brain metastasis initially treated with upfront stereotactic radiosurgery without whole-brain radiation therapy.

PubMed

McTyre, Emory R; Johnson, Adam G; Ruiz, Jimmy; Isom, Scott; Lucas, John T; Hinson, William H; Watabe, Kounosuke; Laxton, Adrian W; Tatter, Stephen B; Chan, Michael D

2017-04-01

In this study we attempted to discern the factors predictive of neurologic death in patients with brain metastasis treated with upfront stereotactic radiosurgery (SRS) without whole brain radiation therapy (WBRT) while accounting for the competing risk of nonneurologic death. We performed a retrospective single-institution analysis of patients with brain metastasis treated with upfront SRS without WBRT. Competing risks analysis was performed to estimate the subdistribution hazard ratios (HRs) for neurologic and nonneurologic death for predictor variables of interest. Of 738 patients treated with upfront SRS alone, neurologic death occurred in 226 (30.6%), while nonneurologic death occurred in 309 (41.9%). Multivariate competing risks analysis identified an increased hazard of neurologic death associated with diagnosis-specific graded prognostic assessment (DS-GPA) ≤ 2 (P = .005), melanoma histology (P = .009), and increased number of brain metastases (P<.001), while there was a decreased hazard associated with higher SRS dose (P = .004). Targeted agents were associated with a decreased HR of neurologic death in the first 1.5 years (P = .04) but not afterwards. An increased hazard of nonneurologic death was seen with increasing age (P =.03), nonmelanoma histology (P<.001), presence of extracranial disease (P<.001), and progressive systemic disease (P =.004). Melanoma, DS-GPA, number of brain metastases, and SRS dose are predictive of neurologic death, while age, nonmelanoma histology, and more advanced systemic disease are predictive of nonneurologic death. Targeted agents appear to delay neurologic death. © The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

Legislative Enforcement of Nonconsensual Determination of Neurological (Brain) Death in Muslim Patients: A Violation of Religious Rights.

PubMed

Rady, Mohamed Y; Verheijde, Joseph L

2018-04-01

Death is defined in the Quran with a single criterion of irreversible separation of the ruh (soul) from the body. The Quran is a revelation from God to man, and the primary source of Islamic knowledge. The secular concept of death by neurological criteria, or brain death, is at odds with the Quranic definition of death. The validity of this secular concept has been contested scientifically and philosophically. To legitimize brain death for the purpose of organ donation and transplantation in Muslim communities, Chamsi-Pasha and Albar (concurring with the US President's Council on Bioethics) have argued that irreversible loss of capacity for consciousness and breathing (apneic coma) in brain death defines true death in accordance with Islamic sources. They have postulated that the absence of nafs (personhood) and nafas (breath) in apneic coma constitutes true death because of departure of the soul (ruh) from the body. They have also asserted that general anesthesia is routine in brain death before surgical procurement. Their argument is open to criticism because: (1) the ruh is described as the essence of life, whereas the nafs and nafas are merely human attributes; (2) unlike true death, the ruh is still present even with absent nafs and nafas in apneic coma; and (3) the routine use of general anesthesia indicates the potential harm to brain-dead donors from surgical procurement. Postmortem general anesthesia is not required for autopsy. Therefore, the conclusion must be that legislative enforcement of nonconsensual determination of neurological (brain) death and termination of life-support and medical treatment violates the religious rights of observant Muslims.

Numbers of Brain Deaths and Deceased Donors in Hospitals in Istanbul Region That Have Transplantation Units: A Retrospective Analysis Between the Years 2005 and 2015.

PubMed

Harmanci Seren, A K; Yavuz, H

2017-04-01

Turkey is one of the countries facing a serious organ shortage problem, with thousands of patients with end-stage organ failure. The Social Security Institution started to increase the reimbursement for transplantation operations in 2007 to solve this problem, and this policy has continued since then. Although the number of transplantation centers and operations in Turkey increased in this term, according to organ donation and transplantation statistics from the Ministry of Health, the rate of organ retrieval from deceased organ donors has decreased. This study was performed with the purpose of retrospectively analyzing (between the years 2005 and 2015) the number of brain deaths and donors after brain death in hospitals that are affiliated with the Istanbul Regional Coordination Office and have transplantation units. Data were collected via the website of the Ministry of Health. Hospitals were categorized as those directly affiliated with the Ministry of Health, university hospitals, and private hospitals. This study found that the number of transplantation centers has increased >3 times since 2005, and the number of private transplantation centers has increased 9 times for the same period. We also found that the number of brain deaths, donors after brain death in hospitals, and number of brain deaths and donors after brain death per hospital had varied throughout the study years. Although the number of transplantation centers has increased since 2005, the number of brain deaths and donors after brain death has not increased to the same extent for this period in these hospitals that have transplantation units. Copyright © 2017 Elsevier Inc. All rights reserved.

Ethical and medical management of a pregnant woman with brain stem death resulting in delivery of a healthy child and organ donation.

PubMed

Gopčević, A; Rode, B; Vučić, M; Horvat, A; Širanović, M; Gavranović, Ž; Košec, V; Košec, A

2017-11-01

Maternal brain death during pregnancy remains an exceedingly complex situation that requires not only a well-considered medical management plan, but also careful decision-making in a legally and ethically delicate situation. Management of brain dead pregnant patients needs to adhere to special strategies that support the mother in a way that she can deliver a viable and healthy child. Brain death in pregnant women is very rare, with only a few published cases. We present a case of a pregnant woman with previously diagnosed multiple brain cavernomas that led to intracranial hemorrhage and brain stem death during the 21st week of pregnancy. The condition that can be proven unequivocally, using tests that do not endanger viability of the fetus, is brain stem death, diagnosed through absence of cranial reflexes. The patient was successfully treated until delivery of a healthy female child at 29weeks of gestation. The patient received continuous hormone substitution therapy, fetal monitoring and extrinsic regulation of maternal homeostasis over 64days. After delivery, the final diagnosis of brain death was established through multi-slice computerized tomography pan-angiography. This challenging case discusses ethical and medical circumstances arising from a diagnosis of maternal brain death, while showing that prolongation of somatic life support in a multidisciplinary setting can result in a successful pregnancy outcome. Copyright © 2017 Elsevier Ltd. All rights reserved.

Brain death revisited: it is not 'complete death' according to Islamic sources.

PubMed

Bedir, Ahmet; Aksoy, Sahin

2011-05-01

Concepts, such as death, life and spirit cannot be known in their quintessential nature, but can be defined in accordance with their effects. In fact, those who think within the mode of pragmatism and Cartesian logic have ignored the metaphysical aspects of these terms. According to Islam, the entity that moves the body is named the soul. And the aliment of the soul is air. Cessation of breathing means leaving of the soul from the body. Those who agree on the diagnosis of brain death may not able to agree unanimously on the rules that lay down such diagnosis. That is to say, there are a heap of suspicions regarding the diagnosis of brain death, and these suspicions are on the increase. In fact, Islamic jurisprudence does not put provisions, decisions on suspicious grounds. By virtue of these facts, it can be asserted that brain death is not absolute death according to Islamic sources; for in the patients diagnosed with brain death the soul still has not abandoned the body. Therefore, these patients suffer in every operation performed on them.

Brain dead or not? CT angiogram yielding false-negative result on brain death confirmation.

PubMed

Johnston, Robyn; Kaliaperumal, Chandrasekaran; Wyse, Gerald; Kaar, George

2013-01-08

We describe a case of severe traumatic brain injury with multiple facial and skull fractures where CT angiogram (CTA) failed to yield a definite result of brain death as an ancillary test. A 28-year-old man was admitted following a road traffic accident with a Glasgow Coma Score (GCS) of 3/15 and fixed pupils. CT brain revealed uncal herniation and diffuse cerebral oedema with associated multiple facial and skull fractures. 72 h later, his clinical condition remained the same with high intracranial pressure refractory to medical management. Clinical confirmation on brain death was not feasible owing to facial injuries. A CTA, performed to determine brain perfusion, yielded a 'false-negative' result. Skull fractures have possibly led to venous prominence in the cortical and deep venous drainage system. This point needs to be borne in mind while considering CTA as an ancillary test to confirm brain death.

Brain dead or not? CT angiogram yielding false-negative result on brain death confirmation

PubMed Central

Johnston, Robyn; Kaliaperumal, Chandrasekaran; Wyse, Gerald; Kaar, George

2013-01-01

We describe a case of severe traumatic brain injury with multiple facial and skull fractures where CT angiogram (CTA) failed to yield a definite result of brain death as an ancillary test. A 28-year-old man was admitted following a road traffic accident with a Glasgow Coma Score (GCS) of 3/15 and fixed pupils. CT brain revealed uncal herniation and diffuse cerebral oedema with associated multiple facial and skull fractures. 72 h later, his clinical condition remained the same with high intracranial pressure refractory to medical management. Clinical confirmation on brain death was not feasible owing to facial injuries. A CTA, performed to determine brain perfusion, yielded a ‘false-negative’ result. Skull fractures have possibly led to venous prominence in the cortical and deep venous drainage system. This point needs to be borne in mind while considering CTA as an ancillary test to confirm brain death. PMID:23302550

Current status of pregnancy-related maternal mortality in Japan: a report from the Maternal Death Exploratory Committee in Japan.

PubMed

Hasegawa, Junichi; Sekizawa, Akihiko; Tanaka, Hiroaki; Katsuragi, Shinji; Osato, Kazuhiro; Murakoshi, Takeshi; Nakata, Masahiko; Nakamura, Masamitsu; Yoshimatsu, Jun; Sadahiro, Tomohito; Kanayama, Naohiro; Ishiwata, Isamu; Kinoshita, Katsuyuki; Ikeda, Tomoaki

2016-03-21

To clarify the problems related to maternal deaths in Japan, including the diseases themselves, causes, treatments and the hospital or regional systems. Descriptive study. Maternal death registration system established by the Japan Association of Obstetricians and Gynecologists (JAOG). Women who died during pregnancy or within a year after delivery, from 2010 to 2014, throughout Japan (N=213). The preventability and problems in each maternal death. Maternal deaths were frequently caused by obstetric haemorrhage (23%), brain disease (16%), amniotic fluid embolism (12%), cardiovascular disease (8%) and pulmonary disease (8%). The Committee considered that it was impossible to prevent death in 51% of the cases, whereas they considered prevention in 26%, 15% and 7% of the cases to be slightly, moderately and highly possible, respectively. It was difficult to prevent maternal deaths due to amniotic fluid embolism and brain disease. In contrast, half of the deaths due to obstetric haemorrhage were considered preventable, because the peak duration between the initial symptoms and initial cardiopulmonary arrest was 1-3 h. A range of measures, including individual education and the construction of good relationships among regional hospitals, should be established in the near future, to improve primary care for patients with maternal haemorrhage and to save the lives of mothers in Japan. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Portrayal of Brain Death in Film and Television.

PubMed

Lewis, A; Weaver, J; Caplan, A

2017-03-01

We sought to evaluate whether television and cinematic coverage of brain death is educational or misleading. We identified 24 accessible productions that addressed brain death using the archives of the Paley Center for Media (160 000 titles) and the Internet Movie Database (3.7 million titles). Productions were reviewed by two board-certified neurologists. Although 19 characters were pronounced brain dead, no productions demonstrated a complete examination to assess for brain death (6 included an assessment for coma, 9 included an evaluation of at least 1 brainstem reflex, but none included an assessment of every brainstem reflex, and 2 included an apnea test). Subjectively, both authors believed only a small fraction of productions (13% A.L., 13% J.W.) provided the public a complete and accurate understanding of brain death. Organ donation was addressed in 17 productions (71%), but both reviewers felt that the discussions about organ donation were professional in a paucity of productions (9% for A.L., 27% for J.W.). Because television and movies serve as a key source for public education, the quality of productions that feature brain death must be improved. © Copyright 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.

Is donation after cardiac death reducing the brain-dead donor pool in Australia?

PubMed

Sampson, Brett G; O'Callaghan, Gerry P; Russ, Graeme R

2013-03-01

Donation after cardiac death (DCD) has increased faster than donation after brain death (DBD) in Australia. However, DBD is the preferred pathway because it provides more organs per donor, the donation process is simpler and transplant outcomes are optimised. To determine if the increase in DCD has reduced the brain-dead donor pool in Australia. Retrospective analysis of records of organ donors (intended and actual) with brain injury as the cause of death from 2001 to 2011 in Australian intensive care units. Change in median ventilation period, over time, before brain-death determination in DBD donors (as DCD increased); a decreased median ventilation period in DBD donors being consistent with the conversion of DBD to DCD. As DCD (n = 311) increased, the median ventilation period in DBD donors (n = 2218) did not fall overall (P = 0.83), in all jurisdictions (P > 0.25) and for all causes of death (P > 0.3). The proportion of patients ventilated for less than 2 days was unchanged over time in both DBD (P = 1) and DCD (P = 0.99). The overall ventilation period in DCD donors (3.8 days; interquartile range [IQR], 2.1-6.3 days), exceeded the ventilation period in DBD donors (1.3 days; IQR, 1.0-2.4 days; P < 0.0001). DCD ventilation period was significantly longer in all jurisdictions, for all causes of death and annually (P < 0.05). In Australia, brain-injured donors appear to be ventilated long enough to allow progression to brain death before proceeding to DCD. Therefore, DCD is unlikely to have reduced the brain-dead donor pool.

Intensive care medicine and organ donation: exploring the last frontiers?

PubMed

Escudero, D; Otero, J

2015-01-01

The main, universal problem for transplantation is organ scarcity. The gap between offer and demand grows wider every year and causes many patients in waiting list to die. In Spain, 90% of transplants are done with organs taken from patients deceased in brain death but this has a limited potential. In order to diminish organ shortage, alternative strategies such as donations from living donors, expanded criteria donors or donation after circulatory death, have been developed. Nevertheless, these types of donors also have their limitations and so are not able to satisfy current organ demand. It is necessary to reduce family denial and to raise donation in brain death thus generalizing, among other strategies, non-therapeutic elective ventilation. As intensive care doctors, cornerstone to the national donation programme, we must consolidate our commitment with society and organ transplantation. We must contribute with the values proper to our specialization and try to reach self-sufficiency by rising organ obtainment. Copyright © 2015 Elsevier España, S.L.U. and SEMICYUC. All rights reserved.

Multicolor Fluorescence Imaging of Traumatic Brain Injury in a Cryolesion Mouse Model

PubMed Central

2012-01-01

Traumatic brain injury is characterized by initial tissue damage, which then can lead to secondary processes such as cell death and blood-brain-barrier disruption. Clinical and preclinical studies of traumatic brain injury typically employ anatomical imaging techniques and there is a need for new molecular imaging methods that provide complementary biochemical information. Here, we assess the ability of a targeted, near-infrared fluorescent probe, named PSS-794, to detect cell death in a brain cryolesion mouse model that replicates certain features of traumatic brain injury. In short, the model involves brief contact of a cold rod to the head of a living, anesthetized mouse. Using noninvasive whole-body fluorescence imaging, PSS-794 permitted visualization of the cryolesion in the living animal. Ex vivo imaging and histological analysis confirmed PSS-794 localization to site of brain cell death. The nontargeted, deep-red Tracer-653 was validated as a tracer dye for monitoring blood-brain-barrier disruption, and a binary mixture of PSS-794 and Tracer-653 was employed for multicolor imaging of cell death and blood-brain-barrier permeability in a single animal. The imaging data indicates that at 3 days after brain cryoinjury the amount of cell death had decreased significantly, but the integrity of the blood-brain-barrier was still impaired; at 7 days, the blood-brain-barrier was still three times more permeable than before cryoinjury. PMID:22860222

Gray Matter-White Matter De-Differentiation on Brain Computed Tomography Predicts Brain Death Occurrence.

PubMed

Vigneron, C; Labeye, V; Cour, M; Hannoun, S; Grember, A; Rampon, F; Cotton, F

2016-01-01

Previous studies have shown that a loss of distinction between gray matter (GM) and white matter (WM) on unenhanced CT scans was predictive of poor outcome after cardiac arrest. The aim of this study was to identify a marker/predictor of imminent brain death. In this retrospective study, 15 brain-dead patients after anoxia and cardiac arrest were included. Patients were paired (1:1) with normal control subjects. Only patients' unenhanced CT scans performed before brain death and during the 24 hours after initial signs were analyzed. WM and GM densities were measured in predefined regions of interest (basal ganglia level, centrum semi-ovale level, high convexity level, brainstem level). At each level, GM and WM density and GM/WM ratio for brain-dead patients and normal control subjects were compared using the Wilcoxon signed-rank test. At each level, a lower GM/WM ratio and decreased GM and WM densities were observed in brain-dead patients' CT scans when compared with normal control subject CT scans. A cut-off value of 1.21 at the basal ganglia level was identified, below which brain death systematically occurred. GM/WM dedifferentiation on unenhanced CT scan is measurable before the occurrence of brain death, highlighting its importance in brain death prediction. The mechanism of GM/WM differentiation loss could be explained by the lack of oxygen caused by ischemia initially affecting the mitochondrial system. Copyright © 2016 Elsevier Inc. All rights reserved.

A narrative review of the empirical evidence on public attitudes on brain death and vital organ transplantation: the need for better data to inform policy.

PubMed

Shah, Seema K; Kasper, Kenneth; Miller, Franklin G

2015-04-01

Vital organ transplantation is premised on 'the dead donor rule': donors must be declared dead according to medical and legal criteria prior to donation. However, it is controversial whether individuals diagnosed as 'brain dead' are really dead in accordance with the established biological conception of death-the irreversible cessation of the functioning of the organism as a whole. A basic understanding of brain death is also relevant for giving valid, informed consent to serve as an organ donor. There is therefore a need for reliable empirical data on public understanding of brain death and vital organ transplantation. We conducted a review of the empirical literature that identified 43 articles with approximately 18,603 study participants. These data demonstrate that participants generally do not understand three key issues: (1) uncontested biological facts about brain death, (2) the legal status of brain death and (3) that organs are procured from brain dead patients while their hearts are still beating and before their removal from ventilators. These data suggest that, despite scholarly claims of widespread public support for organ donation from brain dead patients, the existing data on public attitudes regarding brain death and organ transplantation reflect substantial public confusion. Our review raises questions about the validity of consent for vital organ transplantation and suggests that existing data are of little assistance in developing policy proposals for organ transplantation from brain dead patients. New approaches to rigorous empirical research with educational components and evaluations of understanding are urgently needed. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

The ambiguity about death in Japan: an ethical implication for organ procurement.

PubMed Central

McConnell, J R

1999-01-01

In the latter half of the twentieth century, developed countries of the world have made tremendous strides in organ donation and transplantation. However, in this area of medicine, Japan has been slow to follow. Japanese ethics, deeply rooted in religion and tradition, have affected their outlook on life and death. Because the Japanese have only recently started to acknowledge the concept of brain death, transplantation of major organs has been hindered in that country. Currently, there is a dual definition of death in Japan, intended to satisfy both sides of the issue. This interesting paradox, which still stands to be fully resolved, illustrates the contentious conflict between medical ethics and medical progress in Japan. PMID:10461595

Role of NMDA Receptor-Mediated Glutamatergic Signaling in Chronic and Acute Neuropathologies

PubMed Central

2016-01-01

N-Methyl-D-aspartate receptors (NMDARs) have two opposing roles in the brain. On the one hand, NMDARs control critical events in the formation and development of synaptic organization and synaptic plasticity. On the other hand, the overactivation of NMDARs can promote neuronal death in neuropathological conditions. Ca2+ influx acts as a primary modulator after NMDAR channel activation. An imbalance in Ca2+ homeostasis is associated with several neurological diseases including schizophrenia, Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. These chronic conditions have a lengthy progression depending on internal and external factors. External factors such as acute episodes of brain damage are associated with an earlier onset of several of these chronic mental conditions. Here, we will review some of the current evidence of how traumatic brain injury can hasten the onset of several neurological conditions, focusing on the role of NMDAR distribution and the functional consequences in calcium homeostasis associated with synaptic dysfunction and neuronal death present in this group of chronic diseases. PMID:27630777

A Double-Edged Sword Role for Ubiquitin-Proteasome System in Brain Stem Cardiovascular Regulation During Experimental Brain Death

PubMed Central

Wu, Carol H. Y.; Chan, Julie Y. H.; Chan, Samuel H. H.; Chang, Alice Y. W.

2011-01-01

Background Brain stem cardiovascular regulatory dysfunction during brain death is underpinned by an upregulation of nitric oxide synthase II (NOS II) in rostral ventrolateral medulla (RVLM), the origin of a life-and-death signal detected from blood pressure of comatose patients that disappears before brain death ensues. Furthermore, the ubiquitin-proteasome system (UPS) may be involved in the synthesis and degradation of NOS II. We assessed the hypothesis that the UPS participates in brain stem cardiovascular regulation during brain death by engaging in both synthesis and degradation of NOS II in RVLM. Methodology/Principal Findings In a clinically relevant experimental model of brain death using Sprague-Dawley rats, pretreatment by microinjection into the bilateral RVLM of proteasome inhibitors (lactacystin or proteasome inhibitor II) antagonized the hypotension and reduction in the life-and-death signal elicited by intravenous administration of Escherichia coli lipopolysaccharide (LPS). On the other hand, pretreatment with an inhibitor of ubiquitin-recycling (ubiquitin aldehyde) or ubiquitin C-terminal hydrolase isozyme L1 (UCH-L1) potentiated the elicited hypotension and blunted the prevalence of the life-and-death signal. Real-time polymerase chain reaction, Western blot, electrophoresis mobility shift assay, chromatin immunoprecipitation and co-immunoprecipitation experiments further showed that the proteasome inhibitors antagonized the augmented nuclear presence of NF-κB or binding between NF-κB and nos II promoter and blunted the reduced cytosolic presence of phosphorylated IκB. The already impeded NOS II protein expression by proteasome inhibitor II was further reduced after gene-knockdown of NF-κB in RVLM. In animals pretreated with UCH-L1 inhibitor and died before significant increase in nos II mRNA occurred, NOS II protein expression in RVLM was considerably elevated. Conclusions/Significance We conclude that UPS participates in the defunct and maintained brain stem cardiovascular regulation during experimental brain death by engaging in both synthesis and degradation of NOS II at RVLM. Our results provide information on new therapeutic initiatives against this fatal eventuality. PMID:22110641

Molecular insights into melanoma brain metastases.

PubMed

Westphal, Dana; Glitza Oliva, Isabella C; Niessner, Heike

2017-06-01

Substantial proportions of patients with metastatic melanoma develop brain metastases during the course of their disease, often resulting in significant morbidity and death. Despite recent advances with BRAF/MEK and immune-checkpoint inhibitors in the treatment of patients who have melanoma with extracerebral metastases, patients who have melanoma brain metastases still have poor overall survival, highlighting the need for further therapy options. A deeper understanding of the molecular pathways involved in the development of melanoma brain metastases is required to develop more brain-specific therapies. Here, the authors summarize the currently known preclinical data and describe steps involved in the development of melanoma brain metastases. Only by knowing the molecular background is it possible to design new therapeutic agents that can be used to improve the outcome of patients with melanoma brain metastases. Cancer 2017;123:2163-75. © 2017 American Cancer Society. © 2017 American Cancer Society.

Brain Death and Islam

PubMed Central

Ziad-Miller, Amna; Elamin, Elamin M.

2014-01-01

How one defines death may vary. It is important for clinicians to recognize those aspects of a patient’s religious beliefs that may directly influence medical care and how such practices may interface with local laws governing the determination of death. Debate continues about the validity and certainty of brain death criteria within Islamic traditions. A search of PubMed, Scopus, EMBASE, Web of Science, PsycNet, Sociological Abstracts, DIALOGUE ProQuest, Lexus Nexus, Google, and applicable religious texts was conducted to address the question of whether brain death is accepted as true death among Islamic scholars and clinicians and to discuss how divergent opinions may affect clinical care. The results of the literature review inform this discussion. Brain death has been acknowledged as representing true death by many Muslim scholars and medical organizations, including the Islamic Fiqh Academies of the Organization of the Islamic Conference and the Muslim World League, the Islamic Medical Association of North America, and other faith-based medical organizations as well as legal rulings by multiple Islamic nations. However, consensus in the Muslim world is not unanimous, and a sizable minority accepts death by cardiopulmonary criteria only. PMID:25287999

Pupillometry in brain death: differences in pupillary diameter between paediatric and adult subjects.

PubMed

Olgun, Gokhan; Newey, Christopher R; Ardelt, Agnieszka

2015-11-01

The determination of brain death in neonates, infants, children and adults relies on a clinical diagnosis based on the absence of neurological function with a known irreversible cause of brain injury. Evaluation of pupil size and non-reactivity is a requisite for determination of brain death. There are no studies in the literature that quantitatively assess pupil size in brain dead children and adults. Infants, children and adults diagnosed with brain death were included in the study. Pupils were measured with a quantitative pupillometer (Forsite; Neuroptics, Irvine, CA, USA). Median, minimum and maximum pupil sizes were documented and the results were adjudicated for age, vasopressor use and temperature. Median right and left pupil sizes were 5.01 ± 0.85 mm and 5.12 ± 0.87 mm, respectively, with a range between 3.69 and 7.34 mm. Paediatric pupils were larger than adult pupils (right pupil 5.53 vs 4.73 mm p: 0.018; left pupil 5.87 vs 4.77 mm P: 0.03), and there was no correlation of pupil size with temperature or increasing number of vasopressors. This is the first study in the literature objectively evaluating pupil sizes in infants, children and adults diagnosed with brain death. We observed variation between observed pupil size and that expected based on brain death determination guidelines.

[Prolonged clinical pattern of brain death in patients under barbiturate sedation: usefulness of transcranial Doppler].

PubMed

Segura, T; Jiménez, P; Jerez, P; García, F; Córcoles, V

2002-04-01

Throughout the world, is fully accepted that a person is dead when brain death exists. In most situations, neurological criteria permit the diagnosis of brain death, but in some instances, as when high-dose barbiturate therapy has been used, confirmatory testing are required by law. We report the case of a 17 year-old women who suffered high-dose barbiturate therapy due to post traumatic intracranial hypertension. During the period of the barbiturate infusion and until six days after the suppression of this therapy, neurological exploration and EEG findings seem to confirm brain death, while transcranial Doppler (TCD) study remained normal. TCD is a fast, simple and accurate confirmatory testing in the determination of brain death and its findings are not affected by high-dose barbiturate therapy. We think that TCD must be present in all hospitals where mechanical ventilation and support of patients are carried out.

Use of Ancillary Tests When Determining Brain Death in Pediatric Patients in the United States.

PubMed

Lewis, Ariane; Adams, Nellie; Chopra, Arun; Kirschen, Matthew P

2017-10-01

Although pediatric brain death guidelines stipulate when ancillary testing should be used during brain death determination, little is known about the way these recommendations are implemented in clinical practice. We conducted a survey of pediatric intensivists and neurologists in the United States on the use of ancillary testing. Although most respondents noted they only performed an ancillary test if the clinical examination and apnea test could not be completed, 20% of 195 respondents performed an ancillary test for other reasons, including (1) to convince a family that objected to the brain death determination that a patient is truly dead (n = 21), (2) personal preference (n = 14), and (3) institutional requirement (n = 5). Our findings suggest that pediatricians use ancillary tests for a variety of reasons during brain death determination. Medical societies and governmental regulatory bodies must reinforce the need for homogeneity in practice.

[Determination of irreversibility of clinical brain death. Electroencephalography and evoked potentials].

PubMed

Buchner, H; Ferbert, A

2016-02-01

Principally, in the fourth update of the rules for the procedure to finally determine the irreversible cessation of function of the cerebrum, the cerebellum and the brainstem, the importance of an electroencephalogram (EEG), somatosensory evoked potentials (SEP) and brainstem auditory evoked potentials (BAEP) are confirmed. This paper presents the reliability and validity of the electrophysiological diagnosis, discusses the amendments in the fourth version of the guidelines and introduces the practical application, problems and sources of error.An EEG is the best established supplementary diagnostic method for determining the irreversibility of clinical brain death syndrome. It should be noted that residual brain activity can often persist for many hours after the onset of brain death syndrome, particularly in patients with primary brainstem lesions. The derivation and analysis of an EEG requires a high level of expertise to be able to safely distinguish artefacts from primary brain activity. The registration of EEGs to demonstrate the irreversibility of clinical brain death syndrome is extremely time consuming.The BAEPs can only be used to confirm the irreversibility of brain death syndrome in serial examinations or in the rare cases of a sustained wave I or sustained waves I and II. Very often, an investigation cannot be reliably performed because of existing sound conduction disturbances or failure of all potentials even before the onset of clinical brain death syndrome. This explains why BAEPs are only used in exceptional cases.The SEPs of the median nerve can be very reliably derived, are technically simple and with few sources of error. A serial investigation is not required and the time needed for examination is short. For these reasons SEPs are given preference over EEGs and BAEPs for establishing the irreversibility of clinical brain death syndrome.

Analysis of knowledge of the general population and health professionals on organ donation after cardiac death.

PubMed

Bedenko, Ramon Correa; Nisihara, Renato; Yokoi, Douglas Shun; Candido, Vinícius de Mello; Galina, Ismael; Moriguchi, Rafael Massayuki; Ceulemans, Nico; Salvalaggio, Paolo

2016-09-01

To evaluate the knowledge and acceptance of the public and professionals working in intensive care units regarding organ donation after cardiac death. The three hospitals with the most brain death notifications in Curitiba were selected, and two groups of respondents were established for application of the same questionnaire: the general public (i.e., visitors of patients in intensive care units) and health professionals working in the same intensive care unit. The questionnaire contained questions concerning demographics, intention to donate organs and knowledge of current legislation regarding brain death and donation after cardiac death. In total, 543 questionnaires were collected, including 442 from family members and 101 from health professionals. There was a predominance of women and Catholics in both groups. More females intended to donate. Health professionals performed better in the knowledge comparison. The intention to donate organs was significantly higher in the health professionals group (p = 0.01). There was no significant difference in the intention to donate in terms of education level or income. There was a greater acceptance of donation after uncontrolled cardiac death among Catholics than among evangelicals (p < 0.001). Most of the general population intended to donate, with greater intentions expressed by females. Education and income did not affect the decision. The type of transplant that used a donation after uncontrolled cardiac death was not well accepted in the study population, indicating the need for more clarification for its use in our setting.

Brain stem death and organ donation.

PubMed

Davies, C

1996-01-01

Our understanding of the concept and definition of death has changed over time. The British contribution to the body of knowledge on the diagnosis of brain steam death was the publication by the medical royal colleges (1976) of diagnostic criteria. Most literature and research which explores the knowledge and attitudes of nurses towards the concept of brain stem death is from the USA. Several issues which arise from the literature are discussed in relation to organ donation. Further UK-based research is required.

Factors Affecting the Occurrence of Spinal Reflexes in Brain Dead Cases.

PubMed

Hosseini, Mahsa Sadat; Ghorbani, Fariba; Ghobadi, Omid; Najafizadeh, Katayoun

2015-08-01

Brain death is defined as the permanent absence of all cortical and brain stem reflexes. A wide range of spontaneous or reflex movements that are considered medullary reflexes are observed in heart beating cases that appear brain dead, which may create uncertainty about the diagnosis of brain death and cause delays in deceased-donor organ donation process. We determined the frequency and type of medullary reflexes and factors affecting their occurrence in brain dead cases. During 1 year, 122 cases who fulfilled the criteria for brain death were admitted to the special intensive care unit for organ procurement of Masih Daneshvari Hospital. Presence of spinal reflexes was evaluated by trained coordinators and was recorded in a form in addition to other information including demographic characteristics, cause of brain death, time from detection of brain death, history of craniotomy, vital signs, serum electrolyte levels, and parameters of arterial blood gas determination. Most cases (63%) included in this study were male, and mean age was 33 ± 15 y. There was > 1 spinal reflex observed in 40 cases (33%). The most frequent reflex was plantar response (17%) following by myoclonus (10%), triple flexion reflex (9%), pronator extension reflex (8%), and undulating toe reflex (7%). Mean systolic blood pressure was significantly higher in cases who exhibited medullary reflexes than other cases (126 ± 19 mm Hg vs 116 ± 17 mm Hg; P = .007). Spinal reflexes occur frequently in brain dead cases, especially when they become hemodynamically stable after treatment in the organ procurement unit. Observing these movements by caregivers and family members has a negative effect on obtaining family consent and organ donation. Increasing awareness about spinal reflexes is necessary to avoid suspicion about the brain death diagnosis and delays in organ donation.

Ethical issues in the use of anencephalic infants as organ donors.

PubMed

Shinnar, S; Arras, J

1989-11-01

For many, the ethical issues raised in the previous sections are sufficient to justify opposition to tampering with either the dead-donor rule or the definition of death in general and the use of anencephalic infants as organ donors in particular regardless of how many organs could be procured. Others will see it as a question of balancing the relative costs and benefits of the proposal. Given, the likely bad consequences and meager benefits, these protocols are difficult to justify on those grounds as well. The proposals of waiting until brain death has occurred also pose some serious, though not necessarily insurmountable, ethical problems. With supportive care, however, anencephalic infants do not become brain dead in the first week of life. Given the declining incidence of anencephaly, the issue regarding anencephalic infants will probably become moot in the next few years. As the need for organ donors continues to grow, we will undoubtedly be faced with future proposals to harvest vital organs from other "unique" categories of dying or severely impaired patients. We believe that the current dead donor rule and the strict "whole-brain" definition of death are sound public policy and good ethics and should remain the cornerstone of future decisions in this field.

Nicotinamide Inhibits Ethanol-Induced Caspase-3 and PARP-1 Over-activation and Subsequent Neurodegeneration in the Developing Mouse Cerebellum.

PubMed

Ieraci, Alessandro; Herrera, Daniel G

2018-06-01

Fetal alcohol spectrum disorder (FASD) is the principal preventable cause of mental retardation in the western countries resulting from alcohol exposure during pregnancy. Ethanol-induced massive neuronal cell death occurs mainly in immature neurons during the brain growth spurt period. The cerebellum is one of the brain areas that are most sensitive to ethanol neurotoxicity. Currently, there is no effective treatment that targets the causes of these disorders and efficient treatments to counteract or reverse FASD are desirable. In this study, we investigated the effects of nicotinamide on ethanol-induced neuronal cell death in the developing cerebellum. Subcutaneous administration of ethanol in postnatal 4-day-old mice induced an over-activation of caspase-3 and PARP-1 followed by a massive neurodegeneration in the developing cerebellum. Interestingly, treatment with nicotinamide, immediately or 2 h after ethanol exposure, diminished caspase-3 and PARP-1 over-activation and reduced ethanol-induced neurodegeneration. Conversely, treatment with 3-aminobenzadine, a specific PARP-1 inhibitor, was able to completely block PARP-1 activation, but not caspase-3 activation or ethanol-induced neurodegeneration in the developing cerebellum. Our results showed that nicotinamide reduces ethanol-induced neuronal cell death and inhibits both caspase-3 and PARP-1 alcohol-induced activation in the developing cerebellum, suggesting that nicotinamide might be a promising and safe neuroprotective agent for treating FASD and other neurodegenerative disorders in the developing brain that shares similar cell death pathways.

Causes of organ donation failure in Brazil.

PubMed

Dell Agnolo, C M; de Freitas, R A; Toffolo, V J O; de Oliveira, M L F; de Almeida, D F; Carvalho, M D B; Pelloso, S M

2012-10-01

There has been a great improvement in transplantation medicine in Brazil in the last 2 decades. However, there remain several barriers regarding notification of brain and cardiac death as well as completion of the donation process. This retrospective study was performed between January 2008 and December 2010. We reviewed all deaths in a University Hospital, observing the causes of non-notification to the State Transplantation Authority and non-donations. There were 41 notifications of brain death resulting in donation in only 19.5% of those cases. Cardiac death was diagnosed in 21 patients, resulting in 52.4% donations. The main cause for non-donation were family refusal (37.2%), infectious diseases (30.2%), and clinical contraindications (32.6%). Most of the missed possible donors occurred during the night (54.8%) and in the emergency room (80.9%). There is an urgent need for better education of the Brazilian population about organ donation and brain death definitions. Other identified problems include lack of uniformity in brain death determinations among hospitals, rigid contraindications to donation in the State of Parana, physician unawareness or disbelief about brain death diagnostic criteria, and lack of structure of our Hospital. Copyright © 2012. Published by Elsevier Inc.

Progress in legal definition of brain death and consent to remove cadaver organs.

PubMed

Stuart, F P

1977-01-01

The availability of cadaver kidneys for transplantation falls far short of the needs of a rapidly expanding population of patients on chronic hemodialysis. Kidneys with the least ischemic injury come from donors with fatal head injury or stroke; such kidneys can be removed from a "beating-heart" cadaver after declaring death on the basis of brain death. To clarify the legal status of brain death and to encourage salvage of transplantable kidneys with minimal ischemic injury, 12 states already have codified the concept of brain death. Although the first few laws were lengthy and included medical terms, six of the last seven laws have used one or two models proposed by the American Bar Association (ABA) and the Institute of Society, Ethics and Life Sciences, Hastings-on-Hudson, N. Y. The ABA proposal is the simpler of the two models and should provide the basis for future state laws. In addition, the National Conference of Commissioners on Uniform State Laws plans to present a model law to define death and the liabilities of a physician who declares death on the basis of brain death by mid 1977. While state legislatures have written laws that establish the legality of the concept of brain death, medical groups have sought to define the medical criteria for its determination. The most recent list of criteria comes from a National Institutes of Health-supported Collaborative Study on Cerebral Survival, as follows: (1) unresponsivity, (2) apnea, (3) dilated pupils and absent cephalic reflexes, (4) electrocerebral silence, (5) a confirmatory test of absent cerebral blood flow (angiography, isotope bolus curve, retinoscopy, or echoencephalography).

Ethical issues in critical care and cardiac arrest: clinical research, brain death, and organ donation.

PubMed

Donatelli, Luke A; Geocadin, Romergryko G; Williams, Michael A

2006-09-01

Cardiac arrest results in global hypoxic-ischemic brain injury from which there is a range of possible neurological outcomes. In most cases, patients may require a surrogate to make decisions regarding end-of-life care, including the withdrawal of life-sustaining therapies. This article reviews ethical considerations that arise in the clinical care of patients following cardiac arrest, including decisions to continue or withdraw life-sustaining therapies; brain death determination; and organ donation in the context of brain death and cardiac death (so-called non-heart-beating donation). This article also discusses ethical concerns pertaining to the design and conduct of resuscitation research that is necessary for the development of effective therapies to prevent anoxic brain injury or promote neurological recovery.

Never Declared Brain Dead Potential Organ Donors-An Additional Source of Donor Organs?

PubMed

Webster, Patricia A; Markham, Lori E

2018-03-01

Patients never declared brain dead may represent an additional source of donor organs. To determine the number of likely brain dead potential donors who are never declared brain dead and to compare them with brain dead and donation after cardiac death potential organ donors. This study was a retrospective chart review of all catastrophically brain-injured patients referred to a single-organ procurement organization (OPO) over a 4-year period. This study identified 159 likely brain dead potential organ donors, 902 brain dead potential organ donors, and 357 potential donation after circulatory death donors over a 4-year period. None. This study did not predetermine outcome measures before data collection because the study group, likely brain dead potential organ donors, had not previously been described. Likely brain dead potential donors were significantly older than brain dead potential donors ( P < .0001) but were otherwise not different demographically. They were more likely to be a late referral to the OPO ( P < .0001) and less likely to be in the donor registry ( P < .0001). The most commonly identified factors associated with a failure to declare brain death were an unwillingness to continue supportive care by the family, premention of donation, a nontimely imminent death referral, known prior objection to donation, terminal instability, and a lack of cooperation with the OPO.

Upregulated miR-29b promotes neuronal cell death by inhibiting Bcl2L2 after ischemic brain injury.

PubMed

Shi, Guodong; Liu, Yang; Liu, Tielong; Yan, Wangjun; Liu, Xiaowei; Wang, Yuan; Shi, Jiangang; Jia, Lianshun

2012-01-01

It is increasingly clear that microRNAs (miRNAs) play an important role in controlling cell survival. However, the functional significance of miRNAs in ischemic brain injury remains poorly understood. In the present study, we assayed the expression levels of miR-29b after ischemic brain injury, and defined the target genes and biological functions of miR-29b. We found that the miR-29b levels were significantly increased in rat brain after transient middle cerebral artery occlusion and neurons after oxygen-glucose deprivation. Moreover, ectopic expression of miR-29b promoted neuronal cell death, whereas its repression decreased cell death. Furthermore, we verified that miR-29b directly targeted and inhibited Bcl2L2 gene expression, and then increased neuronal cell death. Importantly, Bcl2L2 overexpression rescued neuronal cell death induced by miR-29b. These results suggest an important role of miR-29b in regulating neuronal cell death, thus offering a new target for the development of therapeutic agents against ischemic brain injury.

The blood-brain barrier as a target in traumatic brain injury treatment.

PubMed

Thal, Serge C; Neuhaus, Winfried

2014-11-01

Traumatic brain injury (TBI) is one of the most frequent causes of death in the young population. Several clinical trials have unsuccessfully focused on direct neuroprotective therapies. Recently immunotherapeutic strategies shifted into focus of translational research in acute CNS diseases. Cross-talk between activated microglia and blood-brain barrier (BBB) could initiate opening of the BBB and subsequent recruitment of systemic immune cells and mediators into the brain. Stabilization of the BBB after TBI could be a promising strategy to limit neuronal inflammation, secondary brain damage and acute neurodegeneration. This review provides an overview on the pathophysiology of TBI and brain edema formation including definitions and classification of TBI, current clinical treatment strategies, as well as current understanding on the underlying cellular processes. A summary of in vivo and in vitro models to study different aspects of TBI is presented. Three mechanisms proposed for stabilization of the BBB, myosin light chain kinases, glucocorticoid receptors and peroxisome proliferator-activated receptors are reviewed for their influence on barrier-integrity and outcome after TBI. In conclusion, the BBB is recommended as a promising target for the treatment of traumatic brain injury, and it is suggested that a combination of BBB stabilization and neuroprotectants may improve therapeutic success. Copyright © 2015 IMSS. Published by Elsevier Inc. All rights reserved.

Brain death and true patient care

PubMed Central

2016-01-01

The “brain death” standard as a criterion of death is closely associated with the need for transplantable organs from heart-beating donors. Are all of these potential donors really dead, or does the documented evidence of patients destined for organ harvesting who improve, or even recover to live normal lives, call into question the premise underlying “brain death”? The aim of this paper is to re-examine the notion of “brain death,” especially its clinical test-criteria, in light of a broad framework, including medical knowledge in the field of neuro-intensive care and the traditional ethics of the medical profession. I will argue that both the empirical medical evidence and the ethics of the doctor–patient relationship point to an alternative approach toward the severely comatose patient (potential brain-dead donor). Lay Summary: Though legally accepted and widely practiced, the “brain death” standard for the determination of death has remained a controversial issue, especially in view of the occurrence of “chronic brain death” survivors. This paper critically re-evaluates the clinical test-criteria for “brain death,” taking into account what is known about the neuro-critical care of severe brain injury. The medical evidence, together with the understanding of the moral role of the physician toward the patient present before him or her, indicate that an alternative approach should be offered to the deeply comatose patient. PMID:27833207

Brain death and Islam: the interface of religion, culture, history, law, and modern medicine.

PubMed

Miller, Andrew C; Ziad-Miller, Amna; Elamin, Elamin M

2014-10-01

How one defines death may vary. It is important for clinicians to recognize those aspects of a patient's religious beliefs that may directly influence medical care and how such practices may interface with local laws governing the determination of death. Debate continues about the validity and certainty of brain death criteria within Islamic traditions. A search of PubMed, Scopus, EMBASE, Web of Science, PsycNet, Sociological Abstracts, DIALOGUE ProQuest, Lexus Nexus, Google, and applicable religious texts was conducted to address the question of whether brain death is accepted as true death among Islamic scholars and clinicians and to discuss how divergent opinions may affect clinical care. The results of the literature review inform this discussion. Brain death has been acknowledged as representing true death by many Muslim scholars and medical organizations, including the Islamic Fiqh Academies of the Organization of the Islamic Conference and the Muslim World League, the Islamic Medical Association of North America, and other faith-based medical organizations as well as legal rulings by multiple Islamic nations. However, consensus in the Muslim world is not unanimous, and a sizable minority accepts death by cardiopulmonary criteria only.

QuickStats: Brain Cancer Death Rates Among Children and Teens Aged 1-19 Years,* by Sex† and Age Group - United States, 2013-2015.

PubMed

2017-05-05

The death rate for brain cancer, the most common cancer cause of death for children and teens aged 1-19 years, was 24% higher in males (0.73 per 100,000) than females (0.59) aged 1-19 years during 2013-2015. Death rates were higher for males than females for all age groups, but the difference did not reach statistical significance for the age group 5-9 years. Death rates caused by brain cancer were highest at ages 5-9 years (0.98 for males and 0.85 for females).

Attitudes toward death criteria and organ donation among healthcare personnel and the general public.

PubMed

DuBois, James M; Anderson, Emily E

2006-03-01

To examine attitudes toward death criteria and their relation to attitudes and behaviors regarding organ donation. This article reviews empirical studies on the attitudes of healthcare personnel and the general public regarding death criteria and organ donation. The review was restricted to studies that had as a primary focus attitudes toward 1 or more of the following 3 specific criteria for determining death: (1) brain death, the irreversible loss of all functions of the entire brain; (2) higher brain death, the loss of cerebral cortex function alone; and (3) the circulatory-respiratory criteria commonly used in donation after cardiac death. Studies consistently show that the general public and some medical personnel are inadequately familiar with the legal and medical status of brain death; attitudes toward the dead donor rule are strong predictors of willingness to donate organs using controversial criteria; concerns about donation after cardiac death surround the withdrawal of life support more than the actual death criteria used; and concerns about death criteria correlate with less favorable attitudes toward organ donation. Both general and ethical education may serve to guide policy and facilitate family member requests and informed consent dialogues. Furthermore, helping families to understand and accept not only medical and legal criteria for determining death, but also ethical criteria for withdrawing life support may help them be more comfortable with their decisions.

Culture, brain death, and transplantation.

PubMed

Bowman, Kerry W; Richard, Shawn A

2003-09-01

From the social sciences, we know the space between life and death is historically and culturally constructed, fluid and open to dispute. The definition of death has cultural, legal, and political dimensions. As healthcare becomes more culturally diverse, the interface between culture and the delivery of healthcare will increase. In our increasingly pluralistic, interdependent society, there is a growing demand to integrate healthcare, including transplantation, into a broader context that respects both individual and cultural diversity. It is important that we first consider and explore what elements of Western healthcare practices including definitions and advances, such as brain death and organ donation, are culturally influenced. This article highlights some of the cultural influences on brain death by focusing on Western and Japanese perspectives on the permissibility of organ procurement from brain-dead persons. It also offers 4 recommendations for healthcare workers working cross-culturally.

Brain Death and Transplant in Islamic Countries.

PubMed

Altınörs, Nur; Haberal, Mehmet

2016-11-01

The aim of this study was to investigate the present status regarding brain death, its consequences, and transplant activities in Islamic countries. A thorough literature survey was conducted about transplant activities in Islamic countries, and the Turkish Ministry of Health Web site was analyzed. Expert opinions about the issue were obtained. The present status of brain death and transplant activities has shown a heterogeneous appearance in the Islamic world. Our literature survey clearly revealed that transplant is still in its early stages in many Islamic states. The legislative framework, infrastructure, and related education needs radical improvements in these states. The concept of death has to be redefined and a consensus should be reached about brain death. The pioneer countries like Turkey, Iran, and Saudi Arabia. which already have considerable experience in transplant, should share their expertise and knowledge with the countries that need guidance.

Role of ischemic modified albumin in the early diagnosis of increased intracranial pressure and brain death.

PubMed

Kara, I; Pampal, H K; Yildirim, F; Dilekoz, E; Emmez, G; U, F P; Kocabiyik, M; Demirel, C B

Increased intracranial pressure following trauma and subsequent possible development of brain death are important factors for morbidity and mortality due to ischemic changes. We aimed to establish the role of ischemic modified albumin (IMA) in the early diagnosis of the process, starting with increased intracranial pressure and ending with brain death. Eighteen Wistar-Albino rats were divided into three groups; control (CG, n = 6), increased intracranial pressure (ICPG, n = 6), and brain death (BDG, n = 6). Intracranial pressure elevation and brain death were constituted with the inflation of a balloon of a Fogarty catheter in the epidural space. In all three groups, blood samples were drawn before the procedure, and at minutes 150 and 240 for IMA and malondialdehyde (MDA) analysis. Serum IMA levels at 150 and 240 minutes were higher in ICPG than in CG (p < 0.05). IMA levels were similar in ICPG and BDG. Serum MDA levels at 150 and 240 minutes increased in ICPG and BDG groups compared to CG (p < 0.05). MDA levels were similar in ICP and BD groups. IMA should be considered as a biochemical parameter in the process starting from increased intracranial pressure elevation and ending at brain death (Tab. 3, Fig. 5, Ref. 31).

Death revisited: rethinking death and the dead donor rule.

PubMed

Iltis, Ana Smith; Cherry, Mark J

2010-06-01

Traditionally, people were recognized as being dead using cardio-respiratory criteria: individuals who had permanently stopped breathing and whose heart had permanently stopped beating were dead. Technological developments in the middle of the twentieth century and the advent of the intensive care unit made it possible to sustain cardio-respiratory and other functions in patients with severe brain injury who previously would have lost such functions permanently shortly after sustaining a brain injury. What could and should physicians caring for such patients do? Significant advances in human organ transplantation also played direct and indirect roles in discussions regarding the care of such patients. Because successful transplantation requires that organs be removed from cadavers shortly after death to avoid organ damage due to loss of oxygen, there has been keen interest in knowing precisely when people are dead so that organs could be removed. Criteria for declaring death using neurological criteria developed, and today a whole brain definition of death is widely used and recognized by all 50 states in the United States as an acceptable way to determine death. We explore the ongoing debate over definitions of death, particularly over brain death or death determined using neurological criteria, and the relationship between definitions of death and organ transplantation.

Do not resuscitate, brain death, and organ transplantation: Islamic perspective

PubMed Central

Chamsi-Pasha, Hassan; Albar, Mohammed Ali

2017-01-01

Muslim patients and families are often reluctant to discuss and accept fatal diagnoses and prognoses. In many instances, aggressive therapy is requested by a patient's family, prolonging the life of the patient at all costs. Islamic law permits the withdrawal of futile treatment, including life support, from terminally ill patients allowing death to take its natural course. “Do not resuscitate” is permitted in Islamic law in certain situations. Debate continues about the certainty of brain death criteria within Islamic scholars. Although brain death is accepted as true death by the majority of Muslim scholars and medical organizations, the consensus in the Muslim world is not unanimous, and some scholars still accept death only by cardiopulmonary criteria. Organ transplantation has been accepted in Islamic countries (with some resistance from some jurists). Many fatwas (decrees) of Islamic Jurisprudence Councils have been issued and allowed organs to be donated from living competent adult donor; and from deceased (cadavers), provided that they have agreed to donate or their families have agreed to donate after their death (usually these are brain-dead cases). A clear and well-defined policy from the ministry of health regarding do not resuscitate, brain death, and other end-of-life issues is urgently needed for all hospitals and health providers in most (if not all) Muslim and Arab countries. PMID:28469984

Mathematical Models of Blast-Induced TBI: Current Status, Challenges, and Prospects

PubMed Central

Gupta, Raj K.; Przekwas, Andrzej

2013-01-01

Blast-induced traumatic brain injury (TBI) has become a signature wound of recent military activities and is the leading cause of death and long-term disability among U.S. soldiers. The current limited understanding of brain injury mechanisms impedes the development of protection, diagnostic, and treatment strategies. We believe mathematical models of blast wave brain injury biomechanics and neurobiology, complemented with in vitro and in vivo experimental studies, will enable a better understanding of injury mechanisms and accelerate the development of both protective and treatment strategies. The goal of this paper is to review the current state of the art in mathematical and computational modeling of blast-induced TBI, identify research gaps, and recommend future developments. A brief overview of blast wave physics, injury biomechanics, and the neurobiology of brain injury is used as a foundation for a more detailed discussion of multiscale mathematical models of primary biomechanics and secondary injury and repair mechanisms. The paper also presents a discussion of model development strategies, experimental approaches to generate benchmark data for model validation, and potential applications of the model for prevention and protection against blast wave TBI. PMID:23755039

Direct Peritoneal Resuscitation Reduces Leukocyte Infiltration in the Kidney after Acute Brain Death.

PubMed

Weaver, Jessica Lee; Matheson, Paul J; Matheson, Amy; Graham, Victoria S; Downard, Cynthia; Garrison, Richard Neal; Smith, Jason W

2018-04-18

Brain death is associated with significant inflammation within the kidneys, which may contribute to reduced graft survival. Direct peritoneal resuscitation (DPR) has been shown to reduce systemic inflammation after brain death. To determine its effects, brain dead rats were resuscitated with normal saline (targeted intravenous fluid, TIVF) to maintain a mean arterial pressure of 80 mmHg and DPR animals also received 30cc of intraperitoneal peritoneal dialysis solution. Rats were euthanized at zero, two, four, and six hours after brain death. Pro-inflammatory cytokines were measured using ELISA. Levels of IL-1β, TNF-α, and IL-6 in the kidney were significantly increased as early as two hours after brain death and significantly decreased with DPR. Levels of leukocyte adhesion molecules ICAM and VCAM increased after brain death and were decreased with DPR (ICAM 2.33{plus minus}0.14 v 0.42{plus minus}0.04 p=0.002, VCAM 82.6{plus minus}5.8 v 37.3{plus minus}1.9 p=0.002 at four hours) as were E-selectin and P-selectin (E-selectin 25605 v 16144 p=0.005, P-selectin 82.5{plus minus}3.3 v 71.0{plus minus}2.3 p=0.009 at four hours). Use of DPR reduces inflammation and adhesion molecule expression in the kidneys, and is associated with reduced macrophages and neutrophils on immunohistochemistry. Using DPR in brain dead donors has the potential to reduce the immunologic activity of transplanted kidneys and could improve graft survival.

Evidence-based guideline update: determining brain death in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology.

PubMed

Wijdicks, Eelco F M; Varelas, Panayiotis N; Gronseth, Gary S; Greer, David M

2010-06-08

To provide an update of the 1995 American Academy of Neurology guideline with regard to the following questions: Are there patients who fulfill the clinical criteria of brain death who recover neurologic function? What is an adequate observation period to ensure that cessation of neurologic function is permanent? Are complex motor movements that falsely suggest retained brain function sometimes observed in brain death? What is the comparative safety of techniques for determining apnea? Are there new ancillary tests that accurately identify patients with brain death? A systematic literature search was conducted and included a review of MEDLINE and EMBASE from January 1996 to May 2009. Studies were limited to adults. In adults, there are no published reports of recovery of neurologic function after a diagnosis of brain death using the criteria reviewed in the 1995 American Academy of Neurology practice parameter. Complex-spontaneous motor movements and false-positive triggering of the ventilator may occur in patients who are brain dead. There is insufficient evidence to determine the minimally acceptable observation period to ensure that neurologic functions have ceased irreversibly. Apneic oxygenation diffusion to determine apnea is safe, but there is insufficient evidence to determine the comparative safety of techniques used for apnea testing. There is insufficient evidence to determine if newer ancillary tests accurately confirm the cessation of function of the entire brain.

Liver transplant using donors after cardiac death: a single-center approach providing outcomes comparable to donation after brain death.

PubMed

Vanatta, Jason M; Dean, Amanda G; Hathaway, Donna K; Nair, Satheesh; Modanlou, Kian A; Campos, Luis; Nezakatgoo, Nosratollah; Satapathy, Sanjaya K; Eason, James D

2013-04-01

Organ donation after cardiac death remains an available resource to meet the demand for transplant. However, concern persists that outcomes associated with donation after cardiac death liver allografts are not equivalent to those obtained with organ donation after brain death. The aim of this matched case control study was to determine if outcomes of liver transplants with donation after cardiac death donors is equivalent to outcomes with donation after brain death donors by controlling for careful donor and recipient selection, surgical technique, and preservation solution. A retrospective, matched case control study of adult liver transplant recipients at the University of Tennessee/Methodist University Hospital Transplant Institute, Memphis, Tennessee was performed. Thirty-eight donation after cardiac death recipients were matched 1:2, with 76 donation after brain death recipients by recipient age, recipient laboratory Model for End Stage Liver Disease score, and donor age to form the 2 groups. A comprehensive approach that controlled for careful donor and recipient matching, surgical technique, and preservation solution was used to minimize warm ischemia time, cold ischemia time, and ischemia-reperfusion injury. Patient and graft survival rates were similar in both groups at 1 and 3 years (P = .444 and P = .295). There was no statistically significant difference in primary nonfunction, vascular complications, or biliary complications. In particular, there was no statistically significant difference in ischemic-type diffuse intrahepatic strictures (P = .107). These findings provide further evidence that excellent patient and graft survival rates expected with liver transplants using organ donation after brain death donors can be achieved with organ donation after cardiac death donors without statistically higher rates of morbidity or mortality when a comprehensive approach that controls for careful donor and recipient matching, surgical technique, and preservation solution is used.

Police Officers' Knowledge and Attitudes Toward Brain Death and Organ Donation in Korea.

PubMed

Kim, H S; Yoo, Y S; Cho, O-H; Lee, C E; Choi, Y-H; Kim, H J; Park, J Y; Park, H S; Kwon, Y J

2018-05-01

Administrative processing by the police may affect the process involved in organ donation in the event of an accidental brain injury. The purpose of this study was to evaluate the knowledge and attitude of police toward brain-dead donors and organ donation. This was a descriptive research study using a 41-item questionnaire. As of July 19, 2017, 11 police stations in Seoul had collected questionnaires completed by 115 police officers. Data were analyzed using SAS (version 9.4) software. There were statistically significant differences in the scores on knowledge about brain death/donation according to religion (P = .022). Attitude was significantly positively correlated with the knowledge about brain-death organ donation (P = .029). It is necessary to understand and cooperate with the police when processing brain death organs from accidents. Education about organ donation can enhance the information and knowledge of the police and can also help to establish a positive attitude about organ donation. Copyright © 2018 Elsevier Inc. All rights reserved.

Nitrates in drinking water and the risk of death from brain cancer: does hardness in drinking water matter?

PubMed

Ho, Chi-Kung; Yang, Ya-Hui; Yang, Chun-Yuh

2011-01-01

The objectives of this study were to (1) examine the relationship between nitrate levels in public water supplies and risk of death from brain cancer and (2) determine whether calcium (Ca) and magnesium (Mg) levels in drinking water might modify the influence of nitrates on development of brain cancer. A matched cancer case-control study was used to investigate the relationship between the risk of death from brain cancer and exposure to nitrates in drinking water in Taiwan. All brain cancer deaths of Taiwan residents from 2003 through 2008 were obtained from the Bureau of Vital Statistics of the Taiwan Provincial Department of Health. Controls were deaths from other causes and were pair-matched to cancer cases by gender, year of birth, and year of death. Information on the levels of nitrate-nitrogen (NO₃-N), Ca, and Mg in drinking water was obtained from Taiwan Water Supply Corporation (TWSC). The municipality of residence for cancer cases and controls was presumed to be the source of the subject's NO₃-N, Ca, and Mg exposure via drinking water. Relative to individuals whose NO₃-N exposure level was <0.38 ppm, the adjusted OR (95% CI) for brain cancer occurrence was 1.04 (0.85-1.27) for individuals who resided in municipalities served by drinking water with a NO₃-N exposure ≥ 0.38 ppm. No marked effect modification was observed due to Ca and Mg intake via drinking water on brain cancer occurrence.

Gender and neural substrates subserving implicit processing of death-related linguistic cues.

PubMed

Qin, Jungang; Shi, Zhenhao; Ma, Yina; Han, Shihui

2018-02-01

Our recent functional magnetic resonance imaging study revealed decreased activities in the anterior cingulate cortex (ACC) and bilateral insula for women during the implicit processing of death-related linguistic cues. Current work tested whether aforementioned activities are common for women and men and explored potential gender differences. We scanned twenty males while they performed a color-naming task on death-related, negative-valence, and neutral-valence words. Whole-brain analysis showed increased left frontal activity and decreased activities in the ACC and bilateral insula to death-related versus negative-valence words for both men and women. However, relative to women, men showed greater increased activity in the left middle frontal cortex and decreased activity in the right cerebellum to death-related versus negative-valence words. The results suggest, while implicit processing of death-related words is characterized with weakened sense of oneself for both women and men, men may recruit stronger cognitive regulation of emotion than women.

Donations After Circulatory Death in Liver Transplant

PubMed Central

Eren, Emre A.; Latchana, Nicholas; Beal, Eliza; Hayes, Don; Whitson, Bryan; Black, Sylvester M.

2017-01-01

The supply of liver grafts for treatment of end-stage liver disease continues to fall short of ongoing demands. Currently, most liver transplants originate from donations after brain death. Enhanced utilization of the present resources is prudent to address the needs of the population. Donation after circulatory or cardiac death is a mechanism whereby the availability of organs can be expanded. Donations after circulatory death pose unique challenges given their exposure to warm ischemia. Technical principles of donations after circulatory death procurement and pertinent studies investigating patient outcomes, graft outcomes, and complications are highlighted in this review. We also review associated risk factors to suggest potential avenues to achieve improved outcomes and reduced complications. Future considerations and alternative techniques of organ preservation are discussed, which may suggest novel strategies to enhance preservation and donor expansion through the use of marginal donors. Ultimately, without effective measures to bolster organ supply, donations after circulatory death should remain a consideration; however, an understanding of inherent risks and limitations is necessary. PMID:27733105

Donations After Circulatory Death in Liver Transplant.

PubMed

Eren, Emre A; Latchana, Nicholas; Beal, Eliza; Hayes, Don; Whitson, Bryan; Black, Sylvester M

2016-10-01

The supply of liver grafts for treatment of end-stage liver disease continues to fall short of ongoing demands. Currently, most liver transplants originate from donations after brain death. Enhanced utilization of the present resources is prudent to address the needs of the population. Donation after circulatory or cardiac death is a mechanism whereby the availability of organs can be expanded. Donations after circulatory death pose unique challenges given their exposure to warm ischemia. Technical principles of donations after circulatory death procurement and pertinent studies investigating patient outcomes, graft outcomes, and complications are highlighted in this review. We also review associated risk factors to suggest potential avenues to achieve improved outcomes and reduced complications. Future considerations and alternative techniques of organ preservation are discussed, which may suggest novel strategies to enhance preservation and donor expansion through the use of marginal donors. Ultimately, without effective measures to bolster organ supply, donations after circulatory death should remain a consideration; however, an understanding of inherent risks and limitations is necessary.

Medical and ethical dilemma in brain death.

PubMed

Streba, Irina; Damian, Simona; Ioan, Beatrice

2012-01-01

For centuries, death has been defined, medically speaking, as the irreversible cessation of breathing and of nervous and cardiac activity. What radically changed this definition was the introduction of the concept "brain death" in 1968, by the "Ad Hoc Committee of the Harvard Medical School". According to it, the irreversible coma was associated with brain death and considered to be a criterion for the diagnosis of the deceased individual. The evergrowing need for transplant organs (provided this respects the dead honor rule, stipulating that organs can't be harvested unless someone is deceased) lead to making arbitrary decisions regarding the establishment of the exact time of death during the process of "losing life". What actually triggers the controversy related to the concept of brain death is the dilemma of associating this concept with that of biologic death or death of the person, the difference between the two being made by whether the mental characteristics are accepted or not in defining and individualizing the death of the human being. Given these circumstances, a dilemma appears--that of defining the death of the individual: we define death, as it has been for centuries, as the moment when the cardio-respiratory function no longer exists, which leads to the loss of tens of thousands of lives that might have been saved through transplant. Yet, this may lead to manipulating the border between life and death, with the risk of trespassing each individual's right to life.

Agmatine Attenuates Brain Edema and Apoptotic Cell Death after Traumatic Brain Injury.

PubMed

Kim, Jae Young; Lee, Yong Woo; Kim, Jae Hwan; Lee, Won Taek; Park, Kyung Ah; Lee, Jong Eun

2015-07-01

Traumatic brain injury (TBI) is associated with poor neurological outcome, including necrosis and brain edema. In this study, we investigated whether agmatine treatment reduces edema and apoptotic cell death after TBI. TBI was produced by cold injury to the cerebral primary motor cortex of rats. Agmatine was administered 30 min after injury and once daily until the end of the experiment. Animals were sacrificed for analysis at 1, 2, or 7 days after the injury. Various neurological analyses were performed to investigate disruption of the blood-brain barrier (BBB) and neurological dysfunction after TBI. To examine the extent of brain edema after TBI, the expression of aquaporins (AQPs), phosphorylation of mitogen-activated protein kinases (MAPKs), and nuclear translocation of nuclear factor-κB (NF-κB) were investigated. Our findings demonstrated that agmatine treatment significantly reduces brain edema after TBI by suppressing the expression of AQP1, 4, and 9. In addition, agmatine treatment significantly reduced apoptotic cell death by suppressing the phosphorylation of MAPKs and by increasing the nuclear translocation of NF-κB after TBI. These results suggest that agmatine treatment may have therapeutic potential for brain edema and neural cell death in various central nervous system diseases.

Vascular impairment as a pathological mechanism underlying long-lasting cognitive dysfunction after pediatric traumatic brain injury.

PubMed

Ichkova, Aleksandra; Rodriguez-Grande, Beatriz; Bar, Claire; Villega, Frederic; Konsman, Jan Pieter; Badaut, Jerome

2017-12-01

Traumatic brain injury (TBI) is the leading cause of death and disability in children. Indeed, the acute mechanical injury often evolves to a chronic brain disorder with long-term cognitive, emotional and social dysfunction even in the case of mild TBI. Contrary to the commonly held idea that children show better recovery from injuries than adults, pediatric TBI patients actually have worse outcome than adults for the same injury severity. Acute trauma to the young brain likely interferes with the fine-tuned developmental processes and may give rise to long-lasting consequences on brain's function. This review will focus on cerebrovascular dysfunction as an important early event that may lead to long-term phenotypic changes in the brain after pediatric TBI. These, in turn may be associated with accelerated brain aging and cognitive dysfunction. Finally, since no effective treatments are currently available, understanding the unique pathophysiological mechanisms of pediatric TBI is crucial for the development of new therapeutic options. Copyright © 2017 Elsevier Ltd. All rights reserved.

Mortality among Workers Exposed to Polychlorinated Biphenyls (PCBs) in an Electrical Capacitor Manufacturing Plant in Indiana: An Update

PubMed Central

Ruder, Avima M.; Hein, Misty J.; Nilsen, Nancy; Waters, Martha A.; Laber, Patricia; Davis-King, Karen; Prince, Mary M.; Whelan, Elizabeth

2006-01-01

An Indiana capacitor-manufacturing cohort (n = 3,569) was exposed to polychlorinated biphenyls (PCBs) from 1957 to 1977. The original study of mortality through 1984 found excess melanoma and brain cancer; other studies of PCB-exposed individuals have found excess non-Hodgkin lymphoma and rectal, liver, biliary tract, and gallbladder cancer. Mortality was updated through 1998. Analyses have included standardized mortality ratios (SMRs) and 95% confidence intervals (CIs) using rates for Indiana and the United States, standardized rate ratios (SRRs), and Poisson regression rate ratios (RRs). Estimated cumulative exposure calculations used a new job–exposure matrix. Mortality overall was reduced (547 deaths; SMR, 0.81; 95% CI, 0.7–0.9). Non-Hodgkin lymphoma mortality was elevated (9 deaths; SMR, 1.23; 95% CI, 0.6–2.3). Melanoma remained in excess (9 deaths; SMR, 2.43; 95% CI, 1.1–4.6), especially in the lowest tertile of estimated cumulative exposure (5 deaths; SMR, 3.72; 95% CI, 1.2–8.7). Seven of the 12 brain cancer deaths (SMR, 1.91; 95% CI, 1.0–3.3) occurred after the original study. Brain cancer mortality increased with exposure (in the highest tertile, 5 deaths; SMR, 2.71; 95% CI, 0.9–6.3); the SRR dose–response trend was significant (p = 0.016). Among those working ≥90 days, both melanoma (8 deaths; SMR, 2.66; 95% CI, 1.1–5.2) and brain cancer (11 deaths; SMR, 2.12; 95% CI, 1.1–3.8) were elevated, especially for women: melanoma, 3 deaths (SMR, 5.99; 95% CI, 1.2–17.5); brain cancer, 3 deaths (SMR, 2.87; 95% CI, 0.6–8.4). These findings of excess melanoma and brain cancer mortality confirm results of the original study. Melanoma mortality was not associated with estimated cumulative exposure. Brain cancer mortality did not demonstrate a clear dose–response relationship with estimated cumulative exposure. PMID:16393652

The expression of '150-kDa oxygen regulated protein (ORP-150)' in human brain and its relationship with duration time until death.

PubMed

Ikematsu, Kazuya; Tsuda, Ryouichi; Kondo, Toshikazu; Kondo, Hisayoshi; Ozawa, Kentaro; Ogawa, Satoshi; Nakasono, Ichiro

2004-04-01

The expression of oxygen regulated protein 150-kDa (ORP-150) was strongly induced in human brain under the hypoxic conditions. We examined the expression of ORP-150 in the brain samples, and discussed its significance in forensic practice. The cerebral cortexes of 31 cases (asphyxia: 9 cases, hypothermia: 4, exsanguinations: 5, CO intoxication (CO): 6, sudden cardiac death (SCD): 7) were used for this study. Each tissue section was incubated with anti-ORP-150 polyclonal antibody and the number of ORP-150 positive cells were counted. In the multiple linear regression method, the estimated regression coefficient of ORP-150 on age was significant (P=0.039) thus, we could find that the ORP-150 expression level depended on age. Using analysis of covariance, we compared the means of ORP-150, LSMEAN, which means hypothetic average value excluding influence of age, for each cause of death. The LSMEAN+/-SE was 84.74+/-9.03 in hypothermia, 57.52+/-6.34 in asphyxia, 46.68+/-6.70 in CO, 24.84+/-8.05 in exsanguinations, and 16.24+/-7.35 in SCD. As a result of the analysis, the LSMEAN of the ORP-150 expression level was related to the cause of death. There might be differences in the duration of brain ischemia before death. For example, SCD is presumed to be instant death, while brain ischemia continues for several minutes in asphyxia, CO and exsanguinations, and for several hours in hypothermia cases. Therefore, the immunohistochemical and morphometrical analysis of ORP-150 in the brain may be very useful to determine the duration of brain ischemia before death in forensic autopsy cases.

Rapid-releasing of HI-6 via brain-targeted mesoporous silica nanoparticles for nerve agent detoxification

NASA Astrophysics Data System (ADS)

Yang, Jun; Fan, Lixue; Wang, Feijian; Luo, Yuan; Sui, Xin; Li, Wanhua; Zhang, Xiaohong; Wang, Yongan

2016-05-01

The toxic nerve agent (NA) soman is the most toxic artificially synthesized compound that can rapidly penetrate into the brain and irreversibly inhibit acetylcholinesterase (AChE) activity, leading to immediate death. However, there are currently few brain-targeted nanodrugs that can treat acute chemical brain poisoning owing to the limited drug-releasing speed. The present study investigated the effectiveness of a nanodrug against NA toxicity that has high blood-brain barrier penetration and is capable of rapid drug release. Transferrin-modified mesoporous silica nanoparticles (TF-MSNs) were conjugated with the known AChE reactivator HI-6. This nanodrug rapidly penetrated the blood-brain barrier in zebrafish and mice and restored cerebral AChE activity via the released HI-6, preventing the brain damage caused by soman poisoning and increasing the survival rate in mice. Furthermore, there was no toxicity associated with the MSNs in mice or rats. These results demonstrate that TF-MSNs loaded with HI-6 represent the most effective antidote against NA poisoning by soman reported to date, and suggest that MSNs are a safe alternative to conventional drugs and an optimal nanocarrier for treating brain poisoning, which requires acute pulse cerebral administration.The toxic nerve agent (NA) soman is the most toxic artificially synthesized compound that can rapidly penetrate into the brain and irreversibly inhibit acetylcholinesterase (AChE) activity, leading to immediate death. However, there are currently few brain-targeted nanodrugs that can treat acute chemical brain poisoning owing to the limited drug-releasing speed. The present study investigated the effectiveness of a nanodrug against NA toxicity that has high blood-brain barrier penetration and is capable of rapid drug release. Transferrin-modified mesoporous silica nanoparticles (TF-MSNs) were conjugated with the known AChE reactivator HI-6. This nanodrug rapidly penetrated the blood-brain barrier in zebrafish and mice and restored cerebral AChE activity via the released HI-6, preventing the brain damage caused by soman poisoning and increasing the survival rate in mice. Furthermore, there was no toxicity associated with the MSNs in mice or rats. These results demonstrate that TF-MSNs loaded with HI-6 represent the most effective antidote against NA poisoning by soman reported to date, and suggest that MSNs are a safe alternative to conventional drugs and an optimal nanocarrier for treating brain poisoning, which requires acute pulse cerebral administration. Electronic supplementary information (ESI) available. See DOI: 10.1039/c5nr06658a

Imaging transplanted stem cells in real time using an MRI dual-contrast method

PubMed Central

Ngen, Ethel J.; Wang, Lee; Kato, Yoshinori; Krishnamachary, Balaji; Zhu, Wenlian; Gandhi, Nishant; Smith, Barbara; Armour, Michael; Wong, John; Gabrielson, Kathleen; Artemov, Dmitri

2015-01-01

Stem cell therapies are currently being investigated for the repair of brain injuries. Although exogenous stem cell labelling with superparamagnetic iron oxide nanoparticles (SPIONs) prior to transplantation provides a means to noninvasively monitor stem cell transplantation by magnetic resonance imaging (MRI), monitoring cell death is still a challenge. Here, we investigate the feasibility of using an MRI dual-contrast technique to detect cell delivery, cell migration and cell death after stem cell transplantation. Human mesenchymal stem cells were dual labelled with SPIONs and gadolinium-based chelates (GdDTPA). The viability, proliferation rate, and differentiation potential of the labelled cells were then evaluated. The feasibility of this MRI technique to distinguish between live and dead cells was next evaluated using MRI phantoms, and in vivo using both immune-competent and immune-deficient mice, following the induction of brain injury in the mice. All results were validated with bioluminescence imaging. In live cells, a negative (T2/T2*) MRI contrast predominates, and is used to track cell delivery and cell migration. Upon cell death, a diffused positive (T1) MRI contrast is generated in the vicinity of the dead cells, and serves as an imaging marker for cell death. Ultimately, this technique could be used to manage stem cell therapies. PMID:26330231

Therapeutic Time Window for Edaravone Treatment of Traumatic Brain Injury in Mice

PubMed Central

Miyamoto, Kazuyuki; Ohtaki, Hirokazu; Dohi, Kenji; Tsumuraya, Tomomi; Song, Dandan; Kiriyama, Keisuke; Satoh, Kazue; Shimizu, Ai; Aruga, Tohru; Shioda, Seiji

2013-01-01

Traumatic brain injury (TBI) is a major cause of death and disability in young people. No effective therapy is available to ameliorate its damaging effects. Our aim was to investigate the optimal therapeutic time window of edaravone, a free radical scavenger which is currently used in Japan. We also determined the temporal profile of reactive oxygen species (ROS) production, oxidative stress, and neuronal death. Male C57Bl/6 mice were subjected to a controlled cortical impact (CCI). Edaravone (3.0 mg/kg), or vehicle, was administered intravenously at 0, 3, or 6 hours following CCI. The production of superoxide radicals (O2 ∙−) as a marker of ROS, of nitrotyrosine (NT) as an indicator of oxidative stress, and neuronal death were measured for 24 hours following CCI. Superoxide radical production was clearly evident 3 hours after CCI, with oxidative stress and neuronal cell death becoming apparent after 6 hours. Edaravone administration after CCI resulted in a significant reduction in the injury volume and oxidative stress, particularly at the 3-hour time point. Moreover, the greatest decrease in O2 ∙− levels was observed when edaravone was administered 3 hours following CCI. These findings suggest that edaravone could prove clinically useful to ameliorate the devastating effects of TBI. PMID:23710445

Imaging transplanted stem cells in real time using an MRI dual-contrast method.

PubMed

Ngen, Ethel J; Wang, Lee; Kato, Yoshinori; Krishnamachary, Balaji; Zhu, Wenlian; Gandhi, Nishant; Smith, Barbara; Armour, Michael; Wong, John; Gabrielson, Kathleen; Artemov, Dmitri

2015-09-02

Stem cell therapies are currently being investigated for the repair of brain injuries. Although exogenous stem cell labelling with superparamagnetic iron oxide nanoparticles (SPIONs) prior to transplantation provides a means to noninvasively monitor stem cell transplantation by magnetic resonance imaging (MRI), monitoring cell death is still a challenge. Here, we investigate the feasibility of using an MRI dual-contrast technique to detect cell delivery, cell migration and cell death after stem cell transplantation. Human mesenchymal stem cells were dual labelled with SPIONs and gadolinium-based chelates (GdDTPA). The viability, proliferation rate, and differentiation potential of the labelled cells were then evaluated. The feasibility of this MRI technique to distinguish between live and dead cells was next evaluated using MRI phantoms, and in vivo using both immune-competent and immune-deficient mice, following the induction of brain injury in the mice. All results were validated with bioluminescence imaging. In live cells, a negative (T2/T2*) MRI contrast predominates, and is used to track cell delivery and cell migration. Upon cell death, a diffused positive (T1) MRI contrast is generated in the vicinity of the dead cells, and serves as an imaging marker for cell death. Ultimately, this technique could be used to manage stem cell therapies.

Neuroprotection by selective neuronal deletion of Atg7 in neonatal brain injury

PubMed Central

Xie, Cuicui; Ginet, Vanessa; Sun, Yanyan; Koike, Masato; Zhou, Kai; Li, Tao; Li, Hongfu; Li, Qian; Wang, Xiaoyang; Uchiyama, Yasuo; Truttmann, Anita C.; Kroemer, Guido; Puyal, Julien; Blomgren, Klas; Zhu, Changlian

2016-01-01

ABSTRACT Perinatal asphyxia induces neuronal cell death and brain injury, and is often associated with irreversible neurological deficits in children. There is an urgent need to elucidate the neuronal death mechanisms occurring after neonatal hypoxia-ischemia (HI). We here investigated the selective neuronal deletion of the Atg7 (autophagy related 7) gene on neuronal cell death and brain injury in a mouse model of severe neonatal hypoxia-ischemia. Neuronal deletion of Atg7 prevented HI-induced autophagy, resulted in 42% decrease of tissue loss compared to wild-type mice after the insult, and reduced cell death in multiple brain regions, including apoptosis, as shown by decreased caspase-dependent and -independent cell death. Moreover, we investigated the lentiform nucleus of human newborns who died after severe perinatal asphyxia and found increased neuronal autophagy after severe hypoxic-ischemic encephalopathy compared to control uninjured brains, as indicated by the numbers of MAP1LC3B/LC3B (microtubule-associated protein 1 light chain 3)-, LAMP1 (lysosomal-associated membrane protein 1)-, and CTSD (cathepsin D)-positive cells. These findings reveal that selective neuronal deletion of Atg7 is strongly protective against neuronal death and overall brain injury occurring after HI and suggest that inhibition of HI-enhanced autophagy should be considered as a potential therapeutic target for the treatment of human newborns developing severe hypoxic-ischemic encephalopathy. PMID:26727396

Dietary and plant polyphenols exert neuroprotective effects and improve cognitive function in cerebral ischemia.

PubMed

Panickar, Kiran S; Jang, Saebyeol

2013-08-01

Cerebral ischemia is caused by an interruption of blood flow to the brain which generally leads to irreversible brain damage. Ischemic injury is associated with vascular leakage, inflammation, tissue injury, and cell death. Cellular changes associated with ischemia include impairment of metabolism, energy failure, free radical production, excitotoxicity, altered calcium homeostasis, and activation of proteases all of which affect brain functioning and also contribute to longterm disabilities including cognitive decline. Inflammation, mitochondrial dysfunction, increased oxidative/nitrosative stress, and intracellular calcium overload contribute to brain injury including cell death and brain edema. However, there is a paucity of agents that can effectively reduce cerebral damage and hence considerable attention has focused on developing newer agents with more efficacy and fewer side-effects. Polyphenols are natural compounds with variable phenolic structures and are rich in vegetables, fruits, grains, bark, roots, tea, and wine. Most polyphenols have antioxidant, anti-inflammatory, and anti-apoptotic properties and their protective effects on mitochondrial functioning, glutamate uptake, and regulating intracellular calcium levels in ischemic injury in vitro have been demonstrated. This review will assess the current status of the potential effects of polyphenols in reducing cerebral injury and improving cognitive function in ischemia in animal and human studies. In addition, the review will also examine available patents in nutrition and agriculture that relates to cerebral ischemic injury with an emphasis on plant polyphenols.

Methylene Blue Protects Astrocytes against Glucose Oxygen Deprivation by Improving Cellular Respiration

PubMed Central

Roy Choudhury, Gourav; Winters, Ali; Rich, Ryan M.; Ryou, Myoung-Gwi; Gryczynski, Zygmunt; Yuan, Fang; Yang, Shao-Hua; Liu, Ran

2015-01-01

Astrocytes outnumber neurons and serve many metabolic and trophic functions in the mammalian brain. Preserving astrocytes is critical for normal brain function as well as for protecting the brain against various insults. Our previous studies have indicated that methylene blue (MB) functions as an alternative electron carrier and enhances brain metabolism. In addition, MB has been shown to be protective against neurodegeneration and brain injury. In the current study, we investigated the protective role of MB in astrocytes. Cell viability assays showed that MB treatment significantly protected primary astrocytes from oxygen-glucose deprivation (OGD) & reoxygenation induced cell death. We also studied the effect of MB on cellular oxygen and glucose metabolism in primary astrocytes following OGD-reoxygenation injury. MB treatment significantly increased cellular oxygen consumption, glucose uptake and ATP production in primary astrocytes. In conclusion our study demonstrated that MB protects astrocytes against OGD-reoxygenation injury by improving astrocyte cellular respiration. PMID:25848957

[Structural Equation Modeling on Living and Brain Death Organ Donation Intention in Nursing Students].

PubMed

Kim, Eun A; Choi, So Eun

2015-12-01

The purpose of this study was to test and validate a model to predict living and brain death organ donation intention in nursing students. The conceptual model was based on the theory planned behavior. Quota sampling methodology was used to recruit 921 nursing students from all over the country and data collection was done from October 1 to December 20, 2013. The model fit indices for the hypothetical model were suitable for the recommended level. Knowledge, attitude, subjective norm and perceived behavioral control explained 40.2% and 40.1% respectively for both living and brain death organ donation intention. Subjective norm was the most direct influential factor for organ donation intention. Knowledge had significant direct effect on attitude and indirect effect on subjective norm and perceived behavioral control. These effects were higher in brain death organ donation intention than in living donation intention. The overall findings of this study suggest the need to develop systematic education programs to increases knowledge about brain death organ donation. The development, application, and evaluation of intervention programs are required to improve subjective norm.

Arizona Study of Aging and Neurodegenerative Disorders and Brain and Body Donation Program

PubMed Central

Beach, Thomas G.; Adler, Charles H.; Sue, Lucia I.; Serrano, Geidy; Shill, Holly A.; Walker, Douglas G.; Lue, LihFen; Roher, Alex E.; Dugger, Brittany N.; Maarouf, Chera; Birdsill, Alex C.; Intorcia, Anthony; Saxon-Labelle, Megan; Pullen, Joel; Scroggins, Alexander; Filon, Jessica; Scott, Sarah; Hoffman, Brittany; Garcia, Angelica; Caviness, John N.; Hentz, Joseph G.; Driver-Dunckley, Erika; Jacobson, Sandra A.; Davis, Kathryn J.; Belden, Christine M.; Long, Kathy E.; Malek-Ahmadi, Michael; Powell, Jessica J.; Gale, Lisa D.; Nicholson, Lisa R.; Caselli, Richard J.; Woodruff, Bryan K.; Rapscak, Steven Z.; Ahern, Geoffrey L.; Shi, Jiong; Burke, Anna D.; Reiman, Eric M.; Sabbagh, Marwan N.

2015-01-01

The Brain and Body Donation Program (BBDP) at Banner Sun Health Research Institute (http://www.brainandbodydonationprogram.org) started in 1987 with brain-only donations and currently has banked more than 1600 brains. More than 430 whole-body donations have been received since this service was commenced in 2005. The collective academic output of the BBDP is now described as the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND). Most BBDP subjects are enrolled as cognitively normal volunteers residing in the retirement communities of metropolitan Phoenix, Arizona. Specific recruitment efforts are also directed at subjects with Alzheimer’s disease, Parkinson’s disease and cancer. The median age at death is 82. Subjects receive standardized general medical, neurological, neuropsychological and movement disorders assessments during life and more than 90% receive full pathological examinations by medically licensed pathologists after death. The Program has been funded through a combination of internal, federal and state of Arizona grants as well as user fees and pharmaceutical industry collaborations. Subsets of the Program are utilized by the US National Institute on Aging Arizona Alzheimer’s Disease Core Center and the US National Institute of Neurological Disorders and Stroke National Brain and Tissue Resource for Parkinson’s Disease and Related Disorders. Substantial funding has also been received from the Michael J. Fox Foundation for Parkinson’s Research. The Program has made rapid autopsy a priority, with a 3.0-hour median postmortem interval for the entire collection. The median RNA Integrity Number (RIN) for frozen brain and body tissue is 8.9 and 7.4, respectively. More than 2500 tissue requests have been served and currently about 200 are served annually. These requests have been made by more than 400 investigators located in 32 US states and 15 countries. Tissue from the BBDP has contributed to more than 350 publications and more than 200 grant-funded projects. PMID:25619230

End-of-life practices in patients with devastating brain injury in Spain: implications for organ donation.

PubMed

Domínguez-Gil, B; Coll, E; Pont, T; Lebrón, M; Miñambres, E; Coronil, A; Quindós, B; Herrero, J E; Liébanas, C; Marcelo, B; Sanmartín, A M; Matesanz, R

2017-04-01

To describe end-of-life care practices relevant to organ donation in patients with devastating brain injury in Spain. A multicenter prospective study of a retrospective cohort. 1 November 2014 to 30 April 2015. Sixty-eight hospitals authorized for organ procurement. Patients dying from devastating brain injury (possible donors). Age: 1 month-85 years. Type of care, donation after brain death, donation after circulatory death, intubation/ventilation, referral to the donor coordinator. A total of 1,970 possible donors were identified, of which half received active treatment in an Intensive Care Unit (ICU) until brain death (27%), cardiac arrest (5%) or the withdrawal of life-sustaining therapy (19%). Of the rest, 10% were admitted to the ICU to facilitate organ donation, while 39% were not admitted to the ICU. Of those patients who evolved to a brain death condition (n=695), most transitioned to actual donation (n=446; 64%). Of those who died following the withdrawal of life-sustaining therapy (n=537), 45 (8%) were converted into actual donation after circulatory death donors. The lack of a dedicated donation after circulatory death program was the main reason for non-donation. Thirty-seven percent of the possible donors were not intubated/ventilated at death, mainly because the professional in charge did not consider donation alter discarding therapeutic intubation. Thirty-six percent of the possible donors were never referred to the donor coordinator. Although deceased donation is optimized in Spain, there are still opportunities for improvement in the identification of possible donors outside the ICU and in the consideration of donation after circulatory death in patients who die following the withdrawal of life-sustaining therapy. Copyright © 2016 Elsevier España, S.L.U. y SEMICYUC. All rights reserved.

A study on knowledge and attitude toward brain death and organ retrieval among health care professionals in Korea.

PubMed

Jeon, K O; Kim, B N; Kim, H S; Byeon, N-I; Hong, J J; Bae, S H; Son, S Y

2012-05-01

The practice of retrieving vital organs from brain-dead donors is legally and medically accepted in Korea, but health care professionals' beliefs and opinions regarding these matters have not been sufficiently explored. The purpose of this study was to evaluate the knowledge and attitudes of health care professionals to the concepts of brain death and organ retrieval. Data were collected using a 41-item questionnaire during a week in June 2011. Sixty-one doctors and 109 nurses from five hospitals with more than 2000 beds in Seoul, Korea, participated in the survey. The data was analyzed using SPSS version 17.0 (SPSS Inc. Chicago, Illinois, USA). There were statistically significant differences in the scores on knowledge according to marital status (P = .001) education level (P = .019), whether the participants were informed about organ donation from a brain-dead donor (P = .002), and the participant's experience managing potential brain-dead patients (P = .037). There were statistically significant differences in the scores on the attitude according to gender (P < .001), age (P < .001), marital status (P < .001), education level (P = .003), job position (P < .001), and the participant's experience referring brain-dead patients to the hospital-based organ procurement organization (P = .001). Significantly, attitude's positively correlated with knowledge about brain-dead organ donation (P < .001). Compared with previous studies, the knowledge and attitudes of health care professionals' regarding brain death and organ retrieval were not improved. There are passive attitudes to brain death and organ retrieval. More research must be performed to promote knowledge and understanding toward brain death and organ retrieval among health care professionals. Copyright © 2012 Elsevier Inc. All rights reserved.

The model and moral justification for organ procurement in Japan.

PubMed

Bagheri, Alireza; Shoji, Shin'ichi

2005-01-01

Organ replacement therapy is a part of medical practice in today's world and many countries have adopted the required guidelines and regulations. Establishing the basis on which organs can be removed, is still one of the most controversial issues of health policy making in the debate. The critical disparity between supply and demand in organ replacement therapy, even with the existence of social acceptance and organ transplantation law, turns attention towards the importance of an appropriate model of organ procurement. This model should be able to expand the donor pool and increase the organ retrieval rate by converting potential donors to actual ones. In Japan the organ transplantation law which was enacted in 1997 allows organ procurement from brain death as well as non-heart beating cadavers according to restricted conditions. One such condition includes the necessity of both the donor's and the family's written consent. Under current organ procurement policy, organs from only 29 brain death cases have been so far procured. In this paper after examining the current organ procurement system in Japan and the moral justifications behind different organ procurement models we conclude that the Japanese system does not clearly fall into one of the popular organ procurement models.

Absent Cerebellar Circulation With Intact Cerebral Blood Flow on a 99mTc Bicisate "Brain Death" Study.

PubMed

Schmidt, Matthew Q; Schraml, Frank V

2017-12-01

A 55-year old woman presented in an obtunded state and was found to have a subarachnoid hemorrhage. After endovascular repair, her condition deteriorated, and brain death was suspected. A Tc bicisate brain blood flow study was performed, which showed a complete absence of blood flow to the cerebellum despite intact circulation to the cerebral hemispheres. These atypical findings are likely a result of a transient intracranial pressure differential and the timing of the study. A timely and accurate declaration of brain death has important psychosocial and ethical implications, particularly when organ donation is being considered.

Optical imaging of cell death in traumatic brain injury using a heat shock protein-90 alkylator

PubMed Central

Xie, B-W; Park, D; Van Beek, E R; Blankevoort, V; Orabi, Y; Que, I; Kaijzel, E L; Chan, A; Hogg, P J; Löwik, C W G M

2013-01-01

Traumatic brain injury is a major public health concern and is characterised by both apoptotic and necrotic cell death in the lesion. Anatomical imaging is usually used to assess traumatic brain injuries and there is a need for imaging modalities that provide complementary cellular information. We sought to non-invasively image cell death in a mouse model of traumatic brain injury using a near-infrared fluorescent conjugate of a synthetic heat shock protein-90 alkylator, 4-(N-(S-glutathionylacetyl) amino) phenylarsonous acid (GSAO). GSAO labels both apoptotic and necrotic cells coincident with loss of plasma membrane integrity. The optical GSAO specifically labelled apoptotic and necrotic cells in culture and did not accumulate in healthy organs or tissues in the living mouse body. The conjugate is a very effective imager of cell death in brain lesions. The optical GSAO was detected by fluorescence intensity and GSAO bound to dying/dead cells was detected from prolongation of the fluorescence lifetime. An optimal signal-to-background ratio was achieved as early as 3 h after injection of the probe and the signal intensity positively correlated with both lesion size and probe concentration. This optical GSAO offers a convenient and robust means to non-invasively image apoptotic and necrotic cell death in brain and other lesions. PMID:23348587

Diagnosis of brain death by transcranial Doppler sonography.

PubMed

Bode, H; Sauer, M; Pringsheim, W

1988-12-01

The blood flow velocities in the basal cerebral arteries can be recorded at any age by transcranial Doppler sonography. We examined nine children with either initial or developing clinical signs of brain death. Soon after successful resuscitation increased diastolic flow velocities indicated a probable decrease in cerebrovascular resistance; this was of no particular prognostic importance. As soon as there was a clinical deterioration, there was a reduction in flow velocities with retrograde flow during early diastole, probably due to an increase in cerebrovascular resistance; this indicated a doubtful prognosis. In eight of the nine children with clinical signs of brain death a typical reverberating flow pattern was found, which was characterised by a counterbalancing short forward flow in systole and a short retrograde flow in early diastole. This indicated arrest of cerebral blood flow. One newborn showed normal systolic and end diastolic flow velocities in the basal cerebral arteries for two days despite clinical and electroencephalographic signs of brain death. Shunting of blood through the circle of Willis without effective cerebral perfusion may explain this phenomenon. No patient had the typical reverberating flow pattern without being clinically brain dead. Transcranial Doppler sonography is a reliable technique, which can be used at the bedside for the confirmation or the exclusion of brain death in children in addition to the clinical examination.

Diagnosis of brain death by transcranial Doppler sonography.

PubMed Central

Bode, H; Sauer, M; Pringsheim, W

1988-01-01

The blood flow velocities in the basal cerebral arteries can be recorded at any age by transcranial Doppler sonography. We examined nine children with either initial or developing clinical signs of brain death. Soon after successful resuscitation increased diastolic flow velocities indicated a probable decrease in cerebrovascular resistance; this was of no particular prognostic importance. As soon as there was a clinical deterioration, there was a reduction in flow velocities with retrograde flow during early diastole, probably due to an increase in cerebrovascular resistance; this indicated a doubtful prognosis. In eight of the nine children with clinical signs of brain death a typical reverberating flow pattern was found, which was characterised by a counterbalancing short forward flow in systole and a short retrograde flow in early diastole. This indicated arrest of cerebral blood flow. One newborn showed normal systolic and end diastolic flow velocities in the basal cerebral arteries for two days despite clinical and electroencephalographic signs of brain death. Shunting of blood through the circle of Willis without effective cerebral perfusion may explain this phenomenon. No patient had the typical reverberating flow pattern without being clinically brain dead. Transcranial Doppler sonography is a reliable technique, which can be used at the bedside for the confirmation or the exclusion of brain death in children in addition to the clinical examination. PMID:3069052

Neurons have an active glycogen metabolism that contributes to tolerance to hypoxia.

PubMed

Saez, Isabel; Duran, Jordi; Sinadinos, Christopher; Beltran, Antoni; Yanes, Oscar; Tevy, María F; Martínez-Pons, Carlos; Milán, Marco; Guinovart, Joan J

2014-06-01

Glycogen is present in the brain, where it has been found mainly in glial cells but not in neurons. Therefore, all physiologic roles of brain glycogen have been attributed exclusively to astrocytic glycogen. Working with primary cultured neurons, as well as with genetically modified mice and flies, here we report that-against general belief-neurons contain a low but measurable amount of glycogen. Moreover, we also show that these cells express the brain isoform of glycogen phosphorylase, allowing glycogen to be fully metabolized. Most importantly, we show an active neuronal glycogen metabolism that protects cultured neurons from hypoxia-induced death and flies from hypoxia-induced stupor. Our findings change the current view of the role of glycogen in the brain and reveal that endogenous neuronal glycogen metabolism participates in the neuronal tolerance to hypoxic stress.

Neurons have an active glycogen metabolism that contributes to tolerance to hypoxia

PubMed Central

Saez, Isabel; Duran, Jordi; Sinadinos, Christopher; Beltran, Antoni; Yanes, Oscar; Tevy, María F; Martínez-Pons, Carlos; Milán, Marco; Guinovart, Joan J

2014-01-01

Glycogen is present in the brain, where it has been found mainly in glial cells but not in neurons. Therefore, all physiologic roles of brain glycogen have been attributed exclusively to astrocytic glycogen. Working with primary cultured neurons, as well as with genetically modified mice and flies, here we report that—against general belief—neurons contain a low but measurable amount of glycogen. Moreover, we also show that these cells express the brain isoform of glycogen phosphorylase, allowing glycogen to be fully metabolized. Most importantly, we show an active neuronal glycogen metabolism that protects cultured neurons from hypoxia-induced death and flies from hypoxia-induced stupor. Our findings change the current view of the role of glycogen in the brain and reveal that endogenous neuronal glycogen metabolism participates in the neuronal tolerance to hypoxic stress. PMID:24569689

Recent advances in fetal near-infrared spectroscopy

NASA Astrophysics Data System (ADS)

D'Antona, Donato; Aldrich, Clive J.; O'Brien, Patrick; Lawrence, Sally; Delpy, David T.; Wyatt, John S.

1997-01-01

Fetal brain injury resulting from hypoxia and ischemia during labor remains an important cause of death and long- term disability. However, little is known about fetal brain oxygenation and hemodynamics. There are currently no satisfactory clinical techniques for fetal monitoring and there remains a need for a new method to assess brain oxygenation. Fetal near infrared spectroscopy (NIRS) is a new technique that allows noninvasive observation of changes in the cerebral concentrations of oxyhemoglobin and deoxyhemoglobin to be made during labor. A specially designed optical probe is inserted through the dilated cervix and placed against the fetal head. It is then possible to compare changes in NIRS data with other observations of fetal conditions, such as fetal heart rate and acid-base status.

The Effect of Early Detection of Occult Brain Metastases in HER2-Positive Breast Cancer Patients on Survival and Cause of Death

DOE Office of Scientific and Technical Information (OSTI.GOV)

Niwinska, Anna, E-mail: alphaonetau@poczta.onet.p; Tacikowska, Malgorzata; Murawska, Magdalena

2010-07-15

Purpose: The aim of the study is to evaluate disease-free survival, survival from the detection of brain metastases, overall survival, and cause of death in patients with occult brain metastases (Group I) vs. patients with symptomatic brain metastases (Group II). Methods and Materials: In 80 HER2-positive breast cancer patients, treated with trastuzumab and cytostatic agents for metastatic disease, magnetic resonance imaging screening of the brain was performed, and in 29 patients (36%) occult brain metastasis was detected (Group I). Whole-brain radiotherapy was delivered to Group I. This first group was compared with 52 patients who had symptomatic brain metastases (Groupmore » II) and was treated the same way, at the same clinic, during the same time period. Results: Median disease-free survival was 17 months in Group I and 19.9 months in Group II (p = 0.58). The median time interval between the dissemination of the disease and the detection of occult or symptomatic brain metastases was 9 and 15 months, respectively (p = 0.11). When the brain metastases were detected, the median survival was 9 and 8.78 months, respectively (p = 0.80). The median overall survival was 53 and 51 months, respectively (p = 0.94). In the group with occult brain metastases (Group I) 16% of patients died because of progression within the brain. In the group with symptomatic brain metastases (Group II) the rate of cerebral death was 48% (p = 0.009). Conclusions: Whole-brain radiotherapy of occult brain metastases in HER2-positive breast cancer patients with visceral dissemination produces a three-fold decrease in cerebral deaths but does not prolong survival.« less

HIV and Tuberculosis (TB)

MedlinePlus

... or brain. If not treated, TB disease can cause death. HIV weakens the immune system , increasing the risk ... spine, or brain. If not treated, TB can cause death. How does TB spread from person to person? ...

Mortality associated with withdrawal of life-sustaining therapy for patients with severe traumatic brain injury: a Canadian multicentre cohort study

PubMed Central

Turgeon, Alexis F.; Lauzier, François; Simard, Jean-François; Scales, Damon C.; Burns, Karen E.A.; Moore, Lynne; Zygun, David A.; Bernard, Francis; Meade, Maureen O.; Dung, Tran Cong; Ratnapalan, Mohana; Todd, Stephanie; Harlock, John; Fergusson, Dean A.

2011-01-01

Background: Severe traumatic brain injury often leads to death from withdrawal of life-sustaining therapy, although prognosis is difficult to determine. Methods: To evaluate variation in mortality following the withdrawal of life-sustaining therapy and hospital mortality in patients with critical illness and severe traumatic brain injury, we conducted a two-year multicentre retrospective cohort study in six Canadian level-one trauma centres. The effect of centre on hospital mortality and withdrawal of life-sustaining therapy was evaluated using multivariable logistic regression adjusted for baseline patient-level covariates (sex, age, pupillary reactivity and score on the Glasgow coma scale). Results: We randomly selected 720 patients with traumatic brain injury for our study. The overall hospital mortality among these patients was 228/720 (31.7%, 95% confidence interval [CI] 28.4%–35.2%) and ranged from 10.8% to 44.2% across centres (χ2 test for overall difference, p < 0.001). Most deaths (70.2% [160/228], 95% CI 63.9%–75.7%) were associated with withdrawal of life-sustaining therapy, ranging from 45.0% (18/40) to 86.8% (46/53) (χ2 test for overall difference, p < 0.001) across centres. Adjusted odd ratios (ORs) for the effect of centre on hospital mortality ranged from 0.61 to 1.55 (p < 0.001). The incidence of withdrawal of life-sustaining therapy varied by centre, with ORs ranging from 0.42 to 2.40 (p = 0.001). About one half of deaths that occurred following the withdrawal of life-sustaining therapies happened within the first three days of care. Interpretation: We observed significant variation in mortality across centres. This may be explained in part by regional variations in physician, family or community approaches to the withdrawal of life-sustaining therapy. Considering the high proportion of early deaths associated with the withdrawal of life-sustaining therapy and the limited accuracy of current prognostic indicators, caution should be used regarding early withdrawal of life-sustaining therapy following severe traumatic brain injury. PMID:21876014

Care pathways for organ donation after brain death: guidance from available literature?

PubMed

Hoste, Pieter; Vanhaecht, Kris; Ferdinande, Patrick; Rogiers, Xavier; Eeckloo, Kristof; Blot, Stijn; Hoste, Eric; Vogelaers, Dirk; Vandewoude, Koenraad

2016-10-01

A discussion of the literature concerning the impact of care pathways in the complex and by definition multidisciplinary process of organ donation following brain death. Enhancing the quality and safety of organs for transplantation has become a central concern for governmental and professional organizations. At the local hospital level, a donor coordinator can use a range of interventions to improve the donation and procurement process. Care pathways have been proven to represent an effective intervention in several settings for optimizing processes and outcomes. A discussion paper. A systematic review of the Medline, CINAHL, EMBASE and The Cochrane Library databases was conducted for articles published until June 2015, using the keywords donation after brain death and care pathways. Each paper was reviewed to investigate the effects of existing care pathways for donation after brain death. An additional search for unpublished information was conducted. Although literature supports care pathways as an effective intervention in several settings, few studies have explored its use and effectiveness for complex care processes such as donation after brain death. Nurses should be aware of their role in the donation process. Care pathways have the potential to support them, but their effectiveness has been insufficiently explored. Further research should focus on the development and standardization of the clinical content of a care pathway for donation after brain death and the identification of quality indicators. These should be used in a prospective effectiveness assessment of the proposed pathway. © 2016 John Wiley & Sons Ltd.

Redox dynamics of manganese as a mitochondrial life-death switch

PubMed Central

Smith, Matthew Ryan; Fernandes, Jolyn; Go, Young-Mi; Jones, Dean P.

2017-01-01

Sten Orrenius, M.D., Ph.D., pioneered many areas of cellular and molecular toxicology and made seminal contributions to our knowledge of oxidative stress and glutathione (GSH) metabolism, organellar functions and Ca+2-dependent mechanisms of cell death, and mechanisms of apoptosis. On the occasion of his 80th birthday, we summarize current knowledge on redox biology of manganese (Mn) and its role in mechanisms of cell death. Mn is found in all organisms and has critical roles in cell survival and death mechanisms by regulating Mn-containing enzymes such as manganese superoxide dismutase (SOD2) or affecting expression and activity of caspases. Occupational exposures to Mn cause “manganism”, a Parkinson's disease-like condition of neurotoxicity, and experimental studies show that Mn exposure leads to accumulation of Mn in the brain, especially in mitochondria, and neuronal cell death occurs with features of an apoptotic mechanism. Interesting questions are why a ubiquitous metal that is essential for mitochondrial function would accumulate to excessive levels, cause increased H2O2 production and lead to cell death. Is this due to the interactions of Mn with other essential metals, such as iron, or with toxic metals, such as cadmium? Why is the Mn loading in the human brain so variable, and why is there such a narrow window between dietary adequacy and toxicity? Are non-neuronal tissues similarly vulnerable to insufficiency and excess, yet not characterized? We conclude that Mn is an important component of the redox interface between an organism and its environment and warrants detailed studies to understand the role of Mn as a mitochondrial life-death switch. PMID:28212723

Time trends in organ donation after neurologic determination of death: a cohort study

PubMed Central

Kramer, Andreas H.; Baht, Ryan; Doig, Christopher J.

2017-01-01

Background: The cause of brain injury may influence the number of organs that can be procured and transplanted with donation following neurologic determination of death. We investigated whether the distribution of causes responsible for neurologic death has changed over time and, if so, whether this has had an impact on organ quality, transplantation rates and recipient outcomes. Methods: We performed a cohort study involving consecutive brain-dead organ donors in southern Alberta between 2003 and 2014. For each donor, we determined last available measures of organ injury and number of organs transplanted, and compared these variables for various causes of neurologic death. We compared trends to national Canadian data for 2000-2013 (2000-2011 for Quebec). Results: There were 226 brain-dead organ donors over the study period, of whom 100 (44.2%) had anoxic brain injury, 63 (27.9%) had stroke, and 51 (22.6%) had traumatic brain injury. The relative proportion of donors with traumatic brain injury decreased over time (> 30% in 2003-2005 v. 6%-23% in 2012-2014) (p = 0.004), whereas that with anoxic brain injury increased (14%-37% v. 46%-80%, respectively) (p < 0.001). Nationally, the annual number of brain-dead donors with traumatic brain injury decreased from 4.4 to less than 3 per million population between 2000 and 2013, and that with anoxic brain injury increased from 1.1 to 3.1 per million. Donors with anoxic brain injury had higher concentrations of creatinine, alanine aminotransferase and troponin T, and lower PaO2/FIO2 and urine output than donors with other diagnoses. The average number of organs transplanted per donor was 3.6 with anoxic brain injury versus 4.5 with traumatic brain injury or stroke (p = 0.002). Interpretation: Anoxic brain injury has become a leading cause of organ donation after neurologic determination of death in Canada. Organs from donors with anoxic brain injury have a greater degree of injury, and fewer are transplanted. These findings have implications for availability of organs for transplantation in patients with end-stage organ failure. PMID:28401114

Brain death and the historical understanding of bioethics.

PubMed

Belkin, Gary S

2003-07-01

In a 1968 Report, the Ad Hoc Committee of the Harvard Medical School to Examine the Definition of Brain Death promulgated influential criteria for the idea and practice known as "brain death." Before and since the Committee met, brain death has been a focal point of visions and nightmares of medical progress, purpose, and moral authority. Critics of the Committee felt it was deaf to apparently central moral considerations and focused on the self-serving purpose of expanding transplantation. Historical characterizations of the uses and meanings of brain death and the work of the Committee have tended to echo these themes, which means also generally repeating a widely held bioethical self-understanding of how the field appeared-that is, as a necessary antidote of moral expertise. This paper looks at the Committee and finds that historical depictions of it have been skewed by such a bioethical agenda. Entertaining different possibilities as to the motives and historical circumstances behind the Report it famously produced may point to not only different histories of the Committee, but also different perspectives on the historical legacy and role of bioethics as a discourse for addressing anxieties about medicine.

Preventable and Potentially Preventable Traumatic Death Rates in Neurosurgery Department: A Single Center Experience.

PubMed

Ha, Mahnjeong; Kim, Byung Chul; Choi, Seonuoo; Cho, Won Ho; Choi, Hyuk Jin

2016-10-01

Preventable and potentially preventable traumatic death rates is a method to evaluate the preventability of the traumatic deaths in emergency medical department. To evaluate the preventability of the traumatic deaths in patients who were admitted to neurosurgery department, we performed this study. A retrospective review identified 52 patients who admitted to neurosurgery department with severe traumatic brain injuries between 2013 and 2014. Based on radiologic and clinical state at emergency room, each preventability of death was estimated by professional panel discussion. And the final death rates were calculated. The preventable and potentially preventable traumatic death rates was 19.2% in this study. This result is lower than that of the research of 2012, Korean preventable and potentially preventable traumatic death rates. The rate of preventable and potentially preventable traumatic death of operation group is lower than that of conservative treatment group. Also, we confirmed that direct transfer and the time to operation are important to reduce the preventability. We report the preventable and potentially preventable traumatic death rates of our institute for evaluation of preventability in severe traumatic brain injuries during the last 2 years. For decrease of preventable death, we suggest that continuous survey of the death rate of traumatic brain injury patients is required.

Preventable and Potentially Preventable Traumatic Death Rates in Neurosurgery Department: A Single Center Experience

PubMed Central

Ha, Mahnjeong; Kim, Byung Chul; Choi, Seonuoo; Cho, Won Ho

2016-01-01

Objective Preventable and potentially preventable traumatic death rates is a method to evaluate the preventability of the traumatic deaths in emergency medical department. To evaluate the preventability of the traumatic deaths in patients who were admitted to neurosurgery department, we performed this study. Methods A retrospective review identified 52 patients who admitted to neurosurgery department with severe traumatic brain injuries between 2013 and 2014. Based on radiologic and clinical state at emergency room, each preventability of death was estimated by professional panel discussion. And the final death rates were calculated. Results The preventable and potentially preventable traumatic death rates was 19.2% in this study. This result is lower than that of the research of 2012, Korean preventable and potentially preventable traumatic death rates. The rate of preventable and potentially preventable traumatic death of operation group is lower than that of conservative treatment group. Also, we confirmed that direct transfer and the time to operation are important to reduce the preventability. Conclusion We report the preventable and potentially preventable traumatic death rates of our institute for evaluation of preventability in severe traumatic brain injuries during the last 2 years. For decrease of preventable death, we suggest that continuous survey of the death rate of traumatic brain injury patients is required. PMID:27857910

Near-death experience: arising from the borderlands of consciousness in crisis.

PubMed

Nelson, Kevin R

2014-11-01

Brain activity explains the essential features of near-death experience, including the perceptions of envelopment by light, out-of-body, and meeting deceased loved ones or spiritual beings. To achieve their fullest expression, such near-death experiences require a confluence of events and draw upon more than a single physiological or biochemical system, or one anatomical structure. During impaired cerebral blood flow from syncope or cardiac arrest that commonly precedes near-death, the boundary between consciousness and unconsciousness is often indistinct and a person may enter a borderland and be far more aware than is appreciated by others. Consciousness can also come and go if blood flow rises and falls across a crucial threshold. During crisis the brain's prime biologic purpose to keep itself alive lies at the heart of many spiritual experiences and inextricably binds them to the primal brain. Brain ischemia can disrupt the physiological balance between conscious states by leading the brainstem to blend rapid eye movement (REM) and waking into another borderland of consciousness during near-death. Evidence converges from many points to support this notion, including the observation that the majority of people with a near-death experience possess brains predisposed to fusing REM and waking consciousness into an unfamiliar reality, and are as likely to have out-of-body experience while blending REM and waking consciousness as they are to have out-of-body experience during near-death. © 2014 New York Academy of Sciences.

Getting comfortable with near death experiences. Out of one's mind or beyond the brain? The challenge of interpreting near-death experiences.

PubMed

Radin, Dean

2014-01-01

With one exception, near-death experiences (NDEs) may be interpreted as unusual forms of hallucinations associated with the injured or dying brain. The exception involves perceptions described from vantage points outside the body that are later confirmed to be correct and could not have been inferred. Over a century of laboratory studies have investigated whether it is possible in principle for the mind to transcend the physical boundaries of the brain. The cumulative experimental database strongly indicates that it can. It is not clear that this implies the mind is separate from the brain, but it does suggest that a comprehensive explanation for NDEs will require revisions to present scientific assumptions about the brain-mind relationship.

Molecular pathology of brain edema after severe burns in forensic autopsy cases with special regard to the importance of reference gene selection.

PubMed

Wang, Qi; Ishikawa, Takaki; Michiue, Tomomi; Zhu, Bao-Li; Guan, Da-Wei; Maeda, Hitoshi

2013-09-01

Brain edema is believed to be linked to high mortality incidence after severe burns. The present study investigated the molecular pathology of brain damage and responses involving brain edema in forensic autopsy cases of fire fatality (n = 55) compared with sudden cardiac death (n = 11), mechanical asphyxia (n = 13), and non-brain injury cases (n = 22). Postmortem mRNA and immunohistochemical expressions of aquaporins (AQPs), claudin5 (CLDN5), and matrix metalloproteinases (MMPs) were examined. Prolonged deaths due to severe burns showed an increase in brain water content, but relative mRNA quantification, using different normalization methods, showed inconsistent results: in prolonged deaths due to severe burns, higher expression levels were detected for all markers when three previously validated reference genes, PES1, POLR2A, and IPO8, were used for normalization, higher for AQP1 and MMP9 when GAPDH alone was used for normalization and higher for MMP9, but lower for MMP2 when B2M alone was used for normalization. Additionally, when B2M alone was used for normalization, higher expression of AQP4 was detected in acute fire deaths. Furthermore, the expression stability values of these five reference genes calculated by geNorm demonstrated that B2M was the least stable one, followed by GAPDH. In immunostaining, only AQP1 and MMP9 showed differences among the causes of death: they were evident in most prolonged deaths due to severe burns. These findings suggest that systematic analysis of gene expressions using real-time PCR might be a useful procedure in forensic death investigation, and validation of reference genes is crucial.

Enriched Endogenous Omega-3 Fatty Acids in Mice Ameliorate Parenchymal Cell Death After Traumatic Brain Injury.

PubMed

Ren, Huixia; Yang, Zhen; Luo, Chuanming; Zeng, Haitao; Li, Peng; Kang, Jing X; Wan, Jian-Bo; He, Chengwei; Su, Huanxing

2017-07-01

Currently no effective therapies are available for the treatment of traumatic brain injury (TBI). Early intervention that specifically provides neuroprotection is of most importance which profoundly influences the outcome of TBI. In the present study, we adopted a closed-skull mild TBI model to investigate potential roles of omega-3 polyunsaturated fatty acids (ω-3 PUFAs) in protecting against TBI. Using two-photon laser scanning microscopy (2PLSM), parenchymal cell death and reactive oxidative species (ROS) expression were directly observed and recorded after TBI through a thinned skull bone window. Fat-1 mice with high endogenous ω-3 PUFAs significantly inhibited ROS expression and attenuated parenchymal cell death after compression injury during the early injury phase. Elevated generation of glutathione (GSH) and neuroprotectin D1 (NPD1) in the parenchyma of fat-1 mice could be the contributor to the beneficial role of ω-3 PUFAs in TBI. The results of the study suggest that ω-3 PUFAs is an effective neuroprotectant as an early pharmacological intervention for TBI and the information derived from this study may help guide dietary advice for those who are susceptible to repetitive mild TBI.

Tacrine derivatives stimulate human glioma SF295 cell death and alter important proteins related to disease development: An old drug for new targets.

PubMed

Costa Nunes, Fernanda; Silva, Letícia Barros; Winter, Evelyn; Silva, Adny Henrique; de Melo, Leônidas João; Rode, Michele; Martins, Marcos Antônio Pinto; Zanatta, Nilo; Feitosa, Sarah Coelho; Bonacorso, Hélio Gauze; Creczynski-Pasa, Tânia Beatriz

2018-07-01

Glioblastoma is the most common and aggressive glioma, characterized by brain invasion capability. Being very resistant to the current therapies, since even under treatment, surgery, and chemotherapy with temozolomide (TMZ), patients achieve a median survival of one year. In the search for more effective therapies, new molecules have been designed. For nervous system cancers, molecules able to cross the blood-brain barrier are handled with priority. Accordingly, tacrine was chosen for this study and the inclusion of spiro-heterocyclic rings was done in its structure resulting in new compounds. Cytotoxic activity of tacrine derivatives was assayed using glioblastoma cell line (SF295) as well as analyzing cell death mechanism. Increased caspases activities were observed, confirming apoptosis as cell death type. Some derivatives also increased reactive oxygen species formation and decreased the mitochondrial membrane potential. Moreover, compounds acted on several glioblastoma-related proteins including p53, HLA-DR, beta-catenin, Iba-1, MAP2c, Olig-2, and IDH1. Therefore, tacrine derivatives presented promising results for the development of new glioblastoma therapy, particularly to treat those patients resistant to TMZ. Copyright © 2018 Elsevier B.V. All rights reserved.

Acute brain herniation from lead toxicity.

PubMed

Berkowitz, Sheldon; Tarrago, Rod

2006-12-01

A 4-year-old black boy was admitted to the hospital with vomiting, low-grade fever, and dehydration that were thought to be caused by viral gastroenteritis. He proceeded over the next 12 hours to rapidly deteriorate with brain herniation leading to brain death. The ultimate cause of death was found to be acute lead intoxication from a swallowed foreign body.

Hemodynamic resuscitation with arginine vasopressin reduces lung injury after brain death in the transplant donor.

PubMed

Rostron, Anthony J; Avlonitis, Vassilios S; Cork, David M W; Grenade, Danielle S; Kirby, John A; Dark, John H

2008-02-27

The autonomic storm accompanying brain death leads to neurogenic pulmonary edema and triggers development of systemic and pulmonary inflammatory responses. Neurogenic vasoplegia exacerbates the pulmonary injury caused by brain death and primes the lung for ischemia reperfusion injury and primary graft dysfunction in the recipient. Donor resuscitation with norepinephrine ameliorates the inflammatory response to brain death, however norepinephrine has deleterious effects, particularly on the heart. We tested the hypothesis that arginine vasopressin is a suitable alternative to norepinephrine in managing the hypotensive brain dead donor. Brain death was induced in Wistar rats by intracranial balloon inflation. Pulmonary capillary leak was estimated using radioiodinated albumin. Development of pulmonary edema was assessed by measurement of wet and dry lung weights. Cell surface expression of CD11b/CD18 by neutrophils was determined using flow cytometry. Enzyme-linked immunosorbent assays were used to measure the levels of TNFalpha, IL-1beta, CINC-1, and CINC-3 in serum and bronchoalveolar lavage. Quantitative reverse-transcription polymerase chain reaction was used to determine the expression of cytokine mRNA (IL-1beta, CINC-1 and CINC-3) in lung tissue. There was a significant increase in pulmonary capillary permeability, wet/dry lung weight ratios, neutrophil integrin expression and pro-inflammatory cytokines in serum (TNFalpha, IL-1beta, CINC-1 and CINC-3), bronchoalveolar lavage (TNFalpha and IL-1beta) and lung tissue (IL-1beta and CINC-1) in braindead animals compared to controls. Correction of neurogenic hypotension with either arginine vasopressin or norepinephrine limits edema, reduces pulmonary capillary leak, and modulates systemic and pulmonary inflammatory responses to brain death. Arginine vasopressin and norepinephrine are equally effective in treating the hypotensive pulmonary donor in this rodent model.

Organ Transplantation in Iran; Current State and Challenges with a View on Ethical Consideration.

PubMed

Kiani, Mehrzad; Abbasi, Mahmoud; Ahmadi, Mehdi; Salehi, Bahare

2018-03-05

Organ transplantation is a new issue in medical science. It is an important achievement and a sign of the progression and ability of medical centers around the world. Governments, populations, the medical community and people involved in culture, art, and media all have a decisive role in the culture of organ donation, which is the only way to guarantee that the healthy organs of a brain-dead person can continue to work and save the lives of people in need of organ transplantation. The brain death phenomenon and its possible application in organ transplantation, while offering new hope for the salvation of a number of patients, has led to many ethical, cultural, and legal issues. Ethical issues in organ transplantation are very complicated due to many social factors such as religion, culture, and traditions of the affected communities. The ethical and legal points of removing organs from the body of a living or cadaveric source, the definition of brain death, the moral and legal conditions of the donor and the recipient, and the financial relationship between them and many others, are all critical issues in organ transplantation. While there may be no available explicit solution to these issues, they should be rigorously considered by the experts. Efforts to systematically eliminate barriers and solve problems in organ transplantation, can not only reduce the costs of maintaining brain-dead patients and encourage patients that need organ transplantation but can also prevent immoral and illegal activities. In this paper, we have reviewed the most important and current challenges in organ transplantation with a view to the ethical considerations, and we have suggested some strategies to extend it in Iran.

Organ Transplantation in Iran; Current State and Challenges with a View on Ethical Consideration

PubMed Central

Kiani, Mehrzad; Abbasi, Mahmoud

2018-01-01

Organ transplantation is a new issue in medical science. It is an important achievement and a sign of the progression and ability of medical centers around the world. Governments, populations, the medical community and people involved in culture, art, and media all have a decisive role in the culture of organ donation, which is the only way to guarantee that the healthy organs of a brain-dead person can continue to work and save the lives of people in need of organ transplantation. The brain death phenomenon and its possible application in organ transplantation, while offering new hope for the salvation of a number of patients, has led to many ethical, cultural, and legal issues. Ethical issues in organ transplantation are very complicated due to many social factors such as religion, culture, and traditions of the affected communities. The ethical and legal points of removing organs from the body of a living or cadaveric source, the definition of brain death, the moral and legal conditions of the donor and the recipient, and the financial relationship between them and many others, are all critical issues in organ transplantation. While there may be no available explicit solution to these issues, they should be rigorously considered by the experts. Efforts to systematically eliminate barriers and solve problems in organ transplantation, can not only reduce the costs of maintaining brain-dead patients and encourage patients that need organ transplantation but can also prevent immoral and illegal activities. In this paper, we have reviewed the most important and current challenges in organ transplantation with a view to the ethical considerations, and we have suggested some strategies to extend it in Iran. PMID:29510570

Of wholes and parts: A Thomistic refutation of “Brain Death”

PubMed Central

Accad, Michel

2015-01-01

I propose a refutation of the two major arguments that support the concept of “brain death” as an ontological equivalent to death of the human organism. I begin with a critique of the notion that a body part, such as the brain, could act as “integrator” of a whole body. I then proceed with a rebuttal of the argument that destruction of a body part essential for rational operations—such as the brain—necessarily entails that the remaining whole is indisposed to accrue a rational soul. Next, I point to the equivocal use of the terms “alive” or “living” as being at the root of conceptual errors about brain death. I appeal to the Thomistic definition of life and to the hylomorphic concept of “virtual presence” to clarify this confusion. Finally, I show how the Thomistic definition of life supports the traditional criterion for the determination of death. Lay summary: By the mid-1960s, medical technology became available that could keep “alive” the bodies of patients who had sustained complete and irreversible brain injury. The concept of “brain death” emerged to describe such states. Physicians, philosophers, and ethicists then proposed that the state of brain death is equivalent to the state of death traditionally identified by the absence of spontaneous pulse and respiration. This article challenges the major philosophical arguments that have been advanced to draw this equivalence. PMID:26912932

The divided self: near death experiences of resuscitated patients--a review of literature.

PubMed

Cant, Robyn; Cooper, Simon; Chung, Catherine; O'Connor, Margaret

2012-04-01

This paper explores the prevalence of 'near death experience' phenomena associated with a resuscitation event and examines the current state of evidence for causation. Patients' reports of unusual recollections associated with a period of unconsciousness (perceived as approaching death) have fascinated individuals and the medical fraternity. Near death experiences (NDE) are reported in 4-9% of general community members and up to 23% of critical illness patients, although they can occur in healthy individuals who may think they are in peril. One explanation is that paranormal visions that include seeing bright lights, a tunnel and having feelings of peace may be a stage of enlightenment as death approaches. More objective explanations point to neuro-chemical changes in a stressed or dying brain as explanation for nearly all the elements of near death experience. However if this is so, NDE should occur in all patients who are critically ill and near death. In general, patients report positive psychological outcomes after a near death experience. Nurses can support patients during a time of crisis by assisting them and their families to comprehend the experiential event using effective communication and listening skill. Copyright © 2011 Elsevier Ltd. All rights reserved.

Current understanding of neuroinflammation after traumatic brain injury and cell-based therapeutic opportunities.

PubMed

Xiong, Ye; Mahmood, Asim; Chopp, Michael

2018-06-01

Traumatic brain injury (TBI) remains a major cause of death and disability worldwide. Increasing evidence indicates that TBI is an important risk factor for neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and chronic traumatic encephalopathy. Despite improved supportive and rehabilitative care of TBI patients, unfortunately, all late phase clinical trials in TBI have yet to yield a safe and effective neuroprotective treatment. The disappointing clinical trials may be attributed to variability in treatment approaches and heterogeneity of the population of TBI patients as well as a race against time to prevent or reduce inexorable cell death. TBI is not just an acute event but a chronic disease. Among many mechanisms involved in secondary injury after TBI, emerging preclinical studies indicate that posttraumatic prolonged and progressive neuroinflammation is associated with neurodegeneration which may be treatable long after the initiating brain injury. This review provides an overview of recent understanding of neuroinflammation in TBI and preclinical cell-based therapies that target neuroinflammation and promote functional recovery after TBI. Copyright © 2018 Daping Hospital and the Research Institute of Surgery of the Third Military Medical University. Production and hosting by Elsevier B.V. All rights reserved.

D. Alan Shewmon and the PCBE's White Paper on Brain Death: are brain-dead patients dead?

PubMed

Brugger, E Christian

2013-04-01

The December 2008 White Paper (WP) on "Brain Death" published by the President's Council on Bioethics (PCBE) reaffirmed its support for the traditional neurological criteria for human death. It spends considerable time explaining and critiquing what it takes to be the most challenging recent argument opposing the neurological criteria formulated by D. Alan Shewmon, a leading critic of the "whole brain death" standard. The purpose of this essay is to evaluate and critique the PCBE's argument. The essay begins with a brief background on the history of the neurological criteria in the United States and on the preparation of the 2008 WP. After introducing the WP's contents, the essay sets forth Shewmon's challenge to the traditional neurological criteria and the PCBE's reply to Shewmon. The essay concludes by critiquing the WP's novel justification for reaffirming the traditional conclusion, a justification the essay finds wanting.

Death receptors DR6 and TROY regulate brain vascular development.

PubMed

Tam, Stephen J; Richmond, David L; Kaminker, Joshua S; Modrusan, Zora; Martin-McNulty, Baby; Cao, Tim C; Weimer, Robby M; Carano, Richard A D; van Bruggen, Nick; Watts, Ryan J

2012-02-14

Signaling events that regulate central nervous system (CNS) angiogenesis and blood-brain barrier (BBB) formation are only beginning to be elucidated. By evaluating the gene expression profile of mouse vasculature, we identified DR6/TNFRSF21 and TROY/TNFRSF19 as regulators of CNS-specific angiogenesis in both zebrafish and mice. Furthermore, these two death receptors interact both genetically and physically and are required for vascular endothelial growth factor (VEGF)-mediated JNK activation and subsequent human brain endothelial sprouting in vitro. Increasing beta-catenin levels in brain endothelium upregulate DR6 and TROY, indicating that these death receptors are downstream target genes of Wnt/beta-catenin signaling, which has been shown to be required for BBB development. These findings define a role for death receptors DR6 and TROY in CNS-specific vascular development. Copyright © 2012 Elsevier Inc. All rights reserved.

Comparison of outcomes of kidney transplantation from donation after brain death, donation after circulatory death, and donation after brain death followed by circulatory death donors.

PubMed

Chen, Guodong; Wang, Chang; Ko, Dicken Shiu-Chung; Qiu, Jiang; Yuan, Xiaopeng; Han, Ming; Wang, Changxi; He, Xiaoshun; Chen, Lizhong

2017-11-01

There are three categories of deceased donors of kidney transplantation in China, donation after brain death (DBD), donation after circulatory death (DCD), and donation after brain death followed by circulatory death (DBCD) donors. The aim of this study was to compare the outcomes of kidney transplantation from these three categories of deceased donors. We retrospectively reviewed 469 recipients who received deceased kidney transplantation in our hospital from February 2007 to June 2015. The recipients were divided into three groups according to the source of their donor kidneys: DBD, DCD, or DBCD. The primary endpoints were delayed graft function (DGF), graft loss, and patient death. The warm ischemia time was much longer in DCD group compared to DBCD group (18.4 minutes vs 12.9 minutes, P < .001). DGF rate was higher in DCD group than in DBD and DBCD groups (22.5% vs 10.2% and 13.8%, respectively, P = .021). Urinary leakage was much higher in DCD group (P = .049). Kaplan-Meier analysis showed that 1-, 2-, and 3-year patient survivals were all comparable among the three groups. DBCD kidney transplantation has lower incidences of DGF and urinary leakage than DCD kidney transplant. However, the overall patient and graft survival were comparable among DBD, DCD, and DBCD kidney transplantation. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Audit of practice in sudden unexpected death in epilepsy (SUDEP) post mortems and neuropathological findings

PubMed Central

Michalak, Zuzanna; Wright, Gabriella; Dawson, Timothy; Hilton, David; Joshi, Abhijit; Diehl, Beate; Koepp, Matthias; Lhatoo, Samden; Sander, Josemir W.; Sisodiya, Sanjay M.

2015-01-01

Aims Sudden unexpected death in epilepsy (SUDEP) is one of the leading causes of death in people with epilepsy. For classification of definite SUDEP, a post mortem (PM), including anatomical and toxicological examination, is mandatory to exclude other causes of death. We audited PM practice as well as the value of brain examination in SUDEP. Methods We reviewed 145 PM reports in SUDEP cases from four UK neuropathology centres. Data were extracted for clinical epilepsy details, circumstances of death and neuropathological findings. Results Macroscopic brain abnormalities were identified in 52% of cases. Mild brain swelling was present in 28%, and microscopic pathologies relevant to cause or effect of seizures were seen in 89%. Examination based on whole fixed brains (76.6% of all PMs), and systematic regional sampling was associated with higher detection rates of underlying pathology (P < 0.01). Information was more frequently recorded regarding circumstances of death and body position/location than clinical epilepsy history and investigations. Conclusion Our findings support the contribution of examination of the whole fixed brain in SUDEP, with high rates of detection of relevant pathology. Availability of full clinical epilepsy‐related information at the time of PM could potentially further improve detection through targeted tissue sampling. Apart from confirmation of SUDEP, complete neuropathological examination contributes to evaluation of risk factors as well as helping to direct future research into underlying causes. PMID:26300477

Secondary brain injuries in thalamus and hippocampus after focal ischemia caused by mild, transient extradural compression of the somatosensori cortex in the rat.

PubMed

Holmberg, Per; Liljequist, Sture; Wägner, Anna

2009-02-01

The development and distribution of secondary brain lesions, subsequent to ischemic stroke, are of considerable clinical interest but so far only a limited number of studies have investigated the distribution and development of these secondary lesions in detail. In this study, we used an animal model of focal ischemia caused by extradural compression of the sensorimotor cortex. This paradigm of focal ischemia was shown to produce a consistent pattern of secondary lesions located distally from the primary lesion. Functionally the primary brain lesion produced a transient neurological deficit, which was evaluated by daily beam walking tests. Morphological changes were assessed in parallel after the ischemic event using Fluoro-Jade (FJ) staining as a marker of neuronal cell death. Secondary brain lesions were observed in the thalamus as well as in the hippocampus. The first sign of the slowly developing secondary brain lesions was present on day 3 with subsequent lesions being identified until day 16 after the primary ischemia. In addition to the identification of neuronal cell death by the FJ assays, immunostaining for parvalbumin (PA), a marker of GABAergic interneurons, revealed a loss of PA-staining in the pyramidal layer of CA1 on day 3, thus showing a similar time pattern for loss of PA-staining as for the loss of FJ stained cells. Based upon our present results, we suggest that the current animal model of focal ischemia represents a valuable tool for studies concerning the development of secondary remote brain lesions and their association to impaired motor and cognitive functions.

Temporal resolution of misfolded prion protein transport, accumulation, glial activation, and neuronal death in the retinas of mice inoculated with scrapie

USDA-ARS?s Scientific Manuscript database

Currently, there is a lack of pathologic landmarks to describe the progression of prion disease in vivo. The goal of this work was to determine the temporal relationship between the transport of misfolded prion protein from the brain to the retina, the accumulation of PrPSc in the retina, the respon...

Impact of brain death on ischemia/reperfusion injury in liver transplantation.

PubMed

Dziodzio, Tomasz; Biebl, Matthias; Pratschke, Johann

2014-04-01

In liver transplantation, the ischemia/reperfusion injury (IRI) is influenced by factors related to graft quality, organ procurement and the transplant procedure itself. However, in brain-dead donors, the process of death itself also thoroughly affects organ damage through breakdown of the autonomous nervous system and subsequent massive cytokine release. This review highlights the actual knowledge on these proinflammatory effects of brain death on IRI in liver transplantation. Brain death affects IRI either through hemodynamical or molecular effects with proinflammatory activation. Immunological effects are mainly mediated through Kupffer cell activation, leading to TNF-α and TLR4 amplification. Proinflammatory cytokines such as interleukin (IL)-6, IL-10, TNF-β and MIP-1α are released, together with activation of the innate immune system via natural killer cells and natural killer T cells, which promote organ damage and activation of fibrosis. Preprocurement treatment regimens attempt to hamper inflammatory response by the application of methylprednisolone or thymoglobulin to the donor. Selective P-selectin antagonism resulted in improved function in marginal liver grafts. Inhaled nitric oxide was found to reduce apoptosis in liver grafts. Other medications like the immunosuppressant tacrolimus produced conflicting results regarding organ protection. Furthermore, improved organ storage after procurement - such as machine perfusion - can diminish effects of IRI in a clinical setting. Brain death plays a fundamental role in the regulation of molecular markers triggering inflammation and IRI-related tissue damage in liver transplants. Although several treatment options have reached clinical application, to date, the effects of brain death during donor conditioning and organ procurement remain relevant for organ function and survival.

VEGF attenuated increase of outward delayed-rectifier potassium currents in hippocampal neurons induced by focal ischemia via PI3-K pathway.

PubMed

Wu, K W; Yang, P; Li, S S; Liu, C W; Sun, F Y

2015-07-09

We recently indicated that the vascular endothelial growth factor (VEGF) protects neurons against hypoxic death via enhancement of tyrosine phosphorylation of Kv1.2, an isoform of the delayed-rectifier potassium channels through activation of the phosphatidylinositol 3-kinase (PI3-K) signaling pathway. The present study investigated whether VEGF could attenuate ischemia-induced increase of the potassium currents in the hippocampal pyramidal neurons of rats after ischemic injury. Adult male Sprague-Dawley rats were subjected to transient middle cerebral artery occlusion (MCAO) to induce brain ischemia. The whole-cell patch-clamp technique was used to record the potassium currents of hippocampal neurons in brain slices from the ischemically injured brains of the rats 24h after MCAO. We detected that transient MCAO caused a significant increase of voltage-gated potassium currents (Kv) and outward delayed-rectifier potassium currents (IK), but not outward transient potassium currents (IA), in the ipsilateral hippocampus compared with the sham. Moreover, we found that VEGF could acutely, reversibly and voltage-dependently inhibit the ischemia-induced IK increase. This inhibitory effect of VEGF could be completely abolished by wortmannin, an inhibitor of PI3-K. Our data indicate that VEGF attenuates the ischemia-induced increase of IK via activation of the PI3-K signaling pathway. Published by Elsevier Ltd.

Implementation and clinical characteristics of a posttraumatic stress disorder brain collection.

PubMed

Mighdoll, Michelle I; Deep-Soboslay, Amy; Bharadwaj, Rahul A; Cotoia, John A; Benedek, David M; Hyde, Thomas M; Kleinman, Joel E

2018-01-01

A postmortem human brain collection to study posttraumatic stress disorder (PTSD) is critical for uncovering the molecular mechanisms that contribute to this psychiatric disorder. We describe here the PTSD brain collection at the Lieber Institute for Brain Development in Baltimore, Maryland, consisting of postmortem brain donations acquired between 2012 and 2017. Thus far, 87 brains from individuals meeting DSM-5 criteria for PTSD were collected after consent was obtained from legal next-of-kin, and subsequently clinically characterized for molecular studies. PTSD brain donors had high rates of comorbid diagnoses, including depression (62.1%), substance abuse (74.7%), drug-related death (69.0%), and suicide completion (17.2%). PTSD cases were subdivided into two categories: combat-related PTSD (n = 24) and noncombat/domestic PTSD (n = 63). The major differences between the combat-related and domestic PTSD cohorts were sex, drug-related death, and the prevalence of bipolar disorder (BPD) comorbidity. The combat-related group was entirely male, with only one BPD subject (4.2%), and had significantly fewer drug-related deaths (45.8%) in contrast to the domestic group (31.8% male, 36.5% bipolar, and 77.8% drug-related deaths). Medical examiners' offices, particularly in areas with higher military populations, are an excellent source for PTSD brain donations of both combat-related and domestic PTSD. © 2017 Wiley Periodicals, Inc.

Brain Arterial Diameters as a Risk Factor for Vascular Events.

PubMed

Gutierrez, Jose; Cheung, Ken; Bagci, Ahmet; Rundek, Tatjana; Alperin, Noam; Sacco, Ralph L; Wright, Clinton B; Elkind, Mitchell S V

2015-08-06

Arterial luminal diameters are routinely used to assess for vascular disease. Although small diameters are typically considered pathological, arterial dilatation has also been associated with disease. We hypothesize that extreme arterial diameters are biomarkers of the risk of vascular events. Participants in the Northern Manhattan Study who had a time-of-flight magnetic resonance angiography were included in this analysis (N=1034). A global arterial Z-score, called the brain arterial remodeling (BAR) score, was obtained by averaging the measured diameters within each individual. Individuals with a BAR score <-2 SDs were considered to have the smallest diameters, individuals with a BAR score >-2 and <2 SDs had average diameters, and individuals with a BAR score >2 SDs had the largest diameters. All vascular events were recorded prospectively after the brain magnetic resonance imaging. Spline curves and incidence rates were used to test our hypothesis. The association of the BAR score with death (P=0.001), vascular death (P=0.02), any vascular event (P=0.05), and myocardial infarction (P=0.10) was U-shaped except for ischemic stroke (P=0.74). Consequently, incidence rates for death, vascular death, myocardial infarction, and any vascular event were higher in individuals with the largest diameters, whereas individuals with the smallest diameters had a higher incidence of death, vascular death, any vascular event, and ischemic stroke compared with individuals with average diameters. The risk of death, vascular death, and any vascular event increased at both extremes of brain arterial diameters. The pathophysiology linking brain arterial remodeling to systemic vascular events needs further research. © 2015 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

Up-regulation of K{sub ir}2.1 by ER stress facilitates cell death of brain capillary endothelial cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kito, Hiroaki; Yamazaki, Daiju; Department of Biological Chemistry, Kyoto University, Graduate School of Pharmaceutical Sciences, Kyoto

Highlights: {yields} We found that application of endoplasmic reticulum (ER) stress with tunicamycin to brain capillary endothelial cells (BCECs) induced cell death. {yields} The ER stress facilitated the expression of inward rectifier K{sup +} channel (K{sub ir}2.1) and induced sustained membrane hyperpolarization. {yields} The membrane hyperpolarization induced sustained Ca{sup 2+} entry through voltage-independent nonspecific cation channels and consequently facilitated cell death. {yields} The K{sub ir}2.1 up-regulation by ER stress is, at least in part, responsible for cell death of BCECs under pathological conditions. -- Abstract: Brain capillary endothelial cells (BCECs) form blood brain barrier (BBB) to maintain brain homeostasis. Cellmore » turnover of BCECs by the balance of cell proliferation and cell death is critical for maintaining the integrity of BBB. Here we found that stimuli with tunicamycin, endoplasmic reticulum (ER) stress inducer, up-regulated inward rectifier K{sup +} channel (K{sub ir}2.1) and facilitated cell death in t-BBEC117, a cell line derived from bovine BCECs. The activation of K{sub ir} channels contributed to the establishment of deeply negative resting membrane potential in t-BBEC117. The deep resting membrane potential increased the resting intracellular Ca{sup 2+} concentration due to Ca{sup 2+} influx through non-selective cation channels and thereby partly but significantly regulated cell death in t-BBEC117. The present results suggest that the up-regulation of K{sub ir}2.1 is, at least in part, responsible for cell death/cell turnover of BCECs induced by a variety of cellular stresses, particularly ER stress, under pathological conditions.« less

Epidermal Growth Factor Treatment of the Adult Brain Subventricular Zone Leads to Focal Microglia/Macrophage Accumulation and Angiogenesis

PubMed Central

Lindberg, Olle R.; Brederlau, Anke; Kuhn, H. Georg

2014-01-01

Summary One of the major components of the subventricular zone (SVZ) neurogenic niche is the specialized vasculature. The SVZ vasculature is thought to be important in regulating progenitor cell proliferation and migration. Epidermal growth factor (EGF) is a mitogen with a wide range of effects. When stem and progenitor cells in the rat SVZ are treated with EGF, using intracerebroventricular infusion, dysplastic polyps are formed. Upon extended infusion, blood vessels are recruited into the polyps. In the current study we demonstrate how polyps develop through distinct stages leading up to angiogenesis. As polyps progress, microglia/macrophages accumulate in the polyp core concurrent with increasing cell death. Both microglia/macrophage accumulation and cell death peak during angiogenesis and subsequently decline following polyp vascularization. This model of inducible angiogenesis in the SVZ neurogenic niche suggests involvement of microglia/macrophages in acquired angiogenesis and can be used in detail to study angiogenesis in the adult brain. PMID:24749069

Islam, brain death, and transplantation: culture, faith, and jurisprudence.

PubMed

Arbour, Richard; AlGhamdi, Hanan Mesfer Saad; Peters, Linda

2012-01-01

A significant gap exists between availability of organs for transplant and patients with end-stage organ failure for whom organ transplantation is the last treatment option. Reasons for this mismatch include inadequate approach to potential donor families and donor loss as a result of refractory cardiopulmonary instability during and after brainstem herniation. Other reasons include inadequate cultural competence and sensitivity when communicating with potential donor families. Clinicians may not have an understanding of the cultural and religious perspectives of Muslim families of critically ill patients who may be approached about brain death and organ donation. This review analyzes Islamic cultural and religious perspectives on organ donation, transplantation, and brain death, including faith-based directives from Islamic religious authorities, definitions of death in Islam, and communication strategies when discussing brain death and organ donation with Muslim families. Optimal family care and communication are highlighted using case studies and backgrounds illustrating barriers and approaches with Muslim families in the United States and in the Kingdom of Saudi Arabia that can improve cultural competence and family care as well as increase organ availability within the Muslim population and beyond.

POMC Neurons: From Birth to Death

PubMed Central

Toda, Chitoku; Santoro, Anna; Kim, Jung Dae

2017-01-01

The hypothalamus is an evolutionarily conserved brain structure that regulates an organism’s basic functions, such as homeostasis and reproduction. Several hypothalamic nuclei and neuronal circuits have been the focus of many studies to understand their role in regulating these basic functions. Within the hypothalamic neuronal populations, the arcuate melanocortin system plays a major role in controlling homeostatic functions. The arcuate pro-opiomelanocortin (POMC) neurons in particular have been shown to be critical regulators of metabolism and reproduction because of their projections to several brain areas both in and outside of the hypothalamus, such as autonomic regions of the brain stem and spinal cord. Here, we review and discuss the current understanding of POMC neurons from their development and intracellular regulators to their physiological functions and pathological dysregulation. PMID:28192062

Histological quantification of brain tissue inflammatory cell infiltration after focal cerebral infarction: a systematic review.

PubMed

Russek, Natanya S; Jensen, Matthew B

2014-03-01

Ischemic stroke is a leading cause of death and disability, and current treatments to limit tissue injury and improve recovery are limited. Cerebral infarction is accompanied by intense brain tissue inflammation involving many inflammatory cell types that may cause both negative and positive effects on outcomes. Many potential neuroprotective and neurorestorative treatments may affect, and be affected by, this inflammatory cell infiltration, so that accurate quantification of this tissue response is needed. We performed a systematic review of histological methods to quantify brain tissue inflammatory cell infiltration after cerebral infarction. We found reports of multiple techniques to quantify different inflammatory cell types. We found no direct comparison studies and conclude that more research is needed to optimize the assessment of this important stroke outcome.

Genetic Approaches to Reveal the Connectivity of Adult-Born Neurons

PubMed Central

Arenkiel, Benjamin R.

2011-01-01

Much has been learned about the environmental and molecular factors that influence the division, migration, and programmed cell death of adult-born neurons in the mammalian brain. However, detailed knowledge of the mechanisms that govern the formation and maintenance of functional circuit connectivity via adult neurogenesis remains elusive. Recent advances in genetic technologies now afford the ability to precisely target discrete brain tissues, neuronal subtypes, and even single neurons for vital reporter expression and controlled activity manipulations. Here, I review current viral tracing methods, heterologous receptor expression systems, and optogenetic technologies that hold promise toward elucidating the wiring diagrams and circuit properties of adult-born neurons. PMID:21519388

Pathophysiology, treatment, and animal and cellular models of human ischemic stroke

PubMed Central

2011-01-01

Stroke is the world's second leading cause of mortality, with a high incidence of severe morbidity in surviving victims. There are currently relatively few treatment options available to minimize tissue death following a stroke. As such, there is a pressing need to explore, at a molecular, cellular, tissue, and whole body level, the mechanisms leading to damage and death of CNS tissue following an ischemic brain event. This review explores the etiology and pathogenesis of ischemic stroke, and provides a general model of such. The pathophysiology of cerebral ischemic injury is explained, and experimental animal models of global and focal ischemic stroke, and in vitro cellular stroke models, are described in detail along with experimental strategies to analyze the injuries. In particular, the technical aspects of these stroke models are assessed and critically evaluated, along with detailed descriptions of the current best-practice murine models of ischemic stroke. Finally, we review preclinical studies using different strategies in experimental models, followed by an evaluation of results of recent, and failed attempts of neuroprotection in human clinical trials. We also explore new and emerging approaches for the prevention and treatment of stroke. In this regard, we note that single-target drug therapies for stroke therapy, have thus far universally failed in clinical trials. The need to investigate new targets for stroke treatments, which have pleiotropic therapeutic effects in the brain, is explored as an alternate strategy, and some such possible targets are elaborated. Developing therapeutic treatments for ischemic stroke is an intrinsically difficult endeavour. The heterogeneity of the causes, the anatomical complexity of the brain, and the practicalities of the victim receiving both timely and effective treatment, conspire against developing effective drug therapies. This should in no way be a disincentive to research, but instead, a clarion call to intensify efforts to ameliorate suffering and death from this common health catastrophe. This review aims to summarize both the present experimental and clinical state-of-the art, and to guide future research directions. PMID:21266064

Letter: Can Islamic Jurisprudence Justify Procurement of Transplantable Vital Organs in Brain Death?

PubMed

Rady, Mohamed Y

2018-01-01

In their article, "An International Legal Review of the Relationship between Brain Death and Organ Transplantation," in The Journal of Clinical Ethics 29, no. 1, Aramesh, Arima, Gardiner, and Shah reported on diverse international legislative approaches for justifying procurement of transplantable vital organs in brain death. They stated, "In Islamic traditions in particular, the notion of unstable life is a way to justify organ donation from brain-dead patients that we believe has not been fully described previously in the literature." This commentary queries the extent to which this concept is valid in accordance with the primary source of Islamic law, that is, the Quran. Copyright 2018 The Journal of Clinical Ethics. All rights reserved.

Hypoglycemia-Induced Changes in the Electroencephalogram

PubMed Central

Blaabjerg, Lykke; Juhl, Claus B.

2016-01-01

Hypoglycemia is defined by an abnormally low blood glucose level. The condition develops when rates of glucose entry into the systematic circulation are reduced relative to the glucose uptake by the tissues. A cardinal manifestation of hypoglycemia arises from inadequate supply of glucose to the brain, where glucose is the primary metabolic fuel. The brain is one of the first organs to be affected by hypoglycemia. Shortage of glucose in the brain, or neuroglycopenia, results in a gradual loss of cognitive functions causing slower reaction time, blurred speech, loss of consciousness, seizures, and ultimately death, as the hypoglycemia progresses. The electrical activity in the brain represents the metabolic state of the brain cells and can be measured by electroencephalography (EEG). An association between hypoglycemia and changes in the EEG has been demonstrated, although blood glucose levels alone do not seem to predict neuroglycopenia. This review provides an overview of the current literature regarding changes in the EEG during episodes of low blood glucose. PMID:27464753

Transplantation of donor hearts after circulatory or brain death in a rat model.

PubMed

Li, Shiliang; Loganathan, Sivakkanan; Korkmaz, Sevil; Radovits, Tamás; Hegedűs, Peter; Zhou, Yan; Karck, Matthias; Szabó, Gábor

2015-05-01

Heart transplantation represents the only curative treatment for end-stage heart failure. Presently, the donor pool is restricted to brain-dead donors. Based on the lack of suitable donors and the increasing number of patients, we investigated some molecular pathomechanisms of the potential use of hearts after circulatory determination of death (DCDD) in transplantation. Rats were either maintained brain death for 5 h by inflation of a subdurally placed balloon catheter (n = 6) or subjected to cardiac arrest by exsanguinations (n = 6). Additionally, a control group was used (n = 9). Then the hearts were perfused with a cold preservation solution (Custodiol), explanted, stored at 4°C in Custodiol, and heterotopically transplanted. Brain death was associated with decreased left-ventricular contractility (dP/dtmax: 4895 ± 505 versus 8037 ± 565 mm Hg/s; ejection fraction: 27 ± 5 versus 44 ± 5%; Emax: 2.2 ± 0.3 versus 4.2 ± 0.3 mm Hg/μL; preload recruitable stroke work: 59 ± 5 versus 96 ± 6 mm Hg; 5 h after brain death versus before brain death; P < 0.05) and impaired cardiac relaxation (dP/dtmin: -4734 ± 575 versus -9404 ± 550 mm Hg/s and prolonged Tau, P < 0.05) compared with controls. After transplantation, significantly decreased systolic function and prolonged Tau were observed in brain-dead and DCDD groups compared with those in controls. Tumor necrosis factor-alpha, cyclooxygenase-2, nuclear factor-κB, inducible-NOS, and caspase-3 messenger RNA and protein-levels were significantly increased in the brain-dead compared with both control and DCDD groups. Additionally, marked myocardial inflammatory cell infiltration, edema, necrosis, and DNA-strand breaks were observed in the brain-dead group. Our results show that despite the similar functional outcome in DCDD and brain-dead groups, brain-dead hearts showed marked myocardial inflammatory cell infiltration, edema, necrosis, DNA-strand breaks, and increased transcriptional and posttranscriptional expression for markers of apoptosis and inflammatory signaling pathways. Copyright © 2015 Elsevier Inc. All rights reserved.

5-HTTLPR moderates the association between interdependence and brain responses to mortality threats.

PubMed

Luo, Siyang; Yu, Dian; Han, Shihui

2017-12-01

While behavioral research suggests an association between cultural worldview and decreased anxiety of death, the underlying neurobiological mechanisms remain unclear. Using functional MRI, we investigated whether and how the serotonin transporter promoter polymorphism (5-HTTLPR), which has been associated with mental disorders such as anxiety and depression, moderates the associations between a cultural trait (i.e., interdependence) and self-report of death anxiety/depression and between interdependence and brain responses to mortality threats. Long/long and short/short allele carriers of the 5-HTTLPR were scanned using fMRI while they performed a one-back task on death-related, death-unrelated negative, and neutral words. Participants' interdependence and death anxiety/depression were assessed using questionnaires after scanning. We found that participants who assessed themselves with greater interdependence reported lower death anxiety/depression and showed decreased neural response to death-related words in emotion-related brain regions including the anterior cingulate, putamen, and thalamus. However, these results were evident in long/long allele carriers of the 5-HTTLPR but not in short/short allele carriers who even showed positive associations between interdependence and neural activities in the anterior cingulate, putamen and thalamus in response to death-related words. Our findings suggest candidate mechanisms for explaining the complex relationship between genotype, cultural traits, and mental/neural responses to mortality threats. Hum Brain Mapp 38:6157-6171, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Whole brain analysis of postmortem density changes of grey and white matter on computed tomography by statistical parametric mapping.

PubMed

Nishiyama, Yuichi; Kanayama, Hidekazu; Mori, Hiroshi; Tada, Keiji; Yamamoto, Yasushi; Katsube, Takashi; Takeshita, Haruo; Kawakami, Kazunori; Kitagaki, Hajime

2017-06-01

This study examined the usefulness of statistical parametric mapping (SPM) for investigating postmortem changes on brain computed tomography (CT). This retrospective study included 128 patients (23 - 100 years old) without cerebral abnormalities who underwent unenhanced brain CT before and after death. The antemortem CT (AMCT) scans and postmortem CT (PMCT) scans were spatially normalized using our original brain CT template, and postmortem changes of CT values (in Hounsfield units; HU) were analysed by the SPM technique. Compared with AMCT scans, 58.6 % and 98.4 % of PMCT scans showed loss of the cerebral sulci and an unclear grey matter (GM)-white matter (WM) interface, respectively. SPM analysis revealed a significant decrease in cortical GM density within 70 min after death on PMCT scans, suggesting cytotoxic brain oedema. Furthermore, there was a significant increase in the density of the WM, lenticular nucleus and thalamus more than 120 min after death. The SPM technique demonstrated typical postmortem changes on brain CT scans, and revealed that the unclear GM-WM interface on early PMCT scans is caused by a rapid decrease in cortical GM density combined with a delayed increase in WM density. SPM may be useful for assessment of whole brain postmortem changes. • The original brain CT template achieved successful normalization of brain morphology. • Postmortem changes in the brain were independent of sex. • Cortical GM density decreased rapidly after death. • WM and deep GM densities increased following cortical GM density change. • SPM could be useful for assessment of whole brain postmortem changes.

Audit of practice in sudden unexpected death in epilepsy (SUDEP) post mortems and neuropathological findings.

PubMed

Thom, Maria; Michalak, Zuzanna; Wright, Gabriella; Dawson, Timothy; Hilton, David; Joshi, Abhijit; Diehl, Beate; Koepp, Matthias; Lhatoo, Samden; Sander, Josemir W; Sisodiya, Sanjay M

2016-08-01

Sudden unexpected death in epilepsy (SUDEP) is one of the leading causes of death in people with epilepsy. For classification of definite SUDEP, a post mortem (PM), including anatomical and toxicological examination, is mandatory to exclude other causes of death. We audited PM practice as well as the value of brain examination in SUDEP. We reviewed 145 PM reports in SUDEP cases from four UK neuropathology centres. Data were extracted for clinical epilepsy details, circumstances of death and neuropathological findings. Macroscopic brain abnormalities were identified in 52% of cases. Mild brain swelling was present in 28%, and microscopic pathologies relevant to cause or effect of seizures were seen in 89%. Examination based on whole fixed brains (76.6% of all PMs), and systematic regional sampling was associated with higher detection rates of underlying pathology (P < 0.01). Information was more frequently recorded regarding circumstances of death and body position/location than clinical epilepsy history and investigations. Our findings support the contribution of examination of the whole fixed brain in SUDEP, with high rates of detection of relevant pathology. Availability of full clinical epilepsy-related information at the time of PM could potentially further improve detection through targeted tissue sampling. Apart from confirmation of SUDEP, complete neuropathological examination contributes to evaluation of risk factors as well as helping to direct future research into underlying causes. © 2015 The Authors. Neuropathology and Applied Neurobiology published by John Wiley & Sons Ltd on behalf of British Neuropathological Society.

Traumatic Brain and Spinal Cord Fatalities Among High School and College Football Players - United States, 2005-2014.

PubMed

Kucera, Kristen L; Yau, Rebecca K; Register-Mihalik, Johna; Marshall, Stephen W; Thomas, Leah C; Wolf, Susanne; Cantu, Robert C; Mueller, Frederick O; Guskiewicz, Kevin M

2017-01-06

An estimated 1.1 million high school and 75,000 college athletes participate in tackle football annually in the United States. Football is a collision sport; traumatic injuries are frequent (1,2), and can be fatal (3). This report updates the incidence and characteristics of deaths caused by traumatic brain injury and spinal cord injury (4) in high school and college football and presents illustrative case descriptions. Information was analyzed from the National Center for Catastrophic Sport Injury Research (NCCSIR). During 2005-2014, a total of 28 deaths (2.8 deaths per year) from traumatic brain and spinal cord injuries occurred among high school (24 deaths) and college football players (four deaths) combined. Most deaths occurred during competitions and resulted from tackling or being tackled. All four of the college deaths and 14 (58%) of the 24 high school deaths occurred during the last 5 years (2010-2014) of the 10-year study period. These findings support the need for continued surveillance and safety efforts (particularly during competition) to ensure proper tackling techniques, emergency planning for severe injuries, availability of medical care onsite during competitions, and assessment that it is safe to return to play following a concussion.

A consideration of the ethics of brain death--what are the ethical guidelines for physician, family and society in dealing with brain death?

PubMed

Brooks, C M

1985-06-01

There is at present considerable confusion with respect to ethical guidelines that should govern the behavior of society and the physician confronted by problems resulting from recent attainments of medicine and science. The use of life supporting devices raises the problem of determining when death has occurred and what is proper ethical procedure in dealing with the deficient half life caused by "Brain Death." Some guidance is obtained from a consideration of the nature of life, the nature of death, the nature of man, and the essence lost in death of man. A parallel consideration of the nature of ethics, the bases of ethics and of ethical decision can be helpful. An individual may have ideals which control behavior, even elevate ethical standards; others entertain concepts that destroy social ethics. Ethics control and direct social interactions; ethics determine the quality of social behavior--ethics are established by societies not by individuals. Numerous commissions have endeavored to define the requirements of physicians for diagnosing brain death and for appropriate subsequent actions. The rationales presented, however, are not invariably accepted by lay society. The problem is created by numerous trends. Among them are the "rightest" movement which, though possessing many virtues, has its excesses such as expressed in the "right to life movement." These have not been beneficial and have necessitated "right to death movements." Opposition is also due to the fact that society's concepts of the medical profession have changed. The practice of organ transplantation has created problems. Finally, the concept of death as other than evil is no longer generally accepted. As more biological manipulations are possible ever more difficult ethical problems will arise. It is a certainty, however, that when brain death has occurred life of man and that of the individual has ended. Although others might not agree, our ethic requires us to use life assist techniques to preserve the vegetative man, the individual who can still breathe spontaneously though lacking consciousness and behavioral ability. All the codes of medical ethics state that a physician shall not kill--this does not mean he cannot permit the terminal phases of death when the essence of human life is lost. A major question is the ethical responsibility of one society toward another. Can an affluent society squander its resources in the preservation of ineffectual life in the body after "brain death" when others are without the medical assistance which would permit total living?

Effectiveness of a nonpenetrating captive bolt for euthanasia of 3 kg to 9 kg pigs.

PubMed

Casey-Trott, T M; Millman, S T; Turner, P V; Nykamp, S G; Lawlis, P C; Widowski, T M

2014-11-01

The objective of this study was to determine the effectiveness of a nonpenetrating captive bolt, Zephyr-E, for euthanasia of suckling and weaned pigs from 3 to 9 kg (5-49 d of age) using signs of insensibility and death as well as postmortem assessment of traumatic brain injury (TBI). The Zephyr-E was used by 15 stock people to euthanize 150 compromised pigs from 4 farrowing and nursery units from commercial farms and 2 research stations. Brainstem reflexes, convulsions, and heartbeat were used to assess insensibility, time of brain death, and cardiac arrest following Zephyr-E application. Skull fracture displacement (FD) was quantified from computed tomography (CT) scans (n = 24), macroscopic scoring was used to assess brain hemorrhage and skull fracture severity (n = 150), and microscopic scoring was used to assess subdural hemorrhage (SDH) and parenchymal hemorrhage within specific brain regions that are responsible for consciousness and vital function (n = 32). The Zephyr-E caused immediate, sustained insensibility until death in 98.6% of pigs. On average, clonic convulsions (CC) ceased in 82.2 s (± 3.4 SE), brain death was achieved in 144.9 s (± 5.4 SE), and cardiac arrest occurred in 226.5 s (± 8.7 SE). Time of brain death and cardiac arrest differed significantly among stock people (P = 0.0225 and P = 0.0369). Age was positively related to the duration of CC (P = 0.0092), time of brain death (P = 0.0025), and cardiac arrest (P = 0.0068) with shorter durations seen in younger pigs. Average FD was 8.3 mm (± 1.0 SE). Macroscopic scores were significantly different among weight classes for subcutaneous (P = 0.0402) and subdural-ventral (P = 0.0037) hemorrhage with the lowest severity hemorrhage found in the 9-kg weight category. Microscopic scores differed among brain sections (P = 0.0070) for SDH with lower scores found in the brainstem compared to the cerebral cortex and midbrain. Parenchymal hemorrhage differed among brain sections (P = 0.0052) and weight categories (P = 0.0128) with the lowest scores in the midbrain and brainstem and the 7- and 9-kg weight categories. The Zephyr-E was highly effective for the euthanasia of pigs up to 9 kg (49 d) based on immediate insensibility sustained until death. Postmortem results confirmed that severe skull fracture and widespread brain hemorrhage were caused by the Zephyr-E nonpenetrating captive bolt.

Attitudes to brain death and organ procurement among university students and critical care physicians in poland.

PubMed

Kubler, A; Lipinska-Gediga, M; Kedziora, J; Kubler, M

2009-06-01

The practice of retrieving vital organs from brain-dead heart-beating donors is legally and medically accepted in Poland, but public beliefs and opinions regarding these matters have not been sufficiently explored. The purpose of this study was to evaluate the attitude of university students to the concepts of brain death and organ retrieval, compared with the attitude of critical care physicians. The cohorts of 989 students and 139 physicians completed a questionnaire based on a survey instrument developed in an earlier reported study on Ohio residents. Participants assessed 3 scenarios: (1) brain death, (2) coma, and (3) vegetative state. More than 48% of students classified the patient from the brain death scenario as alive, and 51% of them were willing to donate organs of this patient. Ninety percent of students classified the patients in coma and in a vegetative state as alive, but still 34% of them would donate organs of those patients. The group of physicians properly determined the patients' diagnoses, but 10% of them accepted organ procurement from patients in coma and in a vegetative state. Our results supported the earlier observations of low public knowledge and inadequate understanding of brain death criteria and organ procurement processes. The majority of students were willing to accept organ procurement from severely ill but alive patients, in contrast with physicians. A considerable increase in public educational activity in this field is urgently recommended.

Comparison of water-based foam and inert-gas mass emergency depopulation methods.

PubMed

Alphin, R L; Rankin, M K; Johnson, K J; Benson, E R

2010-03-01

Current control strategies for avian influenza (AI) and other highly contagious poultry diseases include surveillance, quarantine, depopulation, disposal, and decontamination. Selection of the best method of emergency mass depopulation involves maximizing human health and safety while minimizing disease spread and animal welfare concerns. Proper selection must ensure that the method is compatible with the species, age, housing type, and disposal options. No one single method is appropriate for all situations. Gassing is one of the accepted methods for euthanatizing poultry. Whole-house, partial-house, or containerized gassing procedures are currently used. The use of water-based foam was developed for emergency mass depopulation and was conditionally approved by the United States Department of Agriculture in 2006. Research has been done comparing these different methods; parameters such as time to brain death, consistency of time to brain death, and pretreatment and posttreatment corticosterone stress levels were considered. In Europe, the use of foam with carbon dioxide is preferred over conventional water-based foam. A recent experiment comparing CO2 gas, foam with CO2 gas, and foam without CO2 gas depopulation methods was conducted with the use of electroencephalometry results. Foam was as consistent as CO2 gassing and more consistent than argon-CO2 gassing. There were no statistically significant differences between foam methods.

Simulation-based training in brain death determination.

PubMed

MacDougall, Benjamin J; Robinson, Jennifer D; Kappus, Liana; Sudikoff, Stephanie N; Greer, David M

2014-12-01

Despite straightforward guidelines on brain death determination by the American Academy of Neurology (AAN), substantial practice variability exists internationally, between states, and among institutions. We created a simulation-based training course on proper determination based on the AAN practice parameters to address and assess knowledge and practice gaps at our institution. Our intervention consisted of a didactic course and a simulation exercise, and was bookended by before and after multiple-choice tests. The 40-min didactic course, including a video demonstration, covered all aspects of the brain death examination. Simulation sessions utilized a SimMan 3G manikin and involved a complete examination, including an apnea test. Possible confounders and signs incompatible with brain death were embedded throughout. Facilitators evaluated performance with a 26-point checklist based on the most recent AAN guidelines. A senior neurologist conducted all aspects of the course, including the didactic session, simulation, and debriefing session. Ninety physicians from multiple specialties have participated in the didactic session, 38 of whom have completed the simulation. Pre-test scores were poor (41.4 %), with attendings scoring higher than residents (46.6 vs. 40.4 %, p = 0.07), and neurologists and neurosurgeons significantly outperforming other specialists (53.9 vs. 38.9 %, p = 0.003). Post-test scores (73.3 %) were notably higher than pre-test scores (45.4 %). Participant feedback has been uniformly positive. Baseline knowledge of brain death determination among providers was low but improved greatly after the course. Our intervention represents an effective model that can be replicated at other institutions to train clinicians in the determination of brain death according to evidence-based guidelines.

Mechanical versus humoral determinants of brain death-induced lung injury

PubMed Central

Dewachter, Laurence; Rorive, Sandrine; Remmelink, Myriam; Weynand, Birgit; Melot, Christian; Hupkens, Emeline; Dewachter, Céline; Creteur, Jacques; Mc Entee, Kathleen; Naeije, Robert; Rondelet, Benoît

2017-01-01

Background The mechanisms of brain death (BD)-induced lung injury remain incompletely understood, as uncertainties persist about time-course and relative importance of mechanical and humoral perturbations. Methods Brain death was induced by slow intracranial blood infusion in anesthetized pigs after randomization to placebo (n = 11) or to methylprednisolone (n = 8) to inhibit the expression of pro-inflammatory mediators. Pulmonary artery pressure (PAP), wedged PAP (PAWP), pulmonary vascular resistance (PVR) and effective pulmonary capillary pressure (PCP) were measured 1 and 5 hours after Cushing reflex. Lung tissue was sampled to determine gene expressions of cytokines and oxidative stress molecules, and pathologically score lung injury. Results Intracranial hypertension caused a transient increase in blood pressure followed, after brain death was diagnosed, by persistent increases in PAP, PCP and the venous component of PVR, while PAWP did not change. Arterial PO2/fraction of inspired O2 (PaO2/FiO2) decreased. Brain death was associated with an accumulation of neutrophils and an increased apoptotic rate in lung tissue together with increased pro-inflammatory interleukin (IL)-6/IL-10 ratio and increased heme oxygenase(HO)-1 and hypoxia inducible factor(HIF)-1 alpha expression. Blood expressions of IL-6 and IL-1β were also increased. Methylprednisolone pre-treatment was associated with a blunting of increased PCP and PVR venous component, which returned to baseline 5 hours after BD, and partially corrected lung tissue biological perturbations. PaO2/FiO2 was inversely correlated to PCP and lung injury score. Conclusions Brain death-induced lung injury may be best explained by an initial excessive increase in pulmonary capillary pressure with increased pulmonary venous resistance, and was associated with lung activation of inflammatory apoptotic processes which were partially prevented by methylprednisolone. PMID:28753621

Frequency and Type of Situational Awareness Errors Contributing to Death and Brain Damage: A Closed Claims Analysis.

PubMed

Schulz, Christian M; Burden, Amanda; Posner, Karen L; Mincer, Shawn L; Steadman, Randolph; Wagner, Klaus J; Domino, Karen B

2017-08-01

Situational awareness errors may play an important role in the genesis of patient harm. The authors examined closed anesthesia malpractice claims for death or brain damage to determine the frequency and type of situational awareness errors. Surgical and procedural anesthesia death and brain damage claims in the Anesthesia Closed Claims Project database were analyzed. Situational awareness error was defined as failure to perceive relevant clinical information, failure to comprehend the meaning of available information, or failure to project, anticipate, or plan. Patient and case characteristics, primary damaging events, and anesthesia payments in claims with situational awareness errors were compared to other death and brain damage claims from 2002 to 2013. Anesthesiologist situational awareness errors contributed to death or brain damage in 198 of 266 claims (74%). Respiratory system damaging events were more common in claims with situational awareness errors (56%) than other claims (21%, P < 0.001). The most common specific respiratory events in error claims were inadequate oxygenation or ventilation (24%), difficult intubation (11%), and aspiration (10%). Payments were made in 85% of situational awareness error claims compared to 46% in other claims (P = 0.001), with no significant difference in payment size. Among 198 claims with anesthesia situational awareness error, perception errors were most common (42%), whereas comprehension errors (29%) and projection errors (29%) were relatively less common. Situational awareness error definitions were operationalized for reliable application to real-world anesthesia cases. Situational awareness errors may have contributed to catastrophic outcomes in three quarters of recent anesthesia malpractice claims.Situational awareness errors resulting in death or brain damage remain prevalent causes of malpractice claims in the 21st century.

A Case Report of Successful Kidney Donation After Brain Death Following Nicotine Intoxication.

PubMed

Räsänen, M; Helanterä, I; Kalliomäki, J; Savikko, J; Parry, M; Lempinen, M

Nicotine intoxication is a rare cause of death and can lead to brain death after respiratory arrest and hypoxic-ischemic encephalopathy. To our knowledge, no previous reports regarding organ donation after nicotine intoxication have been described. We present a successful case of kidney donation after brain death caused by subcutaneous nicotine overdose from liquid nicotine from an e-cigarette cartridge in an attempted suicide. Both kidneys were transplanted successfully with immediate graft function, and both recipients were discharged at postoperative day 9 with normal plasma creatinine levels. Graft function has remained excellent in follow-up. This case suggests that kidneys from a donor with fatal nicotine intoxication may be successfully used for kidney transplantation in the absence of other contraindications for donation. Copyright © 2016 Elsevier Inc. All rights reserved.

Proteomic analysis of differentially expressed proteins in kidneys of brain dead rabbits

PubMed Central

Li, Ling; Li, Ning; He, Chongxiang; Huang, Wei; Fan, Xiaoli; Zhong, Zibiao; Wang, Yanfeng; Ye, Qifa

2017-01-01

A large number of previous clinical studies have reported a delayed graft function for brain dead donors, when compared with living relatives or cadaveric organ transplantations. However, there is no accurate method for the quality evaluation of kidneys from brain-dead donors. In the present study, two-dimensional gel electrophoresis and MALDI-TOF MS-based comparative proteomic analysis were conducted to profile the differentially-expressed proteins between brain death and the control group renal tissues. A total of 40 age- and sex-matched rabbits were randomly divided into donation following brain death (DBD) and control groups. Following the induction of brain death via intracranial progressive pressure, the renal function and the morphological alterations were measured 2, 6 and 8 h afterwards. The differentially expressed proteins were detected from renal histological evidence at 6 h following brain death. Although 904±19 protein spots in control groups and 916±25 in DBD groups were identified in the two-dimensional gel electrophoresis, >2-fold alterations were identified by MALDI-TOF MS and searched by NCBI database. The authors successfully acquired five downregulated proteins, these were: Prohibitin (isoform CRA_b), beta-1,3-N-acetylgalactosaminyltransferase 1, Annexin A5, superoxide dismutase (mitochondrial) and cytochrome b-c1 complex subunit 1 (mitochondrial precursor). Conversely, the other five upregulated proteins were: PRP38 pre-mRNA processing factor 38 (yeast) domain containing A, calcineurin subunit B type 1, V-type proton ATPase subunit G 1, NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 10 and peroxiredoxin-3 (mitochondrial). Immunohistochemical results revealed that the expressions of prohibitin (PHB) were gradually increased in a time-dependent manner. The results indicated that there were alterations in levels of several proteins in the kidneys of those with brain death, even if the primary function and the morphological changes were not obvious. PHB may therefore be a novel biomarker for primary quality evaluation of kidneys from brain-dead donors. PMID:28534953

Roles of inflammation and apoptosis in experimental brain death-induced right ventricular failure.

PubMed

Belhaj, Asmae; Dewachter, Laurence; Rorive, Sandrine; Remmelink, Myriam; Weynand, Birgit; Melot, Christian; Galanti, Laurence; Hupkens, Emeline; Sprockeels, Thomas; Dewachter, Céline; Creteur, Jacques; McEntee, Kathleen; Naeije, Robert; Rondelet, Benoît

2016-12-01

Right ventricular (RV) dysfunction remains the leading cause of early death after cardiac transplantation. Methylprednisolone is used to improve graft quality; however, evidence for that remains empirical. We sought to determine whether methylprednisolone, acting on inflammation and apoptosis, might prevent brain death-induced RV dysfunction. After randomization to placebo (n = 11) or to methylprednisolone (n = 8; 15 mg/kg), 19 pigs were assigned to a brain-death procedure. The animals underwent hemodynamic evaluation at 1 and 5 hours after Cushing reflex (i.e., hypertension and bradycardia). The animals euthanized, and myocardial tissue was sampled. This was repeated in a control group (n = 8). At 5 hours after the Cushing reflex, brain death resulted in increased pulmonary artery pressure (27 ± 2 vs 18 ± 1 mm Hg) and in a 30% decreased ratio of end-systolic to pulmonary arterial elastances (Ees/Ea). Cardiac output and right atrial pressure did not change. This was prevented by methylprednisolone. Brain death-induced RV dysfunction was associated with increased RV expression of heme oxygenase-1, interleukin (IL)-6, IL-10, IL-1β, tumor necrosis factor (TNF)-α, IL-1 receptor-like (ST)-2, signal transducer and activator of transcription-3, intercellular adhesion molecules-1 and -2, vascular cell adhesion molecule-1, and neutrophil infiltration, whereas IL-33 expression decreased. RV apoptosis was confirmed by terminal deoxynucleotide transferase-mediated deoxy uridine triphosphate nick-end labeling staining. Methylprednisolone pre-treatment prevented RV-arterial uncoupling and decreased RV expression of TNF-α, IL-1 receptor-like-2, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and neutrophil infiltration. RV Ees/Ea was inversely correlated to RV TNF-α and IL-6 expression. Brain death-induced RV dysfunction is associated with RV activation of inflammation and apoptosis and is partly limited by methylprednisolone. Copyright © 2016 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

PD-1 immune checkpoint blockade promotes brain leukocyte infiltration and diminishes cyst burden in a mouse model of Toxoplasma infection.

PubMed

Xiao, Jianchun; Li, Ye; Yolken, Robert H; Viscidi, Raphael P

2018-06-15

Tissue cysts, the hallmark of chronic Toxoplasma gondii infection, are predominantly located in the brain making clearance of the parasite difficult. Currently available anti-T. gondii drugs are ineffective on cysts and fail to prevent reactivation of latent toxoplasmosis. We examined whether abrogation of inhibitory signaling pathways that maintain T cells in an exhausted state can be exploited for treating T. gondii tissue cysts. By using a mouse model of chronic toxoplasmosis, we showed immune checkpoint blockade directed against the programmed death-1 (PD-1) pathway results in a significant reduction in brain cyst number (77% lower). We showed leukocyte infiltration (CD3+ T cells, CD8+ T cells, and CD11b + cells) in the leptomeninges, choroid plexus, and subependymal tissue, which are known routes of entry of immune cells into the brain, and in proximal brain parenchyma. Our study provides proof of concept for blockade of immune checkpoint inhibitors as a therapy for chronic toxoplasmosis and potentially for other brain pathogens. Copyright © 2018 Elsevier B.V. All rights reserved.

Integrated But Not Whole? Applying an Ontological Account of Human Organismal Unity to the Brain Death Debate.

PubMed

Moschella, Melissa

2016-10-01

As is clear in the 2008 report of the President's Council on Bioethics, the brain death debate is plagued by ambiguity in the use of such key terms as 'integration' and 'wholeness'. Addressing this problem, I offer a plausible ontological account of organismal unity drawing on the work of Hoffman and Rosenkrantz, and then apply that account to the case of brain death, concluding that a brain dead body lacks the unity proper to a human organism, and has therefore undergone a substantial change. I also show how my view can explain hard cases better than one in which biological integration (as understood by Alan Shewmon and the President's Council) is taken to imply ontological wholeness or unity. © 2016 John Wiley & Sons Ltd.

Brain protection by methylprednisolone in rats with spinal cord injury.

PubMed

Chang, Chia-Mao; Lee, Ming-Hsueh; Wang, Ting-Chung; Weng, Hsu-Huei; Chung, Chiu-Yen; Yang, Jen-Tsung

2009-07-01

Traumatic spinal cord injury is clinically treated by high doses of methylprednisolone. However, the effect of methylprednisolone on the brain in spinal cord injury patients has been little investigated. This experimental study examined Bcl-2 and Bax protein expression and Nissl staining to evaluate an apoptosis-related intracellular signaling event and final neuron death, respectively. Spinal cord injury produced a significant apoptotic change and cell death not only in the spinal cord but also in the supraventricular cortex and hippocampal cornu ammonis 1 region in the rat brains. The treatment of methylprednisolone increased the Bcl-2/Bax ratio and prevented neuron death for 1-7 days after spinal cord injury. These findings suggest that rats with spinal cord injury show ascending brain injury that could be restricted through methylprednisolone management.

Individual choice in the definition of death.

PubMed

Bagheri, A

2007-03-01

While there are numerous doubts, controversies and lack of consensus on alternative definitions of human death, it is argued that it is more ethical to allow people to choose either cessation of cardio-respiratory function or loss of entire brain function as the definition of death based on their own views. This paper presents the law of organ transplantation in Japan, which allows people to decide whether brain death can be used to determine their death in agreement with their family. Arguably, Japan could become a unique example of individual choice in the definition of death if the law is revised to allow individuals choose definition of death independently of their family. It suggests that such an approach is one of the reasonable policy options a country can adopt for legislation on issues related to the definition of death.

Abandoning the dead donor rule? A national survey of public views on death and organ donation

PubMed Central

Nair-Collins, Michael; Green, Sydney R; Sutin, Angelina R

2015-01-01

Brain dead organ donors are the principal source of transplantable organs. However, it is controversial whether brain death is the same as biological death. Therefore, it is unclear whether organ removal in brain death is consistent with the ‘dead donor rule’, which states that organ removal must not cause death. Our aim was to evaluate the public's opinion about organ removal if explicitly described as causing the death of a donor in irreversible apneic coma. We conducted a cross-sectional internet survey of the American public (n=1096). Questionnaire domains included opinions about a hypothetical scenario of organ removal described as causing the death of a patient in irreversible coma, and items measuring willingness to donate organs after death. Some 71% of the sample agreed that it should be legal for patients to donate organs in the scenario described and 67% agreed that they would want to donate organs in a similar situation. Of the 85% of the sample who agreed that they were willing to donate organs after death, 76% agreed that they would donate in the scenario of irreversible coma with organ removal causing death. There appears to be public support for organ donation in a scenario explicitly described as violating the dead donor rule. Further, most but not all people who would agree to donate when organ removal is described as occurring after death would also agree to donate when organ removal is described as causing death in irreversible coma. PMID:25260779

Serum levels of S100B from jugular bulb as a biomarker of poor prognosis in patients with severe acute brain injury.

PubMed

Ballesteros, María A; Rubio-Lopez, María I; San Martín, María; Padilla, Ana; López-Hoyos, Marcos; Llorca, Javier; Miñambres, Eduardo

2018-02-15

To evaluate the correlation between protein S100B concentrations measured in the jugular bulb as well as at peripheral level and the prognostic usefulness of this marker. A prospective study of all patients admitted to the intensive care unit with acute brain damage was carried out. Peripheral and jugular bulb blood samples were collected upon admission and every 24h for three days. The endpoints were brain death diagnosis and the Glasgow Outcome Scale score after 6months. A total of 83 patients were included. Jugular protein S100B levels were greater than systemic levels upon admission and also after 24 and 72h (mean difference>0). Jugular protein S100B levels showed acceptable precision in predicting brain death both upon admission [AUC 0.67 (95% CI 0.53-0.80)] and after 48h [AUC 0.73 (95% CI 0.57-0.89)]. Similar results were obtained regarding the capacity of jugular protein S100B levels upon admission to predict an unfavourable outcome (AUC 0.69 (95% CI 0.56-0.79)). The gradient upon admission (jugular-peripheral levels) showed its capacity to predict the development of brain death [AUC 0.74 (95% CI 0.62-0.86)] and together with the Glasgow Coma Scale constituted the independent factors associated with the development of brain death. Regional protein S100B determinations are higher than systemic determinations, thus confirming the cerebral origin of protein S100B. The transcranial protein S100B gradient is correlated to the development of brain death. Copyright © 2017. Published by Elsevier B.V.

Therapeutic targeting of oxygen-sensing prolyl hydroxylases abrogates ATF4-dependent neuronal death and improves outcomes after brain hemorrhage in several rodent models

PubMed Central

Karuppagounder, Saravanan S.; Alim, Ishraq; Khim, Soah J.; Bourassa, Megan W.; Sleiman, Sama F.; John, Roseleen; Thinnes, Cyrille C.; Yeh, Tzu-Lan; Demetriades, Marina; Neitemeier, Sandra; Cruz, Dana; Gazaryan, Irina; Killilea, David W.; Morgenstern, Lewis; Xi, Guohua; Keep, Richard F.; Schallert, Timothy; Tappero, Ryan V.; Zhong, Jian; Cho, Sunghee; Maxfield, Frederick R.; Holman, Theodore R.; Culmsee, Carsten; Fong, Guo-Hua; Su, Yijing; Ming, Guo-li; Song, Hongjun; Cave, John W.; Schofield, Christopher J.; Colbourne, Frederick; Coppola, Giovanni; Ratan, Rajiv R.

2017-01-01

Disability or death due to intracerebral hemorrhage (ICH) is attributed to blood lysis, liberation of iron, and consequent oxidative stress. Iron chelators bind to free iron and prevent neuronal death induced by oxidative stress and disability due to ICH, but the mechanisms for this effect remain unclear. We show that the hypoxia-inducible factor prolyl hydroxylase domain (HIF-PHD) family of iron-dependent, oxygen-sensing enzymes are effectors of iron chelation. Molecular reduction of the three HIF-PHD enzyme isoforms in the mouse striatum improved functional recovery after ICH. A low-molecular-weight hydroxyquinoline inhibitor of the HIF-PHD enzymes, adaptaquin, reduced neuronal death and behavioral deficits after ICH in several rodent models without affecting total iron or zinc distribution in the brain. Unexpectedly, protection from oxidative death in vitro or from ICH in vivo by adaptaquin was associated with suppression of activity of the prodeath factor ATF4 rather than activation of an HIF-dependent prosurvival pathway. Together, these findings demonstrate that brain-specific inactivation of the HIF-PHD metalloenzymes with the blood-brain barrier-permeable inhibitor adaptaquin can improve functional outcomes after ICH in several rodent models. PMID:26936506

Near-death experiences: the experience of the self as real and not as an illusion.

PubMed

van Lommel, Pim

2011-10-01

Because the publication of several prospective studies on near-death experience (NDE) in survivors of cardiac arrest have shown strikingly similar results and conclusions, the phenomenon of the NDE can no longer be scientifically ignored. The NDE is an authentic experience that cannot be simply reduced to imagination, fear of death, hallucination, psychosis, the use of drugs, or oxygen deficiency. Patients appear to be permanently changed by an NDE during a cardiac arrest of only some minutes' duration. It is a scientific challenge to discuss new hypotheses that could explain the possibility of a clear and enhanced consciousness--with memories, self-identity, cognition, and emotions--during a period of apparent coma. The current materialistic view of the relationship between consciousness and the brain, as held by most physicians, philosophers, and psychologists, seems to be too restricted for a proper understanding of this phenomenon. There are good reasons to assume that our consciousness, with the continuous experience of self, does not always coincide with the functioning of our brain: enhanced or nonlocal consciousness, with unaltered self-identity, apparently can be experienced independently from the lifeless body. People are convinced that the self they experienced during their NDE is a reality and not an illusion. © 2011 New York Academy of Sciences.

Uncontrolled Donation After Circulatory Determination of Death Donors (uDCDDs) as a Source of Lungs for Transplant

PubMed Central

Egan, T. M.; Requard, J. J.

2017-01-01

In April 2014, the American Journal of Transplantation published a report on the first lung transplant in the United States recovered from an uncontrolled donation after circulatory determination of death donor (uDCDD), assessed by ex vivo lung perfusion (EVLP). The article identified logistical and ethical issues related to introduction of lung transplant from uDCDDs. In an open clinical trial, we have Food and Drug Administration and Institutional Review Board approval to transplant lungs recovered from uDCDDs judged suitable after EVLP. Through this project and other experiences with lung recovery from uDCDDs, we have identified solutions to many logistical challenges and have addressed ethical issues surrounding lung transplant from uDCDDs that were mentioned in this case report. Here, we discuss those challenges, including issues related to recovery of other solid organs from uDCDDs. Despite logistical challenges, uDCDDs could solve the critical shortage of lungs for transplant. Furthermore, by avoiding the deleterious impact of brain death and days of positive pressure ventilation, and by using opportunities to treat lungs in the decedent or during EVLP, lungs recovered from uDCDDs may ultimately prove to be better than lungs currently being transplanted from conventional brain-dead organ donors. PMID:25873272

Do Spanish Medical Students Understand the Concept of Brain Death?

PubMed

Ríos, Antonio; López-Navas, A; López-López, A; Gómez, F J; Iriarte, J; Herruzo, R; Blanco, G; Llorca, F J; Asunsolo, A; Sánchez, P; Gutiérrez, P R; Fernández, A; de Jesús, M T; Alarcón, L Martínez; Del Olivo, M; Fuentes, L; Hernández, J R; Virseda, J; Yelamos, J; Bondía, J A; Hernández, A M; Ayala, M A; Ramírez, P; Parrilla, P

2018-03-01

To analyze the level of understanding of the brain death concept among medical students in universities in Spain. This cross-sectional sociological, interdisciplinary, and multicenter study was performed on 9598 medical students in Spain. The sample was stratified by geographical area and academic year. A previously validated self-reported measure of brain death knowledge (questionnaire Proyecto Colaborativo Internacional Donante sobre la Donación y Transplante de Organos) was completed anonymously by students. Respondents completed 9275 surveys for a completion rate of 95.7%. Of those, 67% (n = 6190) of the respondents understood the brain death concept. Of the rest, 28% (n = 2652) did not know what it meant, and the remaining 5% (n = 433) believed that it did not mean that the patient was dead. The variables related to a correct understanding of the concept were: (1) being older ( P < .001), (2) studying at a public university ( P < .001), (3) year of medical school ( P < .001), (4) studying at one of the universities in the south of Spain ( P = .003), (5) having discussed donation and transplantation with the family ( P < .001), (6) having spoken to friends about the matter ( P < .001), (7) a partner's favorable attitude toward donation and transplantation ( P < .001), and (8) religious beliefs ( P < .001). Sixty-seven percent of medical students know the concept of brain death, and knowledge improved as they advanced in their degree.

Early stages of Alzheimer's disease are alarming signs in injury deaths caused by traffic accidents in elderly people (≥60 years of age): A neuropathological study.

PubMed

Wijesinghe, Printha; Gorrie, Catherine; Shankar, S K; Chickabasaviah, Yasha T; Amaratunga, Dhammika; Hulathduwa, Sanjayah; Kumara, K Sunil; Samarasinghe, Kamani; Suh, Yoo-Hun; Steinbusch, H W M; De Silva, K Ranil D

2017-01-01

There is little information available in the literature concerning the contribution of dementia in injury deaths in elderly people (≥60 years). This study was intended to investigate the extent of dementia-related pathologies in the brains of elderly people who died in traffic accidents or by suicide and to compare our findings with age- and sex-matched natural deaths in an elderly population. Autopsy-derived human brain samples from nine injury death victims (5 suicide and 4 traffic accidents) and nine age- and sex-matched natural death victims were screened for neurodegenerative and cerebrovascular pathologies using histopathological and immunohistochemical techniques. For the analysis, Statistical Package for the Social Sciences (SPSS) version 16.0 was used. There was a greater likelihood for Alzheimer's disease (AD)-related changes in the elders who succumbed to traffic accidents (1 out of 4) compared to age- and sex-matched suicides (0 out of 5) or natural deaths (0 out of 9) as assessed by the National Institute on Aging - Alzheimer's Association guidelines. Actual burden of both neurofibrillary tangles (NFTs) and (SPs) was comparatively higher in the brains of traffic accidents, and the mean NFT counts were significantly higher in the region of entorhinal cortex ( P < 0.05). However, associations obtained for other dementia-related pathologies were not statistically important. Our findings suggest that early Alzheimer stages may be a contributing factor to injury deaths caused by traffic accidents in elderly people whereas suicidal brain neuropathologies resembled natural deaths.

Ten Leading Causes of Death and Injury

MedlinePlus

... Brain Injury Violence Prevention Ten Leading Causes of Death and Injury Recommend on Facebook Tweet Share Compartir ... Emergency Departments, United States – 2014 Leading Causes of Death Charts Causes of Death by Age Group 2016 [ ...

The profile of head injuries and traumatic brain injury deaths in Kashmir.

PubMed

Yattoo, Gh; Tabish, Amin

2008-06-21

This study was conducted on patients of head injury admitted through Accident & Emergency Department of Sher-i-Kashmir Institute of Medical Sciences during the year 2004 to determine the number of head injury patients, nature of head injuries, condition at presentation, treatment given in hospital and the outcome of intervention. Traumatic brain injury (TBI) deaths were also studied retrospectively for a period of eight years (1996 to 2003).The traumatic brain injury deaths showed a steady increase in number from year 1996 to 2003 except for 1999 that showed decline in TBI deaths. TBI deaths were highest in age group of 21-30 years (18.8%), followed by 11-20 years age group (17.8%) and 31-40 years (14.3%). The TBI death was more common in males. Maximum number of traumatic brain injury deaths was from rural areas as compared to urban areas.To minimize the morbidity and mortality resulting from head injury there is a need for better maintenance of roads, improvement of road visibility and lighting, proper mechanical maintenance of automobile and other vehicles, rigid enforcement of traffic rules, compulsory wearing of crash helmets by motor cyclist and scooterists and shoulder belt in cars and imparting compulsory road safety education to school children from primary education level. Moreover, appropriate medical care facilities (including trauma centres) need to be established at district level, sub-divisional and block levels to provide prompt and quality care to head injury patients.

Posttraumatic Propofol Neurotoxicity Is Mediated via the Pro-Brain-Derived Neurotrophic Factor-p75 Neurotrophin Receptor Pathway in Adult Mice.

PubMed

Sebastiani, Anne; Granold, Matthias; Ditter, Anja; Sebastiani, Philipp; Gölz, Christina; Pöttker, Bruno; Luh, Clara; Schaible, Eva-Verena; Radyushkin, Konstantin; Timaru-Kast, Ralph; Werner, Christian; Schäfer, Michael K; Engelhard, Kristin; Moosmann, Bernd; Thal, Serge C

2016-02-01

The gamma-aminobutyric acid modulator propofol induces neuronal cell death in healthy immature brains by unbalancing neurotrophin homeostasis via p75 neurotrophin receptor signaling. In adulthood, p75 neurotrophin receptor becomes down-regulated and propofol loses its neurotoxic effect. However, acute brain lesions, such as traumatic brain injury, reactivate developmental-like programs and increase p75 neurotrophin receptor expression, probably to foster reparative processes, which in turn could render the brain sensitive to propofol-mediated neurotoxicity. This study investigates the influence of delayed single-bolus propofol applications at the peak of p75 neurotrophin receptor expression after experimental traumatic brain injury in adult mice. Randomized laboratory animal study. University research laboratory. Adult C57BL/6N and nerve growth factor receptor-deficient mice. Sedation by IV propofol bolus application delayed after controlled cortical impact injury. Propofol sedation at 24 hours after traumatic brain injury increased lesion volume, enhanced calpain-induced αII-spectrin cleavage, and increased cell death in perilesional tissue. Thirty-day postinjury motor function determined by CatWalk (Noldus Information Technology, Wageningen, The Netherlands) gait analysis was significantly impaired in propofol-sedated animals. Propofol enhanced pro-brain-derived neurotrophic factor/brain-derived neurotrophic factor ratio, which aggravates p75 neurotrophin receptor-mediated cell death. Propofol toxicity was abolished both by pharmacologic inhibition of the cell death domain of the p75 neurotrophin receptor (TAT-Pep5) and in mice lacking the extracellular neurotrophin binding site of p75 neurotrophin receptor. This study provides first evidence that propofol sedation after acute brain lesions can have a deleterious impact and implicates a role for the pro-brain-derived neurotrophic factor-p75 neurotrophin receptor pathway. This observation is important as sedation with propofol and other compounds with GABA receptor activity are frequently used in patients with acute brain pathologies to facilitate sedation or surgical and interventional procedures.

Expected Paradigm Shift in Brain Metastases Therapy-Immune Checkpoint Inhibitors.

PubMed

Jindal, Vishal; Gupta, Sorab

2018-01-30

Brain metastasis (BM) is one of the dreadful complications of malignancies. The prognosis after BM is extremely poor and life expectancy is meager. Currently, our treatment modalities are limited to radiotherapy and surgical resection, which also has poor outcomes and leads to various neurological deficits and affects the quality of life of patients. New treatment modality, i.e., immune checkpoint inhibitors, has brought revolution in management of melanoma, renal cancer, and non-small cell lung cancer (NSCLC). Immune checkpoint inhibitors basically enhance the immune response of the body to fight against cancers. Immune response in the brain is highly regulated; therefore, it is challenging to use immune-modulator drugs in BM. The microenvironment of BM is rich in cytotoxic T lymphocytes and which is the target of immune checkpoint inhibitors. Few studies have shown some hope regarding use of immune checkpoint inhibitors in management of BM. It works through inhibiting immune check point gates, i.e., CTLA-4 (cytotoxic T-lymphocyte-associated protein) and PD-1/PD-L1 (programmed cell death protein-1/program death ligand-1). This article explains the basic mechanism of immune check point inhibitors, rationale behind their usage in BM, and some of the clinical studies which have shown the efficacy of immune check point inhibitors in BM.

Brain injury following trial of hypothermia for neonatal hypoxic–ischaemic encephalopathy

PubMed Central

Shankaran, Seetha; Barnes, Patrick D; Hintz, Susan R; Laptook, Abbott R; Zaterka-Baxter, Kristin M; McDonald, Scott A; Ehrenkranz, Richard A; Walsh, Michele C; Tyson, Jon E; Donovan, Edward F; Goldberg, Ronald N; Bara, Rebecca; Das, Abhik; Finer, Neil N; Sanchez, Pablo J; Poindexter, Brenda B; Van Meurs, Krisa P; Carlo, Waldemar A; Stoll, Barbara J; Duara, Shahnaz; Guillet, Ronnie; Higgins, Rosemary D

2013-01-01

Objective The objective of our study was to examine the relationship between brain injury and outcome following neonatal hypoxic–ischaemic encephalopathy treated with hypothermia. Design and patients Neonatal MRI scans were evaluated in the National Institute of Child Health and Human Development (NICHD) randomised controlled trial of whole-body hypothermia and each infant was categorised based upon the pattern of brain injury on the MRI findings. Brain injury patterns were assessed as a marker of death or disability at 18–22 months of age. Results Scans were obtained on 136 of 208 trial participants (65%); 73 in the hypothermia and 63 in the control group. Normal scans were noted in 38 of 73 infants (52%) in the hypothermia group and 22 of 63 infants (35%) in the control group. Infants in the hypothermia group had fewer areas of infarction (12%) compared to infants in the control group (22%). Fifty-one of the 136 infants died or had moderate or severe disability at 18 months. The brain injury pattern correlated with outcome of death or disability and with disability among survivors. Each point increase in the severity of the pattern of brain injury was independently associated with a twofold increase in the odds of death or disability. Conclusions Fewer areas of infarction and a trend towards more normal scans were noted in brain MRI following whole-body hypothermia. Presence of the NICHD pattern of brain injury is a marker of death or moderate or severe disability at 18–22 months following hypothermia for neonatal encephalopathy. PMID:23080477

Brain Death and Human Organismal Integration: A Symposium on the Definition of Death

PubMed Central

Moschella, Melissa

2016-01-01

Does the ability of some brain dead bodies to maintain homeostasis with the help of artificial life support actually imply that those bodies are living human organisms? Or might it be possible that a brain dead body on life support is a mere collection of still-living cells, organs and tissues which can coordinate with one another, but which lack the genuine integration that is the hallmark of a unified human organism as a whole? To foster further study of these difficult and timely questions, a Symposium on the Definition of Death was held at The Catholic University of America in June 2014. The Symposium brought together scholars from a variety of disciplines—law, medicine, biology, philosophy and theology—who all share a commitment to the dead donor rule and to a biological definition of death, but who have differing opinions regarding the validity of neurological criteria for human death. The papers found in this special issue are among the fruits of this Symposium. PMID:27107428

Transcranial Doppler ultrasound in the diagnosis of brain death. Is it useful or does it delay the diagnosis?

PubMed

Escudero, D; Otero, J; Quindós, B; Viña, L

2015-05-01

Transcranial Doppler ultrasound is able to demonstrate cerebral circulatory arrest associated to brain death, being especially useful in sedated patients, or in those in which complete neurological exploration is not possible. Transcranial Doppler ulstrasound is a portable, noninvasive and high-availability technique. Among its limitations, mention must be made of the absence of acoustic windows and false-negative cases. In patients clinically diagnosed with brain death, with open skulls or with anoxia as the cause of death, cerebral blood flow can be observed by ultrasound, since cerebral circulatory arrest is not always synchronized to the clinical diagnosis. The diagnostic rate is therefore time-dependent, and this fact that must be recognized in order to avoid delays in death certification. Despite its limitations, transcranial Doppler ulstrasound helps solve common diagnostic problems, avoids the unnecessary consumption of resources, and can optimize organ harvesting for transplantation. Copyright © 2014 Elsevier España, S.L.U. and SEMICYUC. All rights reserved.

Growth of melanoma brain tumors monitored by photoacoustic microscopy

NASA Astrophysics Data System (ADS)

Staley, Jacob; Grogan, Patrick; Samadi, Abbas K.; Cui, Huizhong; Cohen, Mark S.; Yang, Xinmai

2010-07-01

Melanoma is a primary malignancy that is known to metastasize to the brain and often causes death. The ability to image the growth of brain melanoma in vivo can provide new insights into its evolution and response to therapies. In our study, we use a reflection mode photoacoustic microscopy (PAM) system to detect the growth of melanoma brain tumor in a small animal model. The melanoma tumor cells are implanted in the brain of a mouse at the beginning of the test. Then, PAM is used to scan the region of implantation in the mouse brain, and the growth of the melanoma is monitored until the death of the animal. It is demonstrated that PAM is capable of detecting and monitoring the brain melanoma growth noninvasively in vivo.

Copper brain protein protection against free radical-induced neuronal death: Survival ratio in SH-SY5Y neuroblastoma cell cultures.

PubMed

Deloncle, Roger; Fauconneau, Bernard; Guillard, Olivier; Delaval, José; Lesage, Gérard; Pineau, Alain

2017-01-01

In Creutzfeldt Jakob, Alzheimer and Parkinson diseases, copper metalloproteins such as prion, amyloid protein precursor and α-synuclein are able to protect against free radicals by reduction from cupric Cu +2 to cupreous Cu + . In these pathologies, a regional copper (Cu) brain decrease correlated with an iron, zinc or manganese (Mn) increase has previously been observed, leading to local neuronal death and abnormal deposition of these metalloproteins in β-sheet structures. In this study we demonstrate the protective effect of Cu metalloproteins against deleterious free-radical effects. With neuroblastoma SH-SY5Y cell cultures, we show that bovine brain prion protein in Cu but not Mn form prevents free radical-induced neuronal death. The survival ratio of SH-SY5Y cells has been measured after UV irradiation (free radical production), when the incubating medium is supplemented with bovine brain homogenate in native, Cu or Mn forms. This ratio, about 28% without any addition or with bovine brain protein added in Mn form, increases by as much as 54.73% with addition to the culture medium of native bovine brain protein and by as much as 95.95% if the addition is carried out in cupric form. This protective effect of brain copper protein against free radical-induced neuronal death has been confirmed with Inductively Coupled Plasma Mass Spectrometry Mn and Cu measurement in bovine brain homogenates: respectively lower than detection limit and 9.01μg/g dry weight for native form; lower than detection limit and 825.85μg/g dry weight for Cu-supplemented form and 1.75 and 68.1μg/g dry weight in Mn-supplemented brain homogenate. Copyright © 2016 Elsevier GmbH. All rights reserved.

Neuroprotective effect of p-coumaric acid in mice with cerebral ischemia reperfusion injuries.

PubMed

Sakamula, Romgase; Thong-Asa, Wachiryah

2018-06-01

Cerebral ischemia reperfusion (IR) is associated with neuronal death, which leads to disability and cognitive decline. The pathomechanism occurs because ischemia is exacerbated during the reperfusion period. Neuronal damage susceptibility depends on the affected brain areas and the duration of ischemia. Prevention and supplementation to neurons may help them endure during IR and further benefit them in rehabilitation. We investigated the protective effect of p-coumaric acid (PC) on cerebral IR injuries in mice. We randomly divided 30 male ICR mice into 3 groups of Sham (received vehicle and not induced IR), Control-IR (received vehicle and induced IR) and PC-IR (received 100 mg/kg PC and induced IR). We orally administered vehicle or 100 mg/kg of p-coumaric acid for 2 weeks before inducing the cerebral IR injuries by using 30 min of a bilateral common carotid artery occlusion followed by a 45-min reperfusion. We induced the IR condition in the Control-IR and PC-IR groups but not the Sham group, and only the PC-IR group received p-coumaric acid. After IR induction, we sacrificed all the mice and collected their brain tissues to evaluate their oxidative statuses, whole brain infarctions and vulnerable neuronal deaths. We studied the whole-brain infarction volume by 2, 3, 5-triethyltetrazoliumchloride staining of sections. We performed a histological investigation of the vulnerable neuronal population in the dorsal hippocampus by staining brain sections with 0.1% cresyl violet. The results indicated that IR caused significant increases in calcium and malondialdehyde (MDA) levels, whole brain infarction volume and hippocampal neuronal death. Pretreatment with p-coumaric acid significantly reduced MDA levels, whole-brain infarction volume and hippocampal neuronal death together and increased catalase and superoxide dismutase activities. We conclude here that pretreating animals with p-coumaric acid can prevent IR-induced brain oxidative stress, infarction size and neuronal vulnerability to death in cerebral IR injuries.

Accelerated death rate in population-based cohort of persons with traumatic brain injury.

PubMed

Selassie, Anbesaw W; Cao, Yue; Church, Elizabeth C; Saunders, Lee L; Krause, James

2014-01-01

To determine the influence of preexisting heart, liver, kidney, cancer, stroke, and mental health problems and examine the influence of low socioeconomic status on mortality after discharge from acute care facilities for individuals with traumatic brain injury. Population-based retrospective cohort study of 33695 persons discharged from acute care hospital with traumatic brain injury in South Carolina, 1999-2010. Days elapsing from the dates of injury to death established the survival time (T). Data were censored at the 145th month. Multivariable Cox regression was used to examine the independent effect of the variables on death. Age-adjusted cumulative probability of death for each chronic disease of interest was plotted. By the 70th month of follow-up, rate of death was accelerated from 10-fold for heart diseases to 2.5-fold for mental health problems. Adjusted hazard ratios for diseases of the heart (2.13), liver-renal (3.25), cancer (2.64), neurological diseases and stroke (2.07), diabetes (1.89), hypertension (1.43), and mental health problems (1.59) were highly significant (each with P < .001). Compared with persons with private insurance, the hazard ratio was significantly elevated with Medicaid (1.67), Medicare (1.54), and uninsured (1.27) (each with P < .001). Specific chronic diseases strongly influenced postdischarge mortality after traumatic brain injury. Low socioeconomic status as measured by the type of insurance elevated the risk of death.

Involvement of Programmed Cell Death in Neurotoxicity of Metallic Nanoparticles: Recent Advances and Future Perspectives

NASA Astrophysics Data System (ADS)

Song, Bin; Zhou, Ting; Liu, Jia; Shao, LongQuan

2016-11-01

The widespread application of metallic nanoparticles (NPs) or NP-based products has increased the risk of exposure to NPs in humans. The brain is an important organ that is more susceptible to exogenous stimuli. Moreover, any impairment to the brain is irreversible. Recently, several in vivo studies have found that metallic NPs can be absorbed into the animal body and then translocated into the brain, mainly through the blood-brain barrier and olfactory pathway after systemic administration. Furthermore, metallic NPs can cross the placental barrier to accumulate in the fetal brain, causing developmental neurotoxicity on exposure during pregnancy. Therefore, metallic NPs become a big threat to the brain. However, the mechanisms underlying the neurotoxicity of metallic NPs remain unclear. Programmed cell death (PCD), which is different from necrosis, is defined as active cell death and is regulated by certain genes. PCD can be mainly classified into apoptosis, autophagy, necroptosis, and pyroptosis. It is involved in brain development, neurodegenerative disorders, psychiatric disorders, and brain injury. Given the pivotal role of PCD in neurological functions, we reviewed relevant articles and tried to summarize the recent advances and future perspectives of PCD involvement in the neurotoxicity of metallic NPs, with the purpose of comprehensively understanding the neurotoxic mechanisms of NPs.

Relative brain displacement and deformation during constrained mild frontal head impact.

PubMed

Feng, Y; Abney, T M; Okamoto, R J; Pless, R B; Genin, G M; Bayly, P V

2010-12-06

This study describes the measurement of fields of relative displacement between the brain and the skull in vivo by tagged magnetic resonance imaging and digital image analysis. Motion of the brain relative to the skull occurs during normal activity, but if the head undergoes high accelerations, the resulting large and rapid deformation of neuronal and axonal tissue can lead to long-term disability or death. Mathematical modelling and computer simulation of acceleration-induced traumatic brain injury promise to illuminate the mechanisms of axonal and neuronal pathology, but numerical studies require knowledge of boundary conditions at the brain-skull interface, material properties and experimental data for validation. The current study provides a dense set of displacement measurements in the human brain during mild frontal skull impact constrained to the sagittal plane. Although head motion is dominated by translation, these data show that the brain rotates relative to the skull. For these mild events, characterized by linear decelerations near 1.5g (g = 9.81 m s⁻²) and angular accelerations of 120-140 rad s⁻², relative brain-skull displacements of 2-3 mm are typical; regions of smaller displacements reflect the tethering effects of brain-skull connections. Strain fields exhibit significant areas with maximal principal strains of 5 per cent or greater. These displacement and strain fields illuminate the skull-brain boundary conditions, and can be used to validate simulations of brain biomechanics.

A model to predict progression in brain-injured patients.

PubMed

Tommasino, N; Forteza, D; Godino, M; Mizraji, R; Alvarez, I

2014-11-01

The study of brain death (BD) epidemiology and the acute brain injury (ABI) progression profile is important to improve public health programs, organ procurement strategies, and intensive care unit (ICU) protocols. The purpose of this study was to analyze the ABI progression profile among patients admitted to ICUs with a Glasgow Coma Score (GCS) ≤8, as well as establishing a prediction model of probability of death and BD. This was a retrospective analysis of prospective data that included all brain-injured patients with GCS ≤8 admitted to a total of four public and private ICUs in Uruguay (N = 1447). The independent predictor factors of death and BD were studied using logistic regression analysis. A hierarchical model consisting of 2 nested logit regression models was then created. With these models, the probabilities of death, BD, and death by cardiorespiratory arrest were analyzed. In the first regression, we observed that as the GCS decreased and age increased, the probability of death rose. Each additional year of age increased the probability of death by 0.014. In the second model, however, BD risk decreased with each year of age. The presence of swelling, mass effect, and/or space-occupying lesion increased BD risk for the same given GCS. In the presence of injuries compatible with intracranial hypertension, age behaved as a protective factor that reduced the probability of BD. Based on the analysis of the local epidemiology, a model to predict the probability of death and BD can be developed. The organ potential donation of a country, region, or hospital can be predicted on the basis of this model, customizing it to each specific situation.

Early stages of Alzheimer's disease are alarming signs in injury deaths caused by traffic accidents in elderly people (≥60 years of age): A neuropathological study

PubMed Central

Wijesinghe, Printha; Gorrie, Catherine; Shankar, S. K.; Chickabasaviah, Yasha T.; Amaratunga, Dhammika; Hulathduwa, Sanjayah; Kumara, K. Sunil; Samarasinghe, Kamani; Suh, Yoo-Hun; Steinbusch, H. W. M.; De Silva, K. Ranil D.

2017-01-01

Background: There is little information available in the literature concerning the contribution of dementia in injury deaths in elderly people (≥60 years). Aim: This study was intended to investigate the extent of dementia-related pathologies in the brains of elderly people who died in traffic accidents or by suicide and to compare our findings with age- and sex-matched natural deaths in an elderly population. Materials and Methods: Autopsy-derived human brain samples from nine injury death victims (5 suicide and 4 traffic accidents) and nine age- and sex-matched natural death victims were screened for neurodegenerative and cerebrovascular pathologies using histopathological and immunohistochemical techniques. For the analysis, Statistical Package for the Social Sciences (SPSS) version 16.0 was used. Results: There was a greater likelihood for Alzheimer's disease (AD)-related changes in the elders who succumbed to traffic accidents (1 out of 4) compared to age- and sex-matched suicides (0 out of 5) or natural deaths (0 out of 9) as assessed by the National Institute on Aging – Alzheimer's Association guidelines. Actual burden of both neurofibrillary tangles (NFTs) and (SPs) was comparatively higher in the brains of traffic accidents, and the mean NFT counts were significantly higher in the region of entorhinal cortex (P < 0.05). However, associations obtained for other dementia-related pathologies were not statistically important. Conclusion: Our findings suggest that early Alzheimer stages may be a contributing factor to injury deaths caused by traffic accidents in elderly people whereas suicidal brain neuropathologies resembled natural deaths. PMID:29497190

When organ donation from living donors serves as the main source of organ procurement: a critical examination of the ethical and legal challenges to Turkey's recent efforts to overcome organ shortage.

PubMed

Sert, G; Guven, T; Gorkey, S

2013-01-01

Despite the fact that Turkey has implemented a number of legislative and regulatory efforts to increase cadaveric donations, live donors still serve as the main source of organ procurement in this country. To address this problem, Turkey's regulatory authorities have sought to increase the number of brain death declarations. A new regulation issued in 2012 repeats the criteria for brain death that were first issued in 1993. This paper argues that these efforts are far from adequate owing to a number of complicated, ethical, and legal challenges that must be addressed to increase cadaveric organ donations. After examining these factors, which are completely neglected in current policies, we conclude that Turkey needs a realistic ethically justifiable organ procurement policy that must be supported by a framework of patient rights to implement the concept of patient autonomy and respect for human dignity in health care services as the primary goal. Copyright © 2013 Elsevier Inc. All rights reserved.

Near-death experiences between science and prejudice.

PubMed

Facco, Enrico; Agrillo, Christian

2012-01-01

Science exists to refute dogmas; nevertheless, dogmas may be introduced when undemonstrated scientific axioms lead us to reject facts incompatible with them. Several studies have proposed psychobiological interpretations of near-death experiences (NDEs), claiming that NDEs are a mere byproduct of brain functions gone awry; however, relevant facts incompatible with the ruling physicalist and reductionist stance have been often neglected. The awkward transcendent look of NDEs has deep epistemological implications, which call for: (a) keeping a rigorously neutral position, neither accepting nor refusing anything a priori; and (b) distinguishing facts from speculations and fallacies. Most available psychobiological interpretations remain so far speculations to be demonstrated, while brain disorders and/or drug administration in critical patients yield a well-known delirium in intensive care and anesthesia, the phenomenology of which is different from NDEs. Facts can be only true or false, never paranormal. In this sense, they cannot be refused a priori even when they appear implausible with respect to our current knowledge: any other stance implies the risk of turning knowledge into dogma and the adopted paradigm into a sort of theology.

Near-death experiences between science and prejudice

PubMed Central

Facco, Enrico; Agrillo, Christian

2012-01-01

Science exists to refute dogmas; nevertheless, dogmas may be introduced when undemonstrated scientific axioms lead us to reject facts incompatible with them. Several studies have proposed psychobiological interpretations of near-death experiences (NDEs), claiming that NDEs are a mere byproduct of brain functions gone awry; however, relevant facts incompatible with the ruling physicalist and reductionist stance have been often neglected. The awkward transcendent look of NDEs has deep epistemological implications, which call for: (a) keeping a rigorously neutral position, neither accepting nor refusing anything a priori; and (b) distinguishing facts from speculations and fallacies. Most available psychobiological interpretations remain so far speculations to be demonstrated, while brain disorders and/or drug administration in critical patients yield a well-known delirium in intensive care and anesthesia, the phenomenology of which is different from NDEs. Facts can be only true or false, never paranormal. In this sense, they cannot be refused a priori even when they appear implausible with respect to our current knowledge: any other stance implies the risk of turning knowledge into dogma and the adopted paradigm into a sort of theology. PMID:22826697

Organ donation in adults: a critical care perspective.

PubMed

Citerio, Giuseppe; Cypel, Marcelo; Dobb, Geoff J; Dominguez-Gil, Beatriz; Frontera, Jennifer A; Greer, David M; Manara, Alex R; Shemie, Sam D; Smith, Martin; Valenza, Franco; Wijdicks, Eelco F M

2016-03-01

The shortage of organs for transplantation is an important medical and societal problem because transplantation is often the best therapeutic option for end-stage organ failure. We review the potential deceased organ donation pathways in adult ICU practice, i.e. donation after brain death (DBD) and controlled donation after circulatory death (cDCD), which follows the planned withdrawal of life-sustaining treatments (WLST) and subsequent confirmation of death using cardiorespiratory criteria. Strategies in the ICU to increase the number of organs available for transplantation are discussed. These include timely identification of the potential organ donor, optimization of the brain-dead donor by aggressive management of the physiological consequence of brain death, implementation of cDCD protocols, and the potential for ex vivo perfusion techniques. Organ donation should be offered as a routine component of the end-of-life care plan of every patient dying in the ICU where appropriate, and intensivists are the key professional in this process.

Characteristics of memories for near-death experiences.

PubMed

Moore, Lauren E; Greyson, Bruce

2017-05-01

Near-death experiences are vivid, life-changing experiences occurring to people who come close to death. Because some of their features, such as enhanced cognition despite compromised brain function, challenge our understanding of the mind-brain relationship, the question arises whether near-death experiences are imagined rather than real events. We administered the Memory Characteristics Questionnaire to 122 survivors of a close brush with death who reported near-death experiences. Participants completed Memory Characteristics Questionnaires for three different memories: that of their near-death experience, that of a real event around the same time, and that of an event they had imagined around the same time. The Memory Characteristics Questionnaire score was higher for the memory of the near-death experience than for that of the real event, which in turn was higher than that of the imagined event. These data suggest that memories of near-death experiences are recalled as "realer" than real events or imagined events. Copyright © 2017 Elsevier Inc. All rights reserved.

Autophagy inhibition overcomes multiple mechanisms of resistance to BRAF inhibition in brain tumors

PubMed Central

Mulcahy Levy, Jean M; Zahedi, Shadi; Griesinger, Andrea M; Morin, Andrew; Davies, Kurtis D; Aisner, Dara L; Kleinschmidt-DeMasters, BK; Fitzwalter, Brent E; Goodall, Megan L; Thorburn, Jacqueline; Amani, Vladimir; Donson, Andrew M; Birks, Diane K; Mirsky, David M; Hankinson, Todd C; Handler, Michael H; Green, Adam L; Vibhakar, Rajeev; Foreman, Nicholas K; Thorburn, Andrew

2017-01-01

Kinase inhibitors are effective cancer therapies, but tumors frequently develop resistance. Current strategies to circumvent resistance target the same or parallel pathways. We report here that targeting a completely different process, autophagy, can overcome multiple BRAF inhibitor resistance mechanisms in brain tumors. BRAFV600Emutations occur in many pediatric brain tumors. We previously reported that these tumors are autophagy-dependent and a patient was successfully treated with the autophagy inhibitor chloroquine after failure of the BRAFV600E inhibitor vemurafenib, suggesting autophagy inhibition overcame the kinase inhibitor resistance. We tested this hypothesis in vemurafenib-resistant brain tumors. Genetic and pharmacological autophagy inhibition overcame molecularly distinct resistance mechanisms, inhibited tumor cell growth, and increased cell death. Patients with resistance had favorable clinical responses when chloroquine was added to vemurafenib. This provides a fundamentally different strategy to circumvent multiple mechanisms of kinase inhibitor resistance that could be rapidly tested in clinical trials in patients with BRAFV600E brain tumors. DOI: http://dx.doi.org/10.7554/eLife.19671.001 PMID:28094001

Therapeutic targeting of oxygen-sensing prolyl hydroxylases abrogates ATF4-dependent neuronal death and improves outcomes after brain hemorrhage in several rodent models

DOE PAGES

Karuppagounder, Saravanan S.; Alim, Ishraq; Khim, Soah J.; ...

2016-03-02

Disability or death due to intracerebral hemorrhage (ICH) is attributed to blood lysis, liberation of iron and consequent oxidative stress. Iron chelators bind to free iron and prevent neuronal death induced by oxidative stress and disability due to ICH, but the mechanisms for this effect remain unclear. Here we show that the hypoxia-inducible factor prolyl-hydroxylase (HIF- PHD) family of iron-dependent oxygen sensing enzymes are effectors of iron chelation. Molecular reduction of the three HIF-PHD enzyme isoforms in mouse striatum improved functional recovery following ICH. A low molecular weight hydroxyquinoline inhibitor of the HIF-PHDs, adaptaquin, reduced neuronal death and behavioral deficitsmore » following ICH in several rodent models without affecting total iron or zinc distribution in the brain. Unexpectedly, protection from oxidative death in vitro or from ICH in vivo by adaptaquin was associated with suppression of expression of the prodeath factor ATF4 rather than activation of a HIF-dependent prosurvival pathway. In conclusion, together these findings demonstrate that brain-specific inactivation of the HIF-PHD metalloenzymes with the blood-brain barrier permeable inhibitor adaptaquin can improve functional outcomes following ICH in multiple rodent species.« less

Therapeutic targeting of oxygen-sensing prolyl hydroxylases abrogates ATF4-dependent neuronal death and improves outcomes after brain hemorrhage in several rodent models

DOE Office of Scientific and Technical Information (OSTI.GOV)

Karuppagounder, Saravanan S.; Alim, Ishraq; Khim, Soah J.

Disability or death due to intracerebral hemorrhage (ICH) is attributed to blood lysis, liberation of iron and consequent oxidative stress. Iron chelators bind to free iron and prevent neuronal death induced by oxidative stress and disability due to ICH, but the mechanisms for this effect remain unclear. Here we show that the hypoxia-inducible factor prolyl-hydroxylase (HIF- PHD) family of iron-dependent oxygen sensing enzymes are effectors of iron chelation. Molecular reduction of the three HIF-PHD enzyme isoforms in mouse striatum improved functional recovery following ICH. A low molecular weight hydroxyquinoline inhibitor of the HIF-PHDs, adaptaquin, reduced neuronal death and behavioral deficitsmore » following ICH in several rodent models without affecting total iron or zinc distribution in the brain. Unexpectedly, protection from oxidative death in vitro or from ICH in vivo by adaptaquin was associated with suppression of expression of the prodeath factor ATF4 rather than activation of a HIF-dependent prosurvival pathway. In conclusion, together these findings demonstrate that brain-specific inactivation of the HIF-PHD metalloenzymes with the blood-brain barrier permeable inhibitor adaptaquin can improve functional outcomes following ICH in multiple rodent species.« less

Changes of cerebral blood flow during the secondary expansion of a cortical contusion assessed by 14C-iodoantipyrine autoradiography in mice using a non-invasive protocol.

PubMed

Engel, Doortje C; Mies, Günter; Terpolilli, Nicole A; Trabold, Raimund; Loch, Alexander; De Zeeuw, Chris I; Weber, John T; Maas, Andrew I R; Plesnila, Nikolaus

2008-07-01

Although changes of cerebral blood flow (CBF) in and around traumatic contusions are well documented, the role of CBF for the delayed death of neuronal cells in the traumatic penumbra ultimately resulting in secondary contusion expansion remains unclear. The aim of the current study was therefore to investigate the relationship between changes of CBF and progressive peri-contusional cell death following traumatic brain injury (TBI). CBF and contusion size were measured in C57Bl6 mice under continuous on-line monitoring of (ETp)CO2 before, and at 15 min and 24 h following controlled cortical impact by 14C-iodoantipyrine autoradiography (IAP-AR; n = 5-6 per group) and by Nissl staining, respectively. Contused and ischemic (CBF < 10%) tissue volumes were calculated and compared over time. Cortical CBF in not injured mice varied between 69 and 93 mL/100mg/min depending on the anatomical location. Fifteen minutes after trauma, CBF decreased in the whole brain by approximately 50% (39 +/- 18 mL/100mg/min; p < 0.05), except in contused tissue where it fell by more than 90% (3 +/- 2 mL/100mg/min; p < 0.001). Within 24 h after TBI, CBF recovered to normal values in all brain areas except the contusion where it remained reduced by more than 90% (p < 0.001). Contusion volume expanded from 24.9 to 35.5 mm3 (p < 0.01) from 15 min to 24 h after trauma (+43%), whereas the area of severe ischemia (CBF < 10%) showed only a minimal (+13%) and not significant increase (22.3 to 25.1 mm3). The current data therefore suggest that the delayed secondary expansion of a cortical contusion following traumatic brain injury may not be caused by a reduction of CBF alone.

Recovery from a possible cytomegalovirus meningoencephalitis-induced apparent brain stem death in an immunocompetent man: a case report.

PubMed

Rahardjo, Theresia Monica; Maskoen, Tinni Trihartini; Redjeki, Ike Sri

2016-08-26

Recovery from cytomegalovirus meningoencephalitis with brain stem death in an immunocompetent patient is almost impossible. We present a remarkable recovery from a possible cytomegalovirus infection in an immunocompetent man who had severe neurological syndromes, suggesting brain stem death complicated by pneumonia and pleural effusion. A 19-year-old Asian man presented at our hospital's emergency department with reduced consciousness and seizures following high fever, headache, confusion, and vomitus within a week before arrival. He was intubated and sent to our intensive care unit. He had nuchal rigidity and tetraparesis with accentuated tendon reflexes. Electroencephalography findings suggested an acute structural lesion at his right temporal area or an epileptic state. A cerebral spinal fluid examination suggested viral infection. A computed tomography scan was normal at the early stage of disease. Immunoglobulin M, immunoglobulin G anti-herpes simplex virus, and immunoglobulin M anti-cytomegalovirus were negative. However, immunoglobulin G anti-cytomegalovirus was positive, which supported a diagnosis of cytomegalovirus meningoencephalitis. His clinical condition deteriorated, spontaneous respiration disappeared, cranial reflexes became negative, and brain stem death was suspected. Therapy included antivirals, corticosteroids, antibiotics, anticonvulsant, antipyretics, antifungal agents, and a vasopressor to maintain hemodynamic stability. After 1 month, he showed a vague response to painful stimuli at his supraorbital nerve and respiration started to appear the following week. After pneumonia and pleural effusion were resolved, he was weaned from the ventilator and moved from the intensive care unit on day 90. This case highlights several important issues that should be considered. First, the diagnosis of brain stem death must be confirmed with caution even if there are negative results of brain stem death test for a long period. Second, cytomegalovirus meningoencephalitis should be considered in the differential diagnosis even for an immunocompetent adult. Third, accurate therapy and simultaneous intensive care have very important roles in the recovery process of patients with cytomegalovirus meningoencephalitis.

Usefulness of venous oxygen saturation in the jugular bulb for the diagnosis of brain death: report of 118 patients.

PubMed

Díaz-Regañón, Genaro; Miñambres, Eduardo; Holanda, Marisol; González-Herrera, Segundo; López-Espadas, Francisco; Garrido-Díaz, Carlos

2002-12-01

To assess the usefulness of venous oxygen saturation in the jugular bulb (SjO(2)) as a complementary test for the diagnosis of brain death. Prospective observational study. Polytrauma intensive care unit (ICU) of an acute-care teaching hospital in Santander, Spain. We studied 118 (44%) out of 270 patients with severe head injury and intracranial hemorrhage meeting criteria of brain death (lack of cardiac response to atropine, unresponsive apnea, and iso-electric EEG in the absence of shock, hypotension and treatment with muscle relaxants and/or central nervous system (CNS) depressant drugs). At the moment at which clinical diagnosis of brain death was made and an iso-electric EEG was obtained, simultaneous oxygen saturation in central venous blood (right atrium) (SvO(2)) and jugular venous bulb (SjO(2)) samples was measured. The ratio between SvO(2) and SjO(2), expressed as CvjO(2) (the so-called central venous-jugular bulb oxygen saturation rate; CvjO(2) = SvO(2)/SjO(2)) was calculated. CvjO(2) less than 1 was obtained in 114 patients [mean (SD): 0.89 (0.02)], whereas CvjO(2) greater than 1 was obtained in only 4 (3.38%). In the group of 152 survivors, a single patient was discharged from the ICU in a vegetative state in which CvjO(2) was below 1. CvjO(2)as a complementary test for the diagnosis of brain death showed 96.6% sensitivity, 99.3% specificity, and 99.1% and 97.4% positive and negative predictive values, respectively. Central venous-jugular bulb oxygen saturation rate below 1 together with accepted clinical criteria (unresponsive coma with brainstem areflexia) provides non-invasive assessment of cerebral circulatory arrest that can help to suspect brain death.

Brain endothelial TAK1 and NEMO safeguard the neurovascular unit

PubMed Central

Ridder, Dirk A.; Wenzel, Jan; Müller, Kristin; Töllner, Kathrin; Tong, Xin-Kang; Assmann, Julian C.; Stroobants, Stijn; Weber, Tobias; Niturad, Cristina; Fischer, Lisanne; Lembrich, Beate; Wolburg, Hartwig; Grand’Maison, Marilyn; Papadopoulos, Panayiota; Korpos, Eva; Truchetet, Francois; Rades, Dirk; Sorokin, Lydia M.; Schmidt-Supprian, Marc; Bedell, Barry J.; Pasparakis, Manolis; Balschun, Detlef; D’Hooge, Rudi; Löscher, Wolfgang; Hamel, Edith

2015-01-01

Inactivating mutations of the NF-κB essential modulator (NEMO), a key component of NF-κB signaling, cause the genetic disease incontinentia pigmenti (IP). This leads to severe neurological symptoms, but the mechanisms underlying brain involvement were unclear. Here, we show that selectively deleting Nemo or the upstream kinase Tak1 in brain endothelial cells resulted in death of endothelial cells, a rarefaction of brain microvessels, cerebral hypoperfusion, a disrupted blood–brain barrier (BBB), and epileptic seizures. TAK1 and NEMO protected the BBB by activating the transcription factor NF-κB and stabilizing the tight junction protein occludin. They also prevented brain endothelial cell death in a NF-κB–independent manner by reducing oxidative damage. Our data identify crucial functions of inflammatory TAK1–NEMO signaling in protecting the brain endothelium and maintaining normal brain function, thus explaining the neurological symptoms associated with IP. PMID:26347470

Serpins Promote Cancer Cell Survival and Vascular Cooption in Brain Metastasis

PubMed Central

Valiente, Manuel; Obenauf, Anna C.; Jin, Xin; Chen, Qing; Zhang, Xiang H.-F.; Lee, Derek J.; Chaft, Jamie E.; Kris, Mark G.; Huse, Jason T.; Brogi, Edi; Massagué, Joan

2014-01-01

Brain metastasis is an ominous complication of cancer, yet most cancer cells that infiltrate the brain die of unknown causes. Here we identify plasmin from the reactive brain stroma as a defense against metastatic invasion, and plasminogen activator (PA) inhibitory serpins in cancer cells as a shield against this defense. Plasmin suppresses brain metastasis in two ways: by converting membrane-bound astrocytic FasL into a paracrine death signal for cancer cells, and by inactivating the axon pathfinding molecule L1CAM that metastatic cells express for spreading along brain capillaries and for metastatic outgrowth. Brain metastatic cells from lung cancer and breast cancer express high levels of anti-PA serpins, including neuroserpin and serpin B2, to prevent plasmin generation and its deleterious consequences. By protecting cancer cells from death signals and fostering vascular cooption, anti-PA serpins provide a unifying mechanism for the initiation of brain metastasis in lung and breast cancers. PMID:24581498

Genetic polymorphisms and their association with brain and behavioural measures in heterogeneous stock mice

PubMed Central

Janecka, Magdalena; Marzi, Sarah J.; Parsons, Michael J.; Liu, Lin; Paya-Cano, Jose L.; Smith, Rebecca G.; Fernandes, Cathy; Schalkwyk, Leonard C.

2017-01-01

Although the search for quantitative trait loci for behaviour remains a considerable challenge, the complicated genetic architecture of quantitative traits is beginning to be understood. The current project utilised heterogeneous stock (HS) male mice (n = 580) to investigate the genetic basis for brain weights, activity, anxiety and cognitive phenotypes. We identified 126 single nucleotide polymorphisms (SNPs) in genes involved in regulation of neurotransmitter systems, nerve growth/death and gene expression, and subsequently investigated their associations with changes in behaviour and/or brain weights in our sample. We found significant associations between four SNP-phenotype pairs, after controlling for multiple testing. Specificity protein 2 (Sp2, rs3708840), tryptophan hydroxylase 1 (Tph1, rs262731280) and serotonin receptor 3A (Htr3a, rs50670893) were associated with activity/anxiety behaviours, and microtubule-associated protein 2 (Map2, rs13475902) was associated with cognitive performance. All these genes except for Tph1 were expressed in the brain above the array median, and remained significantly associated with relevant behaviours after controlling for the family structure. Additionally, we found evidence for a correlation between Htr3a expression and activity. We discuss our findings in the light of the advantages and limitations of currently available mouse genetic tools, suggesting further directions for association studies in rodents. PMID:28145470

A clinical comparison of penetrating and blunt traumatic brain injuries.

PubMed

Santiago, Luis A; Oh, Bryan C; Dash, Pramod K; Holcomb, John B; Wade, Charles E

2012-01-01

Traumatic brain injury (TBI) is a leading cause of injury death and long-term disability in the USA. It commonly results from blunt (closed) or penetrating trauma. The majority of civilian TBI is caused by falls or motor vehicle collisions, whereas military TBI mainly results from explosions. Although penetrating injuries are less common than closed injuries in the civilian population, they are far more lethal. Unfortunately, the pathophysiologic differences between penetrating and closed TBI remain poorly understood due to the lack of studies on the subject. Many studies on the prognostic factors of mortality and functional outcome after TBI exclude penetrating brain injuries from their series because they are believed to have a different pathophysiology. 125 Articles regarding brain injury were reviewed and summarized for this report. Despite the absence of a clear delineation between penetrating and blunt TBI, the current guidelines for penetrating TBI suggest defaulting to management strategies used for closed TBI with limited supportive evidence. Thus, injuries that appear to have different pathophysiologies and outcomes are managed equally and perhaps not optimally. In view of the incomplete understanding of the impact of mechanism of injury on TBI outcomes, as demonstrated in the current review, new research studies are required to improve evidence-based TBI guidelines tailored especially for penetrating injuries.

The distribution of apolipoprotein E alleles in Scottish perinatal deaths

PubMed Central

Becher, J‐C; Keeling, J W; McIntosh, N; Wyatt, B; Bell, J

2006-01-01

Background The apolipoprotein E (ApoE) polymorphism has been well studied in the adult human population, in part because the e4 allele is a known risk factor for Alzheimer's disease. Little is known of the distribution of ApoE alleles in newborns, and their association with perinatal brain damage has not been investigated. Methods ApoE genotyping was undertaken in a Scottish cohort of perinatal deaths (n = 261), some of whom had prenatal brain damage. The distribution of ApoE alleles in perinatal deaths was compared with that in healthy liveborn infants and in adults in Scotland. Results ApoE e2 was over‐represented in 251 perinatal deaths (13% v 8% in healthy newborns, odds ratio (OR) = 1.63, 95% confidence interval (CI) 1.13 to 2.36 and 13% v 8% in adults, OR = 1.67, 95% CI 1.16 to 2.41), both in liveborn and stillborn perinatal deaths. In contrast, the prevalence of ApoE e4 was raised in healthy liveborn infants (19%) compared with stillbirths (13%, OR = 1.59, 95% CI 1.11 to 2.26) and with adults (15%, OR = 1.35, 95% CI 1.04 to 1.76). However, no correlation was found between ApoE genotype and the presence or absence of perinatal brain damage. Conclusions This study shows a shift in ApoE allelic distribution in early life compared with adults. The raised prevalence of ApoE e2 associated with perinatal death suggests that this allele is detrimental to pregnancy outcome, whereas ApoE e4 may be less so. However, ApoE genotype did not appear to influence the vulnerability for perinatal hypoxic/ischaemic brain damage, in agreement with findings in adult brains and in animal models. PMID:16183800

Temporal resolution of PrPSc transport, PrPSc accumulation, activation of glia and neuronal death in retinas from C57Bl/6 mice inoculated with RML scrapie: Relevance to biomarkers of prion disease progression

USDA-ARS?s Scientific Manuscript database

Currently, there is a lack of pathologic landmarks to objectively evaluate the progression of prion disease in vivo. The goal of this work was to determine the temporal relationship between transport of misfolded prion protein to the retina from the brain, accumulation of PrPSc in the retina, the re...

The fate of medications evaluated for ischemic stroke pharmacotherapy over the period 1995-2015.

PubMed

Chen, Xiaoling; Wang, Kewei

2016-11-01

Stroke is a brain damage caused by a loss of blood supply to a portion of the brain, which requires prompt and effective treatment. The current pharmacotherapy for ischemic stroke primarily relies on thrombolysis using recombinant tissue plasminogen activators (rt-PAs) to breakdown blood clots. Neuroprotective agents that inhibit excitatory neurotransmitters are also used to treat ischemic stroke but have failed to translate into clinical benefits. This poses a major challenge in biomedical research to understand what causes the progressive brain cell death after stroke and how to develop an effective pharmacotherapy for stroke. This brief review analyzes the fate of about 430 potentially useful stroke medications over the period 1995-2015 and describes in detail those that successfully reached the market. Hopefully, the information from this analysis will shed light on how future stroke research can improve stroke drug discovery.

Therapeutic options to enhance coma arousal after traumatic brain injury: state of the art of current treatments to improve coma recovery.

PubMed

Cossu, Giulia

2014-04-01

Traumatic brain injury is a leading cause of death and disability. Optimizing the recovery from coma is a priority in seeking to improve patients' functional outcomes. Standards of care have not been established: pharmacological interventions, right median nerve and sensory stimulation, dorsal column stimulation (DCS), deep brain stimulation, transcranial magnetic stimulation, hyperbaric oxygen therapy and cell transplantation have all been utilized with contrasting results. The aim of this review is to clarify the indications for the various techniques and to guide the clinical practice towards an earlier coma arousal. A systematic bibliographic search was undertaken using the principal search engines (Pubmed, Embase, Ovid and Cochrane databases) to locate the most pertinent studies. Traumatic injury is a highly individualized process, and subsequent impairments are dependent on multiple factors: this heterogeneity influences and determines therapeutic responses to the various interventions.

Intrapulmonary aquaporin-5 expression as a possible biomarker for discriminating smothering and choking from sudden cardiac death: a pilot study.

PubMed

Wang, Qi; Ishikawa, Takaki; Michiue, Tomomi; Zhu, Bao-Li; Guan, Da-Wei; Maeda, Hitoshi

2012-07-10

The diagnosis of mechanical asphyxia as a cause of death, especially smothering and choking lacking evident injury, is one of the most difficult tasks in forensic pathology. The present study investigated the intrapulmonary expressions of aquaporins (AQPs; AQP-1 and AQP-5), as markers of water homeostasis, in forensic autopsy cases (total n=64, within 48 h postmortem) of mechanical asphyxiation due to neck compression (strangulation, n=24), including manual/ligature strangulation (n=12) and atypical hanging (n=12), smothering (n=7) and choking (n=8), compared with sudden cardiac death (n=14) and acute brain injury (n=11). Quantification of mRNA using a Taqman real-time PCR assay system demonstrated suppressed expression of AQP-5, but not AQP-1, in smothering and choking, compared with that in strangulation as well as sudden cardiac death and acute brain injury death. Immunostaining of AQP-5 was weakly detected in a linear pattern in the type I alveolar epithelial cells in smothering and choking cases, while cardiac and brain injury death showed marked positivity, and most strangulation cases had AQP-5-positive granular aggregates and fragments in intra-alveolar spaces. These observations indicate a partial difference in pulmonary molecular pathology among these causes of death, suggesting a procedure for possible discrimination of smothering and choking from sudden cardiac death. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Blocking NMDA receptors delays death in rats with acute liver failure by dual protective mechanisms in kidney and brain.

PubMed

Cauli, Omar; González-Usano, Alba; Cabrera-Pastor, Andrea; Gimenez-Garzó, Carla; López-Larrubia, Pilar; Ruiz-Sauri, Amparo; Hernández-Rabaza, Vicente; Duszczyk, Malgorzata; Malek, Michal; Lazarewicz, Jerzy W; Carratalá, Arturo; Urios, Amparo; Miguel, Alfonso; Torregrosa, Isidro; Carda, Carmen; Montoliu, Carmina; Felipo, Vicente

2014-06-01

Treatment of patients with acute liver failure (ALF) is unsatisfactory and mortality remains unacceptably high. Blocking NMDA receptors delays or prevents death of rats with ALF. The underlying mechanisms remain unclear. Clarifying these mechanisms will help to design more efficient treatments to increase patient's survival. The aim of this work was to shed light on the mechanisms by which blocking NMDA receptors delays rat's death in ALF. ALF was induced by galactosamine injection. NMDA receptors were blocked by continuous MK-801 administration. Edema and cerebral blood flow were assessed by magnetic resonance. The time course of ammonia levels in brain, muscle, blood, and urine; of glutamine, lactate, and water content in brain; of glomerular filtration rate and kidney damage; and of hepatic encephalopathy (HE) and intracranial pressure was assessed. ALF reduces kidney glomerular filtration rate (GFR) as reflected by reduced inulin clearance. GFR reduction is due to both reduced renal perfusion and kidney tubular damage as reflected by increased Kim-1 in urine and histological analysis. Blocking NMDA receptors delays kidney damage, allowing transient increased GFR and ammonia elimination which delays hyperammonemia and associated changes in brain. Blocking NMDA receptors does not prevent cerebral edema or blood-brain barrier permeability but reduces or prevents changes in cerebral blood flow and brain lactate. The data show that dual protective effects of MK-801 in kidney and brain delay cerebral alterations, HE, intracranial pressure increase and death. NMDA receptors antagonists may increase survival of patients with ALF by providing additional time for liver transplantation or regeneration.

Microdialysis Monitoring in Clinical Traumatic Brain Injury and Its Role in Neuroprotective Drug Development.

PubMed

Thelin, Eric Peter; Carpenter, Keri L H; Hutchinson, Peter J; Helmy, Adel

2017-03-01

Injuries to the central nervous system continue to be vast contributors to morbidity and mortality; specifically, traumatic brain injury (TBI) is the most common cause of death during the first four decades of life. Several modalities are used to monitor patients suffering from TBI in order to prevent detrimental secondary injuries. The microdialysis (MD) technique, introduced during the 1990s, presents the treating physician with a robust monitoring tool for brain chemistry in addition to conventional intracranial pressure monitoring. Nevertheless, some limitations remain, such as limited spatial resolution. Moreover, while there have been several attempts to develop new potential pharmacological therapies in TBI, there are currently no available drugs which have shown clinical efficacy that targets the underlying pathophysiology, despite various trials investigating a plethora of pharmaceuticals. Specifically in the brain, MD is able to demonstrate penetration of the drug through the blood-brain barrier into the brain extracellular space at potential site of action. In addition, the downstream effects of drug action can be monitored directly. In the future, clinical MD, together with other monitoring modalities, can identify specific pathological substrates which require tailored treatment strategies for patients suffering from TBI.

Abandoning the dead donor rule? A national survey of public views on death and organ donation.

PubMed

Nair-Collins, Michael; Green, Sydney R; Sutin, Angelina R

2015-04-01

Brain dead organ donors are the principal source of transplantable organs. However, it is controversial whether brain death is the same as biological death. Therefore, it is unclear whether organ removal in brain death is consistent with the 'dead donor rule', which states that organ removal must not cause death. Our aim was to evaluate the public's opinion about organ removal if explicitly described as causing the death of a donor in irreversible apneic coma. We conducted a cross-sectional internet survey of the American public (n=1096). Questionnaire domains included opinions about a hypothetical scenario of organ removal described as causing the death of a patient in irreversible coma, and items measuring willingness to donate organs after death. Some 71% of the sample agreed that it should be legal for patients to donate organs in the scenario described and 67% agreed that they would want to donate organs in a similar situation. Of the 85% of the sample who agreed that they were willing to donate organs after death, 76% agreed that they would donate in the scenario of irreversible coma with organ removal causing death. There appears to be public support for organ donation in a scenario explicitly described as violating the dead donor rule. Further, most but not all people who would agree to donate when organ removal is described as occurring after death would also agree to donate when organ removal is described as causing death in irreversible coma. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Traumatic Brain Injury (TBI) Data and Statistics

MedlinePlus

... data.cdc.gov . Emergency Department Visits, Hospitalizations, and Deaths Rates of TBI-related Emergency Department Visits, Hospitalizations, ... related Hospitalizations by Age Group and Injury Mechanism Deaths Rates of TBI-related Deaths by Sex Rates ...

Pope John Paul II and the neurological standard for the determination of death: A critical analysis of his address to the Transplantation Society

PubMed Central

2017-01-01

The introduction of the “brain death” criterion constitutes a significant paradigm shift in the determination of death. The perception of the public at large is that the Catholic Church has formally endorsed this neurological standard. However, a critical reading of the only magisterial document on this subject, Pope John Paul II’s 2000 address, shows that the pope’s acceptance of the neurological criterion is conditional in that it entails a twofold requirement. It requires that certain medical presuppositions of the neurological standard are fulfilled, and that its philosophical premise coheres with the Church’s teaching on the body-soul union. This article demonstrates that the medical presuppositions are not fulfilled, and that the doctrine of the brain as the central somatic integrator of the body does not cohere either with the current holistic understanding of the human organism or with the Church’s Thomistic doctrine of the soul as the form of the body. Summary The concept of “brain death” (the neurological basis for legally declaring a person dead) has caused much controversy since its inception. In this regard, it has been generally perceived that the Catholic Church has officially affirmed the “brain death” criterion. The address of Pope John Paul II in 2000 shows, however, that he only gave it a conditional acceptance, one which requires that several medical and philosophical presuppositions of the “brain death” standard be fulfilled. This article demonstrates, taking into consideration both the empirical evidence and the Church’s Thomistic anthropology, that the presuppositions have not been fulfilled. PMID:28698708

Proteomic analysis of differentially expressed proteins in kidneys of brain dead rabbits.

PubMed

Li, Ling; Li, Ning; He, Chongxiang; Huang, Wei; Fan, Xiaoli; Zhong, Zibiao; Wang, Yanfeng; Ye, Qifa

2017-07-01

A large number of previous clinical studies have reported a delayed graft function for brain dead donors, when compared with living relatives or cadaveric organ transplantations. However, there is no accurate method for the quality evaluation of kidneys from brain‑dead donors. In the present study, two‑dimensional gel electrophoresis and MALDI‑TOF MS‑based comparative proteomic analysis were conducted to profile the differentially‑expressed proteins between brain death and the control group renal tissues. A total of 40 age‑ and sex‑matched rabbits were randomly divided into donation following brain death (DBD) and control groups. Following the induction of brain death via intracranial progressive pressure, the renal function and the morphological alterations were measured 2, 6 and 8 h afterwards. The differentially expressed proteins were detected from renal histological evidence at 6 h following brain death. Although 904±19 protein spots in control groups and 916±25 in DBD groups were identified in the two‑dimensional gel electrophoresis, >2‑fold alterations were identified by MALDI‑TOF MS and searched by NCBI database. The authors successfully acquired five downregulated proteins, these were: Prohibitin (isoform CRA_b), beta-1,3‑N-acetylgalactosaminyltransferase 1, Annexin A5, superoxide dismutase (mitochondrial) and cytochrome b‑c1 complex subunit 1 (mitochondrial precursor). Conversely, the other five upregulated proteins were: PRP38 pre‑mRNA processing factor 38 (yeast) domain containing A, calcineurin subunit B type 1, V‑type proton ATPase subunit G 1, NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 10 and peroxiredoxin‑3 (mitochondrial). Immunohistochemical results revealed that the expressions of prohibitin (PHB) were gradually increased in a time‑dependent manner. The results indicated that there were alterations in levels of several proteins in the kidneys of those with brain death, even if the primary function and the morphological changes were not obvious. PHB may therefore be a novel biomarker for primary quality evaluation of kidneys from brain‑dead donors.

Redox dynamics of manganese as a mitochondrial life-death switch

DOE Office of Scientific and Technical Information (OSTI.GOV)

Smith, Matthew Ryan; Fernandes, Jolyn; Go, Young-Mi

Sten Orrenius, M.D., Ph.D., pioneered many areas of cellular and molecular toxicology and made seminal contributions to our knowledge of oxidative stress and glutathione (GSH) metabolism, organellar functions and Ca{sup +2}-dependent mechanisms of cell death, and mechanisms of apoptosis. On the occasion of his 80{sup th} birthday, we summarize current knowledge on redox biology of manganese (Mn) and its role in mechanisms of cell death. Mn is found in all organisms and has critical roles in cell survival and death mechanisms by regulating Mn-containing enzymes such as manganese superoxide dismutase (SOD2) or affecting expression and activity of caspases. Occupational exposuresmore » to Mn cause “manganism”, a Parkinson's disease-like condition of neurotoxicity, and experimental studies show that Mn exposure leads to accumulation of Mn in the brain, especially in mitochondria, and neuronal cell death occurs with features of an apoptotic mechanism. Interesting questions are why a ubiquitous metal that is essential for mitochondrial function would accumulate to excessive levels, cause increased H{sub 2}O{sub 2} production and lead to cell death. Is this due to the interactions of Mn with other essential metals, such as iron, or with toxic metals, such as cadmium? Why is the Mn loading in the human brain so variable, and why is there such a narrow window between dietary adequacy and toxicity? Are non-neuronal tissues similarly vulnerable to insufficiency and excess, yet not characterized? We conclude that Mn is an important component of the redox interface between an organism and its environment and warrants detailed studies to understand the role of Mn as a mitochondrial life-death switch. - Highlights: • Either insufficient or excess manganese activates mitochondria-mediated cell death. • The optimal healthy Mn exposure window is very narrow. • Mitochondrial H{sub 2}O{sub 2} production depends on Mn across physiologic to toxicologic range. • Integrative omics needed to understand complex Mn interaction in cell fate. • Mn is central to redox interface between an organism and its environment.« less

What's the difference? Comparison of American and Japanese medical practice.

PubMed

Kitano, Masami

2007-09-01

Medical systems in the USA such as EBM., DRG., Informed Consent and Second Opinion have already been introduced into the Japanese medical system. However, some of these systems have met resistance from a part of the population due to the differences of social structures, morals and customs between the two countries. Briefly, I described the medical education and licensure, the private practice and "open hospital system" of the USA. The following 4 topics which drew great interest in Japan will be discussed. 1) CEREBRAL DEATH AND BIOETHICS: Cerebral death has been restrictively accepted as human death since the 1980's only in terms of terminal cares in clinical medicine. The rather simplified current neurological criteria for death are approved in the USA. In order for an organ transplant to take place, a potential donor must be diagnosed as brain dead. However, Japanese society has not accepted the concept of cerebral death completely because of an accident in the 1960's where an organ was improperly removed when the donor who was not in the state of brain death. Recently, more people in Japan are showing interest in Dignity and Euthanasia from the point of view of "Right to die". 2) MALPRACTICE AND LITIGATION: "To err is human" was introduced by the Institute of Medicine for Risk Management. Accidental deaths of patients under medical care ranks No.8 in total number of deaths in the USA. There are 100,000 malpractice cases in the "Lawsuit Society" of America, which is 100 times that of Japan. Furthermore, the legal fees and insurance premiums are extremely high in the US as opposed to very low in Japan. 3) HEALTH CARE INSURANCE: To reduce medical costs, the insurance companies introduced "Competitive Managed Care" which resulted in the formation of "Health Maintenance Organizations" (HMO). Furthermore, when you compare the two countries in respect to those who have health insurance, 44 million in the USA carry no health insurance, whereas in Japan, the government cover for everybody's health insurance. 4) DISCLOSURES IN THE USA: Medical bills and statements are sent to all patients. Maintenance records belong to the patient. The Medical Board discloses those physicians who are facing disciplinary action.

Understanding the Full Spectrum of Organ Injury Following Intrapartum Asphyxia

PubMed Central

LaRosa, Domenic A.; Ellery, Stacey J.; Walker, David W.; Dickinson, Hayley

2017-01-01

Birth asphyxia is a significant global health problem, responsible for ~1.2 million neonatal deaths each year worldwide. Those who survive often suffer from a range of health issues including brain damage—manifesting as cerebral palsy (CP)—respiratory insufficiency, cardiovascular collapse, and renal dysfunction, to name a few. Although the majority of research is directed toward reducing the brain injury that results from intrapartum birth asphyxia, the multi-organ injury observed in surviving neonates is of equal importance. Despite the advent of hypothermia therapy for the treatment of hypoxic–ischemic encephalopathy (HIE), treatment options following asphyxia at birth remain limited, particularly in low-resource settings where the incidence of birth asphyxia is highest. Furthermore, although cooling of the neonate results in improved neurological outcomes for a small proportion of treated infants, it does not provide any benefit to the other organ systems affected by asphyxia at birth. The aim of this review is to summarize the current knowledge of the multi-organ effects of intrapartum asphyxia, with particular reference to the findings from our laboratory using the precocial spiny mouse to model birth asphyxia. Furthermore, we reviewed the current treatments available for neonates who have undergone intrapartum asphyxia, and highlight the emergence of maternal dietary creatine supplementation as a preventative therapy, which has been shown to provide multi-organ protection from birth asphyxia-induced injury in our preclinical studies. This cheap and effective nutritional supplement may be the key to reducing birth asphyxia-induced death and disability, particularly in low-resource settings where current treatments are unavailable. PMID:28261573

The efficiency of utilization of potential donors for organ transplantation in Saudi Arabia: a pilot study.

PubMed

Al Sebayel, M I M; Khalaf, H A

2004-09-01

Organ shortage has been the main obstacle in the progress of organ transplantation in Saudi Arabia. The aim of this pilot study was to determine the percentage of potential donors among all deaths in Riyadh hospital intensive care units (ICUs). Mortality data were collected by a medical professional in each ICU and analyzed on weekly basis for 1 year (June 2001 through May 2002): The final analysis at the end of the year showed the number of brain death cases in all hospitals to be 114 out of 542 deaths. Fifty-four percent occurred in one hospital. Thirty-eight cases were reported to the Saudi Center for Organ Transplantation (33%). Documentation was completed in only 23 cases (60%). Only four cases became actual donors. In conclusion, there is underreporting of brain death cases. Dealing with the reported cases is inefficient since only four cases became actual donors out of 38. Improving the efficiency of ICUs in dealing with brain death cases (reporting, documentation, maintenance and consent) will require solving several problems at the medical, administrative, religious, and mass media levels.

Humanin Derivatives Inhibit Necrotic Cell Death in Neurons

PubMed Central

Cohen, Aviv; Lerner-Yardeni, Jenny; Meridor, David; Kasher, Roni; Nathan, Ilana; Parola, Abraham H

2015-01-01

Humanin and its derivatives are peptides known for their protective antiapoptotic effects against Alzheimer’s disease. Herein, we identify a novel function of the humanin-derivative AGA(C8R)-HNG17 (namely, protection against cellular necrosis). Necrosis is one of the main modes of cell death, which was until recently considered an unmoderated process. However, recent findings suggest the opposite. We have found that AGA(C8R)-HNG17 confers protection against necrosis in the neuronal cell lines PC-12 and NSC-34, where necrosis is induced in a glucose-free medium by either chemohypoxia or by a shift from apoptosis to necrosis. Our studies in traumatic brain injury models in mice, where necrosis is the main mode of neuronal cell death, have shown that AGA(C8R)-HNG17 has a protective effect. This result is demonstrated by a decrease in a neuronal severity score and by a reduction in brain edema, as measured by magnetic resonance imaging (MRI). An insight into the peptide’s antinecrotic mechanism was attained through measurements of cellular ATP levels in PC-12 cells under necrotic conditions, showing that the peptide mitigates a necrosis-associated decrease in ATP levels. Further, we demonstrate the peptide’s direct enhancement of the activity of ATP synthase activity, isolated from rat-liver mitochondria, suggesting that AGA(C8R)-HNG17 targets the mitochondria and regulates cellular ATP levels. Thus, AGA(C8R)-HNG17 has potential use for the development of drug therapies for necrosis-related diseases, for example, traumatic brain injury, stroke, myocardial infarction, and other conditions for which no efficient drug-based treatment is currently available. Finally, this study provides new insight into the mechanisms underlying the antinecrotic mode of action of AGA(C8R)-HNG17. PMID:26062019

In vitro and in vivo effects of a novel dimeric inhibitor of PSD-95 on excitotoxicity and functional recovery after experimental traumatic brain injury.

PubMed

Sommer, Jens Bak; Bach, Anders; Malá, Hana; Strømgaard, Kristian; Mogensen, Jesper; Pickering, Darryl S

2017-01-01

PSD-95 inhibitors have been shown to be neuroprotective in stroke, but have only to a very limited extent been evaluated in the treatment of traumatic brain injury (TBI) that has pathophysiological mechanisms in common with stroke. The aims of the current study were to assess the effects of a novel dimeric inhibitor of PSD-95, UCCB01-147, on histopathology and long-term cognitive outcome after controlled cortical impact (CCI) in rats. As excitotoxic cell death is thought to be a prominent part of the pathophysiology of TBI, we also investigated the neuroprotective effects of UCCB01-147 and related compounds on NMDA-induced cell death in cultured cortical neurons. Anesthetized rats were given a CCI or sham injury, and were randomized to receive an injection of either UCCB01-147 (10 mg/kg), the non-competitive NMDAR-receptor antagonist MK-801 (1 mg/kg) or saline immediately after injury. At 2 and 4 weeks post-trauma, spatial learning and memory were assessed in a water maze, and at 3 months, brains were removed for estimation of lesion volumes. Overall, neither treatment with UCCB01-147 nor MK-801 resulted in significant improvements of cognition and histopathology after CCI. Although MK-801 provided robust neuroprotection against NMDA-induced toxicity in cultured cortical neurons, UCCB01-147 failed to reduce cell death and became neurotoxic at high doses. The data suggest potential differential effects of PSD-95 inhibition in stroke and TBI that should be investigated further in future studies taking important experimental factors such as timing of treatment, dosage, and anesthesia into consideration. © 2016 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

Targeted brain proteomics uncover multiple pathways to Alzheimer's dementia.

PubMed

Yu, Lei; Petyuk, Vladislav A; Gaiteri, Chris; Mostafavi, Sara; Young-Pearse, Tracy; Shah, Raj C; Buchman, Aron S; Schneider, Julie A; Piehowski, Paul D; Sontag, Ryan L; Fillmore, Thomas L; Shi, Tujin; Smith, Richard D; De Jager, Philip L; Bennett, David A

2018-06-16

Previous gene expression analysis identified a network of co-expressed genes that is associated with β-amyloid neuropathology and cognitive decline in older adults. The current work targeted influential genes in this network with quantitative proteomics to identify potential novel therapeutic targets. Data came from 834 community-based older persons who were followed annually, died and underwent brain autopsy. Uniform structured postmortem evaluations assessed the burden of β-amyloid and other common age-related neuropathologies. Selected reaction monitoring quantified cortical protein abundance of 12 genes prioritized from a molecular network of aging human brain that is implicated in Alzheimer's dementia. Regression and linear mixed models examined the protein associations with β-amyloid load and other neuropathologic indices as well as cognitive decline over multiple years prior to death. The average age at death was 88.6 years. 349 participants (41.9%) had Alzheimer's dementia at death. A higher level of PLXNB1 abundance was associated with more β-amyloid load (p=1.0 × 10 -7 ) and higher PHFtau tangle density (p=2.3 × 10 -7 ), and the association of PLXNB1 with cognitive decline is mediated by these known Alzheimer's disease pathologies. On the other hand, higher IGFBP5, HSPB2, AK4 and lower ITPK1 levels were associated with faster cognitive decline and, unlike PLXNB1, these associations were not fully explained by common neuropathologic indices, suggesting novel mechanisms leading to cognitive decline. Using targeted proteomics, this work identified cortical proteins involved in Alzheimer's dementia and begins to dissect two different molecular pathways: one affecting β-amyloid deposition and another affecting resilience without a known pathologic footprint. This article is protected by copyright. All rights reserved. © 2018 American Neurological Association.

[Deceased donation in renal transplantation].

PubMed

Thuret, R; Kleinclauss, F; Terrier, N; Timsit, M O

2016-11-01

To review epidemiologic data's and medical results of deceased donation in renal transplantation. Relevant publications were identified through Medline (http://www.ncbi.nlm.nih.gov) and Embase (http://www.embase.com) database using the following keywords, alone or in association, "brain death; cardiac arrest; deceased donation; organ procurement; transplantation". Articles were selected according to methods, language of publication and relevance. The reference lists were used to identify additional historical studies of interest. Both prospective and retrospective series, in French and English, as well as review articles and recommendations were selected. In addition, French national transplant and health agencies (http://www.agence-biomedecine.fr and http://www.has-sante.fr) databases were screened using identical keywords. A total of 2498 articles, 8 official reports and 17 newspaper articles were identified; after careful selection 157 publications were eligible for our review. Deceased donation may involve either brain death or non-heartbeating donors (NHBD). Organ shortage led to the procurement of organs from expanded-criteria donors, with an increased age at donation and extended vascular disease, leading to inferior results after transplantation and underlining the need for careful donor management during brain death or cardiac arrest. Evolution of French legislation covering bioethics allowed procurement from Maastricht categories II and recently III non-heartbeating donors. The increase of organ shortage emphasizes the need for a rigorous surgical technique during procurement to avoid loss of transplants. A history or current neoplasm in deceased-donors, requires attention to increase the pool of organs without putting the recipients at risk for cancer transmission. French NHBD program, especially from Maastricht category III, may stand for a potential source of valuable organs. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

miR-Let7A Controls the Cell Death and Tight Junction Density of Brain Endothelial Cells under High Glucose Condition

PubMed Central

Song, Juhyun; Yoon, So Ra

2017-01-01

Hyperglycemia-induced stress in the brain of patients with diabetes triggers the disruption of blood-brain barrier (BBB), leading to diverse neurological diseases including stroke and dementia. Recently, the role of microRNA becomes an interest in the research for deciphering the mechanism of brain endothelial cell damage under hyperglycemia. Therefore, we investigated whether mircoRNA Let7A (miR-Let7A) controls the damage of brain endothelial (bEnd.3) cells against high glucose condition. Cell viability, cell death marker expressions (p-53, Bax, and cleaved poly ADP-ribose polymerase), the loss of tight junction proteins (ZO-1 and claudin-5), proinflammatory response (interleukin-6, tumor necrosis factor-α), inducible nitric oxide synthase, and nitrite production were confirmed using MTT, reverse transcription-PCR, quantitative-PCR, Western blotting, immunofluorescence, and Griess reagent assay. miR-Let7A overexpression significantly prevented cell death and loss of tight junction proteins and attenuated proinflammatory response and nitrite production in the bEnd.3 cells under high glucose condition. Taken together, we suggest that miR-Let7A may attenuate brain endothelial cell damage by controlling cell death signaling, loss of tight junction proteins, and proinflammatory response against high glucose stress. In the future, the manipulation of miR-Let7A may be a novel solution in controlling BBB disruption which leads to the central nervous system diseases. PMID:28680530

miR-Let7A Controls the Cell Death and Tight Junction Density of Brain Endothelial Cells under High Glucose Condition.

PubMed

Song, Juhyun; Yoon, So Ra; Kim, Oh Yoen

2017-01-01

Hyperglycemia-induced stress in the brain of patients with diabetes triggers the disruption of blood-brain barrier (BBB), leading to diverse neurological diseases including stroke and dementia. Recently, the role of microRNA becomes an interest in the research for deciphering the mechanism of brain endothelial cell damage under hyperglycemia. Therefore, we investigated whether mircoRNA Let7A (miR-Let7A) controls the damage of brain endothelial (bEnd.3) cells against high glucose condition. Cell viability, cell death marker expressions (p-53, Bax, and cleaved poly ADP-ribose polymerase), the loss of tight junction proteins (ZO-1 and claudin-5), proinflammatory response (interleukin-6, tumor necrosis factor- α ), inducible nitric oxide synthase, and nitrite production were confirmed using MTT, reverse transcription-PCR, quantitative-PCR, Western blotting, immunofluorescence, and Griess reagent assay. miR-Let7A overexpression significantly prevented cell death and loss of tight junction proteins and attenuated proinflammatory response and nitrite production in the bEnd.3 cells under high glucose condition. Taken together, we suggest that miR-Let7A may attenuate brain endothelial cell damage by controlling cell death signaling, loss of tight junction proteins, and proinflammatory response against high glucose stress. In the future, the manipulation of miR-Let7A may be a novel solution in controlling BBB disruption which leads to the central nervous system diseases.

Transcriptional up-regulation of nitric oxide synthase II by nuclear factor-kappaB at rostral ventrolateral medulla in a rat mevinphos intoxication model of brain stem death.

PubMed

Chan, Julie Y H; Wu, Carol H Y; Tsai, Ching-Yi; Cheng, Hsiao-Lei; Dai, Kuang-Yu; Chan, Samuel H H; Chang, Alice Y W

2007-06-15

As the origin of a 'life-and-death' signal that reflects central cardiovascular regulatory failure during brain stem death, the rostral ventrolateral medulla (RVLM) is a suitable neural substrate for mechanistic delineation of this vital phenomenon. Using a clinically relevant animal model that employed the organophosphate pesticide mevinphos (Mev) as the experimental insult, we evaluated the hypothesis that transcriptional up-regulation of nitric oxide synthase I or II (NOS I or II) gene expression by nuclear factor-kappaB (NF-kappaB) on activation of muscarinic receptors in the RVLM underlies brain stem death. In Sprague-Dawley rats maintained under propofol anaesthesia, co-microinjection of muscarinic M2R (methoctramine) or M4R (tropicamide), but not M1R (pirenzepine) or M3R (4-diphenylacetoxy-N-dimethylpiperidinium) antagonist significantly reduced the enhanced NOS I-protein kinase G signalling ('pro-life' phase) or augmented NOS II-peroxynitrite cascade ('pro-death' phase) in ventrolateral medulla, blunted the biphasic increase and decrease in baroreceptor reflex-mediated sympathetic vasomotor tone that reflect the transition from life to death, and diminished the elevated DNA binding activity or nucleus-bound translocation of NF-kappaB in RVLM neurons induced by microinjection of Mev into the bilateral RVLM. However, NF-kappaB inhibitors (diethyldithiocarbamate or pyrrolidine dithiocarbamate) or double-stranded kappaB decoy DNA preferentially antagonized the augmented NOS II-peroxynitrite cascade and the associated cardiovascular depression exhibited during the 'pro-death' phase. We conclude that transcriptional up-regulation of NOS II gene expression by activation of NF-kappaB on selective stimulation of muscarinic M2 or M4 subtype receptors in the RVLM underlies the elicited cardiovascular depression during the 'pro-death' phase in our Mev intoxication model of brain stem death.

Development of a head-phantom and measurement setup for lightning effects.

PubMed

Machts, Rene; Hunold, Alexander; Leu, Carsten; Haueisen, Jens; Rock, Michael

2016-08-01

Direct lightning strikes to human heads lead to various effects ranging from Lichtenberg figures, over loss of consciousness to death. The evolution of the induced current distribution in the head is of great interest to understand the effect mechanisms. This work describes a technique to model a simplified head-phantom to investigate effects during direct lightning strike. The head-phantom geometry, conductive and dielectric parameters were chosen similar to that of a human head. Three layers (brain, skull, and scalp) were created for the phantom using agarose hydrogel doped with sodium chloride and carbon. The head-phantom was tested on two different impulse generators, which reproduce approximate lightning impulses. The effective current and the current distribution in each layer were analyzed. The biggest part of the current flowed through the brain layer, approx. 70 % in cases without external flashover. Approx. 23 % of the current flowed through skull layer and 6 % through the scalp layer. However, the current decreased within the head-phantom to almost zero after a complete flashover on the phantom occurred. The flashover formed faster with a higher impulse current level. Exposition time of current through the head decreases with a higher current level of the lightning impulse. This mechanism might explain the fact that people can survive a lightning strike. The experiments help to understand lightning effects on humans.

MicroRNA profiling reveals new aspects of HIV neurodegeneration: caspase-6 regulates astrocyte survival.

PubMed

Noorbakhsh, Farshid; Ramachandran, Rithwik; Barsby, Nicola; Ellestad, Kristofor K; LeBlanc, Andrea; Dickie, Peter; Baker, Glen; Hollenberg, Morley D; Cohen, Eric A; Power, Christopher

2010-06-01

MicroRNAs (miRNAs) are small noncoding RNA molecules, which are known to regulate gene expression in physiological and pathological conditions. miRNA profiling was performed using brain tissue from patients with HIV encephalitis (HIVE), a neuroinflammatory/degenerative disorder caused by HIV infection of the brain. Microarray analysis showed differential expression of multiple miRNAs in HIVE compared to control brains. Target prediction and gene ontology enrichment analysis disclosed targeting of several gene families/biological processes by differentially expressed miRNAs (DEMs), with cell death-related genes, including caspase-6, showing a bias toward down-regulated DEMs. Consistent with the miRNA data, HIVE brains exhibited higher levels of caspase-6 transcripts compared with control patients. Immunohistochemical analysis showed localization of the cleaved form of caspase-6 in astrocytes in HIVE brain sections. Exposure of cultured human primary astrocytes to HIV viral protein R (Vpr) induced p53 up-regulation, loss of mitochondrial membrane potential, and caspase-6 activation followed by cell injury. Transgenic mice, expressing Vpr in microglial cells, demonstrated astrocyte apoptosis in brain, which was associated with caspase-6 activation and neurobehavioral abnormalities. Overall, these data point to previously unrecognized alterations in miRNA profile in the brain during HIV infection, which contribute to cell death through dysregulation of cell death machinery.

Necrostatin-1 attenuates early brain injury after subarachnoid hemorrhage in rats by inhibiting necroptosis.

PubMed

Chen, Fuxiang; Su, Xingfen; Lin, Zhangya; Lin, Yuanxiang; Yu, Lianghong; Cai, Jiawei; Kang, Dezhi; Hu, Liwen

2017-01-01

Necroptosis is programmed cell death that has been recently proposed and reported to be involved in several neurologic diseases. However, the role of necroptosis in early brain injury after subarachnoid hemorrhage (SAH) is still unknown. The purpose of this study was to investigate whether necroptosis was involved in SAH-induced early brain injury, and to assess the possible neuroprotective effect of necrostatin-1 using an endovascular perforation rat model of SAH. Our results showed that the expression levels of necroptosis-related proteins including RIP1, RIP3 and MLKL in the basal cortex all increased at 3 hours after SAH ( P <0.05) and peaked at 48 hours after SAH ( P <0.05). However, they were greatly reduced after treatment with necrostatin-1 ( P <0.05). Concurrently, neurologic outcomes were significantly improved after necrostatin-1 treatment ( P <0.05). Furthermore, brain edema, blood-brain barrier disruption, necrotic cell death and neuroinflammation were also greatly inhibited after necrostatin-1 treatment. These results indicate that necroptosis is an important mechanism of cell death involved in the early brain injury after experimental SAH. Necrostatin-1 perhaps can serve as a promising neuroprotective agent for SAH treatment.

Postmortem Brain and Blood Reference Concentrations of Alprazolam, Bromazepam, Chlordiazepoxide, Diazepam, and their Metabolites and a Review of the Literature.

PubMed

Skov, Louise; Holm, Karen Marie Dollerup; Johansen, Sys Stybe; Linnet, Kristian

2016-09-01

To interpret postmortem toxicology results, reference concentrations for non-toxic and toxic levels are needed. Usually, measurements are performed in blood, but because of postmortem redistribution phenomena this may not be optimal. Rather, measurement in the target organ of psychoactive drugs, the brain, might be considered. Here we present reference concentrations of femoral blood and brain tissue of selected benzodiazepines (BZDs). Using LC-MS/MS, we quantified alprazolam, bromazepam, chlordiazepoxide, diazepam, and the metabolites desmethyldiazepam, oxazepam and temazepam in postmortem femoral blood and brain tissue in 104 cases. BZDs were judged to be unrelated to the cause of death in 88 cases and contributing to death in 16 cases. No cases were found with cause of death solely attributed to BZD poisoning. All BZDs investigated tended to have higher concentrations in brain than in blood with median brain-blood ratios ranging from 1.1 to 2.3. A positive correlation between brain and blood concentrations was found with R(2) values from 0.51 to 0.95. Our reported femoral blood concentrations concur with literature values, but sparse information on brain concentration was available. Drug-metabolite ratios were similar in brain and blood for most compounds. Duplicate measurements of brain samples showed that the pre-analytical variation in brain (5.9%) was relatively low, supporting the notion that brain tissue is a suitable postmortem specimen. The reported concentrations in both brain and blood can be used as reference values when evaluating postmortem cases. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Mechanisms of Neurodegeneration and Regeneration in Alcoholism

PubMed Central

Crews, Fulton T.; Nixon, Kim

2009-01-01

Aims: This is a review of preclinical studies covering alcohol-induced brain neuronal death and loss of neurogenesis as well as abstinence-induced brain cell genesis, e.g. brain regeneration. Efforts are made to relate preclinical studies to human studies. Methods: The studies described are preclinical rat experiments using a 4-day binge ethanol treatment known to induce physical dependence to ethanol. Neurodegeneration and cognitive deficits following binge treatment mimic the mild degeneration and cognitive deficits found in humans. Various histological methods are used to follow brain regional degeneration and regeneration. Results: Alcohol-induced degeneration occurs due to neuronal death during alcohol intoxication. Neuronal death is related to increases in oxidative stress in brain that coincide with the induction of proinflammatory cytokines and oxidative enzymes that insult brain. Degeneration is associated with increased NF-κB proinflammatory transcription and decreased CREB transcription. Corticolimbic brain regions are most sensitive to binge-induced degeneration and induce relearning deficits. Drugs that block oxidative stress and NF-κB transcription or increase CREB transcription block binge-induced neurodegeneration, inhibition of neurogenesis and proinflammatory enzyme induction. Regeneration of brain occurs during abstinence following binge ethanol treatment. Bursts of proliferating cells occur across multiple brain regions, with many new microglia across brain after months of abstinence and many new neurons in neurogenic hippocampal dentate gyrus. Brain regeneration may be important to sustain abstinence in humans. Conclusions: Alcohol-induced neurodegeneration occurs primarily during intoxication and is related to increased oxidative stress and proinflammatory proteins that are neurotoxic. Abstinence after binge ethanol intoxication results in brain cell genesis that could contribute to the return of brain function and structure found in abstinent humans. PMID:18940959

Uncontrolled Donation After Circulatory Determination of Death Donors (uDCDDs) as a Source of Lungs for Transplant.

PubMed

Egan, T M; Requard, J J

2015-08-01

In April 2014, the American Journal of Transplantation published a report on the first lung transplant in the United States recovered from an uncontrolled donation after circulatory determination of death donor (uDCDD), assessed by ex vivo lung perfusion (EVLP). The article identified logistical and ethical issues related to introduction of lung transplant from uDCDDs. In an open clinical trial, we have Food and Drug Administration and Institutional Review Board approval to transplant lungs recovered from uDCDDs judged suitable after EVLP. Through this project and other experiences with lung recovery from uDCDDs, we have identified solutions to many logistical challenges and have addressed ethical issues surrounding lung transplant from uDCDDs that were mentioned in this case report. Here, we discuss those challenges, including issues related to recovery of other solid organs from uDCDDs. Despite logistical challenges, uDCDDs could solve the critical shortage of lungs for transplant. Furthermore, by avoiding the deleterious impact of brain death and days of positive pressure ventilation, and by using opportunities to treat lungs in the decedent or during EVLP, lungs recovered from uDCDDs may ultimately prove to be better than lungs currently being transplanted from conventional brain-dead organ donors. © Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.

NAD+ depletion or PAR polymer formation: which plays the role of executioner in ischaemic cell death?

PubMed

Siegel, C; McCullough, L D

2011-09-01

Multiple cell death pathways are activated in cerebral ischaemia. Much of the initial injury, especially in the core of the infarct where cerebral blood flow is severely reduced, is necrotic and secondary to severe energy failure. However, there is considerable evidence that delayed cell death continues for several days, primarily in the penumbral region. As reperfusion therapies grow in number and effectiveness, restoration of blood flow early after injury may lead to a shift towards apoptosis. It is important to elucidate what are the key mediators of apoptotic cell death after stroke, as inhibition of apoptosis may have therapeutic implications. There are two well described pathways that lead to apoptotic cell death; the caspase pathway and the more recently described caspase-independent pathway triggered by poly-ADP-ribose polymers (PARP) activation. Caspase-induced cell death is initiated by release of mitochondrial cytochrome c, formation of the cytosolic apoptosome, and activation of endonucleases leading to a multitude of small randomly cleaved DNA fragments. In contrast caspase-independent cell death is secondary to activation of apoptosis inducing factor (AIF). Mitochondrial AIF translocates to the nucleus, where it induces peripheral chromatin condensation, as well as characteristic high-molecular-weight (50 kbp) DNA fragmentation. Although caspase-independent cell death has been recognized for some time and is known to contribute to ischaemic injury, the upstream triggering events leading to activation of this pathway remain unclear. The two major theories are that ischaemia leads to nicotinamide adenine dinucleotide (NAD+) depletion and subsequent energy failure, or alternatively that cell death is directly triggered by a pro-apoptotic factor produced by activation of the DNA repair enzyme PARP. PARP activation is robust in the ischaemic brain producing variable lengths of poly-ADP-ribose (PAR) polymers as byproducts of PARP activation. PAR polymers may be directly toxic by triggering mitochondrial AIF release independently of NAD+ depletion. Recently, sex differences have been discovered that illustrate the importance of understanding these molecular pathways, especially as new therapeutics targeting apoptotic cell death are developed. Cell death in females proceeds primarily via caspase activation whereas caspase-independent mechanisms triggered by the activation of PARP predominate in the male brain. This review summarizes the current literature in an attempt to clarify the roles of NAD+ and PAR polymers in caspase-independent cell death, and discuss sex specific cell death to provide an example of the possible importance of these downstream mediators. © 2011 The Authors. Acta Physiologica © 2011 Scandinavian Physiological Society.

Evaluation of the law of presumed consent after brain death by Spanish journalism students.

PubMed

Martínez-Alarcón, L; Ríos, A; Sánchez, J; Ramis, G; López-Navas, A; Ramírez, P; Parrilla, P

2010-10-01

Information provided by journalists is crucial to create a climate of social opinion. This is important in organ donation and transplantation (ODT), wherein the participation of the general public is essential to obtain organs. The objective of this study was to determine the knowledge of students taking a degree in journalism about the concept of brain death and the law of presumed consent. The study involved 129 journalism degree students in the 2005-2006 academic year from a university in the south-east of Spain. Attitudes on the psychosocial aspects of ODT were evaluated using a validated questionnaire. The self-administered survey was completed anonymously in classes and compulsory practical sessions. The questionnaire completion rate was 98% (n=126). Of the students surveyed, 43% (n=54) understood the concept of brain death, 44% (n=56) stated that they had doubts, whereas 13% (n=16) believed that a person with brain death can recover and lead a normal life. Their knowledge was more accurate in the final than in the first year (54% vs 47%; P=.016). Most students 66% (n=83) believed that it would be interesting to receive an informative talk about ODT. Concerning legislation, 75% of students were against the law of presumed consent, whereas 25% were in favor. More than 50% of journalism students do not understand the concept of brain death. Furthermore, up to 75% do not accept the law of presumed consent that donation must be made. Copyright © 2010 Elsevier Inc. All rights reserved.

Do the 'brain dead' merely appear to be alive?

PubMed

Nair-Collins, Michael; Miller, Franklin G

2017-11-01

The established view regarding 'brain death' in medicine and medical ethics is that patients determined to be dead by neurological criteria are dead in terms of a biological conception of death, not a philosophical conception of personhood, a social construction or a legal fiction. Although such individuals show apparent signs of being alive, in reality they are (biologically) dead, though this reality is masked by the intervention of medical technology. In this article, we argue that an appeal to the distinction between appearance and reality fails in defending the view that the 'brain dead' are dead. Specifically, this view relies on an inaccurate and overly simplistic account of the role of medical technology in the physiology of a 'brain dead' patient. We conclude by offering an explanation of why the conventional view on 'brain death', though mistaken, continues to be endorsed in light of its connection to organ transplantation and the dead donor rule. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Finite element modeling of human brain response to football helmet impacts.

PubMed

Darling, T; Muthuswamy, J; Rajan, S D

2016-10-01

The football helmet is used to help mitigate the occurrence of impact-related traumatic (TBI) and minor traumatic brain injuries (mTBI) in the game of American football. While the current helmet design methodology may be adequate for reducing linear acceleration of the head and minimizing TBI, it however has had less effect in minimizing mTBI. The objectives of this study are (a) to develop and validate a coupled finite element (FE) model of a football helmet and the human body, and (b) to assess responses of different regions of the brain to two different impact conditions - frontal oblique and crown impact conditions. The FE helmet model was validated using experimental results of drop tests. Subsequently, the integrated helmet-human body FE model was used to assess the responses of different regions of the brain to impact loads. Strain-rate, strain, and stress measures in the corpus callosum, midbrain, and brain stem were assessed. Results show that maximum strain-rates of 27 and 19 s(-1) are observed in the brain-stem and mid-brain, respectively. This could potentially lead to axonal injuries and neuronal cell death during crown impact conditions. The developed experimental-numerical framework can be used in the study of other helmet-related impact conditions.

Atomoxetine, a norepinephrine reuptake inhibitor, reduces seizure-induced respiratory arrest.

PubMed

Zhang, Honghai; Zhao, Haiting; Feng, Hua-Jun

2017-08-01

Sudden unexpected death in epilepsy (SUDEP) is a devastating epilepsy complication, and no effective preventive strategies are currently available for this fatal disorder. Clinical and animal studies of SUDEP demonstrate that seizure-induced respiratory arrest (S-IRA) is the primary event leading to death after generalized seizures in many cases. Enhancing brain levels of serotonin reduces S-IRA in animal models relevant to SUDEP, including the DBA/1 mouse. Given that serotonin in the brain plays an important role in modulating respiration and arousal, these findings suggest that deficits in respiration and/or arousal may contribute to S-IRA. It is well known that norepinephrine is an important neurotransmitter that modulates respiration and arousal in the brain as well. Therefore, we hypothesized that enhancing noradrenergic neurotransmission suppresses S-IRA. To test this hypothesis, we examined the effect of atomoxetine, a norepinephrine reuptake inhibitor (NRI), on S-IRA evoked by either acoustic stimulation or pentylenetetrazole in DBA/1 mice. We report the original observation that atomoxetine specifically suppresses S-IRA without altering the susceptibility to seizures evoked by acoustic stimulation, and atomoxetine also reduces S-IRA evoked by pentylenetetrazole in DBA/1 mice. Our data suggest that the noradrenergic signaling is importantly involved in S-IRA, and that atomoxetine, a medication widely used to treat attention deficit hyperactivity disorder (ADHD), is potentially useful to prevent SUDEP. Copyright © 2017 Elsevier Inc. All rights reserved.

Pathophysiology Associated with Traumatic Brain Injury: Current Treatments and Potential Novel Therapeutics.

PubMed

Pearn, Matthew L; Niesman, Ingrid R; Egawa, Junji; Sawada, Atsushi; Almenar-Queralt, Angels; Shah, Sameer B; Duckworth, Josh L; Head, Brian P

2017-05-01

Traumatic brain injury (TBI) is one of the leading causes of death of young people in the developed world. In the United States alone, 1.7 million traumatic events occur annually accounting for 50,000 deaths. The etiology of TBI includes traffic accidents, falls, gunshot wounds, sports, and combat-related events. TBI severity ranges from mild to severe. TBI can induce subtle changes in molecular signaling, alterations in cellular structure and function, and/or primary tissue injury, such as contusion, hemorrhage, and diffuse axonal injury. TBI results in blood-brain barrier (BBB) damage and leakage, which allows for increased extravasation of immune cells (i.e., increased neuroinflammation). BBB dysfunction and impaired homeostasis contribute to secondary injury that occurs from hours to days to months after the initial trauma. This delayed nature of the secondary injury suggests a potential therapeutic window. The focus of this article is on the (1) pathophysiology of TBI and (2) potential therapies that include biologics (stem cells, gene therapy, peptides), pharmacological (anti-inflammatory, antiepileptic, progrowth), and noninvasive (exercise, transcranial magnetic stimulation). In final, the review briefly discusses membrane/lipid rafts (MLR) and the MLR-associated protein caveolin (Cav). Interventions that increase Cav-1, MLR formation, and MLR recruitment of growth-promoting signaling components may augment the efficacy of pharmacologic agents or already existing endogenous neurotransmitters and neurotrophins that converge upon progrowth signaling cascades resulting in improved neuronal function after injury.

Current obstacles to organ transplant in Middle Eastern countries.

PubMed

Shaheen, Faissal A M; Souqiyyeh, Muhammad Ziad

2015-04-01

The Middle Eastern map includes all the Arab countries, Iran, Turkey, Pakistan, and countries of Central Asia. There are common features of organ transplant in these countries such as inadequate preventive medicine, uneven health infrastructure, poor awareness of the medical community and public about the importance of organ donation and transplant, high level of ethnicity, poor government support of organ transplant, and political unrest. In addition, there is inadequate team spirit among transplant physicians, lack of planning for organ procurement and transplant centers, and lack of effective health insurance. Living-donor organ transplant is the most widely practiced type of transplant in the Middle East. Deceased-donor organ donation is not used properly because of continued debate in the medical community about the concept of death according to neurologic criteria (brain death) and inadequate awareness of the public about the importance of organ donation and transplant in many countries in this region. Continuous work is needed to provide solutions to overcome the current obstacles.

Acute Traumatic Brain Injury Does Not Exacerbate Amyotrophic Lateral Sclerosis in the SOD1G93A Rat Model1,2,3

PubMed Central

Thomsen, Gretchen M.

2015-01-01

Abstract Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease in which upper and lower motor neurons degenerate, leading to muscle atrophy, paralysis, and death within 3 to 5 years of onset. While a small percentage of ALS cases are genetically linked, the majority are sporadic with unknown origin. Currently, etiological links are associated with disease onset without mechanistic understanding. Of all the putative risk factors, however, head trauma has emerged as a consistent candidate for initiating the molecular cascades of ALS. Here, we test the hypothesis that traumatic brain injury (TBI) in the SOD1 G93A transgenic rat model of ALS leads to early disease onset and shortened lifespan. We demonstrate, however, that a one-time acute focal injury caused by controlled cortical impact does not affect disease onset or survival. Establishing the negligible involvement of a single acute focal brain injury in an ALS rat model increases the current understanding of the disease. Critically, untangling a single focal TBI from multiple mild injuries provides a rationale for scientists and physicians to increase focus on repeat injuries to hopefully pinpoint a contributing cause of ALS. PMID:26464984

Sudden unexpected death from oligodendroglioma: a case report and review of the literature.

PubMed

Manousaki, Maria; Papadaki, Helen; Papavdi, Asteria; Kranioti, Elena F; Mylonakis, Panagiotis; Varakis, John; Michalodimitrakis, Manolis

2011-12-01

Sudden and unexpected deaths due to asymptomatic 5 primary brain tumors are extremely rare, with an incidence that ranges from 0.16 to 3.2%. Usually, such tumors are glioblastomas or, less commonly, astrocytomas. Asymptomatic oligodendrogliomas causing sudden death are hardly ever reported among medico-legal investigated cases.We report a rare case of sudden and unexpected death from a previously asymptomatic and undiagnosed, well-differentiated, grade II oligodendrogloioma (WHO classification). According to the autopsy and the microscopic findings brain edema as a result of obstruction of the cerebrospinal fluid flow due to hemorrhagic leakage of the oligodendroglioma is incriminated as the most probable physiopathological mechanism for the sudden death. Diagnosis is mainly based on the special microscopic features of the tumor cells (typical "fried-egg" appearance), interrupted by a dense network of branching capillaries. We discuss further the pathophysiological mechanisms of death and present a short review of literature.

Pharmacotherapy for Adults with Tumors of the Central Nervous System

PubMed Central

Schor, Nina F.

2009-01-01

Tumors of the adult central nervous system are among the most common and most chemoresistant neoplasms. Malignant tumors of the brain and spinal cord collectively account for approximately 1.3% of all cancers and 2.2% of all cancer-related deaths. Novel pharmacological approaches to nervous system tumors are urgently needed. This review presents the current approaches and challenges to successful pharmacotherapy of adults with malignant tumors of the central nervous system and discusses novel approaches aimed at overcoming these challenges. PMID:19091301

Experimental Injury Biomechanics of the Pediatric Head and Brain

NASA Astrophysics Data System (ADS)

Margulies, Susan; Coats, Brittany

Traumatic brain injury (TBI) is a leading cause of death and disability among children and young adults in the United States and results in over 2,500 childhood deaths, 37,000 hospitalizations, and 435,000 emergency department visits each year (Langlois et al. 2004). Computational models of the head have proven to be powerful tools to help us understand mechanisms of adult TBI and to determine load thresholds for injuries specific to adult TBI. Similar models need to be developed for children and young adults to identify age-specific mechanisms and injury tolerances appropriate for children and young adults. The reliability of these tools, however, depends heavily on the availability of pediatric tissue material property data. To date the majority of material and structural properties used in pediatric computer models have been scaled from adult human data. Studies have shown significant age-related differences in brain and skull properties (Prange and Margulies 2002; Coats and Margulies 2006a, b), indicating that the pediatric head cannot be modeled as a miniature adult head, and pediatric computer models incorporating age-specific data are necessary to accurately mimic the pediatric head response to impact or rotation. This chapter details the developmental changes of the pediatric head and summarizes human pediatric properties currently available in the literature. Because there is a paucity of human pediatric data, material properties derived from animal tissue are also presented to demonstrate possible age-related differences in the heterogeneity and rate dependence of tissue properties. The chapter is divided into three main sections: (1) brain, meninges, and cerebral spinal fluid (CSF); (2) skull; and (3) scalp.

Ammonium Accumulation and Cell Death in a Rat 3D Brain Cell Model of Glutaric Aciduria Type I

PubMed Central

Jafari, Paris; Braissant, Olivier; Zavadakova, Petra; Henry, Hugues; Bonafé, Luisa; Ballhausen, Diana

2013-01-01

Glutaric aciduria type I (glutaryl-CoA dehydrogenase deficiency) is an inborn error of metabolism that usually manifests in infancy by an acute encephalopathic crisis and often results in permanent motor handicap. Biochemical hallmarks of this disease are elevated levels of glutarate and 3-hydroxyglutarate in blood and urine. The neuropathology of this disease is still poorly understood, as low lysine diet and carnitine supplementation do not always prevent brain damage, even in early-treated patients. We used a 3D in vitro model of rat organotypic brain cell cultures in aggregates to mimic glutaric aciduria type I by repeated administration of 1 mM glutarate or 3-hydroxyglutarate at two time points representing different developmental stages. Both metabolites were deleterious for the developing brain cells, with 3-hydroxyglutarate being the most toxic metabolite in our model. Astrocytes were the cells most strongly affected by metabolite exposure. In culture medium, we observed an up to 11-fold increase of ammonium in the culture medium with a concomitant decrease of glutamine. We further observed an increase in lactate and a concomitant decrease in glucose. Exposure to 3-hydroxyglutarate led to a significantly increased cell death rate. Thus, we propose a three step model for brain damage in glutaric aciduria type I: (i) 3-OHGA causes the death of astrocytes, (ii) deficiency of the astrocytic enzyme glutamine synthetase leads to intracerebral ammonium accumulation, and (iii) high ammonium triggers secondary death of other brain cells. These unexpected findings need to be further investigated and verified in vivo. They suggest that intracerebral ammonium accumulation might be an important target for the development of more effective treatment strategies to prevent brain damage in patients with glutaric aciduria type I. PMID:23326493

Ammonium accumulation and cell death in a rat 3D brain cell model of glutaric aciduria type I.

PubMed

Jafari, Paris; Braissant, Olivier; Zavadakova, Petra; Henry, Hugues; Bonafé, Luisa; Ballhausen, Diana

2013-01-01

Glutaric aciduria type I (glutaryl-CoA dehydrogenase deficiency) is an inborn error of metabolism that usually manifests in infancy by an acute encephalopathic crisis and often results in permanent motor handicap. Biochemical hallmarks of this disease are elevated levels of glutarate and 3-hydroxyglutarate in blood and urine. The neuropathology of this disease is still poorly understood, as low lysine diet and carnitine supplementation do not always prevent brain damage, even in early-treated patients. We used a 3D in vitro model of rat organotypic brain cell cultures in aggregates to mimic glutaric aciduria type I by repeated administration of 1 mM glutarate or 3-hydroxyglutarate at two time points representing different developmental stages. Both metabolites were deleterious for the developing brain cells, with 3-hydroxyglutarate being the most toxic metabolite in our model. Astrocytes were the cells most strongly affected by metabolite exposure. In culture medium, we observed an up to 11-fold increase of ammonium in the culture medium with a concomitant decrease of glutamine. We further observed an increase in lactate and a concomitant decrease in glucose. Exposure to 3-hydroxyglutarate led to a significantly increased cell death rate. Thus, we propose a three step model for brain damage in glutaric aciduria type I: (i) 3-OHGA causes the death of astrocytes, (ii) deficiency of the astrocytic enzyme glutamine synthetase leads to intracerebral ammonium accumulation, and (iii) high ammonium triggers secondary death of other brain cells. These unexpected findings need to be further investigated and verified in vivo. They suggest that intracerebral ammonium accumulation might be an important target for the development of more effective treatment strategies to prevent brain damage in patients with glutaric aciduria type I.

Serpins promote cancer cell survival and vascular co-option in brain metastasis.

PubMed

Valiente, Manuel; Obenauf, Anna C; Jin, Xin; Chen, Qing; Zhang, Xiang H-F; Lee, Derek J; Chaft, Jamie E; Kris, Mark G; Huse, Jason T; Brogi, Edi; Massagué, Joan

2014-02-27

Brain metastasis is an ominous complication of cancer, yet most cancer cells that infiltrate the brain die of unknown causes. Here, we identify plasmin from the reactive brain stroma as a defense against metastatic invasion, and plasminogen activator (PA) inhibitory serpins in cancer cells as a shield against this defense. Plasmin suppresses brain metastasis in two ways: by converting membrane-bound astrocytic FasL into a paracrine death signal for cancer cells, and by inactivating the axon pathfinding molecule L1CAM, which metastatic cells express for spreading along brain capillaries and for metastatic outgrowth. Brain metastatic cells from lung cancer and breast cancer express high levels of anti-PA serpins, including neuroserpin and serpin B2, to prevent plasmin generation and its metastasis-suppressive effects. By protecting cancer cells from death signals and fostering vascular co-option, anti-PA serpins provide a unifying mechanism for the initiation of brain metastasis in lung and breast cancers. Copyright © 2014 Elsevier Inc. All rights reserved.

[Prognosis in pediatric traumatic brain injury. A dynamic cohort study].

PubMed

Vázquez-Solís, María G; Villa-Manzano, Alberto I; Sánchez-Mosco, Dalia I; Vargas-Lares, José de Jesús; Plascencia-Fernández, Irma

2013-01-01

traumatic brain injury is a main cause of hospital admission and death in children. Our objective was to identify prognostic factors of pediatric traumatic brain injury. this was a dynamic cohort study of traumatic brain injury with 6 months follow-up. The exposition was: mild or moderate/severe traumatic brain injury, searching for prognosis (morbidity-mortality and decreased Glasgow scale). Relative risk and logistic regression was estimated for prognostic factors. we evaluated 440 patients with mild traumatic brain injury and 98 with moderate/severe traumatic brain injury. Morbidity for mild traumatic brain injury was 1 %; for moderate/severe traumatic brain injury, 5 %. There were no deaths. Prognostic factors for moderate/severe traumatic brain injury were associated injuries (RR = 133), fractures (RR = 60), street accidents (RR = 17), night time accidents (RR = 2.3) and weekend accidents (RR = 2). Decreased Glasgow scale was found in 9 %, having as prognostic factors: visible injuries (RR = 3), grown-up supervision (RR = 2.5) and time of progress (RR = 1.6). there should be a prognosis established based on kinetic energy of the injury and not only with Glasgow Scale.

Head Trauma with or without Mild Brain Injury Increases the Risk of Future Traumatic Death: A Controlled Prospective 15-Year Follow-Up Study.

PubMed

Vaaramo, Kalle; Puljula, Jussi; Tetri, Sami; Juvela, Seppo; Hillbom, Matti

2015-10-15

Patients who have recovered from traumatic brain injury (TBI) show an increased risk of premature death. To investigate long-term mortality rates in a population admitted to the hospital for head injury (HI), we conducted a population-based prospective case-control, record-linkage study, All subjects who were living in Northern Ostrobothnia, and who were admitted to Oulu University Hospital in 1999 because of HI (n=737), and 2196 controls matched by age, gender, and residence randomly drawn from the population of Northern Ostrobothnia were included. Death rate and causes of death in HI subjects during 15 years of follow-up was compared with the general population controls. The crude mortality rates were 56.9, 18.6, and 23.8% for subjects having moderate-to-severe traumatic brain injury (TBI), mild TBI, and head injury without TBI, respectively. The corresponding approximate annual mortality rates were 6.7%, 1.4%, and 1.9%. All types of index HI predicted a significant risk of traumatic death in the future. Subjects who had HI without TBI had an increased risk of both death from all causes (hazard ratio 2.00; 95% confidence interval 1.57-2.55) and intentional or unintentional traumatic death (4.01, 2.20-7.30), compared with controls. The main founding was that even HI without TBI carries an increased risk of future traumatic death. The reason for this remains unknown and further studies are needed. To prevent such premature deaths, post-traumatic therapy should include an interview focusing on lifestyle factors.

Pathological characteristics of liver allografts from donation after brain death followed by cardiac death in pigs.

PubMed

Ye, Hui; Wang, Dong-Ping; Zhang, Chuan-Zhao; Zhang, Long-Juan; Wang, Hao-Chen; Li, Zhuo-Hui; Chen, Zhen; Zhang, Tao; Cai, Chang-Jie; Ju, Wei-Qiang; Ma, Yi; Guo, Zhi-Yong; He, Xiao-Shun

2014-10-01

Donation after brain death followed by circulatory death (DBCD) is a unique practice in China. The aim of this study was to define the pathologic characteristics of DBCD liver allografts in a porcine model. Fifteen male pigs (25-30 kg) were allocated randomly into donation after brain death (DBD), donation after circulatory death (DCD) and DBCD groups. Brain death was induced by augmenting intracranial pressure. Circulatory death was induced by withdrawal of life support in DBCD group and by venous injection of 40 mL 10% potassium chloride in DCD group. The donor livers were perfused in situ and kept in cold storage for 4 h. Liver tissue and common bile duct samples were collected for hematoxylin and eosin staining, TUNEL testing and electron microscopic examination. Spot necrosis was found in hepatic parenchyma of DBD and DBCD groups, while a large area of necrosis was shown in DCD group. The apoptosis rate of hepatocytes in DBD [(0.56±0.30)%] and DBCD [(0.50 ± 0.11)%] groups was much lower than that in DCD group [(3.78±0.33)%] (P<0.05). And there was no significant difference between DBD group and DBCD group (P>0.05)). The structures of bile duct were intact in both DBD and DBCD groups, while the biliary epithelium was totally damaged in DCD group. Under electron microscope, the DBD hepatocytes were characterized by intact cell membrane, well-organized endoplasmic reticulum, mild mitochondria edema and abundant glycogens. Broken cell membrane, mild inflammatory cell infiltration and sinusoidal epithelium edema, as well as reduced glycogen volume, were found in the DBCD hepatocytes. The DCD hepatocytes had more profound cell organelle injury and much less glycogen storage. In conclusion, the preservation injury of DBCD liver allografts is much less severe than that of un-controlled DCD, but more severe than that of DBD liver allografts under electron microscope, which might reflect post-transplant liver function to some extent.

Adrenergic Blockade Bi-directionally and Asymmetrically Alters Functional Brain-Heart Communication and Prolongs Electrical Activities of the Brain and Heart during Asphyxic Cardiac Arrest

PubMed Central

Tian, Fangyun; Liu, Tiecheng; Xu, Gang; Li, Duan; Ghazi, Talha; Shick, Trevor; Sajjad, Azeem; Wang, Michael M.; Farrehi, Peter; Borjigin, Jimo

2018-01-01

Sudden cardiac arrest is a leading cause of death in the United States. The neurophysiological mechanism underlying sudden death is not well understood. Previously we have shown that the brain is highly stimulated in dying animals and that asphyxia-induced death could be delayed by blocking the intact brain-heart neuronal connection. These studies suggest that the autonomic nervous system plays an important role in mediating sudden cardiac arrest. In this study, we tested the effectiveness of phentolamine and atenolol, individually or combined, in prolonging functionality of the vital organs in CO2-mediated asphyxic cardiac arrest model. Rats received either saline, phentolamine, atenolol, or phentolamine plus atenolol, 30 min before the onset of asphyxia. Electrocardiogram (ECG) and electroencephalogram (EEG) signals were simultaneously collected from each rat during the entire process and investigated for cardiac and brain functions using a battery of analytic tools. We found that adrenergic blockade significantly suppressed the initial decline of cardiac output, prolonged electrical activities of both brain and heart, asymmetrically altered functional connectivity within the brain, and altered, bi-directionally and asymmetrically, functional, and effective connectivity between the brain and heart. The protective effects of adrenergic blockers paralleled the suppression of brain and heart connectivity, especially in the right hemisphere associated with central regulation of sympathetic function. Collectively, our results demonstrate that blockade of brain-heart connection via alpha- and beta-adrenergic blockers significantly prolonged the detectable activities of both the heart and the brain in asphyxic rat. The beneficial effects of combined alpha and beta blockers may help extend the survival of cardiac arrest patients. PMID:29487541

The effect of brain death in rat steatotic and non-steatotic liver transplantation with previous ischemic preconditioning.

PubMed

Jiménez-Castro, Mónica B; Meroño, Noelia; Mendes-Braz, Mariana; Gracia-Sancho, Jordi; Martínez-Carreres, Laia; Cornide-Petronio, Maria Eugenia; Casillas-Ramirez, Araní; Rodés, Juan; Peralta, Carmen

2015-01-01

Most liver grafts undergoing transplantation derive from brain dead donors, which may also show hepatic steatosis, being both characteristic risk factors in liver transplantation. Ischemic preconditioning shows benefits when applied in non-brain dead clinical situations like hepatectomies, whereas it has been less promising in the transplantation from brain dead patients. This study examined how brain death affects preconditioned steatotic and non-steatotic liver grafts undergoing transplantation. Steatotic and non-steatotic grafts from non-brain dead and brain dead-donors were cold stored for 6h and then transplanted. After 2, 4, and 16 h of reperfusion, hepatic damage was analysed. In addition, two therapeutic strategies, ischemic preconditioning and/or acetylcholine pre-treatment, and their underlying mechanisms were characterized. Preconditioning benefits in non-brain dead donors were associated with nitric oxide and acetylcholine generation. In brain dead donors, preconditioning generated nitric oxide but did not promote acetylcholine upregulation, and this resulted in inflammation and damage. Acetylcholine treatment in brain dead donors, through PKC, increased antioxidants and reduced lipid peroxidation, nitrotyrosines and neutrophil accumulation, altogether protecting against damage. The combination of acetylcholine and preconditioning conferred stronger protection against damage, oxidative stress and neutrophil accumulation than acetylcholine treatment alone. These superior beneficial effects were due to a selective preconditioning-mediated generation of nitric oxide and regulation of PPAR and TLR4 pathways, which were not observed when acetylcholine was administered alone. Our findings propose the combination of acetylcholine+preconditioning as a feasible and highly protective strategy to reduce the adverse effects of brain death and to ultimately improve liver graft quality. Copyright © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Adrenergic Blockade Bi-directionally and Asymmetrically Alters Functional Brain-Heart Communication and Prolongs Electrical Activities of the Brain and Heart during Asphyxic Cardiac Arrest.

PubMed

Tian, Fangyun; Liu, Tiecheng; Xu, Gang; Li, Duan; Ghazi, Talha; Shick, Trevor; Sajjad, Azeem; Wang, Michael M; Farrehi, Peter; Borjigin, Jimo

2018-01-01

Sudden cardiac arrest is a leading cause of death in the United States. The neurophysiological mechanism underlying sudden death is not well understood. Previously we have shown that the brain is highly stimulated in dying animals and that asphyxia-induced death could be delayed by blocking the intact brain-heart neuronal connection. These studies suggest that the autonomic nervous system plays an important role in mediating sudden cardiac arrest. In this study, we tested the effectiveness of phentolamine and atenolol, individually or combined, in prolonging functionality of the vital organs in CO 2 -mediated asphyxic cardiac arrest model. Rats received either saline, phentolamine, atenolol, or phentolamine plus atenolol, 30 min before the onset of asphyxia. Electrocardiogram (ECG) and electroencephalogram (EEG) signals were simultaneously collected from each rat during the entire process and investigated for cardiac and brain functions using a battery of analytic tools. We found that adrenergic blockade significantly suppressed the initial decline of cardiac output, prolonged electrical activities of both brain and heart, asymmetrically altered functional connectivity within the brain, and altered, bi-directionally and asymmetrically, functional, and effective connectivity between the brain and heart. The protective effects of adrenergic blockers paralleled the suppression of brain and heart connectivity, especially in the right hemisphere associated with central regulation of sympathetic function. Collectively, our results demonstrate that blockade of brain-heart connection via alpha- and beta-adrenergic blockers significantly prolonged the detectable activities of both the heart and the brain in asphyxic rat. The beneficial effects of combined alpha and beta blockers may help extend the survival of cardiac arrest patients.

Latin American Consensus on the use of transcranial Doppler in the diagnosis of brain death

PubMed Central

2014-01-01

Transcranial Doppler evaluates cerebral hemodynamics in patients with brain injury and is a useful technical tool in diagnosing cerebral circulatory arrest, usually present in the brain-dead patient. This Latin American Consensus was formed by a group of 26 physicians experienced in the use of transcranial Doppler in the context of brain death. The purpose of this agreement was to make recommendations regarding the indications, technique, and interpretation of the study of transcranial ultrasonography in patients with a clinical diagnosis of brain death or in the patient whose clinical diagnosis presents difficulties; a working group was formed to enable further knowledge and to strengthen ties between Latin American physicians working on the same topic. A review of the literature, concepts, and experiences were exchanged in two meetings and via the Internet. Questions about pathophysiology, equipment, techniques, findings, common problems, and the interpretation of transcranial Doppler in the context of brain death were answered. The basic consensus statements are the following: cerebral circulatory arrest is the final stage in the evolution of progressive intracranial hypertension, which is visualized with transcranial Doppler as a "pattern of cerebral circulatory arrest". The following are accepted as the standard of cerebral circulatory arrest: reverberant pattern, systolic spikes, and absence of previously demonstrated flow. Ultrasonography should be used - in acceptable hemodynamic conditions - in the anterior circulation bilaterally (middle cerebral artery) and in the posterior (basilar artery) territory. If no ultrasonographic images are found in any or all of these vessels, their proximal arteries are acceptable to be studied to look for a a pattern of cerebral circulatory arrest. PMID:25295818

Endotoxin-activated microglia injure brain derived endothelial cells via NF-κB, JAK-STAT and JNK stress kinase pathways

PubMed Central

2011-01-01

Background We previously showed that microglia damage blood brain barrier (BBB) components following ischemic brain insults, but the underlying mechanism(s) is/are not well known. Recent work has established the contribution of toll-like receptor 4 (TLR4) activation to several brain pathologies including ischemia, neurodegeneration and sepsis. The present study established the requirement of microglia for lipopolysaccharide (LPS) mediated endothelial cell death, and explored pathways involved in this toxicity. LPS is a classic TLR4 agonist, and is used here to model aspects of brain conditions where TLR4 stimulation occurs. Methods/Results In monocultures, LPS induced death in microglia, but not brain derived endothelial cells (EC). However, LPS increased EC death when cocultured with microglia. LPS led to nitric oxide (NO) and inducible NO synthase (iNOS) induction in microglia, but not in EC. Inhibiting microglial activation by blocking iNOS and other generators of NO or blocking reactive oxygen species (ROS) also prevented injury in these cocultures. To assess the signaling pathway(s) involved, inhibitors of several downstream TLR-4 activated pathways were studied. Inhibitors of NF-κB, JAK-STAT and JNK/SAPK decreased microglial activation and prevented cell death, although the effect of blocking JNK/SAPK was rather modest. Inhibitors of PI3K, ERK, and p38 MAPK had no effect. Conclusions We show that LPS-activated microglia promote BBB disruption through injury to endothelial cells, and the specific blockade of JAK-STAT, NF-κB may prove to be especially useful anti-inflammatory strategies to confer cerebrovascular protection. PMID:21385378

Human Traumatic Brain Injury Results in Oligodendrocyte Death and Increases the Number of Oligodendrocyte Progenitor Cells.

PubMed

Flygt, Johanna; Gumucio, Astrid; Ingelsson, Martin; Skoglund, Karin; Holm, Jonatan; Alafuzoff, Irina; Marklund, Niklas

2016-06-01

Oligodendrocyte (OL) death may contribute to white matter pathology, a common cause of network dysfunction and persistent cognitive problems in patients with traumatic brain injury (TBI). Oligodendrocyte progenitor cells (OPCs) persist throughout the adult CNS and may replace dead OLs. OL death and OPCs were analyzed by immunohistochemistry of human brain tissue samples, surgically removed due to life-threatening contusions and/or focal brain swelling at 60.6 ± 75 hours (range 4-192 hours) postinjury in 10 severe TBI patients (age 51.7 ± 18.5 years). Control brain tissue was obtained postmortem from 5 age-matched patients without CNS disorders. TUNEL and CC1 co-labeling was used to analyze apoptotic OLs, which were increased in injured brain tissue (p < 0.05), without correlation with time from injury until surgery. The OPC markers Olig2, A2B5, NG2, and PDGFR-α were used. In contrast to the number of single-labeled Olig2, A2B5, NG2, and PDGFR-α-positive cells, numbers of Olig2 and A2B5 co-labeled cells were increased in TBI samples (p < 0.05); this was inversely correlated with time from injury to surgery (r = -0.8, p < 0.05). These results indicate that severe focal human TBI results in OL death and increases in OPCs postinjury, which may influence white matter function following TBI. © 2016 American Association of Neuropathologists, Inc. All rights reserved.

Pro-life role for c-Jun N-terminal kinase and p38 mitogen-activated protein kinase at rostral ventrolateral medulla in experimental brain stem death.

PubMed

Chang, Alice Y W

2012-11-17

Based on an experimental brain stem death model, we demonstrated previously that activation of the mitogen-activated protein kinase kinase 1/2 (MEK1/2)/extracellular signal-regulated kinase 1/2 (ERK1/2)/ mitogen-activated protein kinase signal-interacting kinase 1/2 (MNK1/2) cascade plays a pro-life role in the rostral ventrolateral medulla (RVLM), the origin of a life-and-death signal detected from systemic arterial pressure, which sequentially increases (pro-life) and decreases (pro-death) to reflect progressive dysfunction of central cardiovascular regulation during the advancement towards brain stem death in critically ill patients. The present study assessed the hypothesis that, in addition to ERK1/2, c-Jun NH2-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38MAPK), the other two mammalian members of MAPKs that are originally identified as stress-activated protein kinases, are activated specifically by MAPK kinase 4 (MAP2K4) or MAP2K6 and play a pro-life role in RVLM during experimental brain stem death. We further delineated the participation of phosphorylating activating transcriptional factor-2 (ATF-2) and c-Jun, the classical transcription factor activated by JNK or p38MAPK, in this process. An experimental model of brain stem death that employed microinjection of the organophosphate insecticide mevinphos (Mev; 10 nmol) bilaterally into RVLM of Sprague-Dawley rats was used, alongside cardiovascular, pharmacological and biochemical evaluations. Results from ELISA showed that whereas the total JNK, p38MAPK, MAP2K4 and MAP2K6 were not affected, augmented phosphorylation of JNK at Thr183 and Tyr185 and p38MAPK at Thr180 and Tyr182, accompanied by phosphorylation of their upstream activators MAP2K4 at Ser257 and Thr261 and MAP2K6 at Ser207 and Thr211 in RVLM occurred preferentially during the pro-life phase of experimental brain stem death. Moreover, the activity of transcription factors ATF-2 at Thr71 and c-Jun at Ser73, rather than Elk-1 at Ser383 in RVLM were also augmented during the pro-life phase. Furthermore, pretreatment by microinjection into the bilateral RVLM of specific JNK inhibitors, JNK inhibitor I (100 pmol) or SP600125 (5 pmol), or specific p38MAPK inhibitors, p38MAPK inhibitor III (500 pmol) or SB203580 (2 nmol), exacerbated the depressor effect and blunted the augmented life-and-death signal exhibited during the pro-life phase. On the other hand, pretreatment with the negative control for JNK or p38MAPK inhibitor, JNK inhibitor I negative control (100 pmol) or SB202474 (2 nmol), was ineffective in the vehicle-controls and Mev-treatment groups. Our results demonstrated that activation of JNK or p38MAPK in RVLM by their upstream activators MAP2K4 or MAP2K6 plays a preferential pro-life role by sustaining the central cardiovascular regulatory machinery during experimental brain stem death via phosphorylation and activation of nuclear transcription factor ATF-2 or c-Jun.

Donor brain death predisposes human kidney grafts to a proinflammatory reaction after transplantation.

PubMed

de Vries, D K; Lindeman, J H N; Ringers, J; Reinders, M E J; Rabelink, T J; Schaapherder, A F M

2011-05-01

Donor brain death has profound effects on post-transplantation graft function and survival. We hypothesized that changes initiated in the donor influence the graft's response to ischemia and reperfusion. In this study, human brain dead donor kidney grafts were compared to living and cardiac dead donor kidney grafts. Pretransplant biopsies of brain dead donor kidneys contained notably more infiltrating T lymphocytes and macrophages. To assess whether the different donor conditions result in a different response to reperfusion, local cytokine release from the reperfused kidney was studied by measurement of paired arterial and renal venous blood samples. Reperfusion of kidneys from brain dead donors was associated with the instantaneous release of inflammatory cytokines, such as G-CSF, IL-6, IL-9, IL-16 and MCP-1. In contrast, kidneys from living and cardiac dead donors showed a more modest cytokine response with release of IL-6 and small amounts of MCP-1. In conclusion, this study shows that donor brain death initiates an inflammatory state of the graft with T lymphocyte and macrophage infiltration and massive inflammatory cytokine release upon reperfusion. These observations suggest that brain dead donors require a novel approach for donor pretreatment aimed at preventing this inflammatory response to increase graft survival. ©2011 The Authors Journal compilation©2011 The American Society of Transplantation and the American Society of Transplant Surgeons.

Intravascular Inflammation Triggers Intracerebral Activated Microglia and Contributes to Secondary Brain Injury After Experimental Subarachnoid Hemorrhage (eSAH).

PubMed

Atangana, Etienne; Schneider, Ulf C; Blecharz, Kinga; Magrini, Salima; Wagner, Josephin; Nieminen-Kelhä, Melina; Kremenetskaia, Irina; Heppner, Frank L; Engelhardt, Britta; Vajkoczy, Peter

2017-04-01

Activation of innate immunity contributes to secondary brain injury after experimental subarachnoid hemorrhage (eSAH). Microglia accumulation and activation within the brain has recently been shown to induce neuronal cell death after eSAH. In isolated mouse brain capillaries after eSAH, we show a significantly increased gene expression for intercellular adhesion molecule-1 (ICAM-1) and P-selectin. Hence, we hypothesized that extracerebral intravascular inflammatory processes might initiate the previously reported microglia accumulation within the brain tissue. We therefore induced eSAH in knockout mice for ICAM-1 (ICAM-1 -/- ) and P-selectin glycoprotein ligand-1 (PSGL-1 -/- ) to find a significant decrease in neutrophil-endothelial interaction within the first 7 days after the bleeding in a chronic cranial window model. This inhibition of neutrophil recruitment to the endothelium results in significantly ameliorated microglia accumulation and neuronal cell death in knockout animals in comparison to controls. Our results suggest an outside-in activation of the CNS innate immune system at the vessel/brain interface following eSAH. Microglia cells, as part of the brain's innate immune system, are triggered by an inflammatory reaction in the microvasculature after eSAH, thus contributing to neuronal cell death. This finding offers a whole range of new research targets, as well as possible therapy options for patients suffering from eSAH.

Critical Role of the Sphingolipid Pathway in Stroke: a Review of Current Utility and Potential Therapeutic Targets.

PubMed

Sun, Na; Keep, Richard F; Hua, Ya; Xi, Guohua

2016-10-01

Sphingolipids are a series of cell membrane-derived lipids which act as signaling molecules and play a critical role in cell death and survival, proliferation, recognition, and migration. Sphingosine-1-phosphate acts as a key signaling molecule and regulates lymphocyte trafficking, glial cell activation, vasoconstriction, endothelial barrier function, and neuronal death pathways which plays a critical role in numerous neurological conditions. Stroke is a second leading cause of death all over the world and effective therapies are still in great demand, including ischemic stroke and hemorrhagic stroke as well as poststroke repair. Significantly, sphingolipid activities change after stroke and correlate with stroke outcome, which has promoted efforts to testify whether the sphingolipid pathway could be a novel therapeutic target in stroke. The sphingolipid metabolic pathway, the connection between the pathway and stroke, as well as therapeutic interventions to manipulate the pathway to reduce stroke-induced brain injury are discussed in this review.

Process and barriers to organ donation and causes of brain death in northeast of Iran.

PubMed

Bahrami, Abdollah; Khaleghi, Ebrahim; Vakilzadeh, Ali Khorsand; Afzalaghaee, Monavar

2017-02-01

Organ transplantation is the treatment of choice for some diseases. However, the need for cadaveric organ donation has either plateaued or is on a decreasing trend in some countries, especially in developed ones. In this study, we aimed to identify the barriers to organ donation in brain dead patients, who were referred to the organ procurement organizations (OPO) in northeast Iran. In this cross-sectional study during 2006 to 2013, data were collected from medical records of brain dead patients. Demographic information, cause of brain death, the process of obtaining informed consent, and the reasons for declining organ donation were obtained from the OPO records. The data were analyzed using chi-square test by SPSS 13 software. Of 1034 brain dead patients, 751 cases (72.6%) were eligible for organ donation, and, ultimately, 344 cases underwent organ donation. The rate of organ donation increased during the course of the study; medical and legal reasons as well as family refusal to authorize donation were the main barriers to the process. Based on the pattern of mortality, the need for living donors in developing countries, such as Iran and other countries in the Mediterranean region, can be reduced by improving the quality of healthcare, efficient identification of brain death, and obtaining consent with appropriate strategies.

Brain Death and Human Organismal Integration: A Symposium on the Definition of Death.

PubMed

Moschella, Melissa

2016-06-01

Does the ability of some brain dead bodies to maintain homeostasis with the help of artificial life support actually imply that those bodies are living human organisms? Or might it be possible that a brain dead body on life support is a mere collection of still-living cells, organs and tissues which can coordinate with one another, but which lack the genuine integration that is the hallmark of a unified human organism as a whole? To foster further study of these difficult and timely questions, a Symposium on the Definition of Death was held at The Catholic University of America in June 2014. The Symposium brought together scholars from a variety of disciplines-law, medicine, biology, philosophy and theology-who all share a commitment to the dead donor rule and to a biological definition of death, but who have differing opinions regarding the validity of neurological criteria for human death. The papers found in this special issue are among the fruits of this Symposium. © The Author 2016. Published by Oxford University Press, on behalf of the Journal of Medicine and Philosophy Inc. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Anesthesia Management of Organ Donors.

PubMed

Xia, Victor W; Braunfeld, Michelle

2017-09-01

The shortage of suitable organs is the biggest obstacle for transplants. At present, most organs for transplant in the United States are from donation after neurologic determination of death (brain death). Potential organs for transplant need to maintain their viability during a series of insults, including the original disease, physiologic derangements during the dying process, ischemia, and reperfusion. Proper donor management before, during, and after procurement has potential to increase the number and quality of organs from donors. Anesthesiologists need to understand the physiologic derangements associated with brain death and the updated donor management during the periprocurement period. Copyright © 2017 Elsevier Inc. All rights reserved.

Legal Standards for Brain Death and Undue Influence in Euthanasia Laws.

PubMed

Pope, Thaddeus Mason; Okninski, Michaela E

2016-06-01

A major appellate court decision from the United States seriously questions the legal sufficiency of prevailing medical criteria for the determination of death by neurological criteria. There may be a mismatch between legal and medical standards for brain death, requiring the amendment of either or both. In South Australia, a Bill seeks to establish a legal right for a defined category of persons suffering unbearably to request voluntary euthanasia. However, an essential criterion of a voluntary decision is that it is not tainted by undue influence, and this Bill falls short of providing adequate guidance to assess for undue influence.

Alcohol-induced apoptosis of oligodendrocytes in the fetal macaque brain.

PubMed

Creeley, Catherine E; Dikranian, Krikor T; Johnson, Stephen A; Farber, Nuri B; Olney, John W

2013-06-12

In utero exposure of the fetal non-human primate (NHP) brain to alcohol on a single occasion during early or late third-trimester gestation triggers widespread acute apoptotic death of cells in both gray and white matter (WM) regions of the fetal brain. In a prior publication, we documented that the dying gray matter cells are neurons, and described the regional distribution and magnitude of this cell death response. Here, we present new findings regarding the magnitude, identity and maturational status of the dying WM cells in these alcohol-exposed fetal NHP brains. Our findings document that the dying WM cells belong to the oligodendrocyte (OL) lineage. OLs become vulnerable when they are just beginning to generate myelin basic protein in preparation for myelinating axons, and they remain vulnerable throughout later stages of myelination. We found no evidence linking astrocytes, microglia or OL progenitors to this WM cell death response. The mean density (profiles per mm3) of dying WM cells in alcohol-exposed brains was 12.7 times higher than the mean density of WM cells dying by natural apoptosis in drug-naive control brains. In utero exposure of the fetal NHP brain to alcohol on a single occasion triggers widespread acute apoptotic death of neurons (previous study) and of OLs (present study) throughout WM regions of the developing brain. The rate of OL apoptosis in alcohol-exposed brains was 12.7 times higher than the natural OL apoptosis rate. OLs become sensitive to the apoptogenic action of alcohol when they are just beginning to generate constituents of myelin in their cytoplasm, and they remain vulnerable throughout later stages of myelination. There is growing evidence for a similar apoptotic response of both neurons and OLs following exposure of the developing brain to anesthetic and anticonvulsant drugs. Collectively, this body of evidence raises important questions regarding the role that neuro and oligo apoptosis may play in the human condition known as fetal alcohol spectrum disorder (FASD), and also poses a question whether other apoptogenic drugs, although long considered safe for pediatric/obstetric use, may have the potential to cause iatrogenic FASD-like developmental disability syndromes.

Neuroinflamm-aging and neurodegenerative diseases: an overview.

PubMed

Pizza, Vincenzo; Agresta, Anella; D'Acunto, Cosimo W; Festa, Michela; Capasso, Anna

2011-08-01

Neuroinflammation is considered a chronic activation of the immune response in the central nervous system (CNS) in response to different injuries. This brain immune activation results in various events: circulating immune cells infiltrate the CNS; resident cells are activated; and pro-inflammatory mediators produced and released induce neuroinflammatory brain disease. The effect of immune diffusible mediators on synaptic plasticity might result in CNS dysfunction during neuroinflammatory brain diseases. The CNS dysfunction may induce several human pathological conditions associated with both cognitive impairment and a variable degree of neuroinflammation. Furthermore, age has a powerful effect on enhanced susceptibility to neurodegenerative diseases and age-dependent enhanced neuroinflammatory processes may play an important role in toxin generation that causes death or dysfunction of neurons in neurodegenerative diseases This review will address current understanding of the relationship between ageing, neuroinflammation and neurodegenerative disease by focusing on the principal mechanisms by which the immune system influences the brain plastic phenomena. Also, the present review considers the principal human neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis and psychiatric disorders caused by aging and neuroinflammation.

Nanotechnological strategies for nerve growth factor delivery: Therapeutic implications in Alzheimer's disease.

PubMed

Faustino, Célia; Rijo, Patrícia; Reis, Catarina Pinto

2017-06-01

Alzheimer's disease (AD) is a progressive neurodegenerative disorder associated with amyloid-β peptide misfolding and aggregation. Neurotrophic factors, such as nerve growth factor (NGF), can prevent neuronal damage and rescue the cholinergic neurons that undergo cell death in AD, reverse deposition of extracellular amyloid plaques and improve cognitive deficits. However, NGF administration is hampered by the poor pharmacokinetic profile of the therapeutic protein and its inability to cross the blood-brain barrier, which requires specialised drug delivery systems (DDS) for efficient NGF delivery to the brain. This review covers the main therapeutic approaches that have been developed for NGF delivery targeting the brain, from polymeric implants to gene and cell-based therapies, focusing on the role of nanoparticulate systems for the sustained release of NGF in the brain as a neuroprotective and disease-modifying approach toward AD. Lipid- and polymer-based delivery systems, magnetic nanoparticles and quantum dots are specifically addressed as promising nanotechnological strategies to overcome the current limitations of NGF-based therapies. Copyright © 2017 Elsevier Ltd. All rights reserved.

Site-targeted complement inhibition by a complement receptor 2-conjugated inhibitor (mTT30) ameliorates post-injury neuropathology in mouse brains.

PubMed

Rich, Megan C; Keene, Chesleigh N; Neher, Miriam D; Johnson, Krista; Yu, Zhao-Xue; Ganivet, Antoine; Holers, V Michael; Stahel, Philip F

2016-03-23

Intracerebral complement activation after severe traumatic brain injury (TBI) leads to a cascade of neuroinflammatory pathological sequelae that propagate host-mediated secondary brain injury and adverse outcomes. There are currently no specific pharmacological agents on the market to prevent or mitigate the development of secondary cerebral insults after TBI. A novel chimeric CR2-fH compound (mTT30) provides targeted inhibition of the alternative complement pathway at the site of tissue injury. This experimental study was designed to test the neuroprotective effects of mTT30 in a mouse model of closed head injury. The administration of 500 μg mTT30 i.v. at 1 h, 4 h and 24 h after head injury attenuated complement C3 deposition in injured brains, reduced the extent of neuronal cell death, and decreased post-injury microglial activation, compared to vehicle-injected placebo controls. These data imply that site-targeted alternative pathway complement inhibition may represent a new promising therapeutic avenue for the future management of severe TBI. Copyright © 2016. Published by Elsevier Ireland Ltd.

Chronic neurodegenerative consequences of traumatic brain injury.

PubMed

Chauhan, Neelima B

2014-01-01

Traumatic brain injury (TBI) is a serious public health concern and a major cause of death and disability worldwide. Each year, an estimated 1.7 million Americans sustain TBI of which ~52,000 people die, ~275,000 people are hospitalized and 1,365,000 people are treated as emergency outpatients. Currently there are ~5.3 million Americans living with TBI. TBI is more of a disease process than of an event that is associated with immediate and long-term sensomotor, psychological and cognitive impairments. TBI is the best known established epigenetic risk factor for later development of neurodegenerative diseases and dementia. People sustaining TBI are ~4 times more likely to develop dementia at a later stage than people without TBI. Single brain injury is linked to later development of symptoms resembling Alzheimer's disease while repetitive brain injuries are linked to later development of chronic traumatic encephalopathy (CTE) and/or Dementia Pugilistica (DP). Furthermore, genetic background of ß-amyloid precursor protein (APP), Apolipoprotein E (ApoE), presenilin (PS) and neprilysin (NEP) genes is associated with exacerbation of neurodegenerative process after TBI. This review encompasses acute effects and chronic neurodegenerative consequences after TBI.

Death, democracy and public ethical choice.

PubMed

Cushman, Reid; Holm, Soren

1990-07-01

The Danish Council of Ethics...believed that the brain-death criterion should not be accepted without public education and debate. Following the introduction of a spectrum of educational and related activites, a Gallup poll found that 98% of the survey population was aware of the debate over brain-vs-heart criteria and that 80% favoured the adoption of a supplemental brain-death standard... This raises the fundamental question of decisionmaking in pluralist democratic societies, of the limits of democratic involvement in such choices, and of the role of bodies like the Danish Council of Ethics... It must be part of the mission of a governmental bioethical body to use its peculiar expertise to teach and to lead -- to build a popular consensus out of confusion. But in doing so, such a Commission will be steering a dangerous course....

Neurostimulation to improve level of consciousness in patients with epilepsy.

PubMed

Gummadavelli, Abhijeet; Kundishora, Adam J; Willie, Jon T; Andrews, John P; Gerrard, Jason L; Spencer, Dennis D; Blumenfeld, Hal

2015-06-01

When drug-resistant epilepsy is poorly localized or surgical resection is contraindicated, current neurostimulation strategies such as deep brain stimulation and vagal nerve stimulation can palliate the frequency or severity of seizures. However, despite medical and neuromodulatory therapy, a significant proportion of patients continue to experience disabling seizures that impair awareness, causing disability and risking injury or sudden unexplained death. We propose a novel strategy in which neuromodulation is used not only to reduce seizures but also to ameliorate impaired consciousness when the patient is in the ictal and postictal states. Improving or preventing alterations in level of consciousness may have an effect on morbidity (e.g., accidents, drownings, falls), risk for death, and quality of life. Recent studies may have elucidated underlying networks and mechanisms of impaired consciousness and yield potential novel targets for neuromodulation. The feasibility, benefits, and pitfalls of potential deep brain stimulation targets are illustrated in human and animal studies involving minimally conscious/vegetative states, movement disorders, depth of anesthesia, sleep-wake regulation, and epilepsy. We review evidence that viable therapeutic targets for impaired consciousness associated with seizures may be provided by key nodes of the consciousness system in the brainstem reticular activating system, hypothalamus, basal ganglia, thalamus, and basal forebrain.

Nodding syndrome since 2012: recent progress, challenges and recommendations for future research.

PubMed

Colebunders, R; Post, R; O'Neill, S; Haesaert, G; Opar, B; Lakwo, T; Laudisoit, A; Hendy, A

2015-02-01

We aim to review the current epidemiology of nodding syndrome (NS) and discuss relevant gaps in research. NS and convulsive epilepsy of unknown aetiology are clustered within the same villages and families in onchocerciasis-endemic areas. They are therefore potentially different clinical expressions of the same disease. It has been difficult to perform full autopsies on NS patients who die in remote villages. Adequate fixation of tissue immediately after death is critical for the examination of brain tissue. Therefore, post-mortem transsphenoidal brain biopsies, performed immediately after death by trained nurses, will provide the best option for obtaining tissue for analysis. We suspect that certain blackflies in onchocerciasis-endemic areas may transmit a novel pathogen that could cause NS and epilepsy. This is supported by a recent drop in the number of new NS cases coinciding with vector control activities aimed at reducing blackfly populations in northern Uganda. We propose that metagenomic studies of human samples, blackflies and microfilariae are conducted to screen for pathogens, and that a clinical trial is planned to evaluate the impact of larviciding against NS and epilepsy epidemics. © 2014 John Wiley & Sons Ltd.

Experimental methods for testing the effects of neurotrophic peptide, ADNF-9, against alcohol-induced apoptosis during pregnancy in c57bl/6 mice.

PubMed

Sari, Youssef

2013-04-24

Experimental designs for investigating the effects of prenatal alcohol exposure during early embryonic stages in fetal brain growth are challenging. This is mostly due to the difficulty of microdissection of fetal brains and their sectioning for determination of apoptotic cells caused by prenatal exposure to alcohol. The experiments described here provide visualized techniques from mice breeding to the identification of cell death in fetal brain tissue. This study used C57BL/6 mice as the animal model for studying fetal alcohol exposure and the role of trophic peptide against alcohol-induced apoptosis. The breeding consists of a 2-hr matting window to determine the exact stage of embryonic age. An established fetal alcohol exposure model has been used in this study to determine the effects of prenatal alcohol exposure in fetal brains. This involves free access to alcohol or pair-fed liquid diets as the sole source of nutrients for the pregnant mice. The techniques involving dissection of fetuses and microdissection of fetal brains are described carefully, since the latter can be challenging. Microdissection requires a stereomicroscope and ultra-fine forceps. Step-by-step procedures for dissecting the fetal brains are provided visually. The fetal brains are dissected from the base of the primordium olfactory bulb to the base of the metencephalon. For investigating apoptosis, fetal brains are first embedded in gelatin using a peel-away mold to facilitate their sectioning with a vibratome apparatus. Fetal brains embedded and fixed in paraformaldehyde are easily sectioned, and the free floating sections can be mounted in superfrost plus slides for determination of apoptosis or cell death. TUNEL (TdT-mediated dUTP Nick End Labeling; TdT: terminal deoxynucleotidyl transferase) assay has been used to identify cell death or apoptotic cells. It is noteworthy that apoptosis and cell-mediated cytotoxicity are characterized by DNA fragmentation. Thus, the visualized TUNEL-positive cells are indicative of cell death or apoptotic cells. The experimental designs here provide information about the use of an established liquid diet for studying the effects of alcohol and the role of neurotrophic peptides during pregnancy in fetal brains. This involves breeding and feeding pregnant mice, microdissecting fetal brains, and determining apoptosis. Together, these visual and textual techniques might be a source for investigating prenatal exposure of harmful agents in fetal brains.

Apoptosis and brain ischaemia.

PubMed

Love, Seth

2003-04-01

There is increasing evidence that some neuronal death after brain ischaemia is mediated by the action of cysteine-requiring aspartate-directed proteases (caspases), the proteases responsible for apoptosis in mammals, although this form of neuronal death is not always accompanied by the morphological changes that are typical of apoptosis in other tissues. Caspase-mediated neuronal death is more extensive after transient than permanent focal brain ischaemia and may contribute to delayed loss of neurons from the penumbral region of infarcts. The activation of caspases after brain ischaemia is largely consequent on the translocation of Bax, Bak, and other BH3-only members of the Bcl-2 family to the mitochondrial outer membrane and the release of cytochrome c, procaspase-9, and apoptosis activating factor-1 (Apaf-1) from the mitochondrial intermembrane space. How exactly ischaemia induces this translocation is still poorly understood. NF-kappaB, the c-jun N-terminal kinase-c-Jun pathway, p53, E2F1, and other transcription factors are probably all involved in regulating the expression of BH3-only proteins after brain ischaemia, and mitochondrial translocation of Bad from sequestering cytosolic proteins is promoted by inactivation of the serine-threonine kinase, Akt. Other processes that are probably involved in the activation of caspases after brain ischaemia include the mitochondrial release of the second mitochondrial activator of caspases (Smac) or direct inhibitor-of-apoptosis-binding protein with low pI (DIABLO), the accumulation of products of lipid peroxidation, a marked reduction in protein synthesis, and the aberrant reentry of neurons into the cell cycle. Non-caspase-mediated neuronal apoptosis may also occur, but there is little evidence to date that this makes a significant contribution to brain damage after ischaemia. The intracellular processes that contribute to caspase-mediated neuronal death after ischaemia are all potential targets for therapy. However, anti-apoptotic interventions in stroke patients will require detailed evaluation using a range of outcome measures, as some such interventions seem simply to delay neuronal death and others to preserve neurons but not neuronal function.

Factors associated with resistance to dementia despite high Alzheimer disease pathology.

PubMed

Erten-Lyons, D; Woltjer, R L; Dodge, H; Nixon, R; Vorobik, R; Calvert, J F; Leahy, M; Montine, T; Kaye, J

2009-01-27

Autopsy series have shown that some elderly people remain with normal cognitive function during life despite having high burdens of pathologic lesions associated with Alzheimer disease (AD) at death. Understanding why these individuals show no cognitive decline, despite high AD pathologic burdens, may be key to discovery of neuroprotective mechanisms. A total of 36 subjects who on autopsy had Braak stage V or VI and moderate or frequent neuritic plaque scores based on Consortium to Establish a Registry for Alzheimer's Disease (CERAD) standards were included. Twelve had normal cognitive function and 24 a diagnosis of AD before death. Demographic characteristics, clinical and pathologic data, as well as antemortem brain volumes were compared between the groups. In multiple regression analysis, antemortem hippocampal and total brain volumes were significantly larger in the group with normal cognitive function after adjusting for gender, age at MRI, time from MRI to death, Braak stage, CERAD neuritic plaque score, and overall presence of vascular disease. Larger brain and hippocampal volumes were associated with preserved cognitive function during life despite a high burden of Alzheimer disease (AD) pathologic lesions at death. A better understanding of processes that lead to preservation of brain volume may provide important clues for the discovery of mechanisms that protect the elderly from AD.

Postischemic dementia with Alzheimer phenotype: selectively vulnerable versus resistant areas of the brain and neurodegeneration versus β-amyloid peptide.

PubMed

Pluta, Ryszard; Jabłoński, Mirosław; Czuczwar, Stanisław J

2012-01-01

The road to clarity for postischemic dementia mechanisms has been one fraught with a wide range of complications and numerous revisions with a lack of a final solution. Importantly, brain ischemia is a leading cause of death and cognitive impairment worldwide. However, the mechanisms of progressive cognitive decline following brain ischemia are not yet certain. Data from animal models and clinical pioneering studies of brain ischemia have demonstrated an increase in expression and processing of amyloid precursor protein to a neurotoxin oligomeric β-amyloid peptide. Functional and memory brain restoration after ischemic brain injury is delayed and incomplete due to a lesion related increase in the amount of the neurotoxin amyloid protein. Moreover, ischemic injury is strongly accelerated by aging, too. In this review, we will present our current thinking about biogenesis of amyloid from the amyloid precursor protein in ischemic brain injury, and how this factor presents etiological, therapeutic and diagnostic targets that are now under consideration. Progressive injury of the ischemic brain parenchyma may be caused not only by degeneration of selectively vulnerable neurons destroyed during ischemia but also by acute and chronic damage of resistant areas of the brain and progressive damage in the blood-brain barrier. We propose that in postischemic dementia an initial ischemic injury precedes the cerebrovascular and brain parenchyma accumulation of Alzheimer disease related neurotoxin β-amyloid peptide, which in turn amplifies the neurovascular dysfunction triggering focal ischemic episodes as a vicious cycle preceding final neurodegenerative pathology. Persistent ischemic blood-brain barrier insufficiency with accumulation of neurotoxin β-amyloid protein in the brain tissue, especially in extracellular perivascular space and blood-brain barrier microvessels, may gradually, over a lifetime, progress to brain atrophy and to full-blown ischemic dementia with Alzheimer phenotype.

Brain Swelling and Loss of Gray and White Matter Differentiation in Human Postmortem Cases by Computed Tomography.

PubMed

Shirota, Go; Gonoi, Wataru; Ishida, Masanori; Okuma, Hidemi; Shintani, Yukako; Abe, Hiroyuki; Takazawa, Yutaka; Ikemura, Masako; Fukayama, Masashi; Ohtomo, Kuni

2015-01-01

The purpose of this study was to evaluate the brain by postmortem computed tomography (PMCT) versus antemortem computed tomography (AMCT) using brains from the same patients. We studied 36 nontraumatic subjects who underwent AMCT, PMCT, and pathological autopsy in our hospital between April 2009 and December 2013. PMCT was performed within 20 h after death, followed by pathological autopsy including the brain. Autopsy confirmed the absence of intracranial disorders that might be related to the cause of death or might affect measurements in our study. Width of the third ventricle, width of the central sulcus, and attenuation in gray matter (GM) and white matter (WM) from the same area of the basal ganglia, centrum semiovale, and high convexity were statistically compared between AMCT and PMCT. Both the width of the third ventricle and the central sulcus were significantly shorter in PMCT than in AMCT (P < 0.0001). GM attenuation increased after death at the level of the centrum semiovale and high convexity, but the differences were not statistically significant considering the differences in attenuation among the different computed tomography scanners. WM attenuation significantly increased after death at all levels (P<0.0001). The differences were larger than the differences in scanners. GM/WM ratio of attenuation was significantly lower by PMCT than by AMCT at all levels (P<0.0001). PMCT showed an increase in WM attenuation, loss of GM-WM differentiation, and brain swelling, evidenced by a decrease in the size of ventricles and sulci.

[Post-ischemic innate immunity and its application for novel therapeutic strategy targeting brain inflammation].

PubMed

Ito, Minako; Kondo, Taisuke; Shichita, Takashi; Yoshimura, Akihiko

2013-07-01

Stroke or brain ischemia is one of the major causes of death and disability worldwide. Post-ischemic inflammation is an essential step in the progression of brain ischemia-reperfusion injury. In a mouse stroke model, we have reported that IL-23 produced from infiltrating macrophages induces IL-17 producing T cells. IL-17 is mainly produced from gammadeltaT cells and promotes delayed (day 3-4) ischemic brain damage. We also demonstrated that peroxiredoxin (Prx) family proteins released extracellularly from necrotic brain cells induce expression of inflammatory cytokines including IL-23 in macrophages through activation of Toll-like receptor 2(TLR2) and TLR4, thereby promoting neural cell death. We thus propose that regulation of the IL-23-IL-17 axis including gammadeltaT cells, macrophages, and extracellular Prxs could be a potent neuroprotective tool.

Neurotrophin-4 regulates the survival of gustatory neurons earlier in development using a different mechanism than brain-derived neurotrophic factor.

PubMed

Patel, Ami V; Krimm, Robin F

2012-05-01

The number of neurons in the geniculate ganglion that are available to innervate taste buds is regulated by neurotrophin-4 (NT-4) and brain-derived neurotrophic factor (BDNF). Our goal for the current study was to examine the timing and mechanism of NT-4-mediated regulation of geniculate neuron number during development. We discovered that NT-4 mutant mice lose 33% of their geniculate neuronal cells between E10.5 and E11.5. By E11.5, geniculate axons have just reached the tongue and do not yet innervate their gustatory targets; thus, NT-4 does not function as a target-derived growth factor. At E11.5, no difference was observed in proliferating cells or the rate at which cells exit the cell cycle between NT-4 mutant and wild type ganglia. Instead, there was an increase in TUNEL-labeling, indicating an increase in cell death in Ntf4(-/-) mice compared with wild types. However, activated caspase-3, which is up-regulated in the absence of BDNF, was not increased. This finding indicates that cell death initiated by NT-4-removal occurs through a different cell death pathway than BDNF-removal. We observed no additional postnatal loss of taste buds or neurons in Ntf4(-/-) mice. Thus, during early embryonic development, NT-4 produced in the ganglion and along the projection pathway inhibits cell death through an activated caspase-3 independent mechanism. Therefore, compared to BDNF, NT-4 plays distinct roles in gustatory development; differences include timing, source of neurotrophin, and mechanism of action. Published by Elsevier Inc.

Brain-dead patients are not cadavers: the need to revise the definition of death in Muslim communities.

PubMed

Rady, Mohamed Y; Verheijde, Joseph L

2013-03-01

The utilitarian construct of two alternative criteria of human death increases the supply of transplantable organs at the end of life. Neither the neurological criterion (heart-beating donation) nor the circulatory criterion (non-heart-beating donation) is grounded in scientific evidence but based on philosophical reasoning. A utilitarian death definition can have unintended consequences for dying Muslim patients: (1) the expedited process of determining death for retrieval of transplantable organs can lead to diagnostic errors, (2) the equivalence of brain death with human death may be incorrect, and (3) end-of-life religious values and traditional rituals may be sacrificed. Therefore, it is imperative to reevaluate the two different types and criteria of death introduced by the Resolution (Fatwa) of the Council of Islamic Jurisprudence on Resuscitation Apparatus in 1986. Although we recognize that this Fatwa was based on best scientific evidence available at that time, more recent evidence shows that it rests on outdated knowledge and understanding of the phenomenon of human death. We recommend redefining death in Islam to reaffirm the singularity of this biological phenomenon as revealed in the Quran 14 centuries ago.

Organismal death, the dead-donor rule and the ethics of vital organ procurement.

PubMed

Symons, Xavier; Chua, Reginald Mary

2018-06-19

Several bioethicists have recently discussed the complexity of defining human death, and considered in particular how our definition of death affects our understanding of the ethics of vital organ procurement. In this brief paper, we challenge the mainstream medical definition of human death-namely, that death is equivalent to total brain failure-and argue with Nair-Collins and Miller that integrated biological functions can continue even after total brain failure has occurred. We discuss the implications of Nair-Collins and Miller's argument and suggest that it may be necessary to look for alternative biological markers that reliably indicate the death of a human being. We reject the suggestion that we should abandon the dead-donor criteria for organ donation. Rather than weaken the ethical standards for vital organ procurement, it may be necessary to make them more demanding. The aim of this paper is not to justify the dead donor rule. Rather, we aim to explore the perspective of those who agree with critiques of the whole brain and cardiopulmonary definitions of death but yet disagree with the proposal that we should abandon the dead-donor rule. We will consider what those who want to retain the dead-donor rule must argue in light of Nair-Collins and Miller's critique. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Deaths among adult patients with hypopituitarism: hypocortisolism during acute stress, and de novo malignant brain tumors contribute to an increased mortality.

PubMed

Burman, P; Mattsson, A F; Johannsson, G; Höybye, C; Holmer, H; Dahlqvist, P; Berinder, K; Engström, B E; Ekman, B; Erfurth, E M; Svensson, J; Wahlberg, J; Karlsson, F A

2013-04-01

Patients with hypopituitarism have an increased standardized mortality rate. The basis for this has not been fully clarified. To investigate in detail the cause of death in a large cohort of patients with hypopituitarism subjected to long-term follow-up. All-cause and cause-specific mortality in 1286 Swedish patients with hypopituitarism prospectively monitored in KIMS (Pfizer International Metabolic Database) 1995-2009 were compared to general population data in the Swedish National Cause of Death Registry. In addition, events reported in KIMS, medical records, and postmortem reports were reviewed. Standardized mortality ratios (SMR) were calculated, with stratification for gender, attained age, and calendar year during follow-up. An excess mortality was found, 120 deaths vs 84.3 expected, SMR 1.42 (95% confidence interval: 1.18-1.70). Infections, brain cancer, and sudden death were associated with significantly increased SMRs (6.32, 9.40, and 4.10, respectively). Fifteen patients, all ACTH-deficient, died from infections. Eight of these patients were considered to be in a state of adrenal crisis in connection with death (medical reports and post-mortem examinations). Another 8 patients died from de novo malignant brain tumors, 6 of which had had a benign pituitary lesion at baseline. Six of these 8 subjects had received prior radiation therapy. Two important causes of excess mortality were identified: first, adrenal crisis in response to acute stress and intercurrent illness; second, increased risk of a late appearance of de novo malignant brain tumors in patients who previously received radiotherapy. Both of these causes may be in part preventable by changes in the management of pituitary disease.

Knowledge of the Concept of Encephalic Death: Is This an Obstacle in the Acceptance of Donation and Transplantation of Organs Among Students of Nursing at the Medical University of Warsaw in Poland?

PubMed

Mikla, M; Rios, A; Lopez-Navas, A; Gotlib, J; Kilanska, D; Martinez-Alarcón, L; Ramis, G; Ramirez, P; Lopez Montesinos, M J

2016-09-01

The knowledge and acceptance of the concept of brain death among future health professionals is essential. The objective of this study was to analyze the knowledge of the concept of brain death among nursing students at the Medical University of Warsaw and determine the factors that affect it. Academic year 2011-2012, nursing students of the University of Poland. Sampling points in 5 compulsory-attendance nursing courses with a completion rate >80%. Validated questionnaire (PCID-DTO Rios), anonymous and self-administered. The completion rate was 96% (793/828); 71% (n = 561) knew the concept of brain death, 22% (n = 178) did not know it, and 7% (n = 54) did not know that it implies the death of the patient. Variables related to the correct knowledge: 1) to be studying in 4th year compared with 1st year (85% vs 60%; P ≤ .001); 2) discuss the subject with family (76% vs 61%; P ≤ .001); 3) discuss with friends (73% vs 63%; P = .009); and 4) having a favorable attitude toward organ donation (74% vs 65%; P = .011). In the multivariate analysis, the variables that remained independent were studying in 4th year (odds ratio [OR], 3.809; 95% confidence interval [CI], 2.006-5.823; P ≤ .001) and discussed with family concerning donation and transplantation (OR, 1.718; 95% CI, 1.241-2.381; P ≤ .001). One-third of the nursing students were unfamiliar with the concept of brain death. Copyright © 2016 Elsevier Inc. All rights reserved.

Annual report to the nation on the status of cancer, 1975-2007, featuring tumors of the brain and other nervous system.

PubMed

Kohler, Betsy A; Ward, Elizabeth; McCarthy, Bridget J; Schymura, Maria J; Ries, Lynn A G; Eheman, Christie; Jemal, Ahmedin; Anderson, Robert N; Ajani, Umed A; Edwards, Brenda K

2011-05-04

The American Cancer Society, the Centers for Disease Control and Prevention (CDC), the National Cancer Institute, and the North American Association of Central Cancer Registries (NAACCR) collaborate annually to provide updated information on cancer occurrence and trends in the United States. This year's report highlights brain and other nervous system (ONS) tumors, including nonmalignant brain tumors, which became reportable on a national level in 2004. Cancer incidence data were obtained from the National Cancer Institute, CDC, and NAACCR, and information on deaths was obtained from the CDC's National Center for Health Statistics. The annual percentage changes in age-standardized incidence and death rates (2000 US population standard) for all cancers combined and for the top 15 cancers for men and for women were estimated by joinpoint analysis of long-term (1992-2007 for incidence; 1975-2007 for mortality) trends and short-term fixed interval (1998-2007) trends. Analyses of malignant neuroepithelial brain and ONS tumors were based on data from 1980-2007; data on nonmalignant tumors were available for 2004-2007. All statistical tests were two-sided. Overall cancer incidence rates decreased by approximately 1% per year; the decrease was statistically significant (P < .05) in women, but not in men, because of a recent increase in prostate cancer incidence. The death rates continued to decrease for both sexes. Childhood cancer incidence rates continued to increase, whereas death rates continued to decrease. Lung cancer death rates decreased in women for the first time during 2003-2007, more than a decade after decreasing in men. During 2004-2007, more than 213 500 primary brain and ONS tumors were diagnosed, and 35.8% were malignant. From 1987-2007, the incidence of neuroepithelial malignant brain and ONS tumors decreased by 0.4% per year in men and women combined. The decrease in cancer incidence and mortality reflects progress in cancer prevention, early detection, and treatment. However, major challenges remain, including increasing incidence rates and continued low survival for some cancers. Malignant and nonmalignant brain tumors demonstrate differing patterns of occurrence by sex, age, and race, and exhibit considerable biologic diversity. Inclusion of nonmalignant brain tumors in cancer registries provides a fuller assessment of disease burden and medical resource needs associated with these unique tumors.

Characterization of Death in Neonatal Encephalopathy in the Hypothermia Era.

PubMed

Lemmon, Monica E; Boss, Renee D; Bonifacio, Sonia L; Foster-Barber, Audrey; Barkovich, A James; Glass, Hannah C

2017-03-01

This study aimed to characterize the circumstances of death in encephalopathic neonates treated with therapeutic hypothermia. Patients who died after or during treatment with therapeutic hypothermia between 2007-2014 were identified. Patient circumstance of death was characterized using an established paradigm. Thirty-one of 229 patients died (14%) at a median of 3 days of life. Most who died were severely encephalopathic on examination (90%) and had severely abnormal electroencephalographic (EEG) findings (87%). All those who had magnetic resonance images (n = 13) had evidence of moderate-severe brain injury; 6 had near-total brain injury. Cooling was discontinued prematurely in 61% of patients. Most patients (90%) were physiologically stable at the time of death; 81% died following elective extubation for quality of life considerations. Three patients (10%) died following withholding or removal of artificial hydration and nutrition. Characterization of death in additional cohorts is needed to identify differences in decision making practices over time and between centers.

Life and death of neurons in the aging brain

NASA Technical Reports Server (NTRS)

Morrison, J. H.; Hof, P. R.; Bloom, F. E. (Principal Investigator)

1997-01-01

Neurodegenerative disorders are characterized by extensive neuron death that leads to functional decline, but the neurobiological correlates of functional decline in normal aging are less well defined. For decades, it has been a commonly held notion that widespread neuron death in the neocortex and hippocampus is an inevitable concomitant of brain aging, but recent quantitative studies suggest that neuron death is restricted in normal aging and unlikely to account for age-related impairment of neocortical and hippocampal functions. In this article, the qualitative and quantitative differences between aging and Alzheimer's disease with respect to neuron loss are discussed, and age-related changes in functional and biochemical attributes of hippocampal circuits that might mediate functional decline in the absence of neuron death are explored. When these data are viewed comprehensively, it appears that the primary neurobiological substrates for functional impairment in aging differ in important ways from those in neurodegenerative disorders such as Alzheimer's disease.

[Causes of the people death from drunkenness and alcoholism].

PubMed

Erokhin, Iu A; Paukov, V S; Kirillov, Iu A

2012-01-01

We analyzed causes of 1008 people death, who abused by alcohol. Among them 2 groups were separated out: people died due to drunkenness and due to alcoholism. The structure of the death was similar in the both groups, however depended on alcoholism stages. The major cause of the death in group of drunkenness people was acute heart insufficiency, less commonly--lung pathology, and very rarely--brain vessels pathology and liver cirrhosis. In group of people, who died due to alcoholism, lung pathology was the major cause of these deaths, acute heart insufficiency was occurred less commonly, and very rare brain pathology because of delirium tremens or alcohol withdrawal syndrome, as so liver cirrhosis with complications. Hemorrhagic pancreonecrosis after alcoholic excess was found out in both groups, but it was more often in people, who died due to drunkenness. Obtained results show importance of chronic alcoholism identification as a disease with several stages including drunkenness and alcoholism.

Cylindromatosis mediates neuronal cell death in vitro and in vivo.

PubMed

Ganjam, Goutham K; Terpolilli, Nicole Angela; Diemert, Sebastian; Eisenbach, Ina; Hoffmann, Lena; Reuther, Christina; Herden, Christiane; Roth, Joachim; Plesnila, Nikolaus; Culmsee, Carsten

2018-01-19

The tumor-suppressor cylindromatosis (CYLD) is a deubiquitinating enzyme and key regulator of cell proliferation and inflammation. A genome-wide siRNA screen linked CYLD to receptor interacting protein-1 (RIP1) kinase-mediated necroptosis; however, the exact mechanisms of CYLD-mediated cell death remain unknown. Therefore, we investigated the precise role of CYLD in models of neuronal cell death in vitro and evaluated whether CYLD deletion affects brain injury in vivo. In vitro, downregulation of CYLD increased RIP1 ubiquitination, prevented RIP1/RIP3 complex formation, and protected neuronal cells from oxidative death. Similar protective effects were achieved by siRNA silencing of RIP1 or RIP3 or by pharmacological inhibition of RIP1 with necrostatin-1. In vivo, CYLD knockout mice were protected from trauma-induced brain damage compared to wild-type littermate controls. These findings unravel the mechanisms of CYLD-mediated cell death signaling in damaged neurons in vitro and suggest a cell death-mediating role of CYLD in vivo.

A Study on Nursing Students' Knowledge, Attitude, and Educational Needs for Brain-Death Organ Transplantation and Donation and Intent to Donate Organs.

PubMed

Ju, M K; Sim, M K; Son, S Y

2018-05-01

The purpose of this study was to identify the knowledge, attitude, educational needs, and will of nursing students on organ donation from brain-dead donors. Data were collected by using a 40-item questionnaire to measure knowledge, attitude, educational needs, and will for organ donation of 215 nursing college students in one university in Dangjin city from May 11 to May 31, 2017. The data were analyzed using SPSS 22 program (Data Solution Inc, Seoul). In the general characteristics, 85.1% of the subjects did not receive education on donation, and 99.5% of the subjects responded that education is needed. The desired methods of education were special lecture in school (55.3%), "webtoons" on the Internet (19.5%), formal curriculum (15.8%). Points to improve to increase brain-death organ transplantation and donation included "active publicity through pan-national campaign activities" (56.3%), "respecting prior consent from brain-dead donors" (21.9%), and "encouragement and increased support for organ donors" (12.1%). There was a significant difference in knowledge according to will for organ donation (t = 3.29, P = .001) and consent to brain-death organ donation in family members (t = 3.29, P = .001). There was a statistically significant positive correlation between attitude and knowledge of the subjects regarding brain-death organ donation. The knowledge, attitude, educational need, and will for organ donation of nursing students revealed in this study will be used as basic data to provide systematic transplant education including contents about organ transplantation in the regular nursing curriculum in the future. It will contribute to the activation of organ donation. Copyright © 2018 Elsevier Inc. All rights reserved.

Inhibition of activated NR2B gene- and caspase-3 protein-expression by glutathione following traumatic brain injury in a rat model

PubMed Central

Arifin, Muhammad Zafrullah; Faried, Ahmad; Shahib, Muhammad Nurhalim; Wiriadisastra, Kahdar; Bisri, Tatang

2011-01-01

Background. Traumatic brain injury (TBI) remains a major cause of death and disability. Oxidative stress is an important element of the injury cascade following TBI. Progressive compromise of antioxidant defenses and free radical-mediated lipid peroxidation are one of the major mechanisms of secondary TBI. NR2B is a glutamate receptor and its activation is caused by TBI increasing a brain cell death, along with caspase-3 as a hall mark of apoptosis. Glutathione is a potent free radical scavenger that might prevent secondary TBI damage and inhibited apoptosis. Materials and Methods. In the present study, it aims to demonstrate the effect of glutathione on inhibition of brain oxidative damage in a TBI rat model. Results. In this study, the expressions of mRNA NR2B in placebo group and groups with glutathione administration at 0, 3, and 6 hours after TBI were 328.14, 229.90, 178.50, and 136.14, respectively (P<0.001). The highest caspase-3 expression was shown in placebo group with 66.7% showing strong positive results (>80%); as expected, glutathione administered in 0, 3, and 6 hours groups had lower strong positive results of 50%, 16.7%, and 16.7%, respectively, (P=0.025). Conclusion. In conclusion, this study showed that glutathione administration in a TBI rat model decreased NR2B gene- and caspase-3 protein-expression that lead to the inhibition of brain cell death. Our results suggest that glutathione, as a potent free radical scavenger, has a brain cell protective effect against oxidative damage and cell death induced by TBI in rat model. PMID:22347327

Suicide, fatal injuries, and other causes of premature mortality in patients with traumatic brain injury: a 41-year Swedish population study.

PubMed

Fazel, Seena; Wolf, Achim; Pillas, Demetris; Lichtenstein, Paul; Långström, Niklas

2014-03-01

: Longer-term mortality in individuals who have survived a traumatic brain injury (TBI) is not known. To examine the relationship between TBI and premature mortality, particularly by external causes, and determine the role of psychiatric comorbidity. We studied all persons born in 1954 or later in Sweden who received inpatient and outpatient International Classification of Diseases-based diagnoses of TBI from 1969 to 2009 (n = 218,300). We compared mortality rates 6 months or more after TBI to general population controls matched on age and sex (n = 2,163,190) and to unaffected siblings of patients with TBI (n = 150,513). Furthermore, we specifically examined external causes of death (suicide, injury, or assault). We conducted sensitivity analyses to investigate whether mortality rates differed by sex, age at death, severity (including concussion), and different follow-up times after diagnosis. Adjusted odds ratios (AORs) of premature death by external causes in patients with TBI compared with general population controls. Among those who survived 6 months after TBI, we found a 3-fold increased odds of mortality (AOR, 3.2; 95% CI, 3.0-3.4) compared with general population controls and an adjusted increased odds of mortality of 2.6 (95% CI, 2.3-2.8) compared with unaffected siblings. Risks of mortality from external causes were elevated, including for suicide (AOR, 3.3; 95% CI, 2.9-3.7), injuries (AOR, 4.3; 95% CI, 3.8-4.8), and assault (AOR, 3.9; 95% CI, 2.7-5.7). Among those with TBI, absolute rates of death were high in those with any psychiatric or substance abuse comorbidity (3.8% died prematurely) and those with solely substance abuse (6.2%) compared with those without comorbidity (0.5%). Traumatic brain injury is associated with substantially elevated risks of premature mortality, particularly for suicide, injuries, and assaults, even after adjustment for sociodemographic and familial factors. Current clinical guidelines may need revision to reduce mortality risks beyond the first few months after injury and address high rates of psychiatric comorbidity and substance abuse.

Converging early responses to brain injury pave the road to epileptogenesis.

PubMed

Neuberger, Eric J; Gupta, Akshay; Subramanian, Deepak; Korgaonkar, Akshata A; Santhakumar, Vijayalakshmi

2017-11-29

Epilepsy, characterized by recurrent seizures and abnormal electrical activity in the brain, is one of the most prevalent brain disorders. Over two million people in the United States have been diagnosed with epilepsy and 3% of the general population will be diagnosed with it at some point in their lives. While most developmental epilepsies occur due to genetic predisposition, a class of "acquired" epilepsies results from a variety of brain insults. A leading etiological factor for epilepsy that is currently on the rise is traumatic brain injury (TBI), which accounts for up to 20% of all symptomatic epilepsies. Remarkably, the presence of an identified early insult that constitutes a risk for development of epilepsy provides a therapeutic window in which the pathological processes associated with brain injury can be manipulated to limit the subsequent development of recurrent seizure activity and epilepsy. Recent studies have revealed diverse pathologies, including enhanced excitability, activated immune signaling, cell death, and enhanced neurogenesis within a week after injury, suggesting a period of heightened adaptive and maladaptive plasticity. An integrated understanding of these processes and their cellular and molecular underpinnings could lead to novel targets to arrest epileptogenesis after trauma. This review attempts to highlight and relate the diverse early changes after trauma and their role in development of epilepsy and suggests potential strategies to limit neurological complications in the injured brain. © 2017 Wiley Periodicals, Inc.

Erythropoietin Ameliorates Neonatal Hypoxia-Ischemia-Induced Neurobehavioral Deficits, Neuroinflammation, and Hippocampal Injury in the Juvenile Rat

PubMed Central

Lan, Kuo-Mao; Tien, Lu-Tai; Cai, Zhengwei; Lin, Shuying; Pang, Yi; Tanaka, Sachiko; Rhodes, Philip G.; Bhatt, Abhay J.; Savich, Renate D.; Fan, Lir-Wan

2016-01-01

The hematopoietic growth factor erythropoietin (EPO) has been shown to be neuroprotective against hypoxia-ischemia (HI) in Postnatal Day 7 (P7)–P10 or adult animal models. The current study was aimed to determine whether EPO also provides long-lasting neuroprotection against HI in P5 rats, which is relevant to immature human infants. Sprague-Dawley rats at P5 were subjected to right common carotid artery ligation followed by an exposure to 6% oxygen with balanced nitrogen for 1.5 h. Human recombinant EPO (rEPO, at a dose of 5 units/g) was administered intraperitoneally one hour before or immediately after insult, followed by additional injections at 24 and 48 h post-insult. The control rats were injected with normal saline following HI. Neurobehavioral tests were performed on P8 and P20, and brain injury was examined on P21. HI insult significantly impaired neurobehavioral performance including sensorimotor, locomotor activity and cognitive ability on the P8 and P20 rats. HI insult also resulted in brain inflammation (as indicated by microglia activation) and neuronal death (as indicated by Jade B positive staining) in the white matter, striatum, cortex, and hippocampal areas of the P21 rat. Both pre- and post-treatment with rEPO significantly improved neurobehavioral performance and protected against the HI-induced neuronal death, microglia activation (OX42+) as well as loss of mature oligodendrocytes (APC-CC1+) and hippocampal neurons (Nissl+). The long-lasting protective effects of rEPO in the neonatal rat HI model suggest that to exert neurotrophic activity in the brain might be an effective approach for therapeutic treatment of neonatal brain injury induced by hypoxia-ischemia. PMID:26927081

Pro-life role for c-Jun N-terminal kinase and p38 mitogen-activated protein kinase at rostral ventrolateral medulla in experimental brain stem death

PubMed Central

2012-01-01

Background Based on an experimental brain stem death model, we demonstrated previously that activation of the mitogen-activated protein kinase kinase 1/2 (MEK1/2)/extracellular signal-regulated kinase 1/2 (ERK1/2)/ mitogen-activated protein kinase signal-interacting kinase 1/2 (MNK1/2) cascade plays a pro-life role in the rostral ventrolateral medulla (RVLM), the origin of a life-and-death signal detected from systemic arterial pressure, which sequentially increases (pro-life) and decreases (pro-death) to reflect progressive dysfunction of central cardiovascular regulation during the advancement towards brain stem death in critically ill patients. The present study assessed the hypothesis that, in addition to ERK1/2, c-Jun NH2-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38MAPK), the other two mammalian members of MAPKs that are originally identified as stress-activated protein kinases, are activated specifically by MAPK kinase 4 (MAP2K4) or MAP2K6 and play a pro-life role in RVLM during experimental brain stem death. We further delineated the participation of phosphorylating activating transcriptional factor-2 (ATF-2) and c-Jun, the classical transcription factor activated by JNK or p38MAPK, in this process. Results An experimental model of brain stem death that employed microinjection of the organophosphate insecticide mevinphos (Mev; 10 nmol) bilaterally into RVLM of Sprague–Dawley rats was used, alongside cardiovascular, pharmacological and biochemical evaluations. Results from ELISA showed that whereas the total JNK, p38MAPK, MAP2K4 and MAP2K6 were not affected, augmented phosphorylation of JNK at Thr183 and Tyr185 and p38MAPK at Thr180 and Tyr182, accompanied by phosphorylation of their upstream activators MAP2K4 at Ser257 and Thr261 and MAP2K6 at Ser207 and Thr211 in RVLM occurred preferentially during the pro-life phase of experimental brain stem death. Moreover, the activity of transcription factors ATF-2 at Thr71 and c-Jun at Ser73, rather than Elk-1 at Ser383 in RVLM were also augmented during the pro-life phase. Furthermore, pretreatment by microinjection into the bilateral RVLM of specific JNK inhibitors, JNK inhibitor I (100 pmol) or SP600125 (5 pmol), or specific p38MAPK inhibitors, p38MAPK inhibitor III (500 pmol) or SB203580 (2 nmol), exacerbated the depressor effect and blunted the augmented life-and-death signal exhibited during the pro-life phase. On the other hand, pretreatment with the negative control for JNK or p38MAPK inhibitor, JNK inhibitor I negative control (100 pmol) or SB202474 (2 nmol), was ineffective in the vehicle-controls and Mev-treatment groups. Conclusions Our results demonstrated that activation of JNK or p38MAPK in RVLM by their upstream activators MAP2K4 or MAP2K6 plays a preferential pro-life role by sustaining the central cardiovascular regulatory machinery during experimental brain stem death via phosphorylation and activation of nuclear transcription factor ATF-2 or c-Jun. PMID:23157661

Knowledge and attitudes of nurses on a regional neurological intensive therapy unit towards brain stem death and organ donation.

PubMed

Davies, C

1997-01-01

The study aimed to explore nurses knowledge and attitudes towards brain stem death and organ donation. An ex post facto research design was used to determine relationships between variables. A 16 item questionnaire was used to collect data. Statistical analysis revealed one significant result. The limitations of the sample size is acknowledged and the conclusion suggests a larger study is required.

Apoptotic cell death correlates with ROS overproduction and early cytokine expression after hypoxia-ischemia in fetal lambs.

PubMed

Alonso-Alconada, Daniel; Hilario, Enrique; Álvarez, Francisco José; Álvarez, Antonia

2012-07-01

Despite advances in neonatology, the hypoxic-ischemic injury in the perinatal period remains the single most important cause of brain injury in the newborn, leading to death or lifelong sequelae. Using a sheep model of intrauterine asphyxia, we evaluated the correlation between reactive oxygen species (ROS) overproduction, cytokine expression, and apoptotic cell death. Fetal lambs were assigned to sham group, nonasphyctic animals; and hypoxia-ischemia (HI) group, lambs subjected to 60 minutes of HI) by partial cord occlusion and sacrificed 3 hours later. Different brain regions were separated to quantify the number of apoptotic cells and the same territories were dissociated for flow cytometry studies. Our results suggest that the overproduction of ROS and the early increase in cytokine production after HI in fetal lambs correlate in a significant manner with the apoptotic index, as well as with each brain region evaluated.

Management to optimize organ procurement in brain dead donors.

PubMed

Mascia, L; Mastromauro, I; Viberti, S; Vincenzi, M; Zanello, M

2009-03-01

The demand for donor organs continues to exceed the number of organs available for transplantation. Many reasons may account for this discrepancy, such as the lack of consent, the absence of an experienced coordinator team able to solve logistical problems, the use of strict donor criteria, and suboptimal, unstandardized critical care management of potential organ donors. This has resulted in efforts to improve the medical care delivered to potential organ donors, so as to reduce organ shortages, improve organ procurement, and promote graft survival. The physiological changes that follow brain death entail a high incidence of complications jeopardizing potentially transplantable organs. Adverse events include cardiovascular changes, endocrine and metabolic disturbances, and disruption of internal homeostasis. Brain death also upregulates the release of pro-inflammatory molecules. Recent findings support the hypothesis that a preclinical lung injury characterized by an enhanced inflammatory response is present in potential donors and may predispose recipients to an adverse clinical prognosis following lung transplantation. In clinical practice, hypotension, diabetes insipidus, relative hypothermia, and natremia are more common than disseminated intravascular coagulation, cardiac arrhythmias, pulmonary oedema, acute lung injury, and metabolic acidosis. Strategies for the management of organ donors exist and consist of the normalization of donor physiology. Management has been complicated by the recent use of ''marginal'' donors and donors of advanced age or with ''extended'' criteria. Current guidelines suggest that the priority of critical care management for potential organ donors should be shifted from a ''cerebral protective'' strategy to a multimodal strategy aimed to preserve peripheral organ function.

Brain Volume as an Integrated Marker for the Risk of Death in a Community-Based Sample: Age Gene/Environment Susceptibility--Reykjavik Study.

PubMed

Van Elderen, Saskia S G C; Zhang, Qian; Sigurdsson, Sigudur; Haight, Thaddeus J; Lopez, Oscar; Eiriksdottir, Gudny; Jonsson, Palmi; de Jong, Laura; Harris, Tamara B; Garcia, Melissa; Gudnason, Vilmundar; van Buchem, Mark A; Launer, Lenore J

2016-01-01

Total brain volume is an integrated measure of health and may be an independent indicator of mortality risk independent of any one clinical or subclinical disease state. We investigate the association of brain volume to total and cause-specific mortality in a large nondemented stroke-free community-based cohort. The analysis includes 3,543 men and women (born 1907-1935) participating in the Age, Gene, Environment Susceptibility-Reykjavik Study. Participants with a known brain-related high risk for mortality (cognitive impairment or stroke) were excluded from these analyses. Quantitative estimates of total brain volume, white matter, white matter lesions, total gray matter (GM; cortical GM and subcortical GM separately), and focal cerebral vascular disease were generated from brain magnetic resonance imaging. Brain atrophy was expressed as brain tissue volume divided by total intracranial volume, yielding a percentage. Mean follow-up duration was 7.2 (0-10) years, with 647 deaths. Cox regression was used to analyze the association of mortality to brain atrophy, adjusting for demographics, cardiovascular risk factors, and cerebral vascular disease. Reduced risk of mortality was significantly associated with higher total brain volume (hazard ratio, 95% confidence interval = 0.71, 0.65-0.78), white matter (0.85, 0.78-0.93), total GM (0.74, 0.68-0.81), and cortical GM (0.78, 0.70-0.87). Overall, the associations were similar for cardiovascular and noncardiovascular-related deaths. Independent of multiple risk factors and cerebral vascular damage, global brain volume predicts mortality in a large nondemented stroke-free community-dwelling older cohort. Total brain volume may be an integrated measure reflecting a range of health and with further investigation could be a useful clinical tool when assessing risk for mortality. Published by Oxford University Press on behalf of the Gerontological Society of America 2014.

Cerebral Oximetry as an Auxiliary Diagnostic Tool in the Diagnosis of Brain Death.

PubMed

Tatli, O; Bekar, O; Imamoglu, M; Gonenc Cekic, O; Aygun, A; Eryigit, U; Karaca, Y; Sahin, A; Turkmen, S; Turedi, S

2017-10-01

To investigate the efficacy of cerebral oximetry (CO) as an auxiliary diagnostic tool in brain death (BD). This observational case-control study was performed on patients with suspected BD. Patients with diagnosis of BD confirmed by the brain death committee were enrolled as the BD group and other patients as the non-BD group. CO monitoring was performed at least 6 h, and cerebral tissue oxygen saturation (ScO 2 ) parameters were compared. Mean ScO 2 level in the BD group was lower than non-brain-dead patients: mean difference for right lobe = 6.48 (95% confidence interval [CI] 0.08-12.88) and for left lobe = 6.09 (95% CI -0.22-12.41). Maximum ScO 2 values in the BD group were significantly lower than the non-BD group: mean difference for right lobe = 8.20 (95% CI 1.64-14.77) and for left lobe = 9.54 (95% CI 3.06-16.03). The area under the curve for right lobe maximum ScO 2 was 0.69 (95% CI 0.55-0.81) and for left lobe was 0.72 (95% CI 0.58-0.84). Maximum ScO 2 in brain-dead patients at CO monitoring is significantly low. However, this cannot be used to differentiate brain-dead and non-brain-dead patients. CO monitoring is therefore not an appropriate auxiliary diagnostic tool for confirming BD. Copyright © 2017 Elsevier Inc. All rights reserved.

The profile of potential organ and tissue donors.

PubMed

Moraes, Edvaldo Leal de; Silva, Leonardo Borges de Barros E; Moraes, Tatiana Cristine de; Paixão, Nair Cordeiro dos Santos da; Izumi, Nelly Miyuki Shinohara; Guarino, Aparecida de Jesus

2009-01-01

This study aimed to characterize donors according to gender, age group, cause of brain death; quantify donors with hypernatremia, hyperpotassemia and hypopotassemia; and get to know which organs were the most used in transplantations. This quantitative, descriptive, exploratory and retrospective study was performed at the Organ Procurement Organization of the University of São Paulo Medical School Hospital das Clínicas. Data from the medical records of 187 potential donors were analyzed. Cerebrovascular accidents represented 53.48% of all brain death causes, sodium and potassium disorders occurred in 82.36% of cases and 45.46% of the potential donors were between 41 and 60 years old. The results evidenced that natural death causes exceeded traumatic deaths, and that most donors presented sodium and potassium alterations, likely associated to inappropriate maintenance.

Effects of mechanical ventilation on gene expression profiles in renal allografts from brain dead rats.

PubMed

Hottenrott, Maximilia C; Krebs, Joerg; Pelosi, Paolo; Luecke, Thomas; Rocco, Patricia R M; Sticht, Carsten; Breedijk, Annette; Yard, Benito; Tsagogiorgas, Charalambos

2017-12-01

Pathophysiological changes of brain death (BD) are impairing distal organ function and harming potential renal allografts. Whether ventilation strategies influence the quality of renal allografts from BD donors has not been thoroughly studied. 28 adult male Wistar rats were randomly assigned to four groups: 1) no brain death (NBD) with low tidal volume/low positive endexpiratory pressure (PEEP) titrated to minimal static elastance of the respiratory system (LVT/OLPEEP); 2) NBD with high tidal volume/low PEEP (HVT/LPEEP); 3) brain death (BD) with LVT/OLPEEP; and 4) BD with HVT/LPEEP. We hypothesized that HVT/LPEEP in BD leads to increased interleukin 6 (IL-6) gene expression and impairs potential renal allografts after six hours of mechanical ventilation. We assessed inflammatory cytokines in serum, genome wide gene expression profiles and quantitative PCR (qPCR) in kidney tissue. The influence of BD on renal gene-expression profiles was greater than the influence of the ventilation strategy. In BD, LVT ventilation did not influence the inflammatory parameters or kidney function in our experimental model. Copyright © 2017. Published by Elsevier B.V.

Update of clinical practice guidelines for brain death determination in an academic heath center.

PubMed

Jackson, Jennifer; Willmarth-Stec, Melissa; Shutter, Lori

2015-02-01

Brain death (BD) is determined after a patient has sustained some form of a catastrophic neurologic injury that results in an irreversible loss of cerebral and brain steam function. Variability is caused by the small number of patients who progress to BD annually causing a lack of opportunity for physicians and healthcare staff to stay competent in performing the examination. The current University of Cincinnati Medical Center policy on BD had not been updated since publication of the 2010 American Academy of Neurology guidelines on this subject. The diagnosis of BD in the medical community is an acceptable medical diagnosis, but the examination is difficult to perform, and explaining this diagnosis to a family can be challenging related to the emotions involved with discussing end of life. The goal of updating the current policy was to decrease variability in testing through consistency of practice among clinicians performing the examination. An integrative review of the evidence-based literature was conducted to identify articles discussing both BD confirmation and secondary confirmatory testing. Using this integrative review, results from hospital-based chart reviews, and targeted provider surveys, a policy update was completed. The bedside medical clinicians were provided this policy with evidence-based guidelines regarding performance of the clinical examination and confirmatory testing needed to diagnose BD and then communicate this diagnosis to the family. The current hospital policy lacked two important components of any BD policy: (a) the apnea test techniques and (b) guidance regarding secondary confirmatory testing. Both components were added during revision of the policy. Implementation of the new policy occurred through computer-based training that incorporated both didactic education of the updates and a video demonstration of a BD examination. A better defined policy for determining BD is essential. In addition, the implementation and quality assurance elements of the policy are necessary for efficiency and clinical decision making. By updating the policy within the University of Cincinnati Medical Center, the clinicians have been equipped with the latest evidence to perform the clinical examination for diagnosis of BD and then appropriately communicate this diagnosis to the family.

Using the endocannabinoid system as a neuroprotective strategy in perinatal hypoxic-ischemic brain injury

PubMed Central

Lara-Celador, I.; Goñi-de-Cerio, F.; Alvarez, Antonia; Hilario, Enrique

2013-01-01

One of the most important causes of brain injury in the neonatal period is a perinatal hypoxic-ischemic event. This devastating condition can lead to long-term neurological deficits or even death. After hypoxic-ischemic brain injury, a variety of specific cellular mechanisms are set in motion, triggering cell damage and finally producing cell death. Effective therapeutic treatments against this phenomenon are still unavailable because of complex molecular mechanisms underlying hypoxic-ischemic brain injury. After a thorough understanding of the mechanism underlying neural plasticity following hypoxic-ischemic brain injury, various neuroprotective therapies have been developed for alleviating brain injury and improving long-term outcomes. Among them, the endocannabinoid system emerges as a natural system of neuroprotection. The endocannabinoid system modulates a wide range of physiological processes in mammals and has demonstrated neuroprotective effects in different paradigms of acute brain injury, acting as a natural neuroprotectant. The aim of this review is to study the use of different therapies to induce long-term therapeutic effects after hypoxic-ischemic brain injury, and analyze the important role of the endocannabinoid system as a new neuroprotective strategy against perinatal hypoxic-ischemic brain injury. PMID:25206720

Cerebral and brainstem electrophysiologic activity during euthanasia with pentobarbital sodium in horses.

PubMed

Aleman, M; Williams, D C; Guedes, A; Madigan, J E

2015-01-01

An overdose of pentobarbital sodium administered i.v. is the most commonly used method of euthanasia in veterinary medicine. Determining death after the infusion relies on the observation of physical variables. However, it is unknown when cortical electrical activity and brainstem function are lost in a sequence of events before death. To examine changes in the electrical activity of the cerebral cortex and brainstem during an overdose of pentobarbital sodium solution for euthanasia. Our testing hypothesis is that isoelectric pattern of the brain in support of brain death occurs before absence of electrocardiogram (ECG) activity. Fifteen horses requiring euthanasia. Prospective observational study. Horses with neurologic, orthopedic, and cardiac illnesses were selected and instrumented for recording of electroencephalogram, electrooculogram, brainstem auditory evoked response (BAER), and ECG. Physical and neurologic (brainstem reflexes) variables were monitored. Loss of cortical electrical activity occurred during or within 52 seconds after the infusion of euthanasia solution. Cessation of brainstem function as evidenced by a lack of brainstem reflexes and disappearance of the BAER happened subsequently. Despite undetectable heart sounds, palpable arterial pulse, and mean arterial pressure, recordable ECG was the last variable to be lost after the infusion (5.5-16 minutes after end of the infusion). Overdose of pentobarbital sodium solution administered i.v. is an effective, fast, and humane method of euthanasia. Brain death occurs within 73-261 seconds of the infusion. Although absence of ECG activity takes longer to occur, brain death has already occurred. Copyright © 2015 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.

Deletion of a single allele of the Pex11β gene is sufficient to cause oxidative stress, delayed differentiation and neuronal death in mouse brain

PubMed Central

Ahlemeyer, Barbara; Gottwald, Magdalena; Baumgart-Vogt, Eveline

2012-01-01

SUMMARY Impaired neuronal migration and cell death are commonly observed in patients with peroxisomal biogenesis disorders (PBDs), and in mouse models of this diseases. In Pex11β-deficient mice, we observed that the deletion of a single allele of the Pex11β gene (Pex11β+/− heterozygous mice) caused cell death in primary neuronal cultures prepared from the neocortex and cerebellum, although to a lesser extent as compared with the homozygous-null animals (Pex11β−/− mice). In corresponding brain sections, cell death was rare, but differences between the genotypes were similar to those found in vitro. Because PEX11β has been implicated in peroxisomal proliferation, we searched for alterations in peroxisomal abundance in the brain of heterozygous and homozygous Pex11β-null mice compared with wild-type animals. Deletion of one allele of the Pex11β gene slightly increased the abundance of peroxisomes, whereas the deletion of both alleles caused a 30% reduction in peroxisome number. The size of the peroxisomal compartment did not correlate with neuronal death. Similar to cell death, neuronal development was delayed in Pex11β+/− mice, and to a further extent in Pex11β−/− mice, as measured by a reduced mRNA and protein level of synaptophysin and a reduced protein level of the mature isoform of MAP2. Moreover, a gradual increase in oxidative stress was found in brain sections and primary neuronal cultures from wild-type to heterozygous to homozygous Pex11β-deficient mice. SOD2 was upregulated in neurons from Pex11β+/− mice, but not from Pex11β−/− animals, whereas the level of catalase remained unchanged in neurons from Pex11β+/− mice and was reduced in those from Pex11β−/− mice, suggesting a partial compensation of oxidative stress in the heterozygotes, but a failure thereof in the homozygous Pex11β−/− brain. In conclusion, we report the alterations in the brain caused by the deletion of a single allele of the Pex11β gene. Our data might lead to the reconsideration of the clinical treatment of PBDs and the common way of using knockout mouse models for studying autosomal recessive diseases. PMID:21954064

Resveratrol and pinostilbene confer neuroprotection against aging-related deficits through an ERK1/2 dependent-mechanism

USDA-ARS?s Scientific Manuscript database

Age-related declines in motor function may be due, in part, to an increase in oxidative stress in the aging brain leading to death of brain cells that transmit dopamine (DA), one of the brain chemicals responsible for transmitting signals between brain nerve cells. We examined the neuroprotective ef...

Mechanisms of gender-linked ischemic brain injury

PubMed Central

Liu, Mingyue; Dziennis, Suzan; Hurn, Patricia D.; Alkayed, Nabil J.

2010-01-01

Biological sex is an important determinant of stroke risk and outcome. Women are protected from cerebrovascular disease relative to men, an observation commonly attributed to the protective effect of female sex hormones, estrogen and progesterone. However, sex differences in brain injury persist well beyond the menopause and can be found in the pediatric population, suggesting that the effects of reproductive steroids may not completely explain sexual dimorphism in stroke. We review recent advances in our understanding of sex steroids (estradiol, progesterone and testosterone) in the context of ischemic cell death and neuroprotection. Understanding the molecular and cell-based mechanisms underlying sex differences in ischemic brain injury will lead to a better understanding of basic mechanisms of brain cell death and is an important step toward designing more effective therapeutic interventions in stroke. PMID:19531872

One thousand consecutive in-hospital deaths following severe injury: Has the etiology of traumatic inpatient death changed in Canada?

PubMed Central

Roberts, Derek J.; Harzan, Christina; Kirkpatrick, Andrew W.; Dixon, Elijah; Grondin, Sean C.; McBeth, Paul B.; Kaplan, Gilaad G.

2018-01-01

Summary A wide range of factors have traditionally led to early in-hospital death following severe injury. The primary goal of this commentary was to evaluate the causes of early posttraumatic inpatient deaths over an extended period. Although early posttraumatic in-hospital death remains multifactorial, severe traumatic brain injuries are the dominant cause and have increased in proportion over time. Other traditional causes of death have also decreased owing to improved clinical care. PMID:29806810

Determination of death: Metaphysical and biomedical discourse.

PubMed

Jakušovaitė, Irayda; Luneckaitė, Žydrunė; Peičius, Eimantas; Bagdonaitė, Živilė; Riklikienė, Olga; Stankevičius, Edgaras

2016-01-01

The prominence of biomedical criteria relying on brain death reduces the impact of metaphysical, anthropological, psychosocial, cultural, religious, and legal aspects disclosing the real value and essence of human life. The aim of this literature review is to discuss metaphysical and biomedical approaches toward death and their complimentary relationship in the determination of death. A critical appraisal of theoretical and scientific evidence and legal documents supported analytical discourse. In the metaphysical discourse of death, two main questions about what human death is and how to determine the fact of death clearly separate the ontological and epistemological aspects of death. During the 20th century, various understandings of human death distinguished two different approaches toward the human: the human is a subject of activities or a subject of the human being. Extinction of the difference between the entities and the being, emphasized as rational-logical instrumentation, is not sufficient to understand death thoroughly. Biological criteria of death are associated with biological features and irreversible loss of certain cognitive capabilities. Debating on the question "Does a brain death mean death of a human being?" two approaches are considering: the body-centrist and the mind-centrist. By bridging those two alternatives human death appears not only as biomedical, but also as metaphysical phenomenon. It was summarized that a predominance of clinical criteria for determination of death in practice leads to medicalization of death and limits the holistic perspective toward individual's death. Therefore, the balance of metaphysical and biomedical approaches toward death and its determination would decrease the medicalization of the concept of death. Copyright © 2016 The Lithuanian University of Health Sciences. Production and hosting by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

Moderate zinc deficiency increases cell death after brain injury in the rat.

PubMed

Yeiser, E Carden; Vanlandingham, Jacob W; Levenson, Cathy W

2002-10-01

Zinc supplementation has been used clinically to reduce Zn losses and protein turnover in patients suffering from traumatic brain injury. Despite the known role of zinc in cell survival and integrity, the influence of zinc status on central nervous system wound healing in the weeks and months after brain injury has not been addressed. In this investigation, we examined cell death after unilateral cortical stab wounds in adult rats (n = 5 per group) that were provided diets containing adequate zinc (30 mg Zn/kg diet), supplemental zinc (180 mg/kg), or moderately deficient zinc (5 mg/kg). Four weeks following the brain injury there was a 1.82-2.65-fold increase in terminal deoxynucleotidyl transferase-mediated biotinylated dUTP nick-end labeling (TUNEL)-positive cells with DNA fragmentation at the site of injury in animals receiving a moderately zinc deficient diet compared to animals receiving a zinc-adequate or supplemented diet (p0.05). Examination of the nuclear morphology of these cells suggested the presence of both apoptosis and necrosis. Immunohistochemistry showed that the TUNEL-positive cells expressed both ED-1 and OX-42, identifying them as microglia/macrophages. Thus it appears that adequate zinc status may be necessary to minimize the amount of neuroimmune cell death after brain injury.

Dose-dependent lipopolysaccharide-induced fetal brain injury in the guinea pig.

PubMed

Harnett, Erica L; Dickinson, Michelle A; Smith, Graeme N

2007-08-01

This study determined whether a lipopolysaccharide (LPS) dose-dependent increase in fetal brain injury occurs to further characterize the relationship between maternal inflammation and fetal brain injury. Pregnant guinea pigs (n = 59) at 70% gestation were injected intraperitoneally with 1, 5, 25, 50, 100, 200, or 300 microg LPS per kilogram of maternal body weight or an equivalent volume of vehicle. Animals were killed 7 days later. Maternal serum and amniotic fluid samples were assayed for proinflammatory cytokines tumor necrosis factor-alpha, interleukin-1beta, and interleukin-6 using enzyme-linked immunosorbent assay kits. Fetal brains (n = 72) were stained for evidence of cell death with NeuroTACS stain. Seven days after LPS injections, cytokine concentrations in maternal serum and amniotic fluid were not different (P > .05) from controls. Levels of cell death in all brain regions examined were highest following the maternal administration of 300 mug/kg LPS (P < .05). The dose effect was brain region-dependent (P < .05). A threshold of maternal infection/inflammation exists, beyond which demonstrable fetal brain injury may result.

Clinical uses of brain natriuretic peptide in diagnosing and managing heart failure.

PubMed

Anderson, Kelley M

2008-06-01

To review current issues in the diagnosis, prognosis, and management of heart failure (HF), focusing on the clinical use of brain natriuretic peptide (BNP) as a diagnostic marker. Selective review of scientific literature and clinical practice guidelines. BNP is a useful clinical tool for the diagnosis, prognosis, and management of HF patients. Studies have consistently demonstrated high sensitivity, specificity, and negative predictive value of BNP levels in diagnostic situations. BNP cannot differentiate between systolic and diastolic HF. BNP can be used to assist in diagnosing HF in emergency and outpatient situations, particularly when the presenting symptom is dyspnea; determining HF prognosis, including predicting death and cardiac events; and potentially managing individuals with HF by determining safe discharge levels from acute care to avoid readmissions. BNP levels can vary depending on multiple confounders; therefore, clinical interpretation can be difficult.

The gut-brain interaction in opioid tolerance.

PubMed

Akbarali, Hamid I; Dewey, William L

2017-12-01

The prevailing opioid crisis has necessitated the need to understand mechanisms leading to addiction and tolerance, the major contributors to overdose and death and to develop strategies for developing drugs for pain treatment that lack abuse liability and side-effects. Opioids are commonly used for treatment of pain and symptoms of inflammatory bowel disease. The significant effect of opioids in the gut, both acute and chronic, includes persistent constipation and paradoxically may also worsen pain symptoms. Recent work has suggested a significant role of the gastrointestinal microbiome in behavioral responses to opioids, including the development of tolerance to its pain-relieving effects. In this review, we present current concepts of gut-brain interaction in analgesic tolerance to opioids and suggest that peripheral mechanisms emanating from the gut can profoundly affect central control of opioid function. Copyright © 2017 Elsevier Ltd. All rights reserved.

Neuregulin-1 is Neuroprotective in a Rat Model of Organophosphate-Induced Delayed Neuronal Injury

PubMed Central

Li, Yonggang; Lein, Pamela J.; Liu, Cuimei; Bruun, Donald A.; Giulivi, Cecilia; Ford, Gregory; Tewolde, Teclemichael; Ross-Inta, Catherine; Ford, Byron D.

2012-01-01

Current medical countermeasures against organophosphate (OP) nerve agents are effective in reducing mortality, but do not sufficiently protect the CNS from delayed brain damage and persistent neurological symptoms. In this study, we examined the efficacy of neuregulin-1 (NRG-1) in protecting against delayed neuronal cell death following acute intoxication with the OP diisopropylfluorophosphate (DFP). Adult male Sprague Dawley rats were pretreated with pyridostigmine (0.1 mg/kg BW, i.m.) and atropine methylnitrate (20 mg/kg BW, i.m.) prior to DFP (9 mg/kg BW, i.p.) intoxication to increase survival and reduce peripheral signs of cholinergic toxicity but not prevent DFP-induced seizures or delayed neuronal injury. Pretreatment with NRG-1 did not protect against seizures in rats exposed to DFP. However, neuronal injury was significantly reduced in most brain regions by pretreatment with NRG-1 isoforms NRG-EGF (3.2 μg/kg BW, i.a) or NRG-GGF2 (48 μg/kg BW, i.a.) as determined by FluroJade-B labeling in multiple brain regions at 24 h post-DFP injection. NRG-1 also blocked apoptosis and oxidative stress-mediated protein damage in the brains of DFP-intoxicated rats. Administration of NRG-1 at 1 h after DFP injection similarly provided significant neuroprotection against delayed neuronal injury. These findings identify NRG-1 as a promising adjuvant therapy to current medical countermeasures for enhancing neuroprotection against acute OP intoxication. PMID:22583949

Reye Syndrome

MedlinePlus

Reye syndrome is a rare illness that can affect the blood, liver, and brain of someone who has recently ... a viral illness, seek medical attention immediately. Reye syndrome can lead to a coma and brain death, ...

Improving the Outcomes of Organs Obtained From Controlled Donation After Circulatory Death Donors Using Abdominal Normothermic Regional Perfusion.

PubMed

Miñambres, E; Suberviola, B; Dominguez-Gil, B; Rodrigo, E; Ruiz-San Millan, J C; Rodríguez-San Juan, J C; Ballesteros, M A

2017-08-01

The use of donation after circulatory death (DCD) has increased significantly during the past decade. However, warm ischemia results in a greater risk for transplantation. Indeed, controlled DCD (cDCD) was associated with inferior outcomes compared with donation after brain death. The use of abdominal normothermic regional perfusion (nRP) to restore blood flow before organ recovery in cDCD has been proposed as better than rapid recovery to reverse the effect of ischemia and improve recipients' outcome. Here, the first Spanish series using abdominal nRP as an in situ conditioning method is reported. A specific methodology to avoid restoring circulation to the brain after death determination is described. Twenty-seven cDCD donors underwent abdominal nRP during at least 60 min. Thirty-seven kidneys, 11 livers, six bilateral lungs, and one pancreas were transplanted. The 1-year death-censored kidney survival was 91%, and delayed graft function rate was 27%. The 1-year liver survival rate was 90.1% with no cases of ischemic cholangiopathy. Transplanted lungs and pancreas exhibited primary function. The use of nRP may represent an advance to increase the number and quality of grafts in cDCD. Poor results in cDCD livers could be reversed with nRP. Concerns about restoring brain circulation after death are easily solved. © 2017 The American Society of Transplantation and the American Society of Transplant Surgeons.

Non-invasive monitoring of hemodynamic changes in orthotropic brain tumor

NASA Astrophysics Data System (ADS)

Kashyap, Dheerendra; Sharma, Vikrant; Liu, Hanli

2007-02-01

Radio surgical interventions such as Gamma Knife and Cyberknife have become attractive as therapeutic interventions. However, one of the drawbacks of cyberknife is radionecrosis, which is caused by excessive radiation to surrounding normal tissues. Radionecrosis occurs in about 10-15% of cases and could have adverse effects leading to death. Currently available imaging techniques have failed to reliably distinguish radionecrosis from tumor growth. Development of imaging techniques that could provide distinction between tumor growth and radionecrosis would give us ability to monitor effects of radiation therapy non-invasively. This paper investigates the use of near infrared spectroscopy (NIRS) as a new technique to monitor the growth of brain tumors. Brain tumors (9L glioma cell line) were implanted in right caudate nucleus of rats (250-300 gms, Male Fisher C) through a guide screw. A new algorithm was developed, which used broadband steady-state reflectance measurements made using a single source-detector pair, to quantify absolute concentrations of hemoglobin derivatives and reduced scattering coefficients. Preliminary results from the brain tumors indicated decreases in oxygen saturation, oxygenated hemoglobin concentrations and increases in deoxygenated hemoglobin concentrations with tumor growth. The study demonstrates that NIRS technology could provide an efficient, noninvasive means of monitoring vascular oxygenation dynamics of brain tumors and further facilitate investigations of efficacy of tumor treatments.

C-type natriuretic peptide functions as an innate neuroprotectant in neonatal hypoxic-ischemic brain injury in mouse via natriuretic peptide receptor 2.

PubMed

Ma, Qingyi; Zhang, Lubo

2018-06-01

Neonatal hypoxia-ischemia (HI) is the most common cause of brain injury in neonates, which leads to high neonatal mortality and severe neurological morbidity in later life (Vannucci, 2000; Volpe, 2001). Yet the molecular mechanisms of neuronal death and brain damage induced by neonatal HI remain largely elusive. Herein, using both in vivo and in vitro models, we determine an endogenous neuroprotectant role of c-type natriuretic peptide (CNP) in preserving neuronal survival after HI brain injury in mouse pups. Postnatal day 7 (P7) mouse pups with CNP deficiency (Nppc lbab/lbab ) exhibit increased brain infarct size and worsened long-term locomotor function after neonatal HI compared with wildtype control (Nppc +/+ ). In isolated primary cortical neurons, recombinant CNP dose-dependently protects primary neurons from oxygen-glucose deprivation (OGD) insult. This neuroprotective effect appears to be mediated through its cognate natriuretic peptide receptor 2 (NPR2), in that antagonization of NPR2, but not NPR3, exacerbates neuronal death and counteracts the protective effect of CNP on primary neurons exposed to OGD insult. Immunoblot and confocal microscopy demonstrate the abundant expression of NPR2 in neurons of the neonatal brain and in isolated primary cortical neurons as well. Moreover, similar to CNP deficiency, administration of NPR2 antagonist P19 via intracerebroventricular injection prior to HI results in exacerbated neuronal death and brain injury after HI. Altogether, the present study indicates that CNP and its cognate receptor NPR2 mainly expressed in neurons represent an innate neuroprotective mechanism in neonatal HI brain injury. Copyright © 2018 Elsevier Inc. All rights reserved.

N-acetyl-L-cysteine protects against cadmium-induced neuronal apoptosis by inhibiting ROS-dependent activation of Akt/mTOR pathway in mouse brain

PubMed Central

Chen, Sujuan; Ren, Qian; Zhang, Jinfei; Ye, Yangjing; Zhang, Zhen; Xu, Yijiao; Guo, Min; Ji, Haiyan; Xu, Chong; Gu, Chenjian; Gao, Wei; Huang, Shile; Chen, Long

2014-01-01

Aims This study explores the neuroprotective effects and mechanisms of N-acetyl-L-cysteine (NAC) in mice exposed to cadmium (Cd). Methods NAC (150 mg/kg) was intraperitoneally administered to mice exposed to Cd (10-50 mg/L) in drinking water for 6 weeks. The changes of cell damage and death, reactive oxygen species (ROS), antioxidant enzymes, as well as Akt/mammalian target of rapamycin (mTOR) signaling pathway in brain neurons were assessed. To verify the role of mTOR activation in Cd-induced neurotoxicity, mice also received a subacute regimen of intraperitoneally administered Cd (1 mg/kg) with/without rapamycin (7.5 mg/kg) for 11 days. Results Chronic exposure of mice to Cd induced brain damage or neuronal cell death, due to ROS induction. Co-administration of NAC significantly reduced Cd levels in the plasma and brain of the animals. NAC prevented Cd-induced ROS and significantly attenuated Cd-induced brain damage or neuronal cell death. The protective effect of NAC was mediated, at least partially, by elevating the activities of Cu/Zn-superoxide dismutase, catalase and glutathione peroxidase, as well as the level of glutathione in the brain. Furthermore, Cd-induced activation of Akt/mTOR pathway in the brain was also inhibited by NAC. Rapamycin in vitro and in vivo protected against Cd-induced neurotoxicity. Conclusions NAC protects against Cd-induced neuronal apoptosis in mouse brain partially by inhibiting ROS-dependent activation of Akt/mTOR pathway. The findings highlight that NAC may be exploited for prevention and treatment of Cd-induced neurodegenerative diseases. PMID:24299490

Angiotensin II potentiates zinc-induced cortical neuronal death by acting on angiotensin II type 2 receptor.

PubMed

Park, Mi-Ha; Kim, Ha Na; Lim, Joon Seo; Ahn, Jae-Sung; Koh, Jae-Young

2013-12-01

The angiotensin system has several non-vascular functions in the central nervous system. For instance, inhibition of the brain angiotensin system results in a reduction in neuronal death following acute brain injury such as ischemia and intracerebral hemorrhage, even under conditions of constant blood pressure. Since endogenous zinc has been implicated as a key mediator of ischemic neuronal death, we investigated the possibility that the angiotensin system affects the outcome of zinc-triggered neuronal death in cortical cell cultures. Exposure of cortical cultures containing neurons and astrocytes to 300 μM zinc for 15 min induced submaximal death in both types of cells. Interestingly, addition of angiotensin II significantly enhanced the zinc-triggered neuronal death, while leaving astrocytic cell death relatively unchanged. Both type 1 and 2 angiotensin II receptors (AT1R and AT2R, respectively) were expressed in neurons as well as astrocytes. Zinc neurotoxicity was substantially attenuated by PD123319, a specific inhibitor of AT2R, and augmented by CGP42112, a selective activator of AT2R, indicating a critical role for this receptor subtype in the augmentation of neuronal cell death.Because zinc toxicity occurs largely through oxidative stress, the levels of superoxides in zinc-treated neurons were assessed by DCF fluorescence microscopy. Combined treatment with zinc and angiotensin II substantially increased the levels of superoxides in neurons compared to those induced by zinc alone. This increase in oxidative stress by angiotensin II was completely blocked by the addition of PD123319. Finally, since zinc-induced oxidative stress may be caused by induction and/or activation of NADPH oxidase, the activation status of Rac and the level of the NADPH oxidase subunit p67phox were measured. Angiotensin II markedly increased Rac activity and the levels of p67phox in zinc-treated neurons and astrocytes in a PD123319-dependent manner. The present study shows that the angiotensin system, especially that involving AT2R, may have an oxidative injury-potentiating effect via augmentation of the activity of NADPH oxidase. Hence, blockade of angiotensin signaling cascades in the brain may prove useful in protecting against the oxidative neuronal death that is likely to occur in acute brain injury.

78 FR 48692 - Government-Owned Inventions; Availability for Licensing

Federal Register 2010, 2011, 2012, 2013, 2014

2013-08-09

... Skull as Route of Delivery for Treatment of Brain Injury and Disease Description of Technology: Traumatic Brain injury (TBI) often results from head impact and is a major cause of death and disability. Brain injuries vary in severity and can be associated with hemorrhaging, swelling, inflammation, and...

Electrical conductivity changes during irreversible electroporation treatment of brain cancer.

PubMed

Garcia, Paulo A; Rossmeisl, John H; Davalos, Rafael V

2011-01-01

Irreversible electroporation (IRE) is a new minimally invasive technique to kill tumors and other undesirable tissue in a non-thermal manner. During an IRE treatment, a series of short and intense electric pulses are delivered to the region of interest to destabilize the cell membranes in the tissue and achieve spontaneous cell death. The alteration of the cellular membrane results in a dramatic increase in electrical conductivity during IRE as in other electroporation-based-therapies. In this study, we performed the planning and execution of an IRE brain cancer treatment using MRI reconstructions of the tumor and a multichannel array that served as a stereotactic fiducial and electrode guide. Using the tumor reconstructions within our numerical simulations, we developed equations relating the increase in tumor conductivity to calculated currents and volumes of tumor treated with IRE. We also correlated the experimental current measured during the procedure to an increase in tumor conductivity ranging between 3.42-3.67 times the baseline conductivity, confirming the physical phenomenon that has been detected in other tissues undergoing similar electroporation-based treatments.

The Eye As a Biomarker for Alzheimer's Disease

PubMed Central

Lim, Jeremiah K. H.; Li, Qiao-Xin; He, Zheng; Vingrys, Algis J.; Wong, Vickie H. Y.; Currier, Nicolas; Mullen, Jamie; Bui, Bang V.; Nguyen, Christine T. O.

2016-01-01

Alzheimer's disease (AD) is a progressive neurodegenerative disorder resulting in dementia and eventual death. It is the leading cause of dementia and the number of cases are projected to rise in the next few decades. Pathological hallmarks of AD include the presence of hyperphosphorylated tau and amyloid protein deposition. Currently, these pathological biomarkers are detected either through cerebrospinal fluid analysis, brain imaging or post-mortem. Though effective, these methods are not widely available due to issues such as the difficulty in acquiring samples, lack of infrastructure or high cost. Given that the eye possesses clear optics and shares many neural and vascular similarities to the brain, it offers a direct window to cerebral pathology. These unique characteristics lend itself to being a relatively inexpensive biomarker for AD which carries the potential for wide implementation. The development of ocular biomarkers can have far implications in the discovery of treatments which can improve the quality of lives of patients. In this review, we consider the current evidence for ocular biomarkers in AD and explore potential future avenues of research in this area. PMID:27909396

Genetic defects disrupting glial ion and water homeostasis in the brain.

PubMed

Min, Rogier; van der Knaap, Marjo S

2018-05-01

Electrical activity of neurons in the brain, caused by the movement of ions between intracellular and extracellular compartments, is the basis of all our thoughts and actions. Maintaining the correct ionic concentration gradients is therefore crucial for brain functioning. Ion fluxes are accompanied by the displacement of osmotically obliged water. Since even minor brain swelling leads to severe brain damage and even death, brain ion and water movement has to be tightly regulated. Glial cells, in particular astrocytes, play a key role in ion and water homeostasis. They are endowed with specific channels, pumps and carriers to regulate ion and water flow. Glial cells form a large panglial syncytium to aid the uptake and dispersal of ions and water, and make extensive contacts with brain fluid barriers for disposal of excess ions and water. Genetic defects in glial proteins involved in ion and water homeostasis disrupt brain functioning, thereby leading to neurological diseases. Since white matter edema is often a hallmark disease feature, many of these diseases are characterized as leukodystrophies. In this review we summarize our current understanding of inherited glial diseases characterized by disturbed brain ion and water homeostasis by integrating findings from MRI, genetics, neuropathology and animal models for disease. We discuss how mutations in different glial proteins lead to disease, and highlight the similarities and differences between these diseases. To come to effective therapies for this group of diseases, a better mechanistic understanding of how glial cells shape ion and water movement in the brain is crucial. © 2018 The Authors. Brain Pathology published by John Wiley & Sons Ltd on behalf of International Society of Neuropathology.

Twenty-first century brain banking. Processing brains for research: the Columbia University methods

PubMed Central

del Amaya, Maria Pilar; Keller, Christian E.

2007-01-01

Carefully categorized postmortem human brains are crucial for research. The lack of generally accepted methods for processing human postmortem brains for research persists. Thus, brain banking is essential; however, it cannot be achieved at the cost of the teaching mission of the academic institution by routing brains away from residency programs, particularly when the autopsy rate is steadily decreasing. A consensus must be reached whereby a brain can be utilizable for diagnosis, research, and teaching. The best diagnostic categorization possible must be secured and the yield of samples for basic investigation maximized. This report focuses on integrated, novel methods currently applied at the New York Brain Bank, Columbia University, New York, which are designed to reach accurate neuropathological diagnosis, optimize the yield of samples, and process fresh-frozen samples suitable for a wide range of modern investigations. The brains donated for research are processed as soon as possible after death. The prosector must have a good command of the neuroanatomy, neuropathology, and the protocol. One half of each brain is immersed in formalin for performing the thorough neuropathologic evaluation, which is combined with the teaching task. The contralateral half is extensively dissected at the fresh state. The anatomical origin of each sample is recorded using the map of Brodmann for the cortical samples. The samples are frozen at −160°C, barcode labeled, and ready for immediate disbursement once categorized diagnostically. A rigorous organization of freezer space, coupled to an electronic tracking system with its attached software, fosters efficient access for retrieval within minutes of any specific frozen samples in storage. This report describes how this achievement is feasible with emphasis on the actual processing of brains donated for research. PMID:17985145

Hypothermia broadens the therapeutic time window of mesenchymal stem cell transplantation for severe neonatal hypoxic ischemic encephalopathy.

PubMed

Ahn, So Yoon; Chang, Yun Sil; Sung, Dong Kyung; Sung, Se In; Park, Won Soon

2018-05-16

Recently, we have demonstrated that concurrent hypothermia and mesenchymal stem cells (MSCs) transplantation synergistically improved severe neonatal hypoxic ischemic encephalopathy (HIE). The current study was designed to determine whether hypothermia could extend the therapeutic time window of MSC transplantation for severe neonatal HIE. To induce HIE, newborn rat pups were exposed to 8% oxygen for 2 h following unilateral carotid artery ligation on postnatal day (P) 7. After approving severe HIE involving >50% of the ipsilateral hemisphere volume, hypothermia (32 °C) for 2 days was started. MSCs were transplanted 2 days after HIE modeling. Follow-up brain MRI, sensorimotor function tests, assessment of inflammatory cytokines in the cerebrospinal fluid (CSF), and histological evaluation of peri-infarction area were performed. HIE induced progressively increasing brain infarction area over time, increased cell death, reactive gliosis and brain inflammation, and impaired sensorimotor function. All these damages observed in severe HIE showed better, robust improvement with a combination treatment of hypothermia and delayed MSC transplantation than with either stand-alone therapy. Hypothermia itself did not significantly reduce brain injury, but broadened the therapeutic time window of MSC transplantation for severe newborn HIE.

Annual Report to the Nation on the Status of Cancer, 1975–2007, Featuring Tumors of the Brain and Other Nervous System

PubMed Central

Ward, Elizabeth; McCarthy, Bridget J.; Schymura, Maria J.; Eheman, Christie; Jemal, Ahmedin; Anderson, Robert N.; Ajani, Umed A.; Edwards, Brenda K.

2011-01-01

Background The American Cancer Society, the Centers for Disease Control and Prevention (CDC), the National Cancer Institute, and the North American Association of Central Cancer Registries (NAACCR) collaborate annually to provide updated information on cancer occurrence and trends in the United States. This year’s report highlights brain and other nervous system (ONS) tumors, including nonmalignant brain tumors, which became reportable on a national level in 2004. Methods Cancer incidence data were obtained from the National Cancer Institute, CDC, and NAACCR, and information on deaths was obtained from the CDC’s National Center for Health Statistics. The annual percentage changes in age-standardized incidence and death rates (2000 US population standard) for all cancers combined and for the top 15 cancers for men and for women were estimated by joinpoint analysis of long-term (1992–2007 for incidence; 1975–2007 for mortality) trends and short-term fixed interval (1998–2007) trends. Analyses of malignant neuroepithelial brain and ONS tumors were based on data from 1980–2007; data on nonmalignant tumors were available for 2004–2007. All statistical tests were two-sided. Results Overall cancer incidence rates decreased by approximately 1% per year; the decrease was statistically significant (P < .05) in women, but not in men, because of a recent increase in prostate cancer incidence. The death rates continued to decrease for both sexes. Childhood cancer incidence rates continued to increase, whereas death rates continued to decrease. Lung cancer death rates decreased in women for the first time during 2003–2007, more than a decade after decreasing in men. During 2004–2007, more than 213 500 primary brain and ONS tumors were diagnosed, and 35.8% were malignant. From 1987–2007, the incidence of neuroepithelial malignant brain and ONS tumors decreased by 0.4% per year in men and women combined. Conclusions The decrease in cancer incidence and mortality reflects progress in cancer prevention, early detection, and treatment. However, major challenges remain, including increasing incidence rates and continued low survival for some cancers. Malignant and nonmalignant brain tumors demonstrate differing patterns of occurrence by sex, age, and race, and exhibit considerable biologic diversity. Inclusion of nonmalignant brain tumors in cancer registries provides a fuller assessment of disease burden and medical resource needs associated with these unique tumors. PMID:21454908

Tunicamycin-induced unfolded protein response in the developing mouse brain

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, Haiping; Wang, Xin; Ke, Zun-Ji

Accumulation of unfolded or misfolded proteins in the endoplasmic reticulum (ER) causes ER stress, resulting in the activation of the unfolded protein response (UPR). ER stress and UPR are associated with many neurodevelopmental and neurodegenerative disorders. The developing brain is particularly susceptible to environmental insults which may cause ER stress. We evaluated the UPR in the brain of postnatal mice. Tunicamycin, a commonly used ER stress inducer, was administered subcutaneously to mice of postnatal days (PDs) 4, 12 and 25. Tunicamycin caused UPR in the cerebral cortex, hippocampus and cerebellum of mice of PD4 and PD12, which was evident bymore » the upregulation of ATF6, XBP1s, p-eIF2α, GRP78, GRP94 and MANF, but failed to induce UPR in the brain of PD25 mice. Tunicamycin-induced UPR in the liver was observed at all stages. In PD4 mice, tunicamycin-induced caspase-3 activation was observed in layer II of the parietal and optical cortex, CA1–CA3 and the subiculum of the hippocampus, the cerebellar external germinal layer and the superior/inferior colliculus. Tunicamycin-induced caspase-3 activation was also shown on PD12 but to a much lesser degree and mainly located in the dentate gyrus of the hippocampus, deep cerebellar nuclei and pons. Tunicamycin did not activate caspase-3 in the brain of PD25 mice and the liver of all stages. Similarly, immature cerebellar neurons were sensitive to tunicamycin-induced cell death in culture, but became resistant as they matured in vitro. These results suggest that the UPR is developmentally regulated and the immature brain is more susceptible to ER stress. - Highlights: • Tunicamycin caused a development-dependent UPR in the mouse brain. • Immature brain was more susceptible to tunicamycin-induced endoplasmic reticulum stress. • Tunicamycin caused more neuronal death in immature brain than mature brain. • Tunicamycin-induced neuronal death is region-specific.« less

Rapid brain death caused by a cerebellar abscess with Fusobacterium nucleatum in a young man with drug abuse: a case report.

PubMed

Hischebeth, Gunnar T R; Keil, Vera C; Gentil, Katrin; Boström, Azize; Kuchelmeister, Klaus; Bekeredjian-Ding, Isabelle

2014-06-10

Fusobacterium nucleatum is a strict anaerobic microorganism that causes disease entities such as periodontal and soft tissue abscesses, pulmonary and intraabdominal infections and very rarely intracerebral infections. Here, we report the rare case of a previously healthy 25-year-old German man with a cerebellar abscess caused by Fusobacterium nucleatum that resulted in rapid brain death. Toxicological screening showed positivity for amphetamines and cannabis. The diagnosis was obtained by polymerase chain reaction amplification of bacterial deoxyribonucleic acid in cerebrospinal fluid. In drug users clinicians should think about rare causes of brain abscesses/meningitis. Early diagnosis is necessary and justifies the use of molecular techniques.

Combat veterans, mental health issues, and the death penalty: addressing the impact of post-traumatic stress disorder and traumatic brain injury.

PubMed

Giardino, Anthony E

2009-05-01

More than 1.5 million Americans have participated in combat operations in Iraq and Afghanistan over the past seven years. Some of these veterans have subsequently committed capital crimes and found themselves in our nation's criminal justice system. This Essay argues that combat veterans suffering from post-traumatic stress disorder or traumatic brain injury at the time of their offenses should not be subject to the death penalty.Offering mitigating evidence regarding military training, post-traumatic stress disorder, and traumatic brain injury presents one means that combat veterans may use to argue for their lives during the sentencing phase of their trials. Alternatively, Atkins v. Virginia and Roper v. Simmons offer a framework for establishing a legislatively or judicially created categorical exclusion for these offenders, exempting them from the death penalty as a matter of law. By understanding how combat service and service-related injuries affect the personal culpability of these offenders, the legal system can avoid the consequences of sentencing to death America's mentally wounded warriors, ensuring that only the worst offenders are subject to the ultimate punishment.

Death from undiagnosed glioblastoma multiforme and toxic self-medication presenting with concurrent dysfunctional behavior.

PubMed

Carson, Henry J; Eilers, Stanley G

2008-08-01

We encountered a decedent with an unexpected glioblastoma multiforme. A 61-year-old retired African-American woman was found dead in her home, fully clothed in her bathtub, with a pillow under her head. At autopsy, the brain showed a glioblastoma multiforme. Toxicology showed elevated hydrocodone, propoxyphene, acetaminophen, and positive paroxetine. The presence of a brain tumor likely caused a severe headache. The use of her medications could have indicated a reaction to the escalating pain of the brain trauma, and overuse could be consistent with escalating pain or loss of rational thought processes. The present case is interesting in that it had evidence of behavioral dysfunction that could be related to the brain tumor, and death arising from the glioblastoma multiforme (cerebral hemorrhage and edema) with concurrent multiple drug intoxication.

Competing Risk Analysis of Neurologic versus Nonneurologic Death in Patients Undergoing Radiosurgical Salvage After Whole-Brain Radiation Therapy Failure: Who Actually Dies of Their Brain Metastases?

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lucas, John T., E-mail: jolucas@wakehealth.edu; Colmer, Hentry G.; White, Lance

Purpose: To estimate the hazard for neurologic (central nervous system, CNS) and nonneurologic (non-CNS) death associated with patient, treatment, and systemic disease status in patients receiving stereotactic radiosurgery after whole-brain radiation therapy (WBRT) failure, using a competing risk model. Patients and Methods: Of 757 patients, 293 experienced recurrence or new metastasis following WBRT. Univariate Cox proportional hazards regression identified covariates for consideration in the multivariate model. Competing risks multivariable regression was performed to estimate the adjusted hazard ratio (aHR) and 95% confidence interval (CI) for both CNS and non-CNS death after adjusting for patient, disease, and treatment factors. The resultantmore » model was converted into an online calculator for ease of clinical use. Results: The cumulative incidence of CNS and non-CNS death at 6 and 12 months was 20.6% and 21.6%, and 34.4% and 35%, respectively. Patients with melanoma histology (relative to breast) (aHR 2.7, 95% CI 1.5-5.0), brainstem location (aHR 2.1, 95% CI 1.3-3.5), and number of metastases (aHR 1.09, 95% CI 1.04-1.2) had increased aHR for CNS death. Progressive systemic disease (aHR 0.55, 95% CI 0.4-0.8) and increasing lowest margin dose (aHR 0.97, 95% CI 0.9-0.99) were protective against CNS death. Patients with lung histology (aHR 1.3, 95% CI 1.1-1.9) and progressive systemic disease (aHR 2.14, 95% CI 1.5-3.0) had increased aHR for non-CNS death. Conclusion: Our nomogram provides individual estimates of neurologic death after salvage stereotactic radiosurgery for patients who have failed prior WBRT, based on histology, neuroanatomical location, age, lowest margin dose, and number of metastases after adjusting for their competing risk of death from other causes.« less

Lipid nanoparticles for cancer therapy: state of the art and future prospects.

PubMed

Lasa-Saracibar, Beatriz; Estella-Hermoso de Mendoza, Ander; Guada, Melissa; Dios-Vieitez, Carmen; Blanco-Prieto, María J

2012-10-01

Cancer is a leading cause of death worldwide and it is estimated that deaths from this disease will rise to over 11 million in 2030. Most cases of cancer can be cured with surgery, radiotherapy or chemotherapy if they are detected at an early stage. However, current cancer therapies are commonly associated with undesirable side effects, as most chemotherapy treatments are cytotoxic and present poor tumor targeting. Lipid nanoparticles (LN) are one of the most promising options in this field. LN are made up of biodegradable generally recognized as safe (GRAS) lipids, their formulation includes different techniques, and most are easily scalable to industrial manufacture. LN overcome the limitations imposed by the need for intravenous administration, as they are mainly absorbed via the lymphatic system when they are administered orally, which improves drug bioavailability. Furthermore, depending on their composition, LN present the ability to cross the blood-brain barrier, thus opening up the possibility of targeting brain tumors. The drawbacks of chemotherapeutic agents make it necessary to invest in research to find safer and more effective therapies. Nanotechnology has opened the door to new therapeutic options through the design of formulations that include a wide range of materials and formulations at the nanometer range, which improve drug efficacy through direct or indirect tumor targeting, increased bioavailability and diminished toxicity.

Comparison of water-based foam and carbon dioxide gas mass emergency depopulation of White Pekin ducks.

PubMed

Caputo, M P; Benson, E R; Pritchett, E M; Hougentogler, D P; Jain, P; Patil, C; Johnson, A L; Alphin, R L

2012-12-01

The mass depopulation of production birds remains an effective means of controlling fast-moving, highly infectious diseases such as avian influenza and virulent Newcastle disease. Two experiments were performed to compare the physiological responses of White Pekin commercial ducks during foam depopulation and CO(2) gas depopulation. Both experiment 1 (5 to 9 wk of age) and 2 (8 to 14 wk of age) used electroencephalogram, electrocardiogram, and accelerometer to monitor and evaluate the difference in time to unconsciousness, motion cessation, brain death, altered terminal cardiac activity, duration of bradycardia, and elapsed time from onset of bradycardia to onset of unconsciousness between foam and CO(2) gas. Experiment 2 also added a third treatment, foam + atropine injection, to evaluate the effect of suppressing bradycardia. Experiment 1 resulted in significantly shorter times for all 6 physiological points for CO(2) gas compared with foam, whereas experiment 2 found that there were no significant differences between foam and CO(2) gas for these physiological points except brain death, in which CO(2) was significantly faster than foam and duration of bradycardia, which was shorter for CO(2). Experiment 2 also determined there was a significant positive correlation between duration of bradycardia and time to unconsciousness, motion cessation, brain death, and altered terminal cardiac activity. The time to unconsciousness, motion cessation, brain death, and altered terminal cardiac activity was significantly faster for the treatment foam + atropine injection compared with foam. Both experiments showed that bradycardia can occur as a result of either submersion in foam or exposure to CO(2) gas. The duration of bradycardia has a significant impact on the time it takes White Pekin ducks to reach unconsciousness and death during depopulation.

The efficiency in the utilization of potential donors for organ transplantation in Riyadh, Saudi Arabia.

PubMed

Al-Sebayel, Mohammed I

2003-07-01

Organ transplantation programs have been successful in the Kingdom of Saudi Arabia. This success is limited by organ shortage. The aim of this study is to find out the percentage of actual donors out of all potential donors in intensive care units (ICU), and to look at problems related to the donation process, particularly from the logistical point of view. The study was conducted prospectively for a one year period, June 2001 through to May 2002, in 4 main Riyadh hospitals. Mortality data was collected by a medical professional in each ICU and analyzed on a weekly basis. Final analysis was made at the end of the year. Five hundred and forty-two deaths occurred in these ICUs. Fifty-four percent occurred in one hospital. The number of brain death cases in all hospitals was 114 cases. Thirty-eight cases were reported to the Saudi Center for Organ Transplantation (33%). Documentation was completed in only 23 cases (60%). In these, there was a significant delay in documentation (second test was carried out in 6-12 hours in 4 cases only). We have found that the reporting of brain death cases was low (33%). Dealing with the reported cases is inefficient since only 4 cases were able to become the actual donor out of 38 cases. We found also that there is a gross difference in the number of brain death cases among different hospitals. To improve the efficiency of ICUs in dealing with brain death cases (reporting, documentation, maintenance and consent) will require solving several problems at the medical, administrative, and religious and mass media levels.

Defining human death: an intersection of bioethics and metaphysics.

PubMed

Manninen, Bertha Alvarez

2009-01-01

For many years now, bioethicists, physicians, and others in the medical field have disagreed concerning how to best define human death. Different theories range from the Harvard Criteria of Brain Death, which defines death as the cessation of all brain activity, to the Cognitive Criteria, which is based on the loss of almost all core mental properties, e.g., memory, self-consciousness, moral agency, and the capacity for reason. A middle ground is the Irreversibility Standard, which defines death as occurring when the capacity for consciousness is forever lost. Given all these different theories, how can we begin to approach solving the issue of how to define death? I propose that a necessary starting point is discussing an even more fundamental question that properly belongs in the philosophical field of metaphysics: we must first address the issue of diachronic identity over time, and the persistence conditions of personal identity. In this paper, I illustrate the interdependent relationship between this metaphysical question and questions concerning the definition of death. I also illustrate how it is necessary to antecedently attend to the metaphysical issue of defining death before addressing certain issues in medical ethics, e.g., whether it is morally permissible to euthanize patients in persistent vegetative states or procure organs from anencephalic infants.

Aquaporin-4 polymorphisms and brain/body weight ratio in sudden infant death syndrome (SIDS).

PubMed

Studer, Jacqueline; Bartsch, Christine; Haas, Cordula

2014-07-01

Failure in the regulation of homeostatic water balance in the brain is associated with severe cerebral edema and increased brain weights and may also play an important role in the pathogenesis of sudden infant death syndrome (SIDS). We genotyped three single-nucleotide polymorphisms in the aquaporin-4 water channel-encoding gene (AQP4), which were previously shown to be associated with (i) SIDS in Norwegian infants (rs2075575), (ii) severe brain edema (rs9951307), and (iii) increased brain water permeability (rs3906956). We also determined whether the brain/body weight ratio is increased in SIDS infants compared with sex- and age-matched controls. Genotyping of the three AQP4 single-nucleotide polymorphisms was performed in 160 Caucasian SIDS infants and 181 healthy Swiss adults using a single-base extension method. Brain and body weights were measured during autopsy in 157 SIDS and 59 non-SIDS infants. No differences were detected in the allelic frequencies of the three AQP4 single-nucleotide polymorphisms between SIDS and adult controls. The brain/body weight ratio was similarly distributed in SIDS and non-SIDS infants. Variations in the AQP4 gene seem of limited significance as predisposing factors in Caucasian SIDS infants. Increased brain weights may only become evident in conjunction with environmental or other genetic risk factors.

Antioxidant gene therapy against neuronal cell death

PubMed Central

Navarro-Yepes, Juliana; Zavala-Flores, Laura; Annadurai, Anandhan; Wang, Fang; Skotak, Maciej; Chandra, Namas; Li, Ming; Pappa, Aglaia; Martinez-Fong, Daniel; Razo, Luz Maria Del; Quintanilla-Vega, Betzabet; Franco, Rodrigo

2014-01-01

Oxidative stress is a common hallmark of neuronal cell death associated with neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease, as well as brain stroke/ischemia and traumatic brain injury. Increased accumulation of reactive species of both oxygen (ROS) and nitrogen (RNS) has been implicated in mitochondrial dysfunction, energy impairment, alterations in metal homeostasis and accumulation of aggregated proteins observed in neurodegenerative disorders, which lead to the activation/modulation of cell death mechanisms that include apoptotic, necrotic and autophagic pathways. Thus, the design of novel antioxidant strategies to selectively target oxidative stress and redox imbalance might represent important therapeutic approaches against neurological disorders. This work reviews the evidence demonstrating the ability of genetically encoded antioxidant systems to selectively counteract neuronal cell loss in neurodegenerative diseases and ischemic brain damage. Because gene therapy approaches to treat inherited and acquired disorders offer many unique advantages over conventional therapeutic approaches, we discussed basic research/clinical evidence and the potential of virus-mediated gene delivery techniques for antioxidant gene therapy. PMID:24333264

Trend of brain tumor incidence by histological subtypes in Japan: estimation from the Brain Tumor Registry of Japan, 1973-1993.

PubMed

Kaneko, Satoshi; Nomura, Kazuhiro; Yoshimura, Takesumi; Yamaguchi, Naohito

2002-10-01

In order to estimate the risk of primary brain tumor (PBT), we attempted to estimate the national incidence rates of PBT by histological subtypes using the Brain Tumor Registry of Japan (BTR). The number of deaths due to PBT in a certain year is the sum of the deaths among patients diagnosed in different years. Registered cases in the BTR represent incident cases of PBT in the whole country multiplied by a cover rate. The cover rate is defined as the proportions of PBT cases that the Registry counts in relation to all the cases in the country in a given year. If the survival experience among the registered cases represents the survival experience of all cases, then the rate of registered deaths represents all deaths due to PBT in Japan. By this logic, we estimated the cover rates and incidence rates from 1973 to 1993 using the BTR and National Vital Statistics data. Our estimates showed three patterns of time trends: (1) a gradual linear increasing trend before the 1980s followed by a plateau (total PBT, gliomas, meningioma, and hemangioblastoma), (2) a trend with a step-up increase in the 1980s followed by a plateau (germ cell tumor and pituitary tumor), and (3) a linear increasing trend throughout the observation period with no plateau (malignant lymphoma and neurinoma). Furthermore, obvious sex differences in time trends were observed in rates of meningioma, germ cell tumor, and pituitary tumor. The results of this study demonstrated several distinctive patterns in time trends, which give us insight into the possible etiologies of brain tumors. Further epidemiological study is needed to elucidate these findings.

On the role of phosphatidylinositol 3-kinase, protein kinase b/Akt, and glycogen synthase kinase-3β in photodynamic injury of crayfish neurons and glial cells.

PubMed

Komandirov, Maxim A; Knyazeva, Evgeniya A; Fedorenko, Yulia P; Rudkovskii, Mikhail V; Stetsurin, Denis A; Uzdensky, Anatoly B

2011-10-01

Photodynamic treatment that causes intense oxidative stress and cell death is currently used in neurooncology. However, along with tumor cells, it may damage healthy neurons and glia. To study the involvement of signaling processes in photodynamic injury or protection of neurons and glia, we used crayfish mechanoreceptor consisting of a single neuron surrounded by glial cells. It was photosensitized with alumophthalocyanine Photosens. Application of specific inhibitors showed that phosphatidylinositol 3-kinase did not participate in photoinduced death of neurons and glia. Akt was involved in photoinduced necrosis but not in apoptosis of neurons and glia. Glycogen synthase kinase-3β participated in photoinduced apoptosis of glial cells and in necrosis of neurons. Therefore, phosphatidylinositol 3-kinase/protein kinase Akt/glycogen synthase kinase-3β pathway was not involved as a whole in photodynamic injury of crayfish neurons and glia but its components, Akt and glycogen synthase kinase-3β, independently and cell specifically regulated death of neurons and glial cells. According to these data, necrosis in this system was a controlled but not a non-regulated cell death mode. The obtained results may be used for the search of pharmacological agents selectively modulating death and survival of normal neurons and glial cells during photodynamic therapy of brain tumors.

Near-Infrared Spectroscopy – Electroencephalography-Based Brain-State-Dependent Electrotherapy: A Computational Approach Based on Excitation–Inhibition Balance Hypothesis

PubMed Central

Dagar, Snigdha; Chowdhury, Shubhajit Roy; Bapi, Raju Surampudi; Dutta, Anirban; Roy, Dipanjan

2016-01-01

Stroke is the leading cause of severe chronic disability and the second cause of death worldwide with 15 million new cases and 50 million stroke survivors. The poststroke chronic disability may be ameliorated with early neuro rehabilitation where non-invasive brain stimulation (NIBS) techniques can be used as an adjuvant treatment to hasten the effects. However, the heterogeneity in the lesioned brain will require individualized NIBS intervention where innovative neuroimaging technologies of portable electroencephalography (EEG) and functional-near-infrared spectroscopy (fNIRS) can be leveraged for Brain State Dependent Electrotherapy (BSDE). In this hypothesis and theory article, we propose a computational approach based on excitation–inhibition (E–I) balance hypothesis to objectively quantify the poststroke individual brain state using online fNIRS–EEG joint imaging. One of the key events that occurs following Stroke is the imbalance in local E–I (that is the ratio of Glutamate/GABA), which may be targeted with NIBS using a computational pipeline that includes individual “forward models” to predict current flow patterns through the lesioned brain or brain target region. The current flow will polarize the neurons, which can be captured with E–I-based brain models. Furthermore, E–I balance hypothesis can be used to find the consequences of cellular polarization on neuronal information processing, which can then be implicated in changes in function. We first review the evidence that shows how this local imbalance between E–I leading to functional dysfunction can be restored in targeted sites with NIBS (motor cortex and somatosensory cortex) resulting in large-scale plastic reorganization over the cortex, and probably facilitating recovery of functions. Second, we show evidence how BSDE based on E–I balance hypothesis may target a specific brain site or network as an adjuvant treatment. Hence, computational neural mass model-based integration of neurostimulation with online neuroimaging systems may provide less ambiguous, robust optimization of NIBS, and its application in neurological conditions and disorders across individual patients. PMID:27551273

Neuregulin-1 is neuroprotective in a rat model of organophosphate-induced delayed neuronal injury

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li, Yonggang; Lein, Pamela J.; Liu, Cuimei

2012-07-15

Current medical countermeasures against organophosphate (OP) nerve agents are effective in reducing mortality, but do not sufficiently protect the CNS from delayed brain damage and persistent neurological symptoms. In this study, we examined the efficacy of neuregulin-1 (NRG-1) in protecting against delayed neuronal cell death following acute intoxication with the OP diisopropylflurophosphate (DFP). Adult male Sprague–Dawley rats were pretreated with pyridostigmine (0.1 mg/kg BW, i.m.) and atropine methylnitrate (20 mg/kg BW, i.m.) prior to DFP (9 mg/kg BW, i.p.) intoxication to increase survival and reduce peripheral signs of cholinergic toxicity but not prevent DFP-induced seizures or delayed neuronal injury. Pretreatmentmore » with NRG-1 did not protect against seizures in rats exposed to DFP. However, neuronal injury was significantly reduced in most brain regions by pretreatment with NRG-1 isoforms NRG-EGF (3.2 μg/kg BW, i.a) or NRG-GGF2 (48 μg/kg BW, i.a.) as determined by FluroJade-B labeling in multiple brain regions at 24 h post-DFP injection. NRG-1 also blocked apoptosis and oxidative stress-mediated protein damage in the brains of DFP-intoxicated rats. Administration of NRG-1 at 1 h after DFP injection similarly provided significant neuroprotection against delayed neuronal injury. These findings identify NRG-1 as a promising adjuvant therapy to current medical countermeasures for enhancing neuroprotection against acute OP intoxication. -- Highlights: ► NRG-1 blocked DFP induced neuronal injury. ► NRG-1 did not protect against seizures in rats exposed to DFP. ► NRG-1 blocked apoptosis and oxidative stress in the brains of DFP-intoxicated rats. ► Administration of NRG-1 at 1 h after DFP injection prevented delayed neuronal injury.« less

Outcomes of management for potential deceased donors.

PubMed

Jeong, J C; Kim, M G; Ro, H; Kim, Y J; Park, H C; Kwon, H Y; Jeon, H J; Ha, J; Ahn, C; Yang, J

2012-05-01

Potential deceased donor management optimization is important for organ recovery maximization. Before optimization, the current state of donor management and predictors for organ recovery require analysis. We retrospectively analyzed organ procurement activity and medical management for 2005 to 2010 potential brain death donors at Seoul National University Hospital. Of 316 contacts for potential brain-dead donors, 129 (39.7%) patients were transferred to the donor management team. Among the causes of transfer failure, issues related to proper donor management affected 33%. Expanded criteria donors were 17.9% of transferred donors. Organ recovery was successful in 111 (90.2%) donors. A total of 360 organs were recovered, corresponding to a mean of 2.92 ± 1.37 organs per donor. The absence of organ demand was an important cause of recovery failure among less transplanted organs. Brain death-related complications were identified as follows: acute kidney injury (AKI), defined by AKI network criteria, occurred in 19 (15.4%); cardiopulmonary resuscitation in 5 (3.1%); bacteremia in 12 (9.7%); thrombocytopenia in 24 (19.5%); and diabetes insipidus in 42 (34.1%). AKI was a significant independent risk factor for organ recovery failure in both the liver and kidney (odds ratio [OR] 0.147, 95% confidence interval [0.045, 0.473], P = .001; OR 0.096, 95% confidence interval [0.023, 0.392], P = .001, for kidney and liver, respectively). Both the transfer success rate and rate of organs transplanted per donor of potential deceased donors remained low in Korea. AKI during potential donor management was a risk factor for kidney and liver recovery failure. Copyright © 2012 Elsevier Inc. All rights reserved.

[Short-term outcomes of lung transplant recipients using organs from brain death donors].

PubMed

He, W X; Jiang, C; Liu, X G; Huang, W; Chen, C; Jiang, L; Yang, B; Wu, K; Chen, Q K; Yang, Y; Yu, Y M; Jiang, G N

2016-12-01

Objective: To assess short-term outcomes after lung transplantation with organs procured following brain death. Methods: Between April 2015 and July 2016, all 17 recipients after lung transplantation using organs from brain death donors (DBD) at Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine were enrolled in this study. All patients were male, aging (60±7) years, including 11 chronic obstructive pulmonary disease, 5 idiopathic pulmonary fibrosis, 1 silicosis. Seventeen donors were 16 males and 1 female, with 10 traumatic brain injury, 5 cerebrovascular accident and 2 sudden cardiac death. Of 17 recipients receiving DBD lung transplant, 16 were single lung transplant. Data were collected including intubation duration of mechanical ventilation, hospital length of stay, incidence of pulmonary infection bronchus anastomosis complications, primary graft dysfunction (PGD), and acute rejection, bronchiolitis obliterans syndrome (BOS) as well as mortality of 90-day after lung transplantation. Results: Median duration of intubation were 2 (2) days ( M ( Q R )) in recipients after lung transplantation. The incidence of pulmonary infection and bronchus anastomosis complications were 15/17 and 5/17, respectively. Median length of stay in hospital were 56 (19) days. The ratio of readmission 1 month after discharge were 10/17. Mortality of 90-day post-transplant were 2/17. The incidence of PGD and BOS were 1/17 and 2/17, respectively. Conclusion: Recipients with DBD lung transplantation have an acceptable survival during short-term follow-up, but with higher incidences of complications related to infection post-transplantation.

[Is the brain the creator of psychic phenomena or is a paradigm shift inevitable?].

PubMed

Bonilla, Ernesto

2014-06-01

Every day new scientific information is appearing that cannot be explained using the classical Newtonian model and is calling for the emergence of a new paradigm that would include the explanation of such phenomena as telepathy, clairvoyance, presentiment, precognition, out of the body experiences, psychic healing, after-death communication, near-death experiences and reincarnation. The materialist paradigm which considers the brain as the sole cause of consciousness and psychic phenomena has been challenged by a new paradigm that seems to demonstrate that there is not a cause-effect relationship between brain activity and psychic phenomena but only a correlation between them, since these phenomena can be experienced without the body and appear to have an extra-cerebral origin (cosmic field, cosmic consciousness?). Of course, the brain is intensely involved in the manifestation of consciousness in our daily life but this is not equivalent to affirm that brain creates consciousness. Recent findings force us to consider a non-physical, spiritual and transpersonal aspect of reality.

Sulthiame but not levetiracetam exerts neurotoxic effect in the developing rat brain.

PubMed

Manthey, Daniela; Asimiadou, Stella; Stefovska, Vanya; Kaindl, Angela M; Fassbender, Jessica; Ikonomidou, Chrysanthy; Bittigau, Petra

2005-06-01

Antiepileptic drugs (AEDs) used to treat seizures in pregnant women, infants, and young children can cause cognitive impairment. One mechanism implicated in the development of neurocognitive deficits is a pathologic enhancement of physiologically occurring apoptotic neuronal death in the developing brain. We investigated whether the newer antiepileptic drug levetiracetam (LEV) and the older antiepileptic drug sulthiame (SUL) have neurotoxic properties in the developing rat brain. SUL significantly enhanced neuronal death in the brains of rat pups ages 0 to 7 days at doses of 100 mg/kg and above, whereas LEV did not show this neurotoxic effect. Dosages of both drugs used in the context of this study comply with an effective anticonvulsant dose range applied in rodent seizure models. Thus, LEV is an AED which lacks neurotoxicity in the developing rat brain and should be considered in the treatment of epilepsy in pregnant women, infants, and toddlers once general safety issues have been properly addressed.

Quantitative in vivo detection of brain cell death after hypoxia ischemia using the lipid peak at 1.3 ppm of proton magnetic resonance spectroscopy in neonatal rats.

PubMed

Ahn, So Yoon; Yoo, Hye Soo; Lee, Jang Hoon; Sung, Dong Kyung; Jung, Yu Jin; Sung, Se In; Lim, Keun Ho; Chang, Yun Sil; Lee, Jung Hee; Kim, Ki Soo; Park, Won Soon

2013-07-01

This study was performed to determine the accuracy of proton magnetic spectroscopy ((1)H-MRS) lipid peak as a noninvasive tool for quantitative in vivo detection of brain cell death. Seven day-old Sprague Dawley rats were subjected to 8% oxygen following a unilateral carotid artery ligation. For treatment, cycloheximide was given immediately after hypoxic ischemia (HI). Lipid peak was measured using (1)H-MRS at 24 hr after HI, and then brains were harvested for fluorocytometric analyses with annexin V/propidium iodide (PI) and fluorescent probe JC-1, and for adenosine-5'-triphosphate (ATP) and lactate. Increased lipid peak at 1.3 ppm measured with (1)H-MRS, apoptotic and necrotic cells, and loss of mitochondrial membrane potential (ΔΨ) at 24 hr after HI were significantly improved with cycloheximide treatment. Significantly reduced brain ATP and increased lactate levels observed at 24 hr after HI showed a tendency to improve without statistical significance with cycloheximide treatment. Lipid peak at 1.3 ppm showed significant positive correlation with both apoptotic and necrotic cells and loss of ΔΨ, and negative correlation with normal live cells. Lipid peak at 1.3 ppm measured by (1)H-MRS might be a sensitive and reliable diagnostic tool for quantitative in vivo detection of brain cell death after HI.

Differential DNA damage in response to the neonatal and adult excitotoxic hippocampal lesion in rats.

PubMed

Khaing, Z Z; Weickert, C S; Weinberger, D R; Lipska, B K

2000-12-01

We examined the developmental profile of excitotoxin-induced nuclear DNA fragmentation using the transferase dUTP nick-end labelling (TUNEL) technique, as a marker of DNA damage and cell death in rats with neonatal and adult excitotoxic lesions of the ventral hippocampus. We hypothesized that infusion of neurotoxin may result in a differential pattern of cell death in neonatally and adult lesioned rats, both in the infusion site and in remote brain regions presumably involved in mediating behavioural changes observed in these animals. Brains of rats lesioned at 7 days of age and in adulthood were collected at several survival times 1-21 days after the lesion. In the lesioned neonates 1-3 days postlesion, marked increases in TUNEL-positive cells occurred in the ventral hippocampus, the site of neurotoxin infusion, and in a wide surrounding area. Adult lesioned brains showed more positive cells than controls only at the infusion site. In the lesioned neonates, TUNEL-labelled cells were also present in the striatum and nucleus accumbens 1 day postlesion but not at later survival times. Our findings indicate that cell death in remote regions is more prominent in immature than adult brains, that it may lead to distinct alterations in development of these brain regions, and thus may be responsible for functional differences between neonatally and adult lesioned rats.

The effects of compound 48/80, morphine, and mast cell depletion on electroshock seizure in mice.

PubMed

Yillar, D O; Küçükhüseyin, C

2008-01-01

The effects of compound 48/80 (C48/80), morphine, and mast cell depletion on maximal electroshock seizure (MES) were studied in Swiss albino mice. An electrical current (60Hz, 0.2 msec) inducing convulsions in 50% of the animals (CC50) was assessed as 46 mA. Compound 48/80 (5 mg/kg) and morphine (100mg/kg) were administered subcutaneously. CC50 was applied separately to electroshock-unexposed animal groups at 15, 30, 60, 120, and 240 min after the onset of the experiment. In untreated controls, the percent of seizure induced by CC50 and percent of death among mice having convulsions were 50 and 20, respectively. After C48/80, a significant increase in rates of seizure at 60th and 120th min and death beyond 60th min (p < .0001) indicates a pro-convulsive action of the drug, probably caused by a reduction in MES threshold. In contrast, rate of seizure tended to decrease following mast-cell depletion, which was readily reversed by C48/80 at the 60th min (p < .0001). Mast-cell depletion, alone or plus morphine, significantly increased the death percentage of convulsions. Morphine alone reduced the percentage of seizure induced by the application of CC50 in the mast-cell depleted animals (anticonvulsive action) but increased the percent of dying animals by as much as 100% at the 30th and 60th min (p < .0001). Combined morphine + C48/80 not only augmented the anticonvulsive effect of morphine at the 30th min but also nullified the rate of death among mice having convulsions. We concluded that compound 48/80 (1) penetrates into the central nervous system to produce a central effect; (2) acts as pro-convulsive, and (3) paradoxically augments the anticonvulsive action of morphine, likely caused by the ability of the compound to increase the permeability of blood-brain barrier for morphine or by the release of histamine from mast cells in the brain, acting as anticonvulsant through the stimulation of H1 receptors or both. The precise mechanism of the increased death rate by C48/80 or morphine in intact and in mast-cell-depleted mice appears to involve pro-convulsive effects, cardiovascular impairment, and respiratory depression. The nullification of morphine-induced lethal toxicity by C48/80 could be due to the antagonistic interaction of the drug with opiate receptors in the brain.

Is Overall Mortality the Right Composite Endpoint in Clinical Trials of Acute Respiratory Distress Syndrome?

PubMed

Villar, Jesús; Martínez, Domingo; Mosteiro, Fernando; Ambrós, Alfonso; Añón, José M; Ferrando, Carlos; Soler, Juan A; Montiel, Raquel; Vidal, Anxela; Conesa-Cayuela, Luís A; Blanco, Jesús; Arrojo, Regina; Solano, Rosario; Capilla, Lucía; Del Campo, Rafael; Civantos, Belén; Fernández, María Mar; Aldecoa, César; Parra, Laura; Gutiérrez, Andrea; Martínez-Jiménez, Chanel; González-Martín, Jesús M; Fernández, Rosa L; Kacmarek, Robert M

2018-06-01

Overall mortality in patients with acute respiratory distress syndrome is a composite endpoint because it includes death from multiple causes. In most acute respiratory distress syndrome trials, it is unknown whether reported deaths are due to acute respiratory distress syndrome or the underlying disease, unrelated to the specific intervention tested. We investigated the causes of death after contracting acute respiratory distress syndrome in a large cohort. A secondary analysis from three prospective, multicenter, observational studies. A network of multidisciplinary ICUs. We studied 778 patients with moderate-to-severe acute respiratory distress syndrome treated with lung-protective ventilation. None. We examined death in the ICU from individual causes. Overall ICU mortality was 38.8% (95% CI, 35.4-42.3). Causes of acute respiratory distress syndrome modified the risk of death. Twenty-three percent of deaths occurred from refractory hypoxemia due to nonresolving acute respiratory distress syndrome. Most patients died from causes unrelated to acute respiratory distress syndrome: 48.7% of nonsurvivors died from multisystem organ failure, and cancer or brain injury was involved in 37.1% of deaths. When quantifying the true burden of acute respiratory distress syndrome outcome, we identified 506 patients (65.0%) with one or more exclusion criteria for enrollment into current interventional trials. Overall ICU mortality of the "trial cohort" (21.3%) was markedly lower than the parent cohort (relative risk, 0.55; 95% CI, 0.43-0.70; p < 0.000001). Most deaths in acute respiratory distress syndrome patients are not directly related to lung damage but to extrapulmonary multisystem organ failure. It would be challenging to prove that specific lung-directed therapies have an effect on overall survival.

Medical-encounter mental health diagnoses, non-fatal injury and polypharmacy indicators of risk for accident death in the US Army enlisted soldiers, 2004-2009.

PubMed

Lewandowski-Romps, Lisa; Schroeder, Heather M; Berglund, Patricia A; Colpe, Lisa J; Cox, Kenneth; Hauret, Keith; Hay, Jeffrey D; Jones, Bruce; Little, Roderick J A; Mitchell, Colter; Schoenbaum, Michael; Schulz, Paul; Stein, Murray B; Ursano, Robert J; Heeringa, Steven G

2018-06-01

Accidents are a leading cause of deaths in U.S. active duty personnel. Understanding accident deaths during wartime could facilitate future operational planning and inform risk prevention efforts. This study expands prior research, identifying health risk factors associated with U.S. Army accident deaths during the Afghanistan and Iraq war. Military records for 2004-2009 enlisted, active duty, Regular Army soldiers were analyzed using logistic regression modeling to identify mental health, injury, and polypharmacy (multiple narcotic and/or psychotropic medications) predictors of accident deaths for current, previously, and never deployed groups. Deployed soldiers with anxiety diagnoses showed higher risk for accident deaths. Over half had anxiety diagnoses prior to being deployed, suggesting anticipatory anxiety or symptom recurrence may contribute to high risk. For previously deployed soldiers, traumatic brain injury (TBI) indicated higher risk. Two-thirds of these soldiers had first TBI medical-encounter while non-deployed, but mild, combat-related TBIs may have been undetected during deployments. Post-Traumatic Stress Disorder (PTSD) predicted higher risk for never deployed soldiers, as did polypharmacy which may relate to reasons for deployment ineligibility. Health risk predictors for Army accident deaths are identified and potential practice and policy implications discussed. Further research could test for replicability and expand models to include unobserved factors or modifiable mechanisms related to high risk. PTSD predicted high risk among those never deployed, suggesting importance of identification, treatment, and prevention of non-combat traumatic events. Finally, risk predictors overlapped with those identified for suicides, suggesting effective intervention might reduce both types of deaths. Copyright © 2017 Elsevier Inc. All rights reserved.

Induction of specific micro RNA (miRNA) species by ROS-generating metal sulfates in primary human brain cells

PubMed Central

Lukiw, Walter J.; Pogue, Aileen I.

2007-01-01

Iron- and aluminum-sulfate together, at nanomolar concentrations, trigger the production of reactive oxygen species (ROS) in cultures of human brain cells. Previous studies have shown that following ROS induction, a family of pathogenic brain genes that promote inflammatory signalling, cellular apoptosis and brain cell death is significantly over-expressed. Notably, iron- and aluminum-sulfate induce genes in cultured human brain cells that exhibit expression patterns similar to those observed to be up-regulated in moderate- to late-stage Alzheimer's disease (AD). In this study we have extended our investigations to analyze the expression of micro RNA (miRNA) populations in iron- and aluminum-sulfate treated human neural cells in primary culture. The main finding was that these ROS-generating neurotoxic metal sulfates also up-regulate a specific set of miRNAs that includes miR-9, miR-125b and miR-128. Notably, these same miRNAs are up-regulated in AD brain. These findings further support the idea that iron- and aluminum-sulfates induce genotoxicity via a ROS-mediated up-regulation of specific regulatory elements and pathogenic genes that redirect brain cell fate towards progressive dysfunction and apoptotic cell death. PMID:17629564

Near-Death-Like Experiences without Life-Threatening Conditions or Brain Disorders: A Hypothesis from a Case Report

PubMed Central

Facco, Enrico; Agrillo, Christian

2012-01-01

Near-death experiences (NDEs) are profound psychic experiences commonly occurring in life-threatening conditions. They include feeling a sense of peace, of seeing a bright light, encountering deceased relatives or religious figures, and of transcending space and time. To explain them, it has been suggested that they stem from brain disorders and/or psychological reactions to approaching death, a sort of wishful thinking in response to the perceived threat. This is a report on a case with most of the features typical of NDEs except that it occurred entirely without any life-threatening conditions. This evidence is theoretically incompatible with either of the above hypotheses, suggesting that a broader interpretation of the phenomenon is needed. PMID:23162522

Excess cancer mortality among children and adolescents in residential districts polluted by petrochemical manufacturing plants in Taiwan

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bi Jen Pan; Yu Jue Hong; Gwo Chin Chang

1994-12-31

We have collected data on the cancer deaths of children and adolescents 0-19 yr old living in a residential area near 3 large petroleum and petrochemical complexes in and near Kaohsiung city (petrochemical industrial districts, PIDs) in the period of 1971-1990 and compared these with the cancer deaths of children and adolescents 0-19 yr old among the entire population of Taiwan (national reference) and among the residents of 26 administrative districts, comprising all of Kaohsiung city and Kaohsiung county (local reference), except for 8 sparsely populated, rural districts. Having scrutinized all cancer death certificates, we have identified various statistically significantmore » excess deaths, as compared with the national and local reference, due to cancers at all sites. Cancer of the bone, brain, and bladder in boys and girls 0-9 yr and 10-19 yr of age in the 1981-1990 decade that followed the establishment of petrochemical production in the PIDs was studied. However, excess cancer deaths seemed to have clustered in the 10-19 yr age group, who had been potentially exposed to the petrochemical pollutants for the longest period of time from the youngest age. Almost all bone, brain, and bladder cancer deaths registered were within 3 km of the 3 complexes. Bone and brain cancers in particular occurred in girls in the PIDs more frequently than in boys, even though these are believed to occur more in males than females elsewhere. 32 refs., 1 fig., 6 tabs.« less

Patterns of cell death in the perinatal mouse forebrain.

PubMed

Mosley, Morgan; Shah, Charisma; Morse, Kiriana A; Miloro, Stephen A; Holmes, Melissa M; Ahern, Todd H; Forger, Nancy G

2017-01-01

The importance of cell death in brain development has long been appreciated, but many basic questions remain, such as what initiates or terminates the cell death period. One obstacle has been the lack of quantitative data defining exactly when cell death occurs. We recently created a "cell death atlas," using the detection of activated caspase-3 (AC3) to quantify apoptosis in the postnatal mouse ventral forebrain and hypothalamus, and found that the highest rates of cell death were seen at the earliest postnatal ages in most regions. Here we have extended these analyses to prenatal ages and additional brain regions. We quantified cell death in 16 forebrain regions across nine perinatal ages from embryonic day (E) 17 to postnatal day (P) 11 and found that cell death peaks just after birth in most regions. We found greater cell death in several regions in offspring delivered vaginally on the day of parturition compared with those of the same postconception age but still in utero at the time of collection. We also found massive cell death in the oriens layer of the hippocampus on P1 and in regions surrounding the anterior crossing of the corpus callosum on E18 as well as the persistence of large numbers of cells in those regions in adult mice lacking the pro-death Bax gene. Together these findings suggest that birth may be an important trigger of neuronal cell death and identify transient cell groups that may undergo wholesale elimination perinatally. J. Comp. Neurol. 525:47-64, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Expressions of Mast Cell Tryptase and Brain Natriuretic Peptide in Myocardium of Sudden Death due to Hypersensitivity and Coronary Atherosclerotic Heart Disease.

PubMed

Shi, J R; Tian, C J; Zeng, Q; Guo, X J; Lu, J; Gao, C R

2016-06-01

To explore the value of mast cell tryptase and brain natriuretic peptide（BNP） in the differential diagnostic of sudden death due to hypersensitivity and coronary atherosclerotic heart disease. Totally 30 myocardial samples were collected from the autopsy cases in the Department of Forensic Pathology, Shanxi Medical University during 2010-2015. All samples were divided into three groups： death of craniocerebral injury group, sudden death of hypersensitivity group and sudden death of coronary atherosclerotic heart disease group, 10 cases in each group. Mast cell tryptase and BNP in myocardium were detected by immunofluorescence staining and Western Blotting. Immunofluorescence staining showed that the positive staining mast cell tryptase appeared in myocardium of sudden death of hypersensitivity group and coronary atherosclerotic heart disease group. Among the three groups, the expression of mast cell tryptase showed significantly differences through pairwise comparison （ P <0.05）; The expression level of BNP in sudden death of coronary atherosclerotic heart disease group were significantly higher than the sudden death of hypersensitivity group and death of craniocerebral injury group （ P <0.05）. The difference of the expression level of BNP between the sudden death of hypersensitivity group and the death of craniocerebral injury group had no statistical significance （ P >0.05）. The combined detection of the mast cell tryptase and BNP in myocardium is expected to provide help for the forensic differential diagnosis of sudden death due to hypersensitivity and coronary atherosclerotic heart disease. Copyright© by the Editorial Department of Journal of Forensic Medicine

Tissue residues of dieldrin in relation to mortality in birds and mammals

USGS Publications Warehouse

Stickel, W.H.; Stickel, L.F.; Spann, J.W.; Miller, M.W.; Berg, G.G.

1969-01-01

An experiment was performed with Coturnix to learn what residue levels were indicative of death from dieldrin poisoning. Birds were fed diets containing 250, 50, 10, and 2 ppm dieldrin for periods up to 158 days. The dieldrin was 95% pure HEOD, which is 1,2,3,4,10,10-hexachloro-6, 7.epoxy. l,4,4a,5,6,7,8,8a-octahydro-l,4-endo,exo-5,8- dimethanonaphthalene. When half of a group was dead, the other half was sacrificed for comparison of residues in dead and survivors. Dosage levels controlled time to death, but did not control residue levels in the dead. Residues in liver and carcass proved to be misleading and complicated by changes in lipid content. Brain residues correlated well with death although residues in dead and survivors overlapped. Brain residues of animals killed by dieldrin in the field and in other experiments are listed. Data agree in general for several species of birds and mammals. There is evidence, however, for species differences in average lethal brain residues. It is concluded that brain residues of 4 or 5 ppm (wet weight) or higher indicate that the animal was in the known danger zone and may have died from dieldrin. Brain residues averaged lower in wild than in experimental animals. Possible explanations include species differences, more stress and exertion in the wild, and overrepresentation in the field series of individuals that will die with low but lethal brain residues. The latter is supported by the fact that the first Coturnix to die in each sex and treatment group had the lowest brain residue of its group. Birds receiving 2 ppm dieldrin, and some receiving 10 ppm, were able to maintain low brain residues throughout the experiment. However, birds of the 10 ppm group could withstand little stress and mobilization of toxicant, for a few micrograms in the brain were lethal and bodies contained hundreds or thousands of micrograms.

Good Samaritan surgeon wrongly accused of contributing to President Lincoln's death: an experimental study of the President's fatal wound.

PubMed

Lattimer, J K; Laidlaw, A

1996-05-01

When President Abraham Lincoln was shot in the back of the head at Ford's Theater in Washington, D.C., on April 14, 1865, he was immediately rendered unconscious and apneic. Doctor Charles A. Leale, an Army surgeon, who had special training in the care of brain injuries, rushed to Lincoln's assistance. When Doctor Leale probed the wound in Lincoln's thickened scalp, feeling for the bullet, he dislodged a blood clot, and Lincoln began to breathe again. However, Lincoln progressively deteriorated and died at 7:22 AM on April 15, 1865. During the postmortem examination of Lincoln's body, numerous secondary missiles of bone and metal were found in the track of pultaceous brain tissue, extending completely through the brain to the front of the skull. In February 1995, an article in a popular magazine alleged that Doctor Leale had caused further (fatal) damage to Lincoln's brain by thrusting his finger into the brain through the bullet hole. The article alleged (wrongly) that most bullet wounds of the brain incurred in Civil War times were not fatal. The following study demonstrates that it is impossible to introduce even the tip of the little finger through a hole in the skull resulting from a .41-caliber bullet fired from a derringer. In our study, a .41-caliber derringer was used to fire bullets into numerous fresh skulls; the bullet holes all had razor-sharp edges and were much too small to accommodate a fingertip. Thus, the allegation that President Lincoln's brain was damaged further because Doctor Leale thrust his finger through the bullet hole into the brain parenchyma is not valid. In this study, experimental data are presented to demonstrate the foregoing point. The wound made by John Wilkes Booth's derringer ball in Lincoln's brain was devastating; it was clearly the cause of his death. Good Samaritan surgeon Leale has been falsely accused of contributing to Lincoln's death.

Place of death of pediatric cancer patients in a single institute during 7 years.

PubMed

Yanai, Tomoko; Hirase, Satoshi; Matsunoshita, Natsuki; Yamamoto, Nobuyuki; Ninchoji, Takeshi; Kubokawa, Ikuko; Mori, Takeshi; Hayakawa, Akira; Takeshima, Yasuhiro; Iijima, Kazumoto; Matsuo, Masafumi

2012-06-27

Place of death is an important issue at the end-of-life. It is poorly understood in pediatric cancer patients in Japan. This study aimed to clarify place of death of children with cancer as well as variables associated with place of death. Study population was pediatric cancer patients who died in the Department of Pediatrics at Kobe University Hospital during the last 7 years. The medical records were retrospectively reviewed regardless of cause of death to derive data relating to patients' characteristics and disease. 18 patients were included. Median age at death was 12.2 years old. 6 patients including 5 children in complete remission had hematological disease and 12 patients suffered from solid tumors. 4 patients (22.2%) died at home, whereas 14 patients (77.8%) died in the hospital including 6 ICU deaths. No one died in hospices. Preference of patients was unavailable due to the lack of inquiry. Factors influencing place of death (home, ICU, non-ICU) were disease (hematological disease vs. solid tumor, p=0.010, brain tumor vs. non-brain tumor, p=0.023), disease status (complete remission vs. non-complete remission, p=0.0014) and preference of families (p=0.029). Among 6 families who expressed preference, no disparity was observed between actual and preferred place of death. This is the first English publication of place of death of pediatric cancer patients in Japan. The low percentage of home death, factors influencing place of death and the lack of disparity between actual and preferred place of death were indicated. Further studies are required to better understand place of death.

Innate Immunity and Inflammation Post-Stroke: An α7-Nicotinic Agonist Perspective

PubMed Central

Neumann, Silke; Shields, Nicholas J.; Balle, Thomas; Chebib, Mary; Clarkson, Andrew N.

2015-01-01

Stroke is one of the leading causes of death and long-term disability, with limited treatment options available. Inflammation contributes to damage tissue in the central nervous system across a broad range of neuropathologies, including Alzheimer’s disease, pain, Schizophrenia, and stroke. While the immune system plays an important role in contributing to brain damage produced by ischemia, the damaged brain, in turn, can exert a powerful immune-suppressive effect that promotes infections and threatens the survival of stroke patients. Recently the cholinergic anti-inflammatory pathway, in particular its modulation using α7-nicotinic acetylcholine receptor (α7-nAChR) ligands, has shown potential as a strategy to dampen the inflammatory response and facilitate functional recovery in stroke patients. Here we discuss the current literature on stroke-induced inflammation and the effects of α7-nAChR modulators on innate immune cells. PMID:26690125

Innate Immunity and Inflammation Post-Stroke: An α7-Nicotinic Agonist Perspective.

PubMed

Neumann, Silke; Shields, Nicholas J; Balle, Thomas; Chebib, Mary; Clarkson, Andrew N

2015-12-04

Stroke is one of the leading causes of death and long-term disability, with limited treatment options available. Inflammation contributes to damage tissue in the central nervous system across a broad range of neuropathologies, including Alzheimer's disease, pain, Schizophrenia, and stroke. While the immune system plays an important role in contributing to brain damage produced by ischemia, the damaged brain, in turn, can exert a powerful immune-suppressive effect that promotes infections and threatens the survival of stroke patients. Recently the cholinergic anti-inflammatory pathway, in particular its modulation using α7-nicotinic acetylcholine receptor (α7-nAChR) ligands, has shown potential as a strategy to dampen the inflammatory response and facilitate functional recovery in stroke patients. Here we discuss the current literature on stroke-induced inflammation and the effects of α7-nAChR modulators on innate immune cells.

Neurosteroids for the potential protection of humans against organophosphate toxicity.

PubMed

Reddy, Doodipala Samba

2016-08-01

This article describes the therapeutic potential of neurosteroids as anticonvulsant antidotes for chemical intoxication caused by organophosphate pesticides and nerve agents or gases like sarin and soman. Toxic manifestations following nerve agent exposure, as evident in chemical attacks in Japan and Syria, include hypersecretion, respiratory distress, tremors, convulsions leading to status epilepticus (SE), and death. Benzodiazepines, such as diazepam, are the current anticonvulsants of choice for controlling nerve agent-induced life-threatening seizures, SE, and brain injury. Benzodiazepines can control acute seizures when given early, but they are less effective for delayed treatment of SE, which is characterized by rapid desensitization of synaptic GABA A receptors, benzodiazepine resistance, and brain injury. Neurosteroid-sensitive extrasynaptic GABA A receptors, however, remain unaffected by such events. Thus, anticonvulsant neurosteroids may produce more effective protection than benzodiazepines against a broad spectrum of chemical agents, even when given late after nerve agent exposure. © 2016 New York Academy of Sciences.

Effectiveness of a nonpenetrating captive bolt for euthanasia of piglets less than 3 d of age.

PubMed

Casey-Trott, T M; Millman, S T; Turner, P V; Nykamp, S G; Widowski, T M

2013-11-01

The objective of this study was to determine the effectiveness of a nonpenetrating captive bolt (NPCB), the Zephyr-Euthanasia (Zephyr-E), for euthanasia of neonatal piglets<72 h of age using signs of insensibility and death, as well as postmortem assessment of traumatic brain injury (TBI). The Zephyr-E was used by 10 stock people to euthanize 100 low viability neonatal piglets from 3 commercial farrowing units and 1 research farm. Brainstem reflexes, convulsions, and heartbeat were used to assess insensibility, time of brain death, and cardiac arrest after Zephyr-E application. Hemorrhage severity and skull fracture displacement (FD) were quantified from computed tomography scans (n=10), macroscopic scoring was used to assess brain hemorrhage and skull fracture (SK) severity (n=100), and microscopic scoring was used to assess subdural (SDH) and parenchymal (PH) hemorrhage within specific brain regions that are responsible for consciousness and vital function (n=10). All 100 piglets were rendered immediately insensible without return to sensibility. On average, clonic convulsions (CC) ceased in 101 s (±7.4 SE), brain death was achieved in 229 s (±9.18 SE), and cardiac arrest occurred in 420 s (±13.57 SE). Time of cardiac arrest differed significantly among stock people when either body weight (BW: P=0.0053) or body mass index (BMI: P=0.0059) was used as a covariate. The BMI was inversely related to the duration of CC (P=0.0227). Moderate to severe hemorrhage severity was reported in 9 of 10 piglets. There was no relationship between FD and BW (P=0.8408) or BMI (P=0.6439). Macroscopic analyses indicated moderate to severe hemorrhage and SK in all piglets. No differences were found among brain sections for SDH (P=0.2302); PH was greater in the cerebral cortex than in the midbrain and brainstem (P=0.0328). The Zephyr-E NPCB reliably caused immediate, sustained insensibility followed by death in neonatal piglets. Postmortem assessment confirmed that application of the Zephyr-E caused widespread, irreversible brain damage.

Gender difference in the effect of progesterone on neonatal hypoxic/ischemic brain injury in mouse.

PubMed

Dong, Shuyu; Zhang, Qian; Kong, Delian; Zhou, Chao; Zhou, Jie; Han, Jingjing; Zhou, Yan; Jin, Guoliang; Hua, Xiaodong; Wang, Jun; Hua, Fang

2018-08-01

This study investigated the effects of progesterone (PROG) on neonatal hypoxic/ischemic (NHI) brain injury, the differences in effects between genders, and the underlying mechanisms. NHI brain injury was established in both male and female neonatal mice induced by occlusion of the left common carotid artery followed by hypoxia. The mice were treated with PROG or vehicle. Fluoro-Jade B staining (F-JB), long term behavior testing, and brain magnetic resonance image (MRI) were applied to evaluate neuronal death, neurological function, and brain damage. The underlying molecular mechanisms were also investigated by Western blots. The results showed that, in the male mice, administration of PROG significantly reduced neuronal death, improved the learning and memory function impaired by cerebral HI, decreased infarct size, and maintained the thickness of the cortex after cerebral HI. PROG treatment, however, did not show significant neuroprotective effects on female mice subjected to HI. In addition, the data demonstrated a gender difference in the expression of tumor necrosis factor receptor 1 (TNFR1), TNF receptor associated factor 6 (TRAF6), Fas associated protein with death domain (FADD), and TIR-domain-containing adapter-inducing interferon-β (TRIF) between males and females. Our results indicated that treatment with PROG had beneficial effects on NHI injured brain in acute stage and improved the long term cognitive function impaired by cerebral HI in male mice. In addition, the activation of TNF and TRIF mediated signaling in response to cerebral HI and the treatment of PROG varied between genders, which highly suggested that gender differences should be emphasized in evaluating neonatal HI brain injury and PROG effects, as well as the underlying mechanisms. Copyright © 2018 Elsevier Inc. All rights reserved.

Inadequate Antioxidative Responses in Kidneys of Brain-Dead Rats.

PubMed

Hoeksma, Dane; Rebolledo, Rolando A; Hottenrott, Maximilia; Bodar, Yves S; Wiersema-Buist, Janneke J; Van Goor, Harry; Leuvenink, Henri G D

2017-04-01

Brain death (BD)-related lipid peroxidation, measured as serum malondialdehyde (MDA) levels, correlates with delayed graft function in renal transplant recipients. How BD affects lipid peroxidation is not known. The extent of BD-induced organ damage is influenced by the speed at which intracranial pressure increases. To determine possible underlying causes of lipid peroxidation, we investigated the renal redox balance by assessing oxidative and antioxidative processes in kidneys of brain-dead rats after fast and slow BD induction. Brain death was induced in 64 ventilated male Fisher rats by inflating a 4.0F Fogarty catheter in the epidural space. Fast and slow inductions were achieved by an inflation speed of 0.45 and 0.015 mL/min, respectively, until BD confirmation. Healthy non-brain-dead rats served as reference values. Brain-dead rats were monitored for 0.5, 1, 2, or 4 hours, after which organs and blood were collected. Increased MDA levels became evident at 2 hours of slow BD induction at which increased superoxide levels, decreased glutathione peroxidase (GPx) activity, decreased glutathione levels, increased inducible nitric oxide synthase and heme-oxygenase 1 expression, and increased plasma creatinine levels were evident. At 4 hours after slow BD induction, superoxide, MDA, and plasma creatinine levels increased further, whereas GPx activity remained decreased. Increased MDA and plasma creatinine levels also became evident after 4 hours fast BD induction. Brain death leads to increased superoxide production, decreased GPx activity, decreased glutathione levels, increased inducible nitric oxide synthase and heme-oxygenase 1 expression, and increased MDA and plasma creatinine levels. These effects were more pronounced after slow BD induction. Modulation of these processes could lead to decreased incidence of delayed graft function.

Brain-Dead Donors on Extracorporeal Membrane Oxygenation.

PubMed

Bronchard, Régis; Durand, Louise; Legeai, Camille; Cohen, Johana; Guerrini, Patrice; Bastien, Olivier

2017-10-01

To describe donors after brain death with ongoing extracorporeal membrane oxygenation and to analyze the outcome of organs transplanted from these donors. Retrospective analysis of the national information system run by the French Biomedicine Agency (CRISTAL database). National registry data of all donors after brain death in France and their organ recipients between 2007 and 2013. Donors after brain death and their organ recipients. None. During the study period, there were 22,270 brain-dead patients diagnosed in France, of whom 161 with extracorporeal membrane oxygenation. Among these patients, 64 donors on extracorporeal membrane oxygenation and 10,805 donors without extracorporeal membrane oxygenation had at least one organ retrieved. Donors on extracorporeal membrane oxygenation were significantly younger and had more severe intensive care medical conditions (hemodynamic, biological, renal, and liver insults) than donors without extracorporeal membrane oxygenation. One hundred nine kidneys, 37 livers, seven hearts, and one lung were successfully transplanted from donors on extracorporeal membrane oxygenation. We found no significant difference in 1-year kidney graft survival (p = 0.24) and function between recipients from donors on extracorporeal membrane oxygenation (92.7% [85.9-96.3%]) and matching recipients from donors without extracorporeal membrane oxygenation (95.4% [93.0-97.0%]). We also found no significant difference in 1-year liver recipient survival (p = 0.91): 86.5% (70.5-94.1) from donors on extracorporeal membrane oxygenation versus 80.7% (79.8-81.6) from donors without extracorporeal membrane oxygenation. Brain-dead patients with ongoing extracorporeal membrane oxygenation have more severe medical conditions than those without extracorporeal membrane oxygenation. However, kidney graft survival and function were no different than usual. Brain-dead patients with ongoing extracorporeal membrane oxygenation are suitable for organ procurement.

Management of severe head injury with brain exposure in three loggerhead sea turtles Caretta caretta.

PubMed

Franchini, D; Cavaliere, L; Valastro, C; Carnevali, F; van der Esch, A; Lai, O; Di Bello, A

2016-05-03

The loggerhead Caretta caretta is the most common sea turtle in the Mediterranean. Currently, sea turtles are considered endangered, mainly due to the impact of human activities. Among traumatic lesions, those involving the skull, if complicated by brain exposure, are often life-threatening. In these cases, death could be the outcome of direct trauma of the cerebral tissue or of secondary meningoencephalitis. This uncontrolled study aims to evaluate the use of a plant-derived dressing (1 Primary Wound Dressing®) in 3 sea turtles with severe lesions of the skull exposing the brain. Following surgical curettage, the treatment protocol involved exclusive use of the plant-derived dressing applied on the wound surface as the primary dressing, daily for the first month and then every other day until the end of treatment. The wound and peri-wound skin were covered with a simple secondary dressing without any active compound (non-woven gauze with petroleum jelly). Data presented herein show an excellent healing process in all 3 cases and no side effects due to contact of the medication with the cerebral tissue.

Neuroprotective effects of hydrogen sulfide on sodium azide‑induced autophagic cell death in PC12 cells.

PubMed

Shan, Haiyan; Chu, Yang; Chang, Pan; Yang, Lijun; Wang, Yi; Zhu, Shaohua; Zhang, Mingyang; Tao, Luyang

2017-11-01

Sodium azide (NaN3) is a chemical of rapidly growing commercial importance. It is very acutely toxic and inhibits cytochrome oxidase (COX) by binding irreversibly to the heme cofactor. A previous study from our group demonstrated that hydrogen sulfide (H2S), the third endogenous gaseous mediator identified, had protective effects against neuronal damage induced by traumatic brain injury (TBI). It is well‑known that TBI can reduce the activity of COX and have detrimental effects on the central nervous system metabolism. Therefore, in the present study, it was hypothesized that H2S may provide neuroprotection against NaN3 toxicity. The current results revealed that NaN3 treatment induced non‑apoptotic cell death, namely autophagic cell death, in PC12 cells. Expression of the endogenous H2S‑producing enzymes, cystathionine‑β‑synthase and 3‑mercaptopyruvate sulfurtransferase, decreased in a dose‑dependent manner following NaN3 treatment. Pretreatment with H2S markedly attenuated the NaN3‑induced cell viability loss and autophagic cell death in a dose‑dependent manner. The present study suggests that H2S‑based strategies may have future potential in the prevention and/or therapy of neuronal damage following NaN3 exposure.

Rapid brain death caused by a cerebellar abscess with Fusobacterium nucleatum in a young man with drug abuse: a case report

PubMed Central

2014-01-01

Background Fusobacterium nucleatum is a strict anaerobic microorganism that causes disease entities such as periodontal and soft tissue abscesses, pulmonary and intraabdominal infections and very rarely intracerebral infections. Case presentation Here, we report the rare case of a previously healthy 25-year-old German man with a cerebellar abscess caused by Fusobacterium nucleatum that resulted in rapid brain death. Toxicological screening showed positivity for amphetamines and cannabis. The diagnosis was obtained by polymerase chain reaction amplification of bacterial deoxyribonucleic acid in cerebrospinal fluid. Conclusions In drug users clinicians should think about rare causes of brain abscesses/meningitis. Early diagnosis is necessary and justifies the use of molecular techniques. PMID:24915846

Microscopic analysis of the different regions of three Alzheimer brains aged 93, 94, and 104 years old.

PubMed

Zhu, Yonghong; Xu, Jie; Kwong, Wing Hang; Wai, Sen Mun; Lam, Wai Ping; Yew, David T

2007-10-01

The brains of three Alzheimer patients aged 93, 94, and 104 years old were analyzed. Although cell death was apparent in different cortices, the prefrontal cortex and the Broca's appeared to be hit hardest. The different CA areas of the hippocampal formation all displayed equivalent degrees of cell death but the entorhinal areas showed the most severe degree of cell degeneration. Both apoptosis and necrosis were observed in the different cerebral regions of these very old patients, as expected.

Seeking an ethical and legal way of procuring transplantable organs from the dying without further attempts to redefine human death

PubMed Central

Evans, David Wainwright

2007-01-01

Because complex organs taken from unequivocally dead people are not suitable for transplantation, human death has been redefined so that it can be certified at some earlier stage in the dying process and thereby make viable organs available without legal problems. Redefinitions based on concepts of "brain death" have underpinned transplant practice for many years although those concepts have never found universal philosophical acceptance. Neither is there consensus about the clinical tests which have been held sufficient to diagnose the irreversible cessation of all brain function – or as much of it as is deemed relevant – while the body remains alive. For these reasons, the certification of death for transplant purposes on "brain death" grounds is increasingly questioned and there has been pressure to return to its diagnosis on the basis of cardiac arrest and the consequent cessation of blood circulation throughout the body. While superficially a welcome return to the traditional and universally accepted understanding of human death, examination of the protocols using such criteria for the diagnosis of death prior to organ removal reveals a materially different scenario in which the circulatory arrest is not certainly final and purely nominal periods of arrest are required before surgery begins. Recognizing the probably unresolvable conflict between allowing enough time to pass after truly final circulatory arrest for a safe diagnosis of death and its minimization for the sake of the wanted organs, Verheijde and colleagues follow others in calling for the abandonment of the "dead donor rule" and the enactment of legislation to permit the removal of organs from the dying, without pretence that they are dead before that surgery. While it may be doubted whether such a "paradigm change" in the ethics of organ procurement would be accepted by society, their call for its consideration as a fully and fairly informed basis for organ donation is to be applauded. PMID:17603889

Fisetin as a caloric restriction mimetic protects rat brain against aging induced oxidative stress, apoptosis and neurodegeneration.

PubMed

Singh, Sandeep; Singh, Abhishek Kumar; Garg, Geetika; Rizvi, Syed Ibrahim

2018-01-15

In the present study, attempts have been made to evaluate the potential role of fisetin, a caloric restriction mimetic (CRM), for neuroprotection in D-galactose (D-gal) induced accelerated and natural aging models of rat. Fisetin was supplemented (15mg/kg b.w., orally) to young, D-gal induced aged (D-gal 500mg/kg b.w subcutaneously) and naturally aged rats for 6weeks. Standard protocols were employed to measure pro-oxidants, antioxidants and mitochondrial membrane potential in brain tissues. Gene expression analysis with reverse transcriptase-polymerase chain reaction (RT-PCR) was performed to assess the expression of autophagy, neuronal, aging as well as inflammatory marker genes. We have also evaluated apoptotic cell death and synaptosomal membrane-bound ion transporter activities in brain tissues. Our data demonstrated that fisetin significantly decreased the level of pro-oxidants and increased the level of antioxidants. Furthermore, fisetin also ameliorated mitochondrial membrane depolarization, apoptotic cell death and impairments in the activities of synaptosomal membrane-bound ion transporters in aging rat brain. RT-PCR data revealed that fisetin up-regulated the expression of autophagy genes (Atg-3 and Beclin-1), sirtuin-1 and neuronal markers (NSE and Ngb), and down-regulated the expression of inflammatory (IL-1β and TNF-α) and Sirt-2 genes respectively in aging brain. The present study suggests that fisetin supplementation may provide neuroprotection against aging-induced oxidative stress, apoptotic cell death, neuro-inflammation, and neurodegeneration in rat brain. Copyright © 2017 Elsevier Inc. All rights reserved.

Oxygen-conserving reflexes of the brain: the current molecular knowledge

PubMed Central

Schaller, B; Cornelius, J F; Sandu, N; Ottaviani, G; Perez-Pinzon, M A

2009-01-01

Abstract The trigemino-cardiac reflex (TCR) may be classified as a sub-phenomenon in the group of the so-called ‘oxygen-conserving reflexes’. Within seconds after the initiation of such a reflex, there is neither a powerful and differentiated activation of the sympathetic system with subsequent elevation in regional cerebral blood flow (CBF) with no changes in the cerebral metabolic rate of oxygen (CMRO2) or in the cerebral metabolic rate of glucose (CMRglc). Such an increase in regional CBF without a change of CMRO2 or CMRglc provides the brain with oxygen rapidly and efficiently and gives substantial evidence that the TCR is an oxygen-conserving reflex. This system, which mediates reflex protection projects via currently undefined pathways from the rostral ventrolateral medulla oblongata to the upper brainstem and/or thalamus which finally engage a small population of neurons in the cortex. This cortical centre appears to be dedicated to reflexively transduce a neuronal signal into cerebral vasodilatation and synchronization of electrocortical activity. Sympathetic excitation is mediated by cortical-spinal projection to spinal pre-ganglionic sympathetic neurons whereas bradycardia is mediated via projections to cardiovagal motor medullary neurons. The integrated reflex response serves to redistribute blood from viscera to brain in response to a challenge to cerebral metabolism, but seems also to initiate a preconditioning mechanism. Better and more detailed knowledge of the cascades, transmitters and molecules engaged in such endogenous (neuro) protection may provide new insights into novel therapeutic options for a range of disorders characterized by neuronal death and into cortical organization of the brain. PMID:19438971

Oxygen-conserving reflexes of the brain: the current molecular knowledge.

PubMed

Schaller, B; Cornelius, J F; Sandu, N; Ottaviani, G; Perez-Pinzon, M A

2009-04-01

The trigemino-cardiac reflex (TCR) may be classified as a sub-phenomenon in the group of the so-called 'oxygen-conserving reflexes'. Within seconds after the initiation of such a reflex, there is neither a powerful and differentiated activation of the sympathetic system with subsequent elevation in regional cerebral blood flow (CBF) with no changes in the cerebral metabolic rate of oxygen (CMRO(2)) or in the cerebral metabolic rate of glucose (CMRglc). Such an increase in regional CBF without a change of CMRO(2) or CMRglc provides the brain with oxygen rapidly and efficiently and gives substantial evidence that the TCR is an oxygen-conserving reflex. This system, which mediates reflex protection projects via currently undefined pathways from the rostral ventrolateral medulla oblongata to the upper brainstem and/or thalamus which finally engage a small population of neurons in the cortex. This cortical centre appears to be dedicated to reflexively transduce a neuronal signal into cerebral vasodilatation and synchronization of electrocortical activity. Sympathetic excitation is mediated by cortical-spinal projection to spinal pre-ganglionic sympathetic neurons whereas bradycardia is mediated via projections to cardiovagal motor medullary neurons. The integrated reflex response serves to redistribute blood from viscera to brain in response to a challenge to cerebral metabolism, but seems also to initiate a preconditioning mechanism. Better and more detailed knowledge of the cascades, transmitters and molecules engaged in such endogenous (neuro) protection may provide new insights into novel therapeutic options for a range of disorders characterized by neuronal death and into cortical organization of the brain.

Parental Concussion Education Assessment: A Quality Improvement Initiative

ERIC Educational Resources Information Center

Best, Melanie

2017-01-01

Background of Problem: Brain injury is a leading cause of death and disability in children and adolescents. According to the Brain Injury Association of America (2015) ages 0-4 and 15-19 are the two age groups at greatest risk for traumatic brain injury (TBI) or concussion. Five out of ten concussions are not reported or go undetected. The…

Contesting the Equivalency of Continuous Sedation until Death and Physician-assisted Suicide/Euthanasia: A Commentary on LiPuma.

PubMed

Raho, Joseph A; Miccinesi, Guido

2015-10-01

Patients who are imminently dying sometimes experience symptoms refractory to traditional palliative interventions, and in rare cases, continuous sedation is offered. Samuel H. LiPuma, in a recent article in this Journal, argues that continuous sedation until death is equivalent to physician-assisted suicide/euthanasia based on a higher brain neocortical definition of death. We contest his position that continuous sedation involves killing and offer four objections to the equivalency thesis. First, sedation practices are proportional in a way that physician-assisted suicide/euthanasia is not. Second, continuous sedation may not entirely abolish consciousness. Third, LiPuma's particular version of higher brain neocortical death relies on an implausibly weak construal of irreversibility--a position that is especially problematic in the case of continuous sedation. Finally, we explain why continuous sedation until death is not functionally equivalent to neocortical death and, hence, physician-assisted suicide/euthanasia. Concluding remarks review the differences between these two end-of-life practices. © The Author 2015. Published by Oxford University Press, on behalf of the Journal of Medicine and Philosophy Inc. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

What You Need to Know about Drugs: Ecstasy

MedlinePlus

... his or her body can dangerously overheat during dancing or other physical activities, which can lead to muscle breakdown, kidney, liver and heart damage, and even death. Taking the drug can cause seizures, brain swelling and permanent brain ...

Neuronal gap junctions play a role in the secondary neuronal death following controlled cortical impact.

PubMed

Belousov, Andrei B; Wang, Yongfu; Song, Ji-Hoon; Denisova, Janna V; Berman, Nancy E; Fontes, Joseph D

2012-08-22

In the mammalian CNS, excessive release of glutamate and overactivation of glutamate receptors are responsible for the secondary (delayed) neuronal death following neuronal injury, including ischemia, traumatic brain injury (TBI) and epilepsy. Recent studies in mice showed a critical role for neuronal gap junctions in NMDA receptor-mediated excitotoxicity and ischemia-mediated neuronal death. Here, using controlled cortical impact (CCI) in adult mice, as a model of TBI, and Fluoro-Jade B staining for analysis of neuronal death, we set to determine whether neuronal gap junctions play a role in the CCI-mediated secondary neuronal death. We report that 24h post-CCI, substantial neuronal death is detected in a number of brain regions outside the injury core, including the striatum. The striatal neuronal death is reduced both in wild-type mice by systemic administration of mefloquine (a relatively selective blocker of neuronal gap junctions) and in knockout mice lacking connexin 36 (neuronal gap junction protein). It is also reduced by inactivation of group II metabotropic glutamate receptors (with LY341495) which, as reported previously, control the rapid increase in neuronal gap junction coupling following different types of neuronal injury. The results suggest that neuronal gap junctions play a critical role in the CCI-induced secondary neuronal death. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Thyroid gland and cerebella lesions: New risk factors for sudden cardiac death in schizophrenia?

PubMed

Scorza, Fulvio A; Cavalheiro, Esper A; de Albuquerque, Marly; de Albuquerque, Juliana; Cysneiros, Roberta M; Terra, Vera C; Arida, Ricardo M

2011-02-01

People with schizophrenia show a two to threefold increased risk to die prematurely than those without schizophrenia. Patients' life style, suicide, premature development of cardiovascular disease, high prevalence of metabolic syndrome and sudden cardiac death are well-known causes of the excess mortality. The exact pathophysiological cause of sudden death in schizophrenia is unknown, but it is likely that cardiac arrhythmia and respiratory abnormalities play potential role. Some antipsychotics may be associated with cardiovascular adverse events (e.g., QT interval prolongation) and lesions in specific brain regions, such as cerebella may be associated with respiratory abnormalities, suggesting that metabolic and brain dysfunction could lead to sudden cardiac death in patients with schizophrenia. However, exact knowledge regarding the association of these findings and schizophrenia is lacking. As subclinical hyperthyroidism has been linked with increased risk of cardiovascular disease and cerebella progressive atrophy has been observed in patients with schizophrenia, we propose in this paper that subclinical thyroid dysfunction and cerebella volume loss could be considered as new risk factor for sudden cardiac death in schizophrenia. Copyright © 2010 Elsevier Ltd. All rights reserved.

Inhibition of multidrug resistance protein 1 (MRP1) improves chemotherapy drug response in primary and recurrent glioblastoma multiforme.

PubMed

Tivnan, Amanda; Zakaria, Zaitun; O'Leary, Caitrín; Kögel, Donat; Pokorny, Jenny L; Sarkaria, Jann N; Prehn, Jochen H M

2015-01-01

Glioblastoma multiforme (GBM) is a highly aggressive brain cancer with extremely poor prognostic outcome despite intensive treatment. All chemotherapeutic agents currently used have no greater than 30-40% response rate, many fall into the range of 10-20%, with delivery across the blood brain barrier (BBB) or chemoresistance contributing to the extremely poor outcomes despite treatment. Increased expression of the multidrug resistance protein 1(MRP1) in high grade glioma, and it's role in BBB active transport, highlights this member of the ABC transporter family as a target for improving drug responses in GBM. In this study we show that small molecule inhibitors and gene silencing of MRP1 had a significant effect on GBM cell response to temozolomide (150 μM), vincristine (100 nM), and etoposide (2 μM). Pre-treatment with Reversan (inhibitor of MRP1 and P-glycoprotein) led to a significantly improved response to cell death in the presence of all three chemotherapeutics, in both primary and recurrent GBM cells. The presence of MK571 (inhibitor of MRP1 and multidrug resistance protein 4 (MRP4) led to an enhanced effect of vincristine and etoposide in reducing cell viability over a 72 h period. Specific MRP1 inhibition led to a significant increase in vincristine and etoposide-induced cell death in all three cell lines assessed. Treatment with MK571, or specific MRP1 knockdown, did not have any effect on temozolomide drug response in these cells. These findings have significant implications in providing researchers an opportunity to improve currently used chemotherapeutics for the initial treatment of primary GBM, and improved treatment for recurrent GBM patients.

Tolerance and outcomes of stereotactic radiosurgery combined with anti-programmed cell death-1 (pembrolizumab) for melanoma brain metastases.

PubMed

Nardin, Charlee; Mateus, Christine; Texier, Mathieu; Lanoy, Emilie; Hibat-Allah, Salima; Ammari, Samy; Robert, Caroline; Dhermain, Frederic

2018-04-01

Anti-programmed cell death-1 (anti-PD1) antibodies are currently the first-line treatment for patients with metastatic BRAF wild-type melanoma, alone or combined with the anti-CTLA4 monoclonal antibody, ipilimumab. To date, data on safety and the outcomes of patients treated with the anti-PD1 monoclonal antibodies, pembrolizumab (PB), or nivolumab, combined with stereotactic radiosurgery (SRS), for melanoma brain metastases (MBM) are scarce. We retrospectively reviewed all patients with MBM treated with PB combined with SRS between 2012 and 2015. The primary endpoint was neurotoxicity. The secondary endpoints were local, distant intracranial controls and overall survival (OS). Among 74 patients with MBM treated with SRS, 25 patients with a total of 58 MBM treated with PB combined with SRS within 6 months were included. Radiation necrosis, occurring within a median time of 6.5 months, was observed for four MBM (6.8%) in four patients. No other significant SRS-related adverse event was observed. After a median follow-up of 8.4 months, local control was achieved in 46 (80%) metastases and 17 (68%) patients. Perilesional oedema and intratumour haemorrhage appearing or increasing after SRS were associated with local progression (P<0.001). The median OS was 15.3 months (95% confidence interval: 4.6-26). The timing between SRS and PB administration did not seem to influence the risk of radiation necrosis, intracranial control or OS. SRS combined with PB was well tolerated and achieved local control in 80% of the lesions. Prolonged OS was observed compared with that currently yielded in this population of patients. Prospective studies are required to explore further the optimal ways to combine immunotherapy and SRS.

Activation of the endoplasmic reticulum stress response by the amyloid-beta 1-40 peptide in brain endothelial cells.

PubMed

Fonseca, Ana Catarina R G; Ferreiro, Elisabete; Oliveira, Catarina R; Cardoso, Sandra M; Pereira, Cláudia F

2013-12-01

Neurovascular dysfunction arising from endothelial cell damage is an early pathogenic event that contributes to the neurodegenerative process occurring in Alzheimer's disease (AD). Since the mechanisms underlying endothelial dysfunction are not fully elucidated, this study was aimed to explore the hypothesis that brain endothelial cell death is induced upon the sustained activation of the endoplasmic reticulum (ER) stress response by amyloid-beta (Aβ) peptide, which deposits in the cerebral vessels in many AD patients and transgenic mice. Incubation of rat brain endothelial cells (RBE4 cell line) with Aβ1-40 increased the levels of several markers of ER stress-induced unfolded protein response (UPR), in a time-dependent manner, and affected the Ca(2+) homeostasis due to the release of Ca(2+) from this intracellular store. Finally, Aβ1-40 was shown to activate both mitochondria-dependent and -independent apoptotic cell death pathways. Enhanced release of cytochrome c from mitochondria and activation of the downstream caspase-9 were observed in cells treated with Aβ1-40 concomitantly with caspase-12 activation. Furthermore, Aβ1-40 activated the apoptosis effectors' caspase-3 and promoted the translocation of apoptosis-inducing factor (AIF) to the nucleus demonstrating the involvement of caspase-dependent and -independent mechanisms during Aβ-induced endothelial cell death. In conclusion, our data demonstrate that ER stress plays a significant role in Aβ1-40-induced apoptotic cell death in brain endothelial cells suggesting that ER stress-targeted therapeutic strategies might be useful in AD to counteract vascular defects and ultimately neurodegeneration. © 2013.

A statistical model describing combined irreversible electroporation and electroporation-induced blood-brain barrier disruption.

PubMed

Sharabi, Shirley; Kos, Bor; Last, David; Guez, David; Daniels, Dianne; Harnof, Sagi; Mardor, Yael; Miklavcic, Damijan

2016-03-01

Electroporation-based therapies such as electrochemotherapy (ECT) and irreversible electroporation (IRE) are emerging as promising tools for treatment of tumors. When applied to the brain, electroporation can also induce transient blood-brain-barrier (BBB) disruption in volumes extending beyond IRE, thus enabling efficient drug penetration. The main objective of this study was to develop a statistical model predicting cell death and BBB disruption induced by electroporation. This model can be used for individual treatment planning. Cell death and BBB disruption models were developed based on the Peleg-Fermi model in combination with numerical models of the electric field. The model calculates the electric field thresholds for cell kill and BBB disruption and describes the dependence on the number of treatment pulses. The model was validated using in vivo experimental data consisting of rats brains MRIs post electroporation treatments. Linear regression analysis confirmed that the model described the IRE and BBB disruption volumes as a function of treatment pulses number (r(2) = 0.79; p < 0.008, r(2) = 0.91; p < 0.001). The results presented a strong plateau effect as the pulse number increased. The ratio between complete cell death and no cell death thresholds was relatively narrow (between 0.88-0.91) even for small numbers of pulses and depended weakly on the number of pulses. For BBB disruption, the ratio increased with the number of pulses. BBB disruption radii were on average 67% ± 11% larger than IRE volumes. The statistical model can be used to describe the dependence of treatment-effects on the number of pulses independent of the experimental setup.

Why do I stand against the movement for cardiac transplantation in Japan?

PubMed

Watanabe, Y

1994-11-01

In order to clarify the reason the author stands against the movement for cardiac transplantation in Japan, certain crucial differences between death judged by the classical criteria and so-called brain death are briefly discussed, followed by the presentation of three major arguments. First, various problems associated with postoperative care of organ recipients are delineated, particularly side effects of immunosuppressive drugs and long term prognosis with reference of life expectancy as well as quality of life. Second, it is emphasized that transplantation involves prejudice and inequality, since the number of potential organ recipients far exceeds that of donors and only a small portion of transplant candidates can actually receive the organs while others have to wait in vain. Third, once organ transplantation from brain dead patients is allowed, numerous ethical and social problems would arise including an arbitrary expansion of the criteria for brain death, selection of donors and recipients by taking non-medial factors into consideration, development of organ commerce leading to the involvement of organized crime, and the birth of a trend in transplant candidates to wish for an early death of histocompatible donors. Finally, it is pointed out that we must give serious thought to the danger of "from neck down" transplantation creating a new person from two bodies (which is a brain transplant in actuality) in the future, since the difference between such a procedure and the multiorgan transplantation presently practiced in many developed countries is only quantitative and one cannot find a logical reason to ban the former while retaining the latter.

Neuronal Deletion of Caspase 8 Protects against Brain Injury in Mouse Models of Controlled Cortical Impact and Kainic Acid-Induced Excitotoxicity

PubMed Central

Krajewska, Maryla; You, Zerong; Rong, Juan; Kress, Christina; Huang, Xianshu; Yang, Jinsheng; Kyoda, Tiffany; Leyva, Ricardo; Banares, Steven; Hu, Yue; Sze, Chia-Hung; Whalen, Michael J.; Salmena, Leonardo; Hakem, Razqallah; Head, Brian P.; Reed, John C.; Krajewski, Stan

2011-01-01

Background Acute brain injury is an important health problem. Given the critical position of caspase 8 at the crossroads of cell death pathways, we generated a new viable mouse line (Ncasp8 −/−), in which the gene encoding caspase 8 was selectively deleted in neurons by cre-lox system. Methodology/Principal Findings Caspase 8 deletion reduced rates of neuronal cell death in primary neuronal cultures and in whole brain organotypic coronal slice cultures prepared from 4 and 8 month old mice and cultivated up to 14 days in vitro. Treatments of cultures with recombinant murine TNFα (100 ng/ml) or TRAIL (250 ng/mL) plus cyclohexamide significantly protected neurons against cell death induced by these apoptosis-inducing ligands. A protective role of caspase 8 deletion in vivo was also demonstrated using a controlled cortical impact (CCI) model of traumatic brain injury (TBI) and seizure-induced brain injury caused by kainic acid (KA). Morphometric analyses were performed using digital imaging in conjunction with image analysis algorithms. By employing virtual images of hundreds of brain sections, we were able to perform quantitative morphometry of histological and immunohistochemical staining data in an unbiased manner. In the TBI model, homozygous deletion of caspase 8 resulted in reduced lesion volumes, improved post-injury motor performance, superior learning and memory retention, decreased apoptosis, diminished proteolytic processing of caspases and caspase substrates, and less neuronal degeneration, compared to wild type, homozygous cre, and caspase 8-floxed control mice. In the KA model, Ncasp8 −/− mice demonstrated superior survival, reduced seizure severity, less apoptosis, and reduced caspase 3 processing. Uninjured aged knockout mice showed improved learning and memory, implicating a possible role for caspase 8 in cognitive decline with aging. Conclusions Neuron-specific deletion of caspase 8 reduces brain damage and improves post-traumatic functional outcomes, suggesting an important role for this caspase in pathophysiology of acute brain trauma. PMID:21957448

Neuropathology of SUDEP: Role of inflammation, blood-brain barrier impairment, and hypoxia.

PubMed

Michalak, Zuzanna; Obari, Dima; Ellis, Matthew; Thom, Maria; Sisodiya, Sanjay M

2017-02-07

To seek a neuropathologic signature of sudden unexpected death in epilepsy (SUDEP) in a postmortem cohort by use of immunohistochemistry for specific markers of inflammation, gliosis, acute neuronal injury due to hypoxia, and blood-brain barrier (BBB) disruption, enabling the generation of hypotheses about potential mechanisms of death in SUDEP. Using immunohistochemistry, we investigated the expression of 6 markers (CD163, human leukocyte antigen-antigen D related, glial fibrillary acid protein, hypoxia-inducible factor-1α [HIF-1α], immunoglobulin G, and albumin) in the hippocampus, amygdala, and medulla in 58 postmortem cases: 28 SUDEP (definite and probable), 12 epilepsy controls, and 18 nonepileptic sudden death controls. A semiquantitative measure of immunoreactivity was scored for all markers used, and quantitative image analysis was carried out for selected markers. Immunoreactivity was observed for all markers used within all studied brain regions and groups. Immunoreactivity for inflammatory reaction, BBB leakage, and HIF-1α in SUDEP cases was not different from that seen in control groups. This study represents a starting point to explore by immunohistochemistry the mechanisms underlying SUDEP in human brain tissue. Our approach highlights the potential and importance of considering immunohistochemical analysis to help identify biomarkers of SUDEP. Our results suggest that with the markers used, there is no clear immunohistochemical signature of SUDEP in human brain. Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

Transpulmonary hypothermia: a novel method of rapid brain cooling through augmented heat extraction from the lungs.

PubMed

Kumar, Matthew M; Goldberg, Andrew D; Kashiouris, Markos; Keenan, Lawrence R; Rabinstein, Alejandro A; Afessa, Bekele; Johnson, Larry D; Atkinson, John L D; Nayagam, Vedha

2014-10-01

Delay in instituting neuroprotective measures after cardiac arrest increases death and decreases neuronal recovery. Current hypothermia methods are slow, ineffective, unreliable, or highly invasive. We report the feasibility of rapid hypothermia induction in swine through augmented heat extraction from the lungs. Twenty-four domestic crossbred pigs (weight, 50-55kg) were ventilated with room air. Intraparenchymal brain temperature and core temperatures from pulmonary artery, lower esophagus, bladder, rectum, nasopharynx, and tympanum were recorded. In eight animals, ventilation was switched to cooled helium-oxygen mixture (heliox) and perfluorocarbon (PFC) aerosol and continued for 90min or until target brain temperature of 32°C was reached. Eight animals received body-surface cooling with water-circulating blankets; eight control animals continued to be ventilated with room air. Brain and core temperatures declined rapidly with cooled heliox-PFC ventilation. The brain reached target temperature within the study period (mean [SD], 66 [7.6]min) in only the transpulmonary cooling group. Cardiopulmonary functions and poststudy histopathological examination of the lungs were normal. Transpulmonary cooling is novel, rapid, minimally invasive, and an effective technique to induce therapeutic hypothermia. High thermal conductivity of helium and vaporization of PFC produces rapid cooling of alveolar gases. The thinness and large surface area of alveolar membrane facilitate rapid cooling of the pulmonary circulation. Because of differences in thermogenesis, blood flow, insulation, and exposure to the external environment, the brain cools at a different rate than other organs. Transpulmonary hypothermia was significantly faster than body surface cooling in reaching target brain temperature. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Adult brain cancer in the U.S. black population: a Surveillance, Epidemiology, and End Results (SEER) analysis of incidence, survival, and trends.

PubMed

Gabriel, Abigail; Batey, Jason; Capogreco, Joseph; Kimball, David; Walters, Andy; Tubbs, R Shane; Loukas, Marios

2014-08-25

Despite much epidemiological research on brain cancer in the United States, the etiology for the various subtypes remains elusive. The black population in the United States currently experiences lower incidence but higher survival rates when compared to other races. Thus, the aim of this study is to analyze the trends in incidence and survival for the 6 most common primary brain tumors in the black population of the United States. The Surveillance, Epidemiology, and End Results (SEER) database was utilized in this study to analyze the incidence and survival rates for the 6 most common brain tumor subtypes. Joinpoint 3.5.2 software was used to analyze trends in the incidence of diagnosis from 1973 to 2008. A Kaplan-Meier curve was generated to analyze mean time to death and survival at 60 months. Joinpoint analysis revealed that per year the incidence of brain cancer in the U.S. black population increased by 0.11 between 1973 and 1989. After this period, a moderate decrease by 0.06 per annum was observed from 1989 to 2008. Lymphoma was the most common primary tumor subtype for black individuals ages 20-34, and glioblastoma was identified as the most common tumor subtype for black individuals in the age groups of 35-49, 50-64, 65-79, and 80+. This population-based retrospective study of brain cancer in black adults in the United States revealed significant sex and age differences in the incidence of the 6 most common brain tumor subtypes from 1973 to 2008.

Neuronal survival in the brain: neuron type-specific mechanisms.

PubMed

Pfisterer, Ulrich; Khodosevich, Konstantin

2017-03-02

Neurogenic regions of mammalian brain produce many more neurons that will eventually survive and reach a mature stage. Developmental cell death affects both embryonically produced immature neurons and those immature neurons that are generated in regions of adult neurogenesis. Removal of substantial numbers of neurons that are not yet completely integrated into the local circuits helps to ensure that maturation and homeostatic function of neuronal networks in the brain proceed correctly. External signals from brain microenvironment together with intrinsic signaling pathways determine whether a particular neuron will die. To accommodate this signaling, immature neurons in the brain express a number of transmembrane factors as well as intracellular signaling molecules that will regulate the cell survival/death decision, and many of these factors cease being expressed upon neuronal maturation. Furthermore, pro-survival factors and intracellular responses depend on the type of neuron and region of the brain. Thus, in addition to some common neuronal pro-survival signaling, different types of neurons possess a variety of 'neuron type-specific' pro-survival constituents that might help them to adapt for survival in a certain brain region. This review focuses on how immature neurons survive during normal and impaired brain development, both in the embryonic/neonatal brain and in brain regions associated with adult neurogenesis, and emphasizes neuron type-specific mechanisms that help to survive for various types of immature neurons. Importantly, we mainly focus on in vivo data to describe neuronal survival specifically in the brain, without extrapolating data obtained in the PNS or spinal cord, and thus emphasize the influence of the complex brain environment on neuronal survival during development.

Does phase 1 trial enrollment preclude quality end-of-life care? Phase 1 trial enrollment and end-of-life care characteristics in children with cancer.

PubMed

Levine, Deena R; Johnson, Liza-Marie; Mandrell, Belinda N; Yang, Jie; West, Nancy K; Hinds, Pamela S; Baker, Justin N

2015-05-01

End-of-life care (EOLC) discussions and treatment-related decisions, including phase 1 trial enrollment, in patients with incurable disease are complex and can influence the quality of EOLC received. The current study was conducted in pediatric oncology patients to determine whether end-of-life characteristics differed between those who were and were not enrolled in a phase 1 trial. The authors reviewed the medical records of 380 pediatric oncology patients (aged <22 years at the time of death) who died during a 3.5-year period. Of these, 103 patients with hematologic malignancies were excluded. A total of 277 patients with a diagnosis of a brain tumor or other solid tumor malignancy were divided into 2 groups based on phase 1 trial enrollment: a phase 1 cohort (PIC; 120 patients) and a non-phase 1 cohort (NPIC; 157 patients). The EOLC characteristics of these 2 cohorts were compared using regression analysis and chi-square testing. A comparison of patients in the PIC and NPIC revealed no significant differences in either demographic characteristics (including sex, race, religious affiliation, referral origin, diagnosis, or age at diagnosis, with the exception of age at the time of death [P =.03]) or in EOLC indices (such as use or timing of do not attempt resuscitation orders, hospice use or length of stay, forgoing life-sustaining therapies, location of death, time from first EOLC discussion to death, and total number of EOLC discussions). The results of the current study of a large cohort of deceased pediatric cancer patients indicate that enrollment on a phase 1 trial does not affect EOLC characteristics, suggesting that quality EOLC can be delivered regardless of phase 1 trial participation. © 2014 American Cancer Society.

Neuronal damage and cognitive impairment associated with hypoglycemia: An integrated view.

PubMed

Languren, Gabriela; Montiel, Teresa; Julio-Amilpas, Alberto; Massieu, Lourdes

2013-10-01

The aim of the present review is to offer a current perspective about the consequences of hypoglycemia and its impact on the diabetic disorder due to the increasing incidence of diabetes around the world. The main consequence of insulin treatment in type 1 diabetic patients is the occurrence of repetitive periods of hypoglycemia and even episodes of severe hypoglycemia leading to coma. In the latter, selective neuronal death is observed in brain vulnerable regions both in humans and animal models, such as the cortex and the hippocampus. Cognitive damage subsequent to hypoglycemic coma has been associated with neuronal death in the hippocampus. The mechanisms implicated in selective damage are not completely understood but many factors have been identified including excitotoxicity, oxidative stress, zinc release, PARP-1 activation and mitochondrial dysfunction. Importantly, the diabetic condition aggravates neuronal damage and cognitive failure induced by hypoglycemia. In the absence of coma prolonged and severe hypoglycemia leads to increased oxidative stress and discrete neuronal death mainly in the cerebral cortex. The mechanisms responsible for cell damage in this condition are still unknown. Recurrent moderate hypoglycemia is far more common in diabetic patients than severe hypoglycemia and currently important efforts are being done in order to elucidate the relationship between cognitive deficits and recurrent hypoglycemia in diabetics. Human studies suggest impaired performance mainly in memory and attention tasks in healthy and diabetic individuals under the hypoglycemic condition. Only scarce neuronal death has been observed under moderate repetitive hypoglycemia but studies suggest that impaired hippocampal synaptic function might be one of the causes of cognitive failure. Recent studies have also implicated altered mitochondrial function and mitochondrial oxidative stress. Copyright © 2013 Elsevier Ltd. All rights reserved.

Minocycline causes widespread cell death and increases microglial labeling in the neonatal mouse brain.

PubMed

Strahan, J Alex; Walker, William H; Montgomery, Taylor R; Forger, Nancy G

2017-06-01

Minocycline, an antibiotic of the tetracycline family, inhibits microglia in many paradigms and is among the most commonly used tools for examining the role of microglia in physiological processes. Microglia may play an active role in triggering developmental neuronal cell death, although findings have been contradictory. To determine whether microglia influence developmental cell death, we treated perinatal mice with minocycline (45 mg/kg) and quantified effects on dying cells and microglial labeling using immunohistochemistry for activated caspase-3 (AC3) and ionized calcium-binding adapter molecule 1 (Iba1), respectively. Contrary to our expectations, minocycline treatment from embryonic day 18 to postnatal day (P)1 caused a > tenfold increase in cell death 8 h after the last injection in all brain regions examined, including the primary sensory cortex, septum, hippocampus and hypothalamus. Iba1 labeling was also increased in most regions. Similar effects, although of smaller magnitude, were seen when treatment was delayed to P3-P5. Minocycline treatment from P3 to P5 also decreased overall cell number in the septum at weaning, suggesting lasting effects of the neonatal exposure. When administered at lower doses (4.5 or 22.5 mg/kg), or at the same dose 1 week later (P10-P12), minocycline no longer increased microglial markers or cell death. Taken together, the most commonly used microglial "inhibitor" increases cell death and Iba1 labeling in the neonatal mouse brain. Minocycline is used clinically in infant and pediatric populations; caution is warrented when using minocycline in developing animals, or extrapolating the effects of this drug across ages. © 2016 Wiley Periodicals, Inc. Develop Neurobiol 77: 753-766, 2017. © 2016 Wiley Periodicals, Inc.

Minocycline Causes Widespread Cell Death and Increases Microglial Labeling in the Neonatal Mouse Brain

PubMed Central

Strahan, J. Alex; Walker, William H.; Montgomery, Taylor R.; Forger, Nancy G.

2016-01-01

Minocycline, an antibiotic of the tetracycline family, inhibits microglia in many paradigms, and is among the most commonly used tools for examining the role of microglia in physiological processes. Microglia may play an active role in triggering developmental neuronal cell death, although findings have been contradictory. To determine whether microglia influence developmental cell death, we treated perinatal mice with minocycline (45 mg/kg) and quantified effects on dying cells and microglial labeling using immunohistochemistry for activated caspase-3 (AC3) and ionized calcium-binding adapter molecule 1 (Iba1), respectively. Contrary to our expectations, minocycline treatment from embryonic day 18 to postnatal day (P)1 caused a >10-fold increase in cell death 8 h after the last injection in all brain regions examined, including the primary sensory cortex (S1), septum, hippocampus and hypothalamus. Iba1 labeling was also increased in most regions. Similar effects, although of smaller magnitude, were seen when treatment was delayed to P3-P5. Minocycline treatment from P3-P5 also decreased overall cell number in the septum at weaning, suggesting lasting effects of the neonatal exposure. When administered at lower doses (4.5 or 22.5 mg/kg), or at the same dose one week later (P10-P12), minocycline no longer increased microglial markers or cell death. Taken together, the most commonly used microglial “inhibitor” increases cell death and Iba1 labeling in the neonatal mouse brain. Minocycline is used clinically in infant and pediatric populations; caution is warrented when using minocycline in developing animals, or extrapolating the effects of this drug across ages. PMID:27706925

Statistical evaluation of time-dependent metabolite concentrations: estimation of post-mortem intervals based on in situ 1H-MRS of the brain.

PubMed

Scheurer, Eva; Ith, Michael; Dietrich, Daniel; Kreis, Roland; Hüsler, Jürg; Dirnhofer, Richard; Boesch, Chris

2005-05-01

Knowledge of the time interval from death (post-mortem interval, PMI) has an enormous legal, criminological and psychological impact. Aiming to find an objective method for the determination of PMIs in forensic medicine, 1H-MR spectroscopy (1H-MRS) was used in a sheep head model to follow changes in brain metabolite concentrations after death. Following the characterization of newly observed metabolites (Ith et al., Magn. Reson. Med. 2002; 5: 915-920), the full set of acquired spectra was analyzed statistically to provide a quantitative estimation of PMIs with their respective confidence limits. In a first step, analytical mathematical functions are proposed to describe the time courses of 10 metabolites in the decomposing brain up to 3 weeks post-mortem. Subsequently, the inverted functions are used to predict PMIs based on the measured metabolite concentrations. Individual PMIs calculated from five different metabolites are then pooled, being weighted by their inverse variances. The predicted PMIs from all individual examinations in the sheep model are compared with known true times. In addition, four human cases with forensically estimated PMIs are compared with predictions based on single in situ MRS measurements. Interpretation of the individual sheep examinations gave a good correlation up to 250 h post-mortem, demonstrating that the predicted PMIs are consistent with the data used to generate the model. Comparison of the estimated PMIs with the forensically determined PMIs in the four human cases shows an adequate correlation. Current PMI estimations based on forensic methods typically suffer from uncertainties in the order of days to weeks without mathematically defined confidence information. In turn, a single 1H-MRS measurement of brain tissue in situ results in PMIs with defined and favorable confidence intervals in the range of hours, thus offering a quantitative and objective method for the determination of PMIs. Copyright 2004 John Wiley & Sons, Ltd.

Differences in mushroom bodies morphogenesis in workers, queens and drones of Apis mellifera: neuroblasts proliferation and death.

PubMed

Roat, Thaisa Cristina; da Cruz Landim, Carminda

2010-06-01

Apis mellifera is an interesting model to neurobiological studies. It has a relatively small brain that commands the complex learning and memory tasks demanded by the social organization. An A. mellifera colony is made up of a queen, thousands of workers and a varying number of drones. The latter are males, whereas the former are the two female castes. These three phenotypes differ in morphology, physiology and behavior, correlated with their respective functions in the society. Such differences include the morphology and architecture of their brains. To understand the processes generating such polymorphic brains we characterized the cell division and cell death dynamics which underlie the morphogenesis of the mushroom bodies, through several methods suitable for evidence the time and place of occurrence. Cell death was detected in mushroom bodies of last larval instar and mainly in black-eyed pupae. Cell division was observed in mushroom bodies, primarily at the start of metamorphosis, exhibiting temporal differences among workers, queens and males. Copyright 2010 Elsevier Ltd. All rights reserved.

Vitamin D Increases Aβ140 Plasma Levels and Protects Lymphocytes from Oxidative Death in Mild Cognitive Impairment Patients.

PubMed

SanMartin, Carol D; Henriquez, Mauricio; Chacon, Carlos; Ponce, Daniela P; Salech, Felipe; Rogers, Nicole K; Behrens, Maria I

2018-01-01

Mild cognitive impairment (MCI) has an increased rate of progression to dementia. Alterations of some metabolic factors, such as deficiency of vitamin D, are a risk factor for cognitive deterioration. Vitamin D is involved in the clearance of β-amyloid (Aβ) from the brain. We have reported that lymphocytes from Alzheimer's disease (AD) patients have an increased susceptibility to oxidative death by H2O2 exposure, but currently it is unknown if this characteristic is modifiable in vivo. To determine if correction of low vitamin D levels protects lymphocytes from oxidative death and increases Aβ1-40 plasma levels in MCI and very early AD (VEAD) patients. Sixteen MCI, 11 VEAD and 25 healthy control (HC) voluntaries were evaluated with the Clinical Dementia Rating (CDR), Montreal Cognitive assessment (MoCA), and Memory Index score (MIS). Lymphocyte death was measured by flow cytometry after 20h exposure to H2O2. In patients with low levels of vitamin D -11 MCI, 9 VEAD and 20 HC- lymphocyte H2O2-death, plasma Aβ1-40 levels and cognitive status were evaluated pre- and post-vitamin D supplementation for 6 months. Lymphocytes from MCI and VEAD patients showed increased susceptibility to oxidative death at study entry. In MCI, but not VEAD patients, lymphocyte susceptibility to death and Aβ1-40 levels plasma levels improved after 6 months of vitamin D supplementation. In addition, cognitive status on follow-up (18 months) improved in MCI patients after vitamin D supplementation. Vitamin D supplementation may be beneficial in MCI. The lack of effect in VEAD may be due to a more advanced stage or different characteristics of the neurodegenerative process. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Died of wounds on the battlefield: causation and implications for improving combat casualty care.

PubMed

Eastridge, Brian J; Hardin, Mark; Cantrell, Joyce; Oetjen-Gerdes, Lynne; Zubko, Tamara; Mallak, Craig; Wade, Charles E; Simmons, John; Mace, James; Mabry, Robert; Bolenbaucher, Rose; Blackbourne, Lorne H

2011-07-01

Understanding the epidemiology of death after battlefield injury is vital to combat casualty care performance improvement. The current analysis was undertaken to develop a comprehensive perspective of deaths that occurred after casualties reached a medical treatment facility. Battle injury died of wounds (DOW) deaths that occurred after casualties reached a medical treatment facility from October 2001 to June 2009 were evaluated by reviewing autopsy and other postmortem records at the Office of the Armed Forces Medical Examiners (OAFME). A panel of military trauma experts classified the injuries as nonsurvivable (NS) or potentially survivable (PS), in consultation with an OAFME forensic pathologist. Data including demographics, mechanism of injury, physiologic and laboratory variables, and cause of death were obtained from the Joint Theater Trauma Registry and the OAFME Mortality Trauma Registry. DOW casualties (n = 558) accounted for 4.56% of the nonreturn to duty battle injuries over the study period. DOW casualties were classified as NS in 271 (48.6%) cases and PS in 287 (51.4%) cases. Traumatic brain injury was the predominant injury leading to death in 225 of 271 (83%) NS cases, whereas hemorrhage from major trauma was the predominant mechanism of death in 230 of 287 (80%) PS cases. In the hemorrhage mechanism PS cases, the major body region bleeding focus accounting for mortality were torso (48%), extremity (31%), and junctional (neck, axilla, and groin) (21%). Fifty-one percent of DOW casualties presented in extremis with cardiopulmonary resuscitation upon presentation. Hemorrhage is a major mechanism of death in PS combat injuries, underscoring the necessity for initiatives to mitigate bleeding, particularly in the prehospital environment.

Advanced Pediatric Brain Imaging Research and Training Program

DTIC Science & Technology

2014-10-01

death and disability in children. Recent advances in pediatric magnetic resonance imaging ( MRI ) techniques are revolutionizing our understanding of... MRI , brain injury. 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF ABSTRACT 18. NUMBER OF PAGES 19a. NAME OF RESPONSIBLE PERSON USAMRMC a...principles of pediatric brain injury and recovery following injury, as well as the clinical application of sophisticated MRI techniques that are

Loss of PAFR prevents neuroinflammation and brain dysfunction after traumatic brain injury

PubMed Central

Yin, Xiang-Jie; Chen, Zhen-Yan; Zhu, Xiao-Na; Hu, Jin-Jia

2017-01-01

Traumatic brain injury (TBI) is a principal cause of death and disability worldwide, which is a major public health problem. Death caused by TBI accounts for a third of all damage related illnesses, which 75% TBI occurred in low and middle income countries. With the increasing use of motor vehicles, the incidence of TBI has been at a high level. The abnormal brain functions of TBI patients often show the acute and long-term neurological dysfunction, which mainly associated with the pathological process of malignant brain edema and neuroinflammation in the brain. Owing to the neuroinflammation lasts for months or even years after TBI, which is a pivotal causative factor that give rise to neurodegenerative disease at late stage of TBI. Studies have shown that platelet activating factor (PAF) inducing inflammatory reaction after TBI could not be ignored. The morphological and behavioral abnormalities after TBI in wild type mice are rescued by general knockout of PAFR gene that neuroinflammation responses and cognitive ability are improved. Our results thus define a key inflammatory molecule PAF that participates in the neuroinflammation and helps bring about cerebral dysfunction during the TBI acute phase. PMID:28094295

Transcranial amelioration of inflammation and cell death after brain injury

NASA Astrophysics Data System (ADS)

Roth, Theodore L.; Nayak, Debasis; Atanasijevic, Tatjana; Koretsky, Alan P.; Latour, Lawrence L.; McGavern, Dorian B.

2014-01-01

Traumatic brain injury (TBI) is increasingly appreciated to be highly prevalent and deleterious to neurological function. At present, no effective treatment options are available, and little is known about the complex cellular response to TBI during its acute phase. To gain insights into TBI pathogenesis, we developed a novel murine closed-skull brain injury model that mirrors some pathological features associated with mild TBI in humans and used long-term intravital microscopy to study the dynamics of the injury response from its inception. Here we demonstrate that acute brain injury induces vascular damage, meningeal cell death, and the generation of reactive oxygen species (ROS) that ultimately breach the glial limitans and promote spread of the injury into the parenchyma. In response, the brain elicits a neuroprotective, purinergic-receptor-dependent inflammatory response characterized by meningeal neutrophil swarming and microglial reconstitution of the damaged glial limitans. We also show that the skull bone is permeable to small-molecular-weight compounds, and use this delivery route to modulate inflammation and therapeutically ameliorate brain injury through transcranial administration of the ROS scavenger, glutathione. Our results shed light on the acute cellular response to TBI and provide a means to locally deliver therapeutic compounds to the site of injury.

The frequently used intraperitoneal hyponatraemia model induces hypovolaemic hyponatraemia with possible model-dependent brain sodium loss.

PubMed

Overgaard-Steensen, Christian; Stødkilde-Jørgensen, Hans; Larsson, Anders; Tønnesen, Else; Frøkiaer, Jørgen; Ring, Troels

2016-07-01

What is the central question of this study? The brain response to acute hyponatraemia is usually studied in rodents by intraperitoneal instillation of hypotonic fluids (i.p. model). The i.p. model is described as 'dilutional' and 'syndrome of inappropriate ADH (SIADH)', but the mechanism has not been explored systematically and might affect the brain response. Therefore, in vivo brain and muscle response were studied in pigs. What is the main finding and its importance? The i.p. model induces hypovolaemic hyponatraemia attributable to sodium redistribution, not dilution. A large reduction in brain sodium is observed, probably because of the specific mechanism causing the hyponatraemia. This is not accounted for in current understanding of the brain response to acute hyponatraemia. Hyponatraemia is common clinically, and if it develops rapidly, brain oedema evolves, and severe morbidity and even death may occur. Experimentally, acute hyponatraemia is most frequently studied in small animal models, in which the hyponatraemia is produced by intraperitoneal instillation of hypotonic fluids (i.p. model). This hyponatraemia model is described as 'dilutional' or 'syndrome of inappropriate ADH (SIADH)', but seminal studies contradict this interpretation. To confront this issue, we developed an i.p. model in a large animal (the pig) and studied water and electrolyte responses in brain, muscle, plasma and urine. We hypothesized that hyponatraemia was induced by simple water dilution, with no change in organ sodium content. Moderate hypotonic hyponatraemia was induced by a single i.v. dose of desmopressin and intraperitoneal instillation of 2.5% glucose. All animals were anaesthetized and intensively monitored. In vivo brain and muscle water was determined by magnetic resonance imaging and related to the plasma sodium concentration. Muscle water content increased less than expected as a result of pure dilution, and muscle sodium content decreased significantly (by 28%). Sodium was redistributed to the peritoneal fluid, resulting in a significantly reduced plasma volume. This shows that the i.p. model induces hypovolaemic hyponatraemia and not dilutional/SIADH hyponatraemia. Brain oedema evolved, but brain sodium content decreased significantly (by 21%). To conclude, the i.p. model induces hypovolaemic hyponatraemia attributable to sodium redistribution and not water dilution. The large reduction in brain sodium is probably attributable to the specific mechanism that causes the hyponatraemia. This is not accounted for in the current understanding of the brain response to acute hyponatraemia. © 2016 The Authors. Experimental Physiology © 2016 The Physiological Society.

Cerebral oxygenation and hemodynamic changes during infant cardiac surgery: measurements by near infrared spectroscopy

NASA Astrophysics Data System (ADS)

du Plessis, Adre J.; Volpe, Joseph J.

1996-10-01

Despite dramatic advances in the survival rate among infants undergoing cardiac surgery for congenital heart disease, the incidence of brain injury suffered by survivors remains unacceptably high. This is largely due to our limited understanding of the complex changes in cerebral oxygen utilization and supply occurring during the intraoperative period as a result of hypothermia, neuroactive drugs, and profound circulatory changes. Current techniques for monitoring the adequacy of cerebral oxygen supply and utilization during hypothermic cardiac surgery are inadequate to address this complex problem and consequently to identify the infant at risk for such brain injury. Furthermore, this inability to detect imminent hypoxic- ischemic brain injury is likely to become all the more conspicuous as new neuroprotective strategies, capable of salvaging 'insulated' neuronal tissue form cell death, enter the clinical arena. Near infrared spectroscopy is a relatively new, noninvasive, and portable technique capable of interrogating the oxygenation and hemodynamics of tissue in vivo. These characteristics of the technique have generated enormous interest among clinicians in the ability of near infrared spectroscopy to elucidate the mechanisms of intraoperative brain injury and ultimately to identify infants oat risk for such injury. This paper reviews the experience with this technique to date during infant cardiac surgery.

Blockade and knock-out of CALHM1 channels attenuate ischemic brain damage.

PubMed

Cisneros-Mejorado, Abraham; Gottlieb, Miroslav; Ruiz, Asier; Chara, Juan C; Pérez-Samartín, Alberto; Marambaud, Philippe; Matute, Carlos

2018-06-01

Overactivation of purinergic receptors during cerebral ischemia results in a massive release of neurotransmitters, including adenosine triphosphate (ATP), to the extracellular space which leads to cell death. Some hypothetical pathways of ATP release are large ion channels, such as calcium homeostasis modulator 1 (CALHM1), a membrane ion channel that can permeate ATP. Since this transmitter contributes to postischemic brain damage, we hypothesized that CALHM1 activation may be a relevant target to attenuate stroke injury. Here, we analyzed the contribution of CALHM1 to postanoxic depolarization after ischemia in cultured neurons and in cortical slices. We observed that the onset of postanoxic currents in neurons in those preparations was delayed after its blockade with ruthenium red or silencing of Calhm1 gene by short hairpin RNA, as well as in slices from CALHM1 knockout mice. Subsequently, we used transient middle cerebral artery occlusion and found that ruthenium red, a blocker of CALHM1, or the lack of CALHM1, substantially attenuated the motor symptoms and reduced significantly the infarct volume. These results show that CALHM1 channels mediate postanoxic depolarization in neurons and brain damage after ischemia. Therefore, targeting CALHM1 may have a high therapeutic potential for treating brain damage after ischemia.

Cellular mechanisms of estradiol-mediated sexual differentiation of the brain.

PubMed

Wright, Christopher L; Schwarz, Jaclyn S; Dean, Shannon L; McCarthy, Margaret M

2010-09-01

Gonadal steroids organize the developing brain during a perinatal sensitive period and have enduring consequences for adult behavior. In male rodents testicular androgens are aromatized in neurons to estrogens and initiate multiple distinct cellular processes that ultimately determine the masculine phenotype. Within specific brain regions, overall cell number and dendritic morphology are the principal targets for hormonal organization. Recent advances have been made in elucidating the cellular mechanisms by which the neurological underpinnings of sexually dimorphic physiology and behavior are determined. These include estradiol-mediated prostaglandin synthesis, presynaptic release of glutamate, postsynaptic changes in glutamate receptors and changes in cell adhesion molecules. Sex differences in cell death are mediated by hormonal modulation of survival and death factors such as TNFalpha and Bcl-2/BAX. Copyright 2010 Elsevier Ltd. All rights reserved.

α-Synuclein fibril-induced paradoxical structural and functional defects in hippocampal neurons.

PubMed

Froula, Jessica M; Henderson, Benjamin W; Gonzalez, Jose Carlos; Vaden, Jada H; Mclean, John W; Wu, Yumei; Banumurthy, Gokulakrishna; Overstreet-Wadiche, Linda; Herskowitz, Jeremy H; Volpicelli-Daley, Laura A

2018-05-01

Neuronal inclusions composed of α-synuclein (α-syn) characterize Parkinson's Disease (PD) and Dementia with Lewy bodies (DLB). Cognitive dysfunction defines DLB, and up to 80% of PD patients develop dementia. α-Syn inclusions are abundant in the hippocampus, yet functional consequences are unclear. To determine if pathologic α-syn causes neuronal defects, we induced endogenous α-syn to form inclusions resembling those found in diseased brains by treating hippocampal neurons with α-syn fibrils. At seven days after adding fibrils, α-syn inclusions are abundant in axons, but there is no cell death at this time point, allowing us to assess for potential alterations in neuronal function that are not caused by neuron death. We found that exposure of neurons to fibrils caused a significant reduction in mushroom spine densities, adding to the growing body of literature showing that altered spine morphology is a major pathologic phenotype in synucleinopathies. The reduction in spine densities occurred only in wild type neurons and not in neurons from α-syn knockout mice, suggesting that the changes in spine morphology result from fibril-induced corruption of endogenously expressed α-syn. Paradoxically, reduced postsynaptic spine density was accompanied by increased frequency of miniature excitatory postsynaptic currents (EPSCs) and presynaptic docked vesicles, suggesting enhanced presynaptic function. Action-potential dependent activity was unchanged, suggesting compensatory mechanisms responding to synaptic defects. Although activity at the level of the synapse was unchanged, neurons exposed to α-syn fibrils, showed reduced frequency and amplitudes of spontaneous Ca 2+ transients. These findings open areas of research to determine the mechanisms that alter neuronal function in brain regions critical for cognition at time points before neuron death.

Brain age predicts mortality

PubMed Central

Cole, J H; Ritchie, S J; Bastin, M E; Valdés Hernández, M C; Muñoz Maniega, S; Royle, N; Corley, J; Pattie, A; Harris, S E; Zhang, Q; Wray, N R; Redmond, P; Marioni, R E; Starr, J M; Cox, S R; Wardlaw, J M; Sharp, D J; Deary, I J

2018-01-01

Age-associated disease and disability are placing a growing burden on society. However, ageing does not affect people uniformly. Hence, markers of the underlying biological ageing process are needed to help identify people at increased risk of age-associated physical and cognitive impairments and ultimately, death. Here, we present such a biomarker, ‘brain-predicted age’, derived using structural neuroimaging. Brain-predicted age was calculated using machine-learning analysis, trained on neuroimaging data from a large healthy reference sample (N=2001), then tested in the Lothian Birth Cohort 1936 (N=669), to determine relationships with age-associated functional measures and mortality. Having a brain-predicted age indicative of an older-appearing brain was associated with: weaker grip strength, poorer lung function, slower walking speed, lower fluid intelligence, higher allostatic load and increased mortality risk. Furthermore, while combining brain-predicted age with grey matter and cerebrospinal fluid volumes (themselves strong predictors) not did improve mortality risk prediction, the combination of brain-predicted age and DNA-methylation-predicted age did. This indicates that neuroimaging and epigenetics measures of ageing can provide complementary data regarding health outcomes. Our study introduces a clinically-relevant neuroimaging ageing biomarker and demonstrates that combining distinct measurements of biological ageing further helps to determine risk of age-related deterioration and death. PMID:28439103

Alzheimer's Disease Early Diagnosis Using Manifold-Based Semi-Supervised Learning.

PubMed

Khajehnejad, Moein; Saatlou, Forough Habibollahi; Mohammadzade, Hoda

2017-08-20

Alzheimer's disease (AD) is currently ranked as the sixth leading cause of death in the United States and recent estimates indicate that the disorder may rank third, just behind heart disease and cancer, as a cause of death for older people. Clearly, predicting this disease in the early stages and preventing it from progressing is of great importance. The diagnosis of Alzheimer's disease (AD) requires a variety of medical tests, which leads to huge amounts of multivariate heterogeneous data. It can be difficult and exhausting to manually compare, visualize, and analyze this data due to the heterogeneous nature of medical tests; therefore, an efficient approach for accurate prediction of the condition of the brain through the classification of magnetic resonance imaging (MRI) images is greatly beneficial and yet very challenging. In this paper, a novel approach is proposed for the diagnosis of very early stages of AD through an efficient classification of brain MRI images, which uses label propagation in a manifold-based semi-supervised learning framework. We first apply voxel morphometry analysis to extract some of the most critical AD-related features of brain images from the original MRI volumes and also gray matter (GM) segmentation volumes. The features must capture the most discriminative properties that vary between a healthy and Alzheimer-affected brain. Next, we perform a principal component analysis (PCA)-based dimension reduction on the extracted features for faster yet sufficiently accurate analysis. To make the best use of the captured features, we present a hybrid manifold learning framework which embeds the feature vectors in a subspace. Next, using a small set of labeled training data, we apply a label propagation method in the created manifold space to predict the labels of the remaining images and classify them in the two groups of mild Alzheimer's and normal condition (MCI/NC). The accuracy of the classification using the proposed method is 93.86% for the Open Access Series of Imaging Studies (OASIS) database of MRI brain images, providing, compared to the best existing methods, a 3% lower error rate.

The potential supply of organ donors. An assessment of the efficacy of organ procurement efforts in the United States.

PubMed

Evans, R W; Orians, C E; Ascher, N L

1992-01-08

To estimate the potential supply of organ donors and to measure the efficiency of organ procurement efforts in the United States. A geographic database has been developed consisting of multiple cause of death and sociodemographic data compiled by the National Center for Health Statistics. All deaths are evaluated as to their potential for organ donation. Two classes of potential donors are identified: class 1 estimates are restricted to causes of death involving significant head trauma only, and class 2 estimates include class 1 estimates as well as deaths in which brain death was less probable. Over 23,000 people are currently awaiting a kidney, heart, liver, heart-lung, pancreas, or lung transplantation. Donor supply is inadequate, and the number of donors remained unchanged at approximately 4000 annually for 1986 through 1989, with a modest 9.1% increase in 1990. Between 6900 and 10,700 potential donors are available annually (eg, 28.5 to 43.7 per million population). Depending on the class of donor considered, organ procurement efforts are between 37% and 59% efficient. Efficiency greatly varies by state and organ procurement organization. Many more organ donors are available than are being accessed through existing organ procurement efforts. Realistically, it may be possible to increase by 80% the number of donors available in the United States (up to 7300 annually). It is conceivable, although unlikely, that the supply of donor organs could achieve a level to meet demand.

In vivo inhibition of the mitochondrial H+-ATP synthase in neurons promotes metabolic preconditioning.

PubMed

Formentini, Laura; Pereira, Marta P; Sánchez-Cenizo, Laura; Santacatterina, Fulvio; Lucas, José J; Navarro, Carmen; Martínez-Serrano, Alberto; Cuezva, José M

2014-04-01

A key transducer in energy conservation and signaling cell death is the mitochondrial H(+)-ATP synthase. The expression of the ATPase inhibitory factor 1 (IF1) is a strategy used by cancer cells to inhibit the activity of the H(+)-ATP synthase to generate a ROS signal that switches on cellular programs of survival. We have generated a mouse model expressing a mutant of human IF1 in brain neurons to assess the role of the H(+)-ATP synthase in cell death in vivo. The expression of hIF1 inhibits the activity of oxidative phosphorylation and mediates the shift of neurons to an enhanced aerobic glycolysis. Metabolic reprogramming induces brain preconditioning affording protection against quinolinic acid-induced excitotoxicity. Mechanistically, preconditioning involves the activation of the Akt/p70S6K and PARP repair pathways and Bcl-xL protection from cell death. Overall, our findings provide the first in vivo evidence highlighting the H(+)-ATP synthase as a target to prevent neuronal cell death.

Near death experiences: a multidisciplinary hypothesis

PubMed Central

Bókkon, István; Mallick, Birendra N.; Tuszynski, Jack A.

2013-01-01

Recently, we proposed a novel biophysical concept regarding on the appearance of brilliant lights during near death experiences (NDEs) (Bókkon and Salari, 2012). Specifically, perceiving brilliant light in NDEs has been proposed to arise due to the reperfusion that produces unregulated overproduction of free radicals and energetically excited molecules that can generate a transient enhancement of bioluminescent biophotons in different areas of the brain, including retinotopic visual areas. If this excess of bioluminescent photon emission exceeds a threshold in retinotopic visual areas, this can appear as (phosphene) lights because the brain interprets these intrinsic retinotopic bioluminescent photons as if they originated from the external physical world. Here, we review relevant literature that reported experimental studies (Imaizumi et al., 1984; Suzuki et al., 1985) that essentially support our previously published conception, i.e., that seeing lights in NDEs may be due to the transient enhancement of bioluminescent biophotons. Next, we briefly describe our biophysical visual representation model that may explain brilliant lights experienced during NDEs (by phosphenes as biophotons) and REM sleep associated dream-like intrinsic visual imageries through biophotons in NDEs. Finally, we link our biophysical visual representation notion to self-consciousness that may involve extremely low-energy quantum entanglements. This article is intended to introduce novel concepts for discussion and does not pretend to give the ultimate explanation for the currently unanswerable questions about matter, life and soul; their creation and their interrelationship. PMID:24062655

Energy Drink Administration in Combination with Alcohol Causes an Inflammatory Response and Oxidative Stress in the Hippocampus and Temporal Cortex of Rats.

PubMed

Díaz, Alfonso; Treviño, Samuel; Guevara, Jorge; Muñoz-Arenas, Guadalupe; Brambila, Eduardo; Espinosa, Blanca; Moreno-Rodríguez, Albino; Lopez-Lopez, Gustavo; Peña-Rosas, Ulises; Venegas, Berenice; Handal-Silva, Anabella; Morán-Perales, José Luis; Flores, Gonzalo; Aguilar-Alonso, Patricia

2016-01-01

Energy drinks (EDs) are often consumed in combination with alcohol because they reduce the depressant effects of alcohol. However, different researches suggest that chronic use of these psychoactive substances in combination with alcohol can trigger an oxidative and inflammatory response. These processes are regulated by both a reactive astrogliosis and an increase of proinflammatory cytokines such as IL-1β, TNF-α, and iNOS, causing cell death (apoptosis) at the central and peripheral nervous systems. Currently, mechanisms of toxicity caused by mixing alcohol and ED in the brain are not well known. In this study, we evaluated the effect of chronic alcohol consumption in combination with ED on inflammatory response and oxidative stress in the temporal cortex (TCx) and hippocampus (Hp) of adult rats (90 days old). Our results demonstrated that consuming a mixture of alcohol and ED for 60 days induced an increase in reactive gliosis, IL-1β, TNF-α, iNOS, reactive oxygen species, lipid peroxidation, and nitric oxide, in the TCx and Hp. We also found immunoreactivity to caspase-3 and a decrease of synaptophysin in the same brain regions. The results suggested that chronic consumption of alcohol in combination with ED causes an inflammatory response and oxidative stress, which induced cell death via apoptosis in the TCx and Hp of the adult rats.

Energy Drink Administration in Combination with Alcohol Causes an Inflammatory Response and Oxidative Stress in the Hippocampus and Temporal Cortex of Rats

PubMed Central

Díaz, Alfonso; Treviño, Samuel; Guevara, Jorge; Muñoz-Arenas, Guadalupe; Brambila, Eduardo; Espinosa, Blanca; Moreno-Rodríguez, Albino; Lopez-Lopez, Gustavo; Peña-Rosas, Ulises; Venegas, Berenice; Handal-Silva, Anabella; Morán-Perales, José Luis; Flores, Gonzalo; Aguilar-Alonso, Patricia

2016-01-01

Energy drinks (EDs) are often consumed in combination with alcohol because they reduce the depressant effects of alcohol. However, different researches suggest that chronic use of these psychoactive substances in combination with alcohol can trigger an oxidative and inflammatory response. These processes are regulated by both a reactive astrogliosis and an increase of proinflammatory cytokines such as IL-1β, TNF-α, and iNOS, causing cell death (apoptosis) at the central and peripheral nervous systems. Currently, mechanisms of toxicity caused by mixing alcohol and ED in the brain are not well known. In this study, we evaluated the effect of chronic alcohol consumption in combination with ED on inflammatory response and oxidative stress in the temporal cortex (TCx) and hippocampus (Hp) of adult rats (90 days old). Our results demonstrated that consuming a mixture of alcohol and ED for 60 days induced an increase in reactive gliosis, IL-1β, TNF-α, iNOS, reactive oxygen species, lipid peroxidation, and nitric oxide, in the TCx and Hp. We also found immunoreactivity to caspase-3 and a decrease of synaptophysin in the same brain regions. The results suggested that chronic consumption of alcohol in combination with ED causes an inflammatory response and oxidative stress, which induced cell death via apoptosis in the TCx and Hp of the adult rats. PMID:27069534

Near death experiences: a multidisciplinary hypothesis.

PubMed

Bókkon, István; Mallick, Birendra N; Tuszynski, Jack A

2013-01-01

Recently, we proposed a novel biophysical concept regarding on the appearance of brilliant lights during near death experiences (NDEs) (Bókkon and Salari, 2012). Specifically, perceiving brilliant light in NDEs has been proposed to arise due to the reperfusion that produces unregulated overproduction of free radicals and energetically excited molecules that can generate a transient enhancement of bioluminescent biophotons in different areas of the brain, including retinotopic visual areas. If this excess of bioluminescent photon emission exceeds a threshold in retinotopic visual areas, this can appear as (phosphene) lights because the brain interprets these intrinsic retinotopic bioluminescent photons as if they originated from the external physical world. Here, we review relevant literature that reported experimental studies (Imaizumi et al., 1984; Suzuki et al., 1985) that essentially support our previously published conception, i.e., that seeing lights in NDEs may be due to the transient enhancement of bioluminescent biophotons. Next, we briefly describe our biophysical visual representation model that may explain brilliant lights experienced during NDEs (by phosphenes as biophotons) and REM sleep associated dream-like intrinsic visual imageries through biophotons in NDEs. Finally, we link our biophysical visual representation notion to self-consciousness that may involve extremely low-energy quantum entanglements. This article is intended to introduce novel concepts for discussion and does not pretend to give the ultimate explanation for the currently unanswerable questions about matter, life and soul; their creation and their interrelationship.

Memantine Reduced Cell Death, Astrogliosis, and Functional Deficits in an in vitro Model of Repetitive Mild Traumatic Brain Injury.

PubMed

Effgen, Gwen B; Morrison, Barclay

2017-02-15

Clinical studies suggest that athletes with a history of concussion may be at risk for additional mild traumatic brain injury (mTBI), and repetitive exposure to mTBI acutely increases risk for more significant and persistent symptoms and increases future risk for developing neurodegenerative diseases. Currently, symptoms of mTBI are managed with rest and pain medication; there are no drugs approved by the Food and Drug Administration (FDA) that target the biochemical pathology underlying mTBI to treat or prevent acute and long-term effects of repetitive mTBI. Memantine is an FDA-approved drug for treating Alzheimer's disease, and also was shown to be neuroprotective in rodents following a single, moderate to severe TBI. Therefore, we investigated the potential for memantine to mitigate negative outcomes from repetitive mild stretch injury in organotypical hippocampal slice cultures. Samples received two injuries 24 h apart; injury resulted in significant cell death, loss of long-term potentiation (LTP), and astrogliosis compared with naïve, uninjured samples. Delivery of 1.5 μM memantine 1 h following each stretch significantly reduced the effect of injury for all outcome measures, and did not alter those outcome measures that were unaffected by the injury. Therefore, memantine warrants further pre-clinical and clinical investigation for its therapeutic efficacy to prevent cognitive deficits and neuropathology from multiple mTBIs.

The cerebral cortex of Albert Einstein: a description and preliminary analysis of unpublished photographs.

PubMed

Falk, Dean; Lepore, Frederick E; Noe, Adrianne

2013-04-01

Upon his death in 1955, Albert Einstein's brain was removed, fixed and photographed from multiple angles. It was then sectioned into 240 blocks, and histological slides were prepared. At the time, a roadmap was drawn that illustrates the location within the brain of each block and its associated slides. Here we describe the external gross neuroanatomy of Einstein's entire cerebral cortex from 14 recently discovered photographs, most of which were taken from unconventional angles. Two of the photographs reveal sulcal patterns of the medial surfaces of the hemispheres, and another shows the neuroanatomy of the right (exposed) insula. Most of Einstein's sulci are identified, and sulcal patterns in various parts of the brain are compared with those of 85 human brains that have been described in the literature. To the extent currently possible, unusual features of Einstein's brain are tentatively interpreted in light of what is known about the evolution of higher cognitive processes in humans. As an aid to future investigators, these (and other) features are correlated with blocks on the roadmap (and therefore histological slides). Einstein's brain has an extraordinary prefrontal cortex, which may have contributed to the neurological substrates for some of his remarkable cognitive abilities. The primary somatosensory and motor cortices near the regions that typically represent face and tongue are greatly expanded in the left hemisphere. Einstein's parietal lobes are also unusual and may have provided some of the neurological underpinnings for his visuospatial and mathematical skills, as others have hypothesized. Einstein's brain has typical frontal and occipital shape asymmetries (petalias) and grossly asymmetrical inferior and superior parietal lobules. Contrary to the literature, Einstein's brain is not spherical, does not lack parietal opercula and has non-confluent Sylvian and inferior postcentral sulci.

P43/pro-EMAPII: A Potential Biomarker for Discriminating Traumatic Versus Ischemic Brain Injury

PubMed Central

Yao, Changping; Williams, Anthony J.; Ottens, Andrew K.; Lu, X.-C. May; Liu, Ming Cheng; Hayes, Ronald L.; Wang, Kevin K.; Tortella, Frank C.

2009-01-01

Abstract To gain additional insights into the pathogenic cellular and molecular mechanisms underlying different types of brain injury (e.g., trauma versus ischemia), recently attention has focused on the discovery and study of protein biomarkers. In previous studies, using a high-throughput immunoblotting (HTPI) technique, we reported changes in 29 out of 998 proteins following acute injuries to the rat brain (penetrating traumatic versus focal ischemic). Importantly, we discovered that one protein, endothelial monocyte-activating polypeptide II precursor (p43/pro-EMAPII), was differentially expressed between these two types of brain injury. Among other functions, p43/pro-EMAPII is a known pro-inflammatory cytokine involved in the progression of apoptotic cell death. Our current objective was to verify the changes in p43/pro-EMAPII expression, and to evaluate the potentially important implications that the differential regulation of this protein has on injury development. At multiple time points following either a penetrating ballistic-like brain injury (PBBI), or a transient middle cerebral artery occlusion (MCAo) brain injury, tissue samples (6–72 h), CSF samples (24 h), and blood samples (24 h) were collected from rats for analysis. Changes in protein expression were assessed by Western blot analysis and immunohistochemistry. Our results indicated that p43/pro-EMAPII was significantly increased in brain tissues, CSF, and plasma following PBBI, but decreased after MCAo injury compared to their respective sham control samples. This differential expression of p43/pro-EMAPII may be a useful injury-specific biomarker associated with the underlying pathologies of traumatic versus ischemic brain injury, and provide valuable information for directing injury-specific therapeutics. PMID:19317603

The cerebral cortex of Albert Einstein: a description and preliminary analysis of unpublished photographs

PubMed Central

Lepore, Frederick E.; Noe, Adrianne

2013-01-01

Upon his death in 1955, Albert Einstein’s brain was removed, fixed and photographed from multiple angles. It was then sectioned into 240 blocks, and histological slides were prepared. At the time, a roadmap was drawn that illustrates the location within the brain of each block and its associated slides. Here we describe the external gross neuroanatomy of Einstein’s entire cerebral cortex from 14 recently discovered photographs, most of which were taken from unconventional angles. Two of the photographs reveal sulcal patterns of the medial surfaces of the hemispheres, and another shows the neuroanatomy of the right (exposed) insula. Most of Einstein’s sulci are identified, and sulcal patterns in various parts of the brain are compared with those of 85 human brains that have been described in the literature. To the extent currently possible, unusual features of Einstein’s brain are tentatively interpreted in light of what is known about the evolution of higher cognitive processes in humans. As an aid to future investigators, these (and other) features are correlated with blocks on the roadmap (and therefore histological slides). Einstein’s brain has an extraordinary prefrontal cortex, which may have contributed to the neurological substrates for some of his remarkable cognitive abilities. The primary somatosensory and motor cortices near the regions that typically represent face and tongue are greatly expanded in the left hemisphere. Einstein’s parietal lobes are also unusual and may have provided some of the neurological underpinnings for his visuospatial and mathematical skills, as others have hypothesized. Einstein’s brain has typical frontal and occipital shape asymmetries (petalias) and grossly asymmetrical inferior and superior parietal lobules. Contrary to the literature, Einstein’s brain is not spherical, does not lack parietal opercula and has non-confluent Sylvian and inferior postcentral sulci. PMID:23161163

Use of Lung Allografts from Brain-Dead Donors after Cardiopulmonary Arrest and Resuscitation

PubMed Central

Worni, Mathias; Osho, Asishana A.; Snyder, Laurie D.; Palmer, Scott M.; Pietrobon, Ricardo; Davis, R. Duane; Hartwig, Matthew G.

2013-01-01

Rationale: Patients who progress to brain death after resuscitation from cardiac arrest have been hypothesized to represent an underused source of potential organ donors; however, there is a paucity of data regarding the viability of lung allografts after a period of cardiac arrest in the donor. Objectives: To analyze postoperative complications and survival after lung transplant from brain-dead donors resuscitated after cardiac arrest. Methods: The United Network for Organ Sharing database records donors with cardiac arrest occurring after brain death. Adult recipients of lung allografts from these arrest/resuscitation donors between 2005 and 2011 were compared with nonarrest donors. Propensity score matching was used to reduce the effect of confounding. Postoperative complications and overall survival were assessed using McNemar’s test for correlated binary proportions and Kaplan–Meier methods. Measurements and Main Results: A total of 479 lung transplant recipients from arrest/resuscitation donors were 1:1 propensity matched from a cohort of 9,076 control subjects. Baseline characteristics in the 1:1-matched cohort were balanced. There was no significant difference in perioperative mortality, airway dehiscence, dialysis requirement, postoperative length of stay (P ≥ 0.38 for all), or overall survival (P = 0.52). A subanalysis of the donor arrest group demonstrated similar survival when stratified by resuscitation time quartile (P = 0.38). Conclusions: There is no evidence of inferior outcomes after lung transplant from brain-dead donors who have had a period of cardiac arrest provided that good lung function is preserved and the donor is otherwise deemed acceptable for transplantation. Potential expansion of the donor pool to include cardiac arrest as the cause of brain death requires further study. PMID:23777361

Apoptosis and Acute Brain Ischemia in Ischemic Stroke.

PubMed

Radak, Djordje; Katsiki, Niki; Resanovic, Ivana; Jovanovic, Aleksandra; Sudar-Milovanovic, Emina; Zafirovic, Sonja; Mousad, Shaker A; Isenovic, Esma R

2017-01-01

Apoptosis may contribute to a significant proportion of neuron death following acute brain ischemia (ABI), but the underlying mechanisms are still not fully understood. Brain ischemia may lead to stroke, which is one of the main causes of long-term morbidity and mortality in both developed and developing countries. Therefore, stroke prevention and treatment is clinically important. There are two important separate areas of the brain during ABI: the ischemic core and the ischemic penumbra. The ischemic core of the brain experiences a sudden reduction of blood flow, just minutes after ischemic attack with irreversible injury and subsequent cell death. On the other hand, apoptosis within the ischemic penumbra may occur after several hours or days, while necrosis starts in the first hours after the onset of ABI in the ischemic core. ABI is characterized by key molecular events that initiate apoptosis in many cells, such as overproduction of free radicals, Ca2+ overload and excitotoxicity. These changes in cellular homeostasis may trigger either necrosis or apoptosis, which often depends on cell type, cell age, and location in the brain. Apoptosis results in DNA fragmentation, degradation of cytoskeletal and nuclear proteins, cross-linking of proteins, formation of apoptotic bodies, expression of ligands for phagocytic cell receptors and finally uptake by phagocytic cells. This review focuses on recent findings based on animal and human studies regarding the apoptotic mechanisms of neuronal death following ABI and the development of potential neuroprotective agents that reduce morbidity. The effects of statins on stroke prevention and treatment as well as on apoptotic mediators are also considered. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Causes of death in remote symptomatic epilepsy.

PubMed

Day, S M; Wu, Y W; Strauss, D J; Shavelle, R M; Reynolds, R J

2005-07-26

To determine the causes of death of individuals with developmental disabilities that occur more frequently among those with remote symptomatic epilepsy (i.e., epilepsy occurring in persons with developmental delay or identified brain lesions) than for those without. The authors compared causes of mortality in persons with (n = 10,030) and without (n = 96,163) history of epilepsy in a California population of persons with mild developmental disabilities, 1988 to 2002. Subjects had traumatic brain injury, cerebral palsy, Down syndrome, autism, or a developmental disability with other or unknown etiology. There were 721,759 person-years of data, with 2,397 deaths. Underlying causes of death were determined from the State of California's official mortality records. Cause-specific death rates and standardized mortality ratios (SMRs) were computed for those with and without epilepsy relative to subjects in the California general population. Comparisons were then made between SMRs of those with and without epilepsy, and CIs on the ratios of SMRs were determined. Death rates for persons with epilepsy were elevated for several causes. The greatest excess was due to seizures (International Classification of Diseases-9 [ICD-9] 345; SMR 53.1, 95% CI 28.0 to 101.0) and convulsions (ICD-9 780.3; SMR 25.2, 95% CI 11.7 to 54.2). Other causes occurring more frequently in those with epilepsy included brain cancer (SMR 5.2, 95% CI 2.2 to 12.1), respiratory diseases (SMR 1.7, 95% CI 1.2 to 2.5), circulatory diseases (SMR 1.3, 95% CI 1.0 to 1.7), and accidents (SMR 2.7, 95% CI 1.9 to 3.7), especially accidental drowning (SMR 12.8, 95% CI 7.0 to 23.2). Remote symptomatic epilepsy is associated with an increased risk of death. Seizures, aspiration pneumonia, and accidental drowning are among the leading contributors.

Sugar for the brain: the role of glucose in physiological and pathological brain function

PubMed Central

Mergenthaler, Philipp; Lindauer, Ute; Dienel, Gerald A.; Meisel, Andreas

2013-01-01

The mammalian brain depends upon glucose as its main source of energy, and tight regulation of glucose metabolism is critical for brain physiology. Consistent with its critical role for physiological brain function, disruption of normal glucose metabolism as well as its interdependence with cell death pathways forms the pathophysiological basis for many brain disorders. Here, we review recent advances in understanding how glucose metabolism sustains basic brain physiology. We aim at synthesizing these findings to form a comprehensive picture of the cooperation required between different systems and cell types, and the specific breakdowns in this cooperation which lead to disease. PMID:23968694

Inhaled 45-50% argon augments hypothermic brain protection in a piglet model of perinatal asphyxia.

PubMed

Broad, Kevin D; Fierens, Igor; Fleiss, Bobbi; Rocha-Ferreira, Eridan; Ezzati, Mojgan; Hassell, Jane; Alonso-Alconada, Daniel; Bainbridge, Alan; Kawano, Go; Ma, Daqing; Tachtsidis, Ilias; Gressens, Pierre; Golay, Xavier; Sanders, Robert D; Robertson, Nicola J

2016-03-01

Cooling to 33.5°C in babies with neonatal encephalopathy significantly reduces death and disability, however additional therapies are needed to maximize brain protection. Following hypoxia-ischemia we assessed whether inhaled 45-50% Argon from 2-26h augmented hypothermia neuroprotection in a neonatal piglet model, using MRS and aEEG, which predict outcome in babies with neonatal encephalopathy, and immunohistochemistry. Following cerebral hypoxia-ischemia, 20 Newborn male Large White piglets<40h were randomized to: (i) Cooling (33°C) from 2-26h (n=10); or (ii) Cooling and inhaled 45-50% Argon (Cooling+Argon) from 2-26h (n=8). Whole-brain phosphorus-31 and regional proton MRS were acquired at baseline, 24 and 48h after hypoxia-ischemia. EEG was monitored. At 48h after hypoxia-ischemia, cell death (TUNEL) was evaluated over 7 brain regions. There were no differences in body weight, duration of hypoxia-ischemia or insult severity; throughout the study there were no differences in heart rate, arterial blood pressure, blood biochemistry and inotrope support. Two piglets in the Cooling+Argon group were excluded. Comparing Cooling+Argon with Cooling there was preservation of whole-brain MRS ATP and PCr/Pi at 48h after hypoxia-ischemia (p<0.001 for both) and lower (1)H MRS lactate/N acetyl aspartate in white (p=0.03 and 0.04) but not gray matter at 24 and 48h. EEG background recovery was faster (p<0.01) with Cooling+Argon. An overall difference between average cell-death of Cooling versus Cooling+Argon was observed (p<0.01); estimated cells per mm(2) were 23.9 points lower (95% C.I. 7.3-40.5) for the Cooling+Argon versus Cooling. Inhaled 45-50% Argon from 2-26h augmented hypothermic protection at 48h after hypoxia-ischemia shown by improved brain energy metabolism on MRS, faster EEG recovery and reduced cell death on TUNEL. Argon may provide a cheap and practical therapy to augment cooling for neonatal encephalopathy. Copyright © 2015. Published by Elsevier Inc.

Association of BDNF Val66Met Polymorphism and Brain BDNF Levels with Major Depression and Suicide.

PubMed

Youssef, Mariam M; Underwood, Mark D; Huang, Yung-Yu; Hsiung, Shu-Chi; Liu, Yan; Simpson, Norman R; Bakalian, Mihran J; Rosoklija, Gorazd B; Dwork, Andrew J; Arango, Victoria; Mann, J John

2018-06-01

Brain-derived neurotrophic factor is implicated in the pathophysiology of major depressive disorder and suicide. Both are partly caused by early life adversity, which reduces brain-derived neurotrophic factor protein levels. This study examines the association of brain-derived neurotrophic factor Val66Met polymorphism and brain brain-derived neurotrophic factor levels with depression and suicide. We hypothesized that both major depressive disorder and early life adversity would be associated with the Met allele and lower brain brain-derived neurotrophic factor levels. Such an association would be consistent with low brain-derived neurotrophic factor mediating the effect of early life adversity on adulthood suicide and major depressive disorder. Brain-derived neurotrophic factor Val66Met polymorphism was genotyped in postmortem brains of 37 suicide decedents and 53 nonsuicides. Additionally, brain-derived neurotrophic factor protein levels were determined by Western blot in dorsolateral prefrontal cortex (Brodmann area 9), anterior cingulate cortex (Brodmann area 24), caudal brainstem, and rostral brainstem. The relationships between these measures and major depressive disorder, death by suicide, and reported early life adversity were examined. Subjects with the Met allele had an increased risk for depression. Depressed patients also have lower brain-derived neurotrophic factor levels in anterior cingulate cortex and caudal brainstem compared with nondepressed subjects. No effect of history of suicide death or early life adversity was observed with genotype, but lower brain-derived neurotrophic factor levels in the anterior cingulate cortex were found in subjects who had been exposed to early life adversity and/or died by suicide compared with nonsuicide decedents and no reported early life adversity. This study provides further evidence implicating low brain brain-derived neurotrophic factor and the brain-derived neurotrophic factor Met allele in major depression risk. Future studies should seek to determine how altered brain-derived neurotrophic factor expression contributes to depression and suicide.

Brain Basics: Preventing Stroke

MedlinePlus

... of death or disability from stroke. With good control, the risk of stroke in most age groups can be kept below that for accidental injury ... of death or disability from stroke. With good control, the risk of stroke in most age groups can be kept below that for accidental injury ...

Advantages of analyzing postmortem brain samples in routine forensic drug screening-Case series of three non-natural deaths tested positive for lysergic acid diethylamide (LSD).

PubMed

Mardal, Marie; Johansen, Sys Stybe; Thomsen, Ragnar; Linnet, Kristian

2017-09-01

Three case reports are presented, including autopsy findings and toxicological screening results, which were tested positive for the potent hallucinogenic drug lysergic acid diethylamide (LSD). LSD and its main metabolites were quantified in brain tissue and femoral blood, and furthermore hematoma and urine when available. LSD, its main metabolite 2-oxo-3-hydroxy-LSD (oxo-HO-LSD), and iso-LSD were quantified in biological samples according to a previously published procedure involving liquid-liquid extraction and ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). LSD was measured in the brain tissue of all presented cases at a concentration level from 0.34-10.8μg/kg. The concentration level in the target organ was higher than in peripheral blood. Additional psychoactive compounds were quantified in blood and brain tissue, though all below toxic concentration levels. The cause of death in case 1 was collision-induced brain injury, while it was drowning in case 2 and 3 and thus not drug intoxication. However, the toxicological findings could help explain the decedent's inability to cope with brain injury or drowning incidents. The presented findings could help establish reference concentrations in brain samples and assist in interpretation of results from forensic drug screening in brain tissue. This is to the author's knowledge the first report of LSD, iso-LSD, and oxo-HO-LSD measured in brain tissue samples. Copyright © 2017 Elsevier B.V. All rights reserved.

Restoration of stressor-induced calcium dysregulation and autophagy inhibition by polyphenol-rich acai (Euterpe sps.) fruit pulp extracts in rodent brain cells in vitro

USDA-ARS?s Scientific Manuscript database

Oxidative damage to lipids, proteins and nucleic acids in brain often causes progressive neuronal degeneration and death which are the focal traits of chronic and acute pathologies in the brain, including those involving cognitive decline. It has been postulated that at least part of the loss of cog...

Increased level of apoptosis in rat brains and SH-SY5Y cells exposed to excessive fluoride--a mechanism connected with activating JNK phosphorylation.

PubMed

Liu, Yan-Jie; Guan, Zhi-Zhong; Gao, Qin; Pei, Jin-Jing

2011-07-28

In order to reveal the mechanism of the brain injury induced by chronic fluorosis, the levels of apoptosis and c-Jun N-terminal kinases (JNK) in brains of rats and SH-SY5Y cells exposed to different concentrations of sodium fluoride (NaF) were detected. The dental fluorosis and fluoride contents in blood, urine and bones of rats were measured to evaluate the exhibition of fluorosis. The apoptotic death rate was measured by flow cytometry and the expression of JNK at protein level by Western blotting. The results showed that as compared with controls, the apoptotic death rate was obviously increased in brains of the rats exposed to high-fluoride (50ppm) for 6 months with a concentration dependent manner, but no significant change for 3 months. In SH-SY5Y cells treated with high concentration (50ppm) of fluoride, the increased apoptotic death rate was obviously observed as compared to controls. In addition, the expressions of phospho-JNK at protein level were raised by 20.5% and 107.6%, respectively, in brains of the rats exposed to low-fluoride (5ppm) and high-fluoride for 6 months; while no significant changes were found between the rats exposed to fluoride and the controls for 3 months. The protein level of phospho-JNK was also increased in SH-SY5Y cells exposed to high-fluoride. There were no changes of total-JNK both in the rats and in the SH-SY5Y cells exposed to excessive fluoride as compared to controls. When SH-SY5Y cells were singly treated with SP600125, an inhibitor of phospho-JNK, the decreased expression of phospho-JNK, but no apoptosis, was detected. Interestingly, after JNK phosphorylation in the cultured cells was inhibited by SP600125, the treatment with high-fluoride did not induce the increase of apoptosis. In addition, there was a positive correlation between the expression of phospho-JNK and the apoptotic death rate in rat brains or SH-SY5Y cells treated with high-fluoride. The results indicated that exposure to excessive fluoride resulted in the increase of apoptosis in rat brains and SH-SY5Y cells, in which one of the mechanisms might be activating JNK phosphorylation. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

[External post-mortem examination].

PubMed

Hartwig, S

2016-09-01

The external post-mortem examination in Germany is a non-delegable medical duty for determination of death, identity of the deceased, cause of death, manner of death, time of death and notifiable infectious diseases. Within the framework of rescue service missions the physician is limited to ascertaining that death has occurred. The determination of death must be reliable and is automatically followed by a complete external post-mortem examination of the body, if necessary by another physician. The certain signs of death are livor mortis, rigor mortis and putrefaction. Reliable features for the occurrence of death are injuries which are not compatible with life and brain death. The external post-mortem examination is the basis for the decision on whether further criminal investigations are necessary. The external post-mortem examination and the accompanying death certification must always be meticulously carried out.

Caspase Activation in Fetal Rat Brain Following Experimental Intrauterine Inflammation

PubMed Central

Sharangpani, Aditi; Takanohashi, Asako; Bell, Michael J.

2009-01-01

Intrauterine inflammation has been implicated in developmental brain injuries, including the development of periventricular leukomalacia (PVL) and cerebral palsy (CP). Previous studies in our rat model of intrauterine inflammation demonstrated apoptotic cell death in fetal brains within the first 5 days after lipopolysaccharide (LPS) administration to mothers and eventual dysmyelination. Cysteine-containing, aspartate-specific proteases, or caspases, are proteins involved with apoptosis through both intracellular (intrinsic pathway) and extracellular (extrinsic pathway) mechanisms. We hypothesized that cell death in our model would occur mainly via activation of the extrinsic pathway. We further hypothesized that Fas, a member of the tumor necrosis factor receptor (TNFR) superfamily, would be increased and the death inducing signaling complex (DISC) would be detectable. Pregnant rats were injected intracervically with LPS at E15 and immunoblotting, immunohistochemical and immunoprecipitation analyses were performed. The presence of the activated form of the effector caspase (caspase-3) was observed 24 h after LPS administration. Caspase activity assays demonstrated rapid increases in (i) caspases-9 and -10 within 1 h, (ii) caspase-8 at 2 h and (iii) caspase-3 at 4 h. At 24 h after LPS, activated caspase-3+/Fas+ cells were observed within the developing white matter. Lastly, the DISC complex (caspase-8, Fas and Fas-associated Death Domain (FADD)) was observed within 30 min by immunoprecipitation. Apoptosis in our model occurs via both extrinsic and intrinsic pathways, and activation of Fas may play a role. Understanding the mechanisms of cell death in models of intrauterine inflammation may affect development of future strategies to mitigate these injuries in children. PMID:18289516

Kidney donation after circulatory death in a country with a high number of brain dead donors: 10-year experience in Belgium.

PubMed

Jochmans, Ina; Darius, Tom; Kuypers, Dirk; Monbaliu, Diethard; Goffin, Eric; Mourad, Michel; Ledinh, Hieu; Weekers, Laurent; Peeters, Patrick; Randon, Caren; Bosmans, Jean-Louis; Roeyen, Geert; Abramowicz, Daniel; Hoang, Anh-Dung; De Pauw, Luc; Rahmel, Axel; Squifflet, Jean-Paul; Pirenne, Jacques

2012-08-01

Worldwide shortage of standard brain dead donors (DBD) has revived the use of kidneys donated after circulatory death (DCD). We reviewed the Belgian DCD kidney transplant (KT) experience since its reintroduction in 2000. Risk factors for delayed graft function (DGF) were identified using multivariate analysis. Five-year patient/graft survival was assessed using Kaplan-Meier curves. The evolution of the kidney donor type and the impact of DCDs on the total KT activity in Belgium were compared with the Netherlands. Between 2000 and 2009, 287 DCD KT were performed. Primary nonfunction occurred in 1% and DGF in 31%. Five-year patient and death-censored graft survival were 93% and 95%, respectively. In multivariate analysis, cold storage (versus machine perfusion), cold ischemic time, and histidine-tryptophan-ketoglutarate solution were independent risk factors for the development of DGF. Despite an increased number of DCD donations and transplantations, the total number of deceased KT did not increase significantly. This could suggest a shift from DBDs to DCDs. To increase KT activity, Belgium should further expand controlled DCD programs while simultaneously improve the identification of all potential DBDs and avoid their referral for donation as DCDs before brain death occurs. Furthermore, living donation remains underused. © 2012 The Authors. Transplant International © 2012 European Society for Organ Transplantation.

Can education alter attitudes, behaviour and knowledge about organ donation? A pretest-post-test study.

PubMed

McGlade, Donal; Pierscionek, Barbara

2013-12-30

The emergence of evidence suggests that student nurses commonly exhibit concerns about their lack of knowledge of organ donation and transplantation. Formal training about organ donation has been shown to positively influence attitude, encourage communication and registration behaviours and improve knowledge about donor eligibility and brain death. The focus of this study was to determine the attitude and behaviour of student nurses and to assess their level of knowledge about organ donation after a programme of study. A quantitative questionnaire was completed before and after participation in a programme of study using a pretest-post-test design. Participants were recruited from a University based in Northern Ireland during the period from February to April 2011. 100 preregistration nurses (female : male=96 : 4) aged 18-50 years (mean (SD) 24.3 (6.0) years) were recruited. Participants' knowledge improved over the programme of study with regard to the suitability of organs that can be donated after death, methods available to register organ donation intentions, organ donation laws, concept of brain death and the likelihood of recovery after brain death. Changes in attitude postintervention were also observed in relation to participants' willingness to accept an informed system of consent and with regard to participants' actual discussion behaviour. The results provide support for the introduction of a programme that helps inform student nurses about important aspects of organ donation.

Mitochondrial permeability transition pore inhibitors prevent ethanol-induced neuronal death in mice.

PubMed

Lamarche, Frederic; Carcenac, Carole; Gonthier, Brigitte; Cottet-Rousselle, Cecile; Chauvin, Christiane; Barret, Luc; Leverve, Xavier; Savasta, Marc; Fontaine, Eric

2013-01-18

Ethanol induces brain injury by a mechanism that remains partly unknown. Mitochondria play a key role in cell death processes, notably through the opening of the permeability transition pore (PTP). Here, we tested the effect of ethanol and PTP inhibitors on mitochondrial physiology and cell viability both in vitro and in vivo. Direct addition of ethanol up to 100 mM on isolated mouse brain mitochondria slightly decreased oxygen consumption but did not affect PTP regulation. In comparison, when isolated from ethanol-treated (two doses of 2 g/kg, 2 h apart) 7-day-old mouse pups, brain mitochondria displayed a transient decrease in oxygen consumption but no change in PTP regulation or H2O2 production. Conversely, exposure of primary cultured astrocytes and neurons to 20 mM ethanol for 3 days led to a transient PTP opening in astrocytes without affecting cell viability and to a permanent PTP opening in 10 to 20% neurons with the same percentage of cell death. Ethanol-treated mouse pups displayed a widespread caspase-3 activation in neurons but not in astrocytes and dramatic behavioral alterations. Interestingly, two different PTP inhibitors (namely, cyclosporin A and nortriptyline) prevented both ethanol-induced neuronal death in vivo and ethanol-induced behavioral modifications. We conclude that PTP opening is involved in ethanol-induced neurotoxicity in the mouse.

Ginkgo biloba extract EGb761 attenuates brain death-induced renal injury by inhibiting pro-inflammatory cytokines and the SAPK and JAK-STAT signalings

PubMed Central

Li, Yifu; Xiong, Yunyi; Zhang, Huanxi; Li, Jun; Wang, Dong; Chen, Wenfang; Yuan, Xiaopeng; Su, Qiao; Li, Wenwen; Huang, Huiting; Bi, Zirong; Liu, Longshan; Wang, Changxi

2017-01-01

This study aimed to investigate the protective effects of EGb761, a Ginkgo Biloba extract, against brain death-induced kidney injury. Sixty male Sprague Dawley rats were randomly divided into six groups: sham, brain-death (BD), BD + EGb b48h (48 hours before BD), BD + EGb 2 h (2 hours after BD), BD + EGb 1 h, and BD + EGb 0.5 h. Six hours after BD, serum sample and kidney tissues were collected for analyses. The levels of blood urea nitrogen (BUN) and serum creatinine significantly elevated in the BD group than in sham group. In all the EGb761-treated BD animals except for the BD + Gb 2 h group, the levels of BUN and serum creatinine significantly reduced (all P < 0.01). EGb761 attenuated tubular injury and lowered the histological score. In addition, the longer duration of drug treatment was, the better protective efficacy could be observed. EGb761 significantly reduced IL-1β, IL-6, TNF-α, MCP-1, IP-10 mRNA expression and macrophage infiltration in the kidney. EGb761 treatment at 48 hour before brain death significantly attenuate the levels of p-JNK-MAPK, p-p38-MAPK, and p-STAT3 proteins (all P < 0.05, compared to BD group). In summary, our data showed that EGb761 treatment protected donor kidney from BD-induced damages by blocking SAPK and JAK-STAT signalings. Early administration of EGb761 can provide better protective efficacy. PMID:28332628

A statistical model describing combined irreversible electroporation and electroporation-induced blood-brain barrier disruption

PubMed Central

Sharabi, Shirley; Kos, Bor; Last, David; Guez, David; Daniels, Dianne; Harnof, Sagi; Miklavcic, Damijan

2016-01-01

Background Electroporation-based therapies such as electrochemotherapy (ECT) and irreversible electroporation (IRE) are emerging as promising tools for treatment of tumors. When applied to the brain, electroporation can also induce transient blood-brain-barrier (BBB) disruption in volumes extending beyond IRE, thus enabling efficient drug penetration. The main objective of this study was to develop a statistical model predicting cell death and BBB disruption induced by electroporation. This model can be used for individual treatment planning. Material and methods Cell death and BBB disruption models were developed based on the Peleg-Fermi model in combination with numerical models of the electric field. The model calculates the electric field thresholds for cell kill and BBB disruption and describes the dependence on the number of treatment pulses. The model was validated using in vivo experimental data consisting of rats brains MRIs post electroporation treatments. Results Linear regression analysis confirmed that the model described the IRE and BBB disruption volumes as a function of treatment pulses number (r2 = 0.79; p < 0.008, r2 = 0.91; p < 0.001). The results presented a strong plateau effect as the pulse number increased. The ratio between complete cell death and no cell death thresholds was relatively narrow (between 0.88-0.91) even for small numbers of pulses and depended weakly on the number of pulses. For BBB disruption, the ratio increased with the number of pulses. BBB disruption radii were on average 67% ± 11% larger than IRE volumes. Conclusions The statistical model can be used to describe the dependence of treatment-effects on the number of pulses independent of the experimental setup. PMID:27069447

Impaired autophagy flux is associated with neuronal cell death after traumatic brain injury

PubMed Central

Sarkar, Chinmoy; Zhao, Zaorui; Aungst, Stephanie; Sabirzhanov, Boris; Faden, Alan I; Lipinski, Marta M

2015-01-01

Dysregulation of autophagy contributes to neuronal cell death in several neurodegenerative and lysosomal storage diseases. Markers of autophagy are also increased after traumatic brain injury (TBI), but its mechanisms and function are not known. Following controlled cortical impact (CCI) brain injury in GFP-Lc3 (green fluorescent protein-LC3) transgenic mice, we observed accumulation of autophagosomes in ipsilateral cortex and hippocampus between 1 and 7 d. This accumulation was not due to increased initiation of autophagy but rather to a decrease in clearance of autophagosomes, as reflected by accumulation of the autophagic substrate SQSTM1/p62 (sequestosome 1). This was confirmed by ex vivo studies, which demonstrated impaired autophagic flux in brain slices from injured as compared to control animals. Increased SQSTM1 peaked at d 1–3 but resolved by d 7, suggesting that the defect in autophagy flux is temporary. The early impairment of autophagy is at least in part caused by lysosomal dysfunction, as evidenced by lower protein levels and enzymatic activity of CTSD (cathepsin D). Furthermore, immediately after injury both autophagosomes and SQSTM1 accumulated predominantly in neurons. This was accompanied by appearance of SQSTM1 and ubiquitin-positive puncta in the affected cells, suggesting that, similar to the situation observed in neurodegenerative diseases, impaired autophagy may contribute to neuronal injury. Consistently, GFP-LC3 and SQSTM1 colocalized with markers of both caspase-dependent and caspase-independent cell death in neuronal cells proximal to the injury site. Taken together, our data indicated for the first time that autophagic clearance is impaired early after TBI due to lysosomal dysfunction, and correlates with neuronal cell death. PMID:25484084

Help, I need to develop communication skills on donation: the "VIDEO" model.

PubMed

Smudla, A; Mihály, S; Hegedüs, K; Nemes, B; Fazakas, J

2011-05-01

Information about brain stem death and donation can be influence the consent rate for donation and its psychosocial effects. The aim of this study was to create a "VIDEO" model that could be used to help physicians to develop communication skills. A video recorded 32 simulations of family interviews: 16 under-age and 16 adult donors. They were analyzed during 8 courses conducted in 2008 and 2009. During the VIDEO process, the visual presentation was followed by participants (n=192) discussing interactively the donation situation. After the transcription of the video records, family interviews were explored retrospectively regarding informing relatives about brain stem death and donation, typical communication gaps and common questions from families. The data were examined qualitatively and semiquantitatively. We think that teaching can be optimized by our results. A comprehensible explanation about brain stem death was provided to relatives in 65.63% of cases. The consent of the family was more important for the physicians than the application of the law in 93.75%; 78.13% of physicians emphasized altruism to support donation. Remarkable mistakes of communication included using the teams coma and brain stem death interchangeably (9.38%); applying expressions connected with life in the present tense (21.88%) and mechanically kept alive (21.88%); organ-focused behavior such as "organs to be usable" (34.38%). The frequent questions and statements of "relatives" were "heart beats" (100%), "did he really die?" (65.63%), "fear of loss of integrity of the corpse" (59.38%), and "wake up from the coma" (46.88%). Interaction with the family requires great preparation. The communication skills of physicians can be developed through the VIDEO model. The results can be integrated into educational programs that consider the particular features of the given country. Copyright © 2011 Elsevier Inc. All rights reserved.

Non-traumatic subdural hematoma secondary to septic brain embolism: A rare cause of unexpected death in a drug addict suffering from undiagnosed bacterial endocarditis.

PubMed

Geisenberger, D; Huppertz, L M; Büchsel, M; Kramer, L; Pollak, S; Große Perdekamp, M

2015-12-01

Acute subdural hematomas are mostly due to blunt traumatization of the head. In rare instances, subdural bleeding occurs without evidence of a previous trauma following spontaneous hemorrhage, e.g. from a ruptured aneurysm or an intracerebral hematoma perforating the brain surface and the arachnoid. The paper presents the morphological, microbiological and toxicological findings in a 38-year-old drug addict who was found by his partner in a dazed state. When brought to a hospital, he underwent trepanation to empty a right-sided subdural hematoma, but he died already 4h after admission. Autopsy revealed previously undiagnosed infective endocarditis of the aortic valve as well as multiple infarctions of brain, spleen and kidneys obviously caused by septic emboli. The subdural hematoma originated from a subcortical brain hemorrhage which had perforated into the subdural space. Microbiological investigation of the polypous vegetations adhering to the aortic valve revealed colonization by Streptococcus mitis and Klebsiella oxytoca. According to the toxicological analysis, no psychotropic substances had contributed to the lethal outcome. The case reported underlines that all deaths of drug addicts should be subjected to complete forensic autopsy, as apart from intoxications also natural and traumatic causes of death have to be taken into consideration. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

[Immunohistochemical studies on neuronal changes in brain stem nucleus of forensic autopsied cases. I. Various cases of asphyxia and respiratory disorder].

PubMed

Kubo, S; Orihara, Y; Gotohda, T; Tokunaga, I; Tsuda, R; Ikematsu, K; Kitamura, O; Yamamoto, A; Nakasono, I

1998-12-01

Several nuclei in brain stem are well known to play an important role in supporting human life. However, the connection between neural changes of brain stem and the cause of death is not yet fully understood. To investigate the correlation of brain stem damage with various cause of respiratory disorders, neural changes of the arcuate nucleus (ARC), the hypoglossal nucleus (HN) and the inferior olivary nucleus (IO) were examined using immunohistochemical technique. Based on the cause of death, the forensic autopsy cases were divided into 5 groups as follows. Group I: hanging, ligature strangulation and manual strangulation, Group II: smothering and choking, Group III: drowning, Group IV: respiratory failure, control group: heat stroke and sun stroke. Brain was fixed with phosphate-buffer formalin, and the brain stem was horizontally dissected at the level of apex, then embedded in paraffin. The sections were stained with the antibodies against microtubule-associated protein 2 (MAP2), muscalinic acetylcholine receptor (mAChR), c-fos gene product (c-Fos) and 72 kD heat-shock protein (HSP70). Three nuclei showed no obvious morphological changes in all examined groups. However, in case of asphyxia (Group I to III), neurons in HN were positively stained with both HSP70 and c-Fos antibodies. This may indicate that the occlusion of upper airway results in the neuronal damage of HN without their morphological changes. Positive staining of HSP70 and c-Fos in IO was more frequently observed in Group III than other 4 groups. Since IO is involved in maintaining body balance which is often disturbed by drowning, it seems possible that neuronal damage in IO observed in drowning may be related to the disturbance of body balance. These observations indicate that immunohistochemical study on the damage to neurons in brain stem nuclei can provide useful information for determining the cause of death.

What Is the Optimal Treatment of Large Brain Metastases? An Argument for a Multidisciplinary Approach

DOE Office of Scientific and Technical Information (OSTI.GOV)

Choi, Clara Y.H.; Chang, Steven D.; Gibbs, Iris C.

2012-11-01

Purpose: Single-modality treatment of large brain metastases (>2 cm) with whole-brain irradiation, stereotactic radiosurgery (SRS) alone, or surgery alone is not effective, with local failure (LF) rates of 50% to 90%. Our goal was to improve local control (LC) by using multimodality therapy of surgery and adjuvant SRS targeting the resection cavity. Patients and Methods: We retrospectively evaluated 97 patients with brain metastases >2 cm in diameter treated with surgery and cavity SRS. Local and distant brain failure (DF) rates were analyzed with competing risk analysis, with death as a competing risk. The overall survival rate was calculated by themore » Kaplain-Meier product-limit method. Results: The median imaging follow-up duration for all patients was 10 months (range, 1-80 months). The 12-month cumulative incidence rates of LF, with death as a competing risk, were 9.3% (95% confidence interval [CI], 4.5%-16.1%), and the median time to LF was 6 months (range, 3-17 months). The 12-month cumulative incidence rate of DF, with death as a competing risk, was 53% (95% CI, 43%-63%). The median survival time for all patients was 15.6 months. The median survival times for recursive partitioning analysis classes 1, 2, and 3 were 33.8, 13.7, and 9.0 months, respectively (p = 0.022). On multivariate analysis, Karnofsky Performance Status ({>=}80 vs. <80; hazard ratio 0.54; 95% CI 0.31-0.94; p = 0.029) and maximum preoperative tumor diameter (hazard ratio 1.41; 95% CI 1.08-1.85; p = 0.013) were associated with survival. Five patients (5%) required intervention for Common Terminology Criteria for Adverse Events v4.02 grade 2 and 3 toxicity. Conclusion: Surgery and adjuvant resection cavity SRS yields excellent LC of large brain metastases. Compared with other multimodality treatment options, this approach allows patients to avoid or delay whole-brain irradiation without compromising LC.« less

Outcomes of surgery followed by local brain radiotherapy compared with surgery followed by whole brain radiotherapy for single brain metastasis.

PubMed

Igaki, Hiroshi; Harada, Ken; Umezawa, Rei; Miyakita, Yasuji; Ohno, Makoto; Takahashi, Masamichi; Sumi, Minako; Inaba, Koji; Murakami, Naoya; Ito, Yoshinori; Narita, Yoshitaka; Itami, Jun

2017-07-31

To determine the clinical efficacy of surgery followed by local brain radiotherapy (LBRT) for patients with a single brain metastasis, by comparing the results with those of postoperative whole brain radiotherapy (WBRT). We performed a retrospective analysis to compare the survival rate, recurrence-free rates, and causes of death for single brain metastasis patients who underwent surgery followed by LBRT or WBRT in the 2010-2015 period. After their surgery, 22 and 32 patients were treated by LBRT and WBRT, respectively. The median survival times for these LBRT and WBRT groups were 18.3 months and 19.2 months, respectively (p = 0.356). The local recurrence-free rates were 81.2% at 1 year and 81.2% at 2 years after LBRT, and 63.8% at 1 year and 58.9% at 2 years after WBRT (p = 0.589). The distant brain recurrence-free rates were 42.5% at 1 year and 25.5% at 2 years after LBRT, and 69.8% at 1 year and 52.4% at 2 years after WBRT (p = 0.044). Distant brain recurrences were observed significantly more frequently in the LBRT group, but the rates of salvage treatment application and survival were not significantly different between the LBRT and WBRT groups. The probability of neurologic death was not significantly higher in the LBRT group compared with the WBRT group. Surgery followed by LBRT for single brain metastasis is not inferior to postoperative WBRT, because survival and the necessity of salvage treatment after LBRT were equivalent to those after WBRT.

Beyond the basics: brain injuries.

PubMed

Duncan, Tim; Krost, William S; Mistovich, Joseph J; Limmer, Daniel

2007-07-01

Increased intracranial pressure can be a catastrophic event that may lead to death or permanent disability. Without prompt recognition and reversal of hypoxia, hypotension, hypercarbia, acidosis and increased intracranial pressure, the cerebral blood flow and resultant cerebral perfusion can be inadequate, leading to an exacerbation of secondary brain injury.

Knowledge, Attitudes, and Beliefs Toward Organ Donation Among Social Media Users.

PubMed

Hajjar, W M; Bin Abdulqader, S A; Aldayel, S S; Alfardan, A W; Alzaidy, N I

2016-09-01

Organ transplantation is the optimal treatment for end-stage organ diseases. The demand for organs has exceeded the available supply, which becomes a major obstacle worldwide. Identifying the factors affecting this gap will help in overcoming this obstacle. The purpose of the work was to study the knowledge, attitudes, and beliefs of organ donation and to determine the knowledge of brain death among social media users. A cross-sectional study was conducted among social media users living in Saudi Arabia. A pre-designed self-administrated questionnaire was distributed online randomly on social media networks in 2015. Of the total 1368 participants, only 913 met the criteria. Most respondents were between 18 and 29 years of age (61.2%) and living in the central region of Saudi Arabia (64.5%). The majority of respondents received their information from television (57%) and social media (50%) networks; 46.4% of respondents knew that the religious fatwa allowed organ donation; 51% of respondents were willing to donate their organs; 46.5% considered the brain-dead to be deceased, whereas 37.7% considered it a coma; 33.3% did not know if someone who was brain-dead would ever wake up; on the other hand, 323 (35.4%) said yes. Our study showed that the vast majority of our sample had enough information about organ donation. On the contrary, they had minimal knowledge about brain death. Moreover, a fair percentage of the participants had positive attitudes toward organ donation. Also, the media had a significant effect on the information about organ donation and brain death. Copyright © 2016 Elsevier Inc. All rights reserved.

Incidence and impact of withdrawal of life-sustaining therapies in clinical trials of severe traumatic brain injury: A systematic review.

PubMed

Leblanc, Guillaume; Boutin, Amélie; Shemilt, Michèle; Lauzier, François; Moore, Lynne; Potvin, Véronique; Zarychanski, Ryan; Archambault, Patrick; Lamontagne, François; Léger, Caroline; Turgeon, Alexis F

2018-06-01

Background Most deaths following severe traumatic brain injury follow decisions to withdraw life-sustaining therapies. However, the incidence of the withdrawal of life-sustaining therapies and its potential impact on research data interpretation have been poorly characterized. The aim of this systematic review was to assess the reporting and the impact of withdrawal of life-sustaining therapies in randomized clinical trials of patients with severe traumatic brain injury. Methods We searched Medline, Embase, Cochrane Central, BIOSIS, and CINAHL databases and references of included trials. All randomized controlled trials published between January 2002 and August 2015 in the six highest impact journals in general medicine, critical care medicine, and neurocritical care (total of 18 journals) were considered for eligibility. Randomized controlled trials were included if they enrolled adult patients with severe traumatic brain injury (Glasgow Coma Scale ≤ 8) and reported data on mortality. Our primary objective was to assess the proportion of trials reporting the withdrawal of life-sustaining therapies in a publication. Our secondary objectives were to describe the overall mortality rate, the proportion of deaths following the withdrawal of life-sustaining therapies, and to assess the impact of the withdrawal of life-sustaining therapies on trial results. Results From 5987 citations retrieved, we included 41 randomized trials (n = 16,364, ranging from 11 to 10,008 patients). Overall mortality was 23% (range = 3%-57%). Withdrawal of life-sustaining therapies was reported in 20% of trials (8/41, 932 patients in trials) and the crude number of deaths due to the withdrawal of life-sustaining therapies was reported in 17% of trials (7/41, 884 patients in trials). In these trials, 63% of deaths were associated with the withdrawal of life-sustaining therapies (105/168). An analysis carried out by imputing a 4% differential rate in instances of withdrawal of life-sustaining therapies between study groups yielded different results and conclusions in one third of the trials. Conclusion Data on the withdrawal of life-sustaining therapies are incompletely reported in randomized controlled trials of patients with severe traumatic brain injury. Given the high proportion of deaths due to the withdrawal of life-sustaining therapies in severe traumatic brain injury patients, and the potential of this medical decision to influence the results of clinical trials, instances of withdrawal of life-sustaining therapies should be systematically reported in clinical trials in this group of patients.

Non-thermal irreversible electroporation (N-TIRE) and adjuvant fractionated radiotherapeutic multimodal therapy for intracranial malignant glioma in a canine patient.

PubMed

Garcia, P A; Pancotto, T; Rossmeisl, J H; Henao-Guerrero, N; Gustafson, N R; Daniel, G B; Robertson, J L; Ellis, T L; Davalos, R V

2011-02-01

Non-thermal irreversible electroporation (N-TIRE) has shown promise as an ablative therapy for a variety of soft-tissue neoplasms. Here we describe the therapeutic planning aspects and first clinical application of N-TIRE for the treatment of an inoperable, spontaneous malignant intracranial glioma in a canine patient. The N-TIRE ablation was performed safely, effectively reduced the tumor volume and associated intracranial hypertension, and provided sufficient improvement in neurological function of the patient to safely undergo adjunctive fractionated radiotherapy (RT) according to current standards of care. Complete remission was achieved based on serial magnetic resonance imaging examinations of the brain, although progressive radiation encephalopathy resulted in the death of the dog 149 days after N-TIRE therapy. The length of survival of this patient was comparable to dogs with intracranial tumors treated via standard excisional surgery and adjunctive fractionated external beam RT. Our results illustrate the potential benefits of N-TIRE for in vivo ablation of undesirable brain tissue, especially when traditional methods of cytoreductive surgery are not possible or ideal, and highlight the potential radiosensitizing effects of N-TIRE on the brain.

Non-Thermal Irreversible Electroporation (N-TIRE) and Adjuvant Fractionated Radiotherapeutic Multimodal Therapy for Intracranial Malignant Glioma in a Canine Patient

PubMed Central

Garcia, P. A.; Pancotto, T.; Rossmeisl, J. H.; Henao-Guerrero, N.; Gustafson, N. R.; Daniel, G. B.; Robertson, J. L.; Ellis, T. L.; Davalos, R. V.

2011-01-01

Non-thermal irreversible electroporation (N-TIRE) has shown promise as an ablative therapy for a variety of soft-tissue neoplasms. Here we describe the therapeutic planning aspects and first clinical application of N-TIRE for the treatment of an inoperable, spontaneous malignant intracranial glioma in a canine patient. The N-TIRE ablation was performed safely, effectively reduced the tumor volume and associated intracranial hypertension, and provided sufficient improvement in neurological function of the patient to safely undergo adjunctive fractionated radiotherapy (RT) according to current standards of care. Complete remission was achieved based on serial magnetic resonance imaging examinations of the brain, although progressive radiation encephalopathy resulted in the death of the dog 149 days after N-TIRE therapy. The length of survival of this patient was comparable to dogs with intracranial tumors treated via standard excisional surgery and adjunctive fractionated external beam RT. Our results illustrate the potential benefits of N-TIRE for in vivo ablation of undesirable brain tissue, especially when traditional methods of cytoreductive surgery are not possible or ideal, and highlight the potential radiosensitizing effects of N-TIRE on the brain. PMID:21214290

Microglia During Development and Aging

PubMed Central

Harry, G. Jean

2013-01-01

Microglia are critical nervous system-specific cells influencing brain development, maintenance of the neural environment, response to injury, and repair. They contribute to neuronal proliferation and differentiation, pruning of dying neurons, synaptic remodeling and clearance of debris and aberrant proteins. Colonization of the brain occurs during gestation with an expansion following birth with localization stimulated by programmed neuronal death, synaptic pruning, andaxonal degeneration. Changes inmicroglia phenotype relate to cellular processes including specific neurotransmitter, pattern recognition, or immune-related receptor activation. Upon activation, microglia cells have the capacity to release a number of substances, e.g., cytokines, chemokines, nitric oxide, and reactive oxygen species, which could be detrimental or beneficial to the surrounding cells. With aging, microglia shift their morphology and may display diminished capacity for normal functions related to migration, clearance, and the ability to shift from a pro-inflammatory to an anti-inflammatory state to regulate injury and repair. This shift in microgliapotentially contributes to increased susceptibility and neurodegeneration as a function of age. In the current review, information is provided on the colonization of the brain by microglia, the expression of various pattern recognition receptors to regulate migration and phagocytosis, and the shift in related functions that occur in normal aging. PMID:23644076

Amyloid-clearing proteins and their epigenetic regulation as a therapeutic target in Alzheimer’s disease

PubMed Central

Nalivaeva, Natalia N.; Belyaev, Nikolai D.; Kerridge, Caroline; Turner, Anthony J.

2014-01-01

Abnormal elevation of amyloid β-peptide (Aβ) levels in the brain is the primary trigger for neuronal cell death specific to Alzheimer’s disease (AD). It is now evident that Aβ levels in the brain are manipulable due to a dynamic equilibrium between its production from the amyloid precursor protein (APP) and removal by amyloid clearance proteins. Clearance can be either enzymic or non-enzymic (binding/transport proteins). Intriguingly several of the main amyloid-degrading enzymes (ADEs) are members of the M13 peptidase family (neprilysin (NEP), NEP2 and the endothelin converting enzymes (ECE-1 and -2)). A distinct metallopeptidase, insulin-degrading enzyme (IDE), also contributes to Aβ degradation in the brain. The ADE family currently embraces more than 20 members, both membrane-bound and soluble, and of differing cellular locations. NEP plays an important role in brain function terminating neuropeptide signals. Its decrease in specific brain areas with age or after hypoxia, ischaemia or stroke contribute significantly to the development of AD pathology. The recently discovered mechanism of epigenetic regulation of NEP (and other genes) by the APP intracellular domain (AICD) and its dependence on the cell type and APP isoform expression suggest possibilities for selective manipulation of NEP gene expression in neuronal cells. We have also observed that another amyloid-clearing protein, namely transthyretin (TTR), is also regulated in the neuronal cell by a mechanism similar to NEP. Dependence of amyloid clearance proteins on histone deacetylases and the ability of HDAC inhibitors to up-regulate their expression in the brain opens new avenues for developing preventive strategies in AD. PMID:25278875

Role of the ubiquitin-proteasome system in brain ischemia: friend or foe?

PubMed

Caldeira, Margarida V; Salazar, Ivan L; Curcio, Michele; Canzoniero, Lorella M T; Duarte, Carlos B

2014-01-01

The ubiquitin-proteasome system (UPS) is a catalytic machinery that targets numerous cellular proteins for degradation, thus being essential to control a wide range of basic cellular processes and cell survival. Degradation of intracellular proteins via the UPS is a tightly regulated process initiated by tagging a target protein with a specific ubiquitin chain. Neurons are particularly vulnerable to any change in protein composition, and therefore the UPS is a key regulator of neuronal physiology. Alterations in UPS activity may induce pathological responses, ultimately leading to neuronal cell death. Brain ischemia triggers a complex series of biochemical and molecular mechanisms, such as an inflammatory response, an exacerbated production of misfolded and oxidized proteins, due to oxidative stress, and the breakdown of cellular integrity mainly mediated by excitotoxic glutamatergic signaling. Brain ischemia also damages protein degradation pathways which, together with the overproduction of damaged proteins and consequent upregulation of ubiquitin-conjugated proteins, contribute to the accumulation of ubiquitin-containing proteinaceous deposits. Despite recent advances, the factors leading to deposition of such aggregates after cerebral ischemic injury remain poorly understood. This review discusses the current knowledge on the role of the UPS in brain function and the molecular mechanisms contributing to UPS dysfunction in brain ischemia with consequent accumulation of ubiquitin-containing proteins. Chemical inhibitors of the proteasome and small molecule inhibitors of deubiquitinating enzymes, which promote the degradation of proteins by the proteasome, were both shown to provide neuroprotection in brain ischemia, and this apparent contradiction is also discussed in this review. Copyright © 2013 Elsevier Ltd. All rights reserved.

An explanation and analysis of how world religions formulate their ethical decisions on withdrawing treatment and determining death.

PubMed

Setta, Susan M; Shemie, Sam D

2015-03-11

This paper explores definitions of death from the perspectives of several world and indigenous religions, with practical application for health care providers in relation to end of life decisions and organ and tissue donation after death. It provides background material on several traditions and explains how different religions derive their conclusions for end of life decisions from the ethical guidelines they proffer. Research took several forms beginning with a review of books and articles written by ethicists and observers of Bön, Buddhism, Christianity, Hinduism, Indigenous Traditions, Islam, Judaism, Shinto and Taoism. It then examined sources to which these authors referred in footnotes and bibliographies. In addition, material was gathered through searches of data bases in religious studies, general humanities, social sciences and medicine along with web-based key word searches for current policies in various traditions. Religious traditions provide their adherents with explanations for the meaning and purpose of life and include ethical analysis for the situations in which their followers find themselves. This paper aims to increase cultural competency in practitioners by demonstrating the reasoning process religions use to determine what they believe to be the correct decision in the face of death. Patterns emerge in the comparative study of religious perspectives on death. Western traditions show their rootedness in Judaism in their understanding of the human individual as a finite, singular creation. Although the many branches of Western religions do not agree on precisely how to determine death, they are all able to locate a moment of death in the body. In Eastern traditions personhood is not defined in physical terms. From prescribing the location of death, to resisting medical intervention and definitions of death, Eastern religions, in their many forms, incorporate the beliefs and practices that preceded them. Adding to the complexity for these traditions is the idea that death is a process that continues after the body has met most empirical criteria for determining death. For Hinduism and Buddhism, the cessation of heart, brain and lung function is the beginning of the process of dying--not the end.

The ethics of extracorporeal membrane oxygenation in brain-dead potential organ donors.

PubMed

Dalle Ave, Anne L; Gardiner, Dale; Shaw, David M

2016-05-01

Organ-preserving extracorporeal membrane oxygenation (OP-ECMO) is defined as the use of extracorporeal support for the primary purpose of preserving organs for transplantation, rather than to save the patient's life. This paper discusses the ethics of using OP-ECMO in donation after brain determination of death (DBDD) to avoid the loss of organs for transplantation. We review case reports in the literature and analyze the ethical issues raised. We conclude that there is little additional ethical concern in continuing OP-ECMO in patients already on ECMO if they become brain dead. The implementation of OP-ECMO in hemodynamically unstable brain-dead patients is ethically permissible in certain clinical situations but requires specific consent from relatives if the patient's wish to donate is not clear. If no evidence of a patient's wish to donate is available, OP-ECMO is not recommended. In countries with presumed consent legislation, failure to opt out should be considered as a positive wish to donate. If a patient is not-yet brain-dead or is undergoing testing for brain death, OP-ECMO is not recommended. Further research on OP-ECMO is needed to better understand the attitudes of professionals, families, and lay people to ensure agreement on key ethical issues. © 2016 Steunstichting ESOT.

Characterization of uniaxial high-speed stretch as an in vitro model of mild traumatic brain injury on the blood-brain barrier.

PubMed

Rosas-Hernandez, Hector; Cuevas, Elvis; Escudero-Lourdes, Claudia; Lantz, Susan M; Sturdivant, Nasya M; Imam, Syed Z; Sarkar, Sumit; Slikker, William; Paule, Merle G; Balachandran, Kartik; Ali, Syed F

2018-04-13

Traumatic brain injury (TBI) occurs when external mechanical forces induce brain damage as result of impact, penetration or rapid acceleration/deceleration that causes deformation of brain tissue. Depending on its severity, TBI can be classified as mild, moderate or severe and can lead to blood-brain barrier (BBB) dysfunction. In the present study, we evaluated the effects of uniaxial high-speed stretch (HSS) at 0, 5, 10 and 15% on a pure culture of primary rat brain endothelial cells as an in vitro model of TBI to the BBB. LDH release, viability and apoptosis analysis, expression of tight junction proteins and endothelial permeability were evaluated 24 h after a single stretch episode. HSS slightly increased cell death and apoptosis at 10 and 15%, while LDH release was increased only at 15% stretch. Occludin expression was increased at 10% stretch, while claudin-5 expression was increased at 5% stretch, which also decreased the endothelial permeability. In summary, 15% HSS induced low levels of cell death, consistent with mild TBI and very low percentages of HSS (5%) enhanced the BBB properties, promoting the formation of a stronger barrier. These data support the use of 15% HSS as valuable tool in the study of mild TBI to the BBB in vitro. Published by Elsevier B.V.

Vulnerability of children and the developing brain to neurotoxic hazards.

PubMed

Weiss, B

2000-06-01

For much of the history of toxicology, the sensitivity of the developing organism to chemical perturbation attracted limited attention. Several tragic episodes and new insights finally taught us that the course of early brain development incurs unique risks. Although the process is exquisitely controlled, its lability renders it highly susceptible to damage from environmental chemicals. Such disturbances, as recognized by current testing protocols and legislation such as the Food Quality Protection Act, can result in outcomes ranging from death to malformations to functional impairment. The latter are the most difficult to determine. First, they require a variety of measures to assay their extent. Second, adult responses may prove an inadequate guide to the response of the developing brain, which is part of the reason for proposing additional safety factors for children. Third, neuropsychological tests are deployed in complex circumstances in which many factors, including economic status, combine to produce a particular effect such as lowered intelligence quotient score. Fourth, the magnitude of the effect, for most environmental exposure levels, may be relatively small but extremely significant for public health. Fifth, changes in brain function occur throughout life, and some consequences of early damage may not even emerge until advanced age. Such factors need to be addressed in estimating the influence of a particular agent or group of agents on brain development and its functional expression. It is especially important to consider ways of dealing with multiple risks and their combinations in addition to the prevailing practice of estimating risks in isolation.

Blast overpressure in rats: recreating a battlefield injury in the laboratory.

PubMed

Long, Joseph B; Bentley, Timothy L; Wessner, Keith A; Cerone, Carolyn; Sweeney, Sheena; Bauman, Richard A

2009-06-01

Blast injury to the brain is the predominant cause of neurotrauma in current military conflicts, and its etiology is largely undefined. Using a compression-driven shock tube to simulate blast effects, we assessed the physiological, neuropathological, and neurobehavioral consequences of airblast exposure, and also evaluated the effect of a Kevlar protective vest on acute mortality in rats and on the occurrence of traumatic brain injury (TBI) in those that survived. This approach provides survivable blast conditions under which TBI can be studied. Striking neuropathological changes were caused by both 126- and 147-kPa airblast exposures. The Kevlar vest, which encased the thorax and part of the abdomen, greatly reduced airblast mortality, and also ameliorated the widespread fiber degeneration that was prominent in brains of rats not protected by a vest during exposure to a 126-kPa airblast. This finding points to a significant contribution of the systemic effects of airblast to its brain injury pathophysiology. Airblast of this intensity also disrupted neurologic and neurobehavioral performance (e.g., beam walking and spatial navigation acquisition in the Morris water maze). When immediately followed by hemorrhagic hypotension, with MAP maintained at 30 mm Hg, airblast disrupted cardiocompensatory resilience, as reflected by reduced peak shed blood volume, time to peak shed blood volume, and time to death. These findings demonstrate that shock tube-generated airblast can cause TBI in rats, in part through systemic mediation, and that the resulting brain injury significantly impacts acute cardiovascular homeostatic mechanisms as well as neurobehavioral function.

Sugar for the brain: the role of glucose in physiological and pathological brain function.

PubMed

Mergenthaler, Philipp; Lindauer, Ute; Dienel, Gerald A; Meisel, Andreas

2013-10-01

The mammalian brain depends upon glucose as its main source of energy, and tight regulation of glucose metabolism is critical for brain physiology. Consistent with its critical role for physiological brain function, disruption of normal glucose metabolism as well as its interdependence with cell death pathways forms the pathophysiological basis for many brain disorders. Here, we review recent advances in understanding how glucose metabolism sustains basic brain physiology. We synthesize these findings to form a comprehensive picture of the cooperation required between different systems and cell types, and the specific breakdowns in this cooperation that lead to disease. Copyright © 2013 Elsevier Ltd. All rights reserved.

Hyperbaric oxygen therapy can improve post concussion syndrome years after mild traumatic brain injury - randomized prospective trial.

PubMed

Boussi-Gross, Rahav; Golan, Haim; Fishlev, Gregori; Bechor, Yair; Volkov, Olga; Bergan, Jacob; Friedman, Mony; Hoofien, Dan; Shlamkovitch, Nathan; Ben-Jacob, Eshel; Efrati, Shai

2013-01-01

Traumatic brain injury (TBI) is the leading cause of death and disability in the US. Approximately 70-90% of the TBI cases are classified as mild, and up to 25% of them will not recover and suffer chronic neurocognitive impairments. The main pathology in these cases involves diffuse brain injuries, which are hard to detect by anatomical imaging yet noticeable in metabolic imaging. The current study tested the effectiveness of Hyperbaric Oxygen Therapy (HBOT) in improving brain function and quality of life in mTBI patients suffering chronic neurocognitive impairments. The trial population included 56 mTBI patients 1-5 years after injury with prolonged post-concussion syndrome (PCS). The HBOT effect was evaluated by means of prospective, randomized, crossover controlled trial: the patients were randomly assigned to treated or crossover groups. Patients in the treated group were evaluated at baseline and following 40 HBOT sessions; patients in the crossover group were evaluated three times: at baseline, following a 2-month control period of no treatment, and following subsequent 2-months of 40 HBOT sessions. The HBOT protocol included 40 treatment sessions (5 days/week), 60 minutes each, with 100% oxygen at 1.5 ATA. "Mindstreams" was used for cognitive evaluations, quality of life (QOL) was evaluated by the EQ-5D, and changes in brain activity were assessed by SPECT imaging. Significant improvements were demonstrated in cognitive function and QOL in both groups following HBOT but no significant improvement was observed following the control period. SPECT imaging revealed elevated brain activity in good agreement with the cognitive improvements. HBOT can induce neuroplasticity leading to repair of chronically impaired brain functions and improved quality of life in mTBI patients with prolonged PCS at late chronic stage. ClinicalTrials.gov NCT00715052.

Improved tumor identification using dual tracer molecular imaging in fluorescence guided brain surgery

NASA Astrophysics Data System (ADS)

Xu, Xiaochun; Torres, Veronica; Straus, David; Brey, Eric M.; Byrne, Richard W.; Tichauer, Kenneth M.

2015-03-01

Brain tumors represent a leading cause of cancer death for people under the age of 40 and the probability complete surgical resection of brain tumors remains low owing to the invasive nature of these tumors and the consequences of damaging healthy brain tissue. Molecular imaging is an emerging approach that has the potential to improve the ability for surgeons to correctly discriminate between healthy and cancerous tissue; however, conventional molecular imaging approaches in brain suffer from significant background signal in healthy tissue or an inability target more invasive sections of the tumor. This work presents initial studies investigating the ability of novel dual-tracer molecular imaging strategies to be used to overcome the major limitations of conventional "single-tracer" molecular imaging. The approach is evaluated in simulations and in an in vivo mice study with animals inoculated orthotopically using fluorescent human glioma cells. An epidermal growth factor receptor (EGFR) targeted Affibody-fluorescent marker was employed as a targeted imaging agent, and the suitability of various FDA approved untargeted fluorescent tracers (e.g. fluorescein & indocyanine green) were evaluated in terms of their ability to account for nonspecific uptake and retention of the targeted imaging agent. Signal-to-background ratio was used to measure and compare the amount of reporter in the tissue between targeted and untargeted tracer. The initial findings suggest that FDA-approved fluorescent imaging agents are ill-suited to act as untargeted imaging agents for dual-tracer fluorescent guided brain surgery as they suffer from poor delivery to the healthy brain tissue and therefore cannot be used to identify nonspecific vs. specific uptake of the targeted imaging agent where current surgery is most limited.

Nitrobenzodiazepines: Postmortem brain and blood reference concentrations.

PubMed

Skov, Louise; Holm, Karen Marie Dollerup; Linnet, Kristian

2016-11-01

Reference concentrations are needed to evaluate postmortem toxicology results and usually femoral blood is the specimen of choice. However, brain tissue has been suggested as a viable alternative specimen, since postmortem blood concentrations can be difficult to interpret due to postmortem redistribution, among other factors. Here we present reference concentrations of postmortem brain and femoral blood of the nitrobenzodiazepines clonazepam, flunitrazepam, and nitrazepam that are of particular interest since they commonly are converted to their corresponding 7-aminometabolites in the postmortem situation. The drugs and metabolites were quantified in both matrices using LC-MS-MS in 69 cases. In 63 cases the compounds were judged not to have been of significance for the death (C cases), whereas they were considered to have been a contributing factor in 6 cases (B cases). No cases were observed with a nitrobenzodiazepine being the sole cause of death (A cases). The brain-blood ratios for clonazepam and nitrazepam were 5.5 and 4.7, respectively, while the brain-blood ratios for the 7-aminometabolites ranged from 0.4 to 0.5. Flunitrazepam only occurred as the 7-aminometabolite. A positive correlation between brain and blood concentrations was found with Spearman's rank correlation coefficients (r s ) ranging from 0.77 to 0.96. The measured femoral blood concentrations agree with literature values, but only few brain concentrations were available for comparison. The drug-metabolite ratios for clonazepam and nitrazepam were 10-12 times higher in brain than in blood. The pre-analytical variation in brain of 5.9% was fairly low, suggesting that brain tissue is a useful alternative to blood. The reported brain and femoral blood concentrations serve as reference values in postmortem investigations. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Dietary and plant polyphenols exert neuroprotective effects and improve cognitive function in cerebral ischemia

USDA-ARS?s Scientific Manuscript database

Cerebral ischemia is caused by an interruption of blood flow to the brain which generally leads to irreversible brain damage. Ischemic injury is associated with vascular leakage, inflammation, tissue injury, and cell death. Cellular changes associated with ischemia include impairment of metabolism, ...

Matrix Metalloproteinase-9 Mediates the Deleterious Effects of α2-Antiplasmin on Blood-Brain Barrier Breakdown and Ischemic Brain Injury in Experimental Stroke.

PubMed

Singh, Satish; Houng, Aiilyan K; Reed, Guy L

2018-04-15

During acute brain ischemia, α2-antiplasmin markedly enhances brain injury, blood-brain barrier breakdown and matrix metalloproteinase-9 (MMP-9) expression. Although α2-antiplasmin inhibits fibrin thrombus-degradation, and MMP-9 is a collagen-degrading enzyme altering blood-brain barrier, both have similar deleterious effects on the ischemic brain. We examined the hypothesis that MMP-9 is an essential downstream mediator of α2-antiplasmin's deleterious effects during brain ischemia. Middle cerebral artery thromboembolic stroke was induced in a randomized, blinded fashion in mice with increased blood levels of α2-antiplasmin. There was a robust increase in MMP-9 expression (immunofluorescence) in the ischemic vs. the non-ischemic hemisphere of MMP-9 +/+ but not MMP-9 -/- mice, 24 h after stroke. Brain swelling and hemorrhage were significantly increased in the ischemic vs. the non-ischemic hemisphere of MMP-9 +/+ mice. By comparison to MMP-9 +/+ mice, the ischemic hemispheres of MMP-9 -/- mice showed a ∼6-fold reduction in brain swelling (p < 0.001) and a ∼9-fold reduction in brain hemorrhage. Brain infarction (p < 0.0001) and TUNEL-positive cell death (p < 0.001) were significantly diminished in the ischemic hemisphere of MMP-9 -/- mice vs. MMP-9 +/+ mice. Ischemic breakdown of the blood-brain barrier and fibrin deposition were also significantly reduced in MMP-9 -/- mice vs. MMP-9 +/+ mice (p < 0.05), as measured by quantitative immunofluorescence. We conclude that MMP-9 deficiency ablates many of the deleterious effects of high α2-antiplasmin levels, significantly reducing blood-brain barrier breakdown, TUNEL-positive cell death, brain hemorrhage, swelling and infarction. This suggests that the two molecules may be in a shared pathway in which MMP-9 is essential downstream for the deleterious effects of α2-antiplasmin in ischemic stroke. Copyright © 2018 IBRO. Published by Elsevier Ltd. All rights reserved.

Mortality in US Army Gulf War Veterans Exposed to 1991 Khamisiyah Chemical Munitions Destruction

PubMed Central

Bullman, Tim A.; Mahan, Clare M.; Kang, Han K.; Page, William F.

2005-01-01

Objectives. We investigated whether US Army Gulf War veterans who were potentially exposed to nerve agents during the March 1991 weapons demolitions at Khamisiyah, Iraq, are at increased risk of cause-specific mortality. Methods. The cause-specific mortality of 100487 exposed US Army Gulf War veterans was compared with that of 224980 unexposed US Army Gulf War veterans. Exposure was determined with the Department of Defense 2000 plume model. Relative risk estimates were derived from Cox proportional hazards models. Results. The risks of most disease-related mortality were similar for exposed and unexposed veterans. However, exposed veterans had an increased risk of brain cancer deaths (relative risk [RR]=1.94; 95% confidence interval [CI]=1.12, 3.34). The risk of brain cancer death was larger among those exposed 2 or more days than those exposed 1 day when both were compared separately to all unexposed veterans (RR=3.26; 95% CI=1.33, 7.96; RR=1.72; 95% CI=0.95,3.10, respectively). Conclusions. Exposure to chemical munitions at Khamisiyah may be associated with an increased risk of brain cancer death. Additional research is required to confirm this finding. PMID:16043669

Mortality in US Army Gulf War veterans exposed to 1991 Khamisiyah chemical munitions destruction.

PubMed

Bullman, Tim A; Mahan, Clare M; Kang, Han K; Page, William F

2005-08-01

We investigated whether US Army Gulf War veterans who were potentially exposed to nerve agents during the March 1991 weapons demolitions at Khamisiyah, Iraq, are at increased risk of cause-specific mortality. The cause-specific mortality of 100487 exposed US Army Gulf War veterans was compared with that of 224980 unexposed US Army Gulf War veterans. Exposure was determined with the Department of Defense 2000 plume model. Relative risk estimates were derived from Cox proportional hazards models. The risks of most disease-related mortality were similar for exposed and unexposed veterans. However, exposed veterans had an increased risk of brain cancer deaths (relative risk [RR]=1.94; 95% confidence interval [CI]=1.12, 3.34). The risk of brain cancer death was larger among those exposed 2 or more days than those exposed 1 day when both were compared separately to all unexposed veterans (RR=3.26; 95% CI=1.33, 7.96; RR=1.72; 95% CI=0.95,3.10, respectively). Exposure to chemical munitions at Khamisiyah may be associated with an increased risk of brain cancer death. Additional research is required to confirm this finding.

Ethical and legal issues in donation after cardiac death in Italy.

PubMed

Bruzzone, P

2010-05-01

In Italy death of a human being must be declared either after brain death or after 20 minutes of cardiac arrest, certified by continuous electrocardiography (EKG) recording. It is my personal opinion that in such circumstances after cardiac death (DCD) will allow at best only the retrieval of few marginal kidneys and some tissues, and therefore will not be very helpful for our waiting list patients. I suggest instead modifying first the Italian law in order to be able to declare cardiac death after only 5 minutes of cardiac arrest, certified by continuous EKG recording. Copyright (c) 2010 Elsevier Inc. All rights reserved.

Sudden infant death syndrome caused by poliomyelitis.

PubMed

Dunne, J W; Harper, C G; Hilton, J M

1984-07-01

Most seemingly well infants who die suddenly and unexpectedly have no adequate cause of death found on thorough postmortem examination. Respiratory and enteric viruses are often present, especially in the upper respiratory tract, but the infective process seems, of itself, insufficient to cause death. In the remainder of the cases, a variety of lesions will be discovered, including viral myocarditis, bronchiolitis, and sepsis. We report a case of sudden and unexpected death in a 5-week-old male infant due to acute anterior poliomyelitis. This case illustrates the importance of a thorough postmortem examination, including histologic studies of the brain stem and spinal cord in cases of sudden infant death syndrome.

[Hypopituitarism following traumatic brain injury: diagnostic and therapeutic issues].

PubMed

Lecoq, A-L; Chanson, P

2015-10-01

Traumatic Brain Injury (TBI) is a well-known public health problem worldwide and is a leading cause of death and disability, particularly in young adults. Besides neurological and psychiatric issues, pituitary dysfunction can also occur after TBI, in the acute or chronic phase. The exact prevalence of post-traumatic hypopituitarism is difficult to assess due to the wide heterogeneity of published studies and bias in interpretation of hormonal test results in this specific population. Predictive factors for hypopituitarism have been proposed and are helpful for the screening. The pathophysiology of pituitary dysfunction after TBI is not well understood but the vascular hypothesis is privileged. Activation of pituitary stem/progenitor cells is probably involved in the recovery of pituitary functions. Those cells also play a role in the induction of pituitary tumors, highlighting their crucial place in pituitary conditions. This review updates the current data related to anterior pituitary dysfunction after TBI and discusses the bias and difficulties encountered in its diagnosis. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Structural Imaging and Parkinson's Disease: Moving Toward Quantitative Markers of Disease Progression.

PubMed

Sterling, N W; Lewis, M M; Du, G; Huang, X

2016-05-27

Parkinson's disease (PD) is a progressive age-related neurodegenerative disorder. Although the pathological hallmark of PD is dopaminergic cell death in the substantia nigra pars compacta, widespread neurodegenerative changes occur throughout the brain as disease progresses. Postmortem studies, for example, have demonstrated the presence of Lewy pathology, apoptosis, and loss of neurotransmitters and interneurons in both cortical and subcortical regions of PD patients. Many in vivo structural imaging studies have attempted to gauge PD-related pathology, particularly in gray matter, with the hope of identifying an imaging biomarker. Reports of brain atrophy in PD, however, have been inconsistent, most likely due to differences in the studied populations (i.e. different disease stages and/or clinical subtypes), experimental designs (i.e. cross-sectional vs. longitudinal), and image analysis methodologies (i.e. automatic vs. manual segmentation). This review attempts to summarize the current state of gray matter structural imaging research in PD in relationship to disease progression, reconciling some of the differences in reported results, and to identify challenges and future avenues.

Suppression of the motor deficit in a mucolipidosis type IV mouse model by bone marrow transplantation

PubMed Central

Walker, Marquis T.; Montell, Craig

2016-01-01

Mucolipidosis IV (MLIV) is a severe lysosomal storage disorder, which results from loss of the TRPML1 channel. MLIV causes multiple impairments in young children, including severe motor deficits. Currently, there is no effective treatment. Using a Drosophila MLIV model, we showed previously that introduction of trpml+ in phagocytic glia rescued the locomotor deficit by removing early dying neurons, thereby preventing amplification of neuronal death from cytotoxicity. Because microglia, which are phagocytic cells in the mammalian brain, are bone marrow derived, and cross the blood–brain barrier, we used a mouse MLIV model to test the efficacy of bone marrow transplantation (BMT). We found that BMT suppressed the reduced myelination and the increased caspase-3 activity due to loss of TRPML1. Using a rotarod test, we demonstrated that early BMT greatly delayed the motor impairment in the mutant mice. These data offer the possibility that BMT might provide the first therapy for MLIV. PMID:27270598

Caffeine Augments Anesthesia Neurotoxicity in the Fetal Macaque Brain.

PubMed

Noguchi, Kevin K; Johnson, Stephen A; Manzella, Francesca M; Masuoka, Kobe L; Williams, Sasha L; Martin, Lauren D; Dissen, Gregory A; Ikonomidou, Chrysanthy; Schenning, Katie J; Olney, John W; Brambrink, Ansgar M

2018-03-28

Caffeine is the most frequently used medication in premature infants. It is the respiratory stimulant of choice for apnea associated with prematurity and has been called the silver bullet in neonatology because of many proven benefits and few known risks. Research has revealed that sedative/anesthetic drugs trigger apoptotic death of neurons and oligodendrocytes in developing mammalian brains. Here we evaluated the influence of caffeine on the neurotoxicity of anesthesia in developing nonhuman primate brains. Fetal macaques (n = 7-8/group), at a neurodevelopmental age comparable to premature human infants, were exposed in utero for 5 hours to no drug (control), isoflurane, or isoflurane + caffeine and examined for evidence of apoptosis. Isoflurane exposure increased apoptosis 3.3 fold for neurons and 3.4 fold for oligodendrocytes compared to control brains. Isoflurane + caffeine caused neuronal apoptosis to increase 8.0 fold compared to control levels but did not augment oligoapoptosis. Neuronal death was particularly pronounced in the basal ganglia and cerebellum. Higher blood levels of caffeine within the range considered therapeutic and safe for human infants correlated with increased neuroapoptosis. Caffeine markedly augments neurotoxicity of isoflurane in the fetal macaque brain and challenges the assumption that caffeine is safe for premature infants.

Glucose and oxygen metabolism after penetrating ballistic-like brain injury

PubMed Central

Gajavelli, Shyam; Kentaro, Shimoda; Diaz, Julio; Yokobori, Shoji; Spurlock, Markus; Diaz, Daniel; Jackson, Clayton; Wick, Alexandra; Zhao, Weizhao; Leung, Lai Y; Shear, Deborah; Tortella, Frank; Bullock, M Ross

2015-01-01

Traumatic brain injury (TBI) is a major cause of death and disability in all age groups. Among TBI, penetrating traumatic brain injuries (PTBI) have the worst prognosis and represent the leading cause of TBI-related morbidity and death. However, there are no specific drugs/interventions due to unclear pathophysiology. To gain insights we looked at cerebral metabolism in a PTBI rat model: penetrating ballistic-like brain injury (PBBI). Early after injury, regional cerebral oxygen tension and consumption significantly decreased in the ipsilateral cortex in the PBBI group compared with the control group. At the same time point, glucose uptake was significantly reduced globally in the PBBI group compared with the control group. Examination of Fluorojade B-stained brain sections at 24 hours after PBBI revealed an incomplete overlap of metabolic impairment and neurodegeneration. As expected, the injury core had the most severe metabolic impairment and highest neurodegeneration. However, in the peri-lesional area, despite similar metabolic impairment, there was lesser neurodegeneration. Given our findings, the data suggest the presence of two distinct zones of primary injury, of which only one recovers. We anticipate the peri-lesional area encompassing the PBBI ischemic penumbra, could be salvaged by acute therapies. PMID:25669903

Glucose and oxygen metabolism after penetrating ballistic-like brain injury.

PubMed

Gajavelli, Shyam; Kentaro, Shimoda; Diaz, Julio; Yokobori, Shoji; Spurlock, Markus; Diaz, Daniel; Jackson, Clayton; Wick, Alexandra; Zhao, Weizhao; Leung, Lai Y; Shear, Deborah; Tortella, Frank; Bullock, M Ross

2015-05-01

Traumatic brain injury (TBI) is a major cause of death and disability in all age groups. Among TBI, penetrating traumatic brain injuries (PTBI) have the worst prognosis and represent the leading cause of TBI-related morbidity and death. However, there are no specific drugs/interventions due to unclear pathophysiology. To gain insights we looked at cerebral metabolism in a PTBI rat model: penetrating ballistic-like brain injury (PBBI). Early after injury, regional cerebral oxygen tension and consumption significantly decreased in the ipsilateral cortex in the PBBI group compared with the control group. At the same time point, glucose uptake was significantly reduced globally in the PBBI group compared with the control group. Examination of Fluorojade B-stained brain sections at 24 hours after PBBI revealed an incomplete overlap of metabolic impairment and neurodegeneration. As expected, the injury core had the most severe metabolic impairment and highest neurodegeneration. However, in the peri-lesional area, despite similar metabolic impairment, there was lesser neurodegeneration. Given our findings, the data suggest the presence of two distinct zones of primary injury, of which only one recovers. We anticipate the peri-lesional area encompassing the PBBI ischemic penumbra, could be salvaged by acute therapies.