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At least 127 records · Page 7Linked to original sources

PubMed1997

The time course of developmental cell death in phenotypically defined dopaminergic neurons of the substantia nigra.

We have previously shown that apoptotic natural cell death occurs within the substantia nigra (SN) pars compacta of the rat postnatally. However, the occurrence of natural cell death in phenotypically defined dopaminergic neurons has not previously been identified, nor has its time course been defined in pre- or postnatal development. We therefore examined the SN at intervals from E19 to P28 using immunostaining for tyrosine hydroxylase with a Nissl counterstain to identify intranuclear apoptotic chromatin clumps. We have found that natural cell death in dopaminergic neurons is biphasic. An initial, broad peak begins at E20, reaches maximum at P2, and abates by P8. A second peak occurs at P14. We conclude that most of the natural cell death in this neuronal population occurs in the early postnatal period.

Animals↗

PubMed2001

Philosophical debates about the definition of death: who cares?

Since the Harvard Committee's bold and highly successful attempt to redefine death in 1968 (Harvard Ad Hoc committee, 1968), multiple controversies have arisen. Stimulated by several factors, including the inherent conceptual weakness of the Harvard Committee's proposal, accumulated clinical experience, and the incessant push to expand the pool of potential organ donors, the lively debate about the definition of death has, for the most part, been confined to a relatively small group of academics who have created a large body of literature of which this issue of the Journal of Medicine and Philosophy is an example. Law and public policy, however, have remained essentially unaffected. This paper will briefly review the multiple controversies about defining death in an attempt to explain why they have and will remain unresolved in the academic community and have even less chance of being understood and resolved by politicians, legislators, and the general public. Considering this, we will end by suggesting the probable course of public policy and clinical practice in the decades ahead.

Bioethics↗

PubMed2000

Protection against dopaminergic nigrostriatal cell death by excitatory input ablation.

The importance of enhanced glutamatergic neurotransmission in the basal ganglia and related structures has recently been highlighted in the development of Parkinson's disease. The pedunculopontine tegmental nucleus (PPN) is the major origin of excitatory, glutamatergic input to dopaminergic nigrostriatal neurons of which degeneration is well known to cause Parkinson's disease. Based on the concept that an excitatory mechanism mediated by glutamatergic neurotransmission underlies the pathogenesis of neurodegenerative disorders, we made an attempt to test the hypothesis that removal of the glutamatergic input to the nigrostriatal neurons by PPN lesions might prevent 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism in the macaque monkey. The PPN was lesioned unilaterally with microinjection of kainic acid, and, then, MPTP was administered systemically. In these monkeys, the degree of parkinsonian motor signs was behaviourally evaluated, and the histological changes in the dopaminergic nigrostriatal system were analysed by means of tyrosine hydroxylase immunohistochemistry. The present results revealed that nigrostriatal cell loss and parkinsonian motor deficits were largely attenuated in the MPTP-treated monkey group whose PPN had been lesioned, compared with the control, MPTP-treated monkey group with the PPN intact. This clearly indicates that the onset of MPTP neurotoxicity is suppressed or delayed by experimental ablation of the glutamatergic input to the nigrostriatal neurons. Such a protective action of excitatory input ablation against nigrostriatal cell death defines evidence that nigral excitation driven by the PPN may be implicated in the pathophysiology of Parkinson's disease.

Animals↗

PubMed1998

[Euthanasia of piglets: gas or injection?].

Methods for the humane killing of animals are watched critically by both the public and the veterinary community. Evaluation of such methods requires assessment of efficacy as well as emotional and ethical aspects. Rapidity of loss of consciousness is a crucial factor in such evaluations. In the present study, four methods for piglet euthanasia were compared with regard to presence of indicators of discomfort (pain, anxiety, stress) and rapidity of onset of death, defined as the absence of breathing, heart beats and reflexes, combined with isoelectricity of the electro-encephalogram (EEG). The study was performed on piglets, which had to be destroyed on account of preventive measures against swine fever. The following methods were applied: CO2 98%, CO2/O2 65/35%, T61 and pentobarbital (Euthesate) injected intracardially. Intracardial injections of T61 and pentobarbital provide fast unconsciousness and death with minimal discomfort to the animal.

Administration, Inhalation↗

PubMed2001

Conduction slowing and sudden arrhythmic death in mice with cardiac-restricted inactivation of connexin43.

Cardiac arrhythmia is a common and often lethal manifestation of many forms of heart disease. Gap junction remodeling has been postulated to contribute to the increased propensity for arrhythmogenesis in diseased myocardium, although a causative role in vivo remains speculative. By generating mice with cardiac-restricted knockout of connexin43 (Cx43), we have circumvented the perinatal lethal developmental defect associated with germline inactivation of this gap junction channel gene and uncovered an essential role for Cx43 in the maintenance of electrical stability. Mice with cardiac-specific loss of Cx43 have normal heart structure and contractile function, and yet they uniformly (28 of 28 conditional Cx43 knockout mice observed) develop sudden cardiac death from spontaneous ventricular arrhythmias by 2 months of age. Optical mapping of the epicardial electrical activation pattern in Cx43 conditional knockout mice revealed that ventricular conduction velocity was significantly slowed by up to 55% in the transverse direction and 42% in the longitudinal direction, resulting in an increase in anisotropic ratio compared with control littermates (2.1+/-0.13 versus 1.66+/-0.06; P:<0.01). This novel genetic murine model of primary sudden cardiac death defines gap junctional abnormalities as a key molecular feature of the arrhythmogenic substrate.

Animals↗

PubMedDate not supplied

The role of ecgonine methyl ester in the interpretation of cocaine concentrations in postmortem blood.

A study of the metabolism of in vivo cocaine (COC) and the stability of in vitro COC suggests that the presence of benzoylecgonine (BE) in unpreserved blood arises from in vivo COC metabolism and that ecgonine methyl ester (EME) in unpreserved blood arises from in vitro COC hydrolysis. Postmortem cases positive for COC were studied to determine if molar concentrations of EME in unpreserved blood could be used to estimate the blood COC concentration at the time of death when added to the molar COC concentrations. COC was analyzed in 10 postmortem blood specimens between 1 and 8 days following death and again 10 to 70 days after further storage. The COC lost was accounted for by its hydrolysis to EME. Good correlation (r = 0.9677, p < 0.001) was observed when the blood COC concentrations in postmortem cases were compared to blood COC concentrations predicted by the addition of blood COC and EME concentrations; hence, analysis for EME and estimation of perimortem COC concentrations can assist in defining deaths associated with COC use.

Adolescent↗

PubMed1991

Passive smoking and the risk of heart attack or coronary death.

OBJECTIVES: To estimate the prevalence of passive smoking in an Australian population, the magnitude of risk of myocardial infarction or coronary death associated with passive smoking and the extent to which fibrinogen concentrations might be affected by passive smoking. DESIGN: A population-based case-control study of myocardial infarction or coronary death and passive smoking, and measurement of fibrinogen in a random sample from the same population. SETTING AND PARTICIPANTS: Residents of the Lower Hunter Region of New South Wales aged 35-69 years in 1988-1989. Case subjects were all those who suffered myocardial infarction or coronary death. Control subjects were participants in a risk factor prevalence survey. OUTCOME MEASURES: Myocardial infarction or coronary death, defined by criteria of the WHO MONICA Project, and fibrinogen concentration (measured in controls only). RESULTS: Prevalence of passive smoking at home was 20% for male case subjects, 13% for male control subjects, 29% for female case subjects and 19% for female control subjects. The corresponding prevalence rates for passive smoking at work were 40%, 44%, 41% and 37%. Odds ratios of myocardial infarction or coronary death for active smokers compared with non-smokers were 4.70 (95% confidence interval [CI], 3.35-6.58) in women and 2.71 (95% CI, 2.07-3.53) in men. For women the odds ratios of myocardial infarction or coronary death for those exposed to passive smoking at home were 2.46 (95% CI, 1.47-4.13) among non-smokers and 1.48 (95% CI, 0.67-3.30) among ex-smokers. For men the odds ratios for passive smoking at home were 0.97 (95% CI, 0.50-1.86) for non-smokers and 1.78 (95% CI, 1.13-2.79) for ex-smokers. The odds ratios for passive smoking at work did not suggest increased risk. Fibrinogen concentrations were generally higher among people exposed to passive smoking at home or work compared with those not exposed but were not as high as concentrations in active smokers. CONCLUSIONS: Passive smoking increases the risk of coronary heart disease and increased fibrinogen concentration provides a marker of its effect.

Adult↗

PubMed1992

Brain death-induced impairment of cardiac contractile performance can be reversed by explantation and may not preclude the use of hearts for transplantation.

The shortage of suitable donor hearts for cardiac transplantation is exacerbated by the exclusion of those that exhibit contractile malfunction during the period after brain death but before excision. We have replicated the phenomenon of brain death-induced hemodynamic deterioration in the rat in vivo. After 60 minutes of brain death (defined as the absence of electrical activity in the brain), a variety of indicators of cardiac contractile function fell by approximately 50% (thus cardiac index fell from 21 +/- 2 to 11 +/- 1 ml/min per 100 g body weight). However, once excised and perfused ex vivo, the hearts recovered a level of cardiac function that was identical to that from control animals that had not been subjected to brain death. Similarly, when hearts were excised, stored (6 hours at 4 degrees C), and reperfused ex vivo with blood, they also recovered a functional capability identical to that of normal hearts from animals that had not been subjected to brain death. Our results question whether hemodynamic instability in brain-dead individuals is necessarily an irreversible detrimental cardiac phenomenon and whether these hearts should be excluded from transplantation.

Animals↗

PubMed1993

Apoptosis: a product of programmed and unprogrammed cell death.

Apoptosis is a form of cell death defined by morphological and biochemical characteristics. Although originally described in 1972, it is only very recently that significant interest in the subject has occurred, possibly as a result of the identification of genes that may either positively or negatively regulate the process. With the rapid expansion of knowledge, it has become apparent that there are multiple pathways that induce apoptosis; some of these may represent programmed events but others are clearly unprogrammed. To clarify the terminology used, it is recommended that apoptosis be used as originally defined to refer only to the end product of these pathways. Furthermore, the realization that a cell can die by multiple pathways suggests caution when translating experimental results. Many potential intermediates may be identified but they may represent components of different pathways. Concern for the use of various inhibitors of apoptosis is also presented. Future directions will be aimed at the definitive identification of the signal mechanisms regulating apoptotic cell death.

Animals↗

PubMed1994

Death from inside out: an overview.

Although a type of cell death strategically suited to participating in developmental processes has been well known for nearly thirty years, it is only in the recent past that the extraordinary ubiquity of such death has been appreciated. Apoptosis, a term first employed to describe such death defined in structural terms, is associated with a stereotyped set of effector processes, and is driven by genes most of which are familiar as oncogenes or oncosuppressor genes. Dysregulation of apoptosis leads to diseases of enormous social importance such as cancer and AIDS.

Acquired Immunodeficiency Syndrome↗

PubMed2001

Ventricular arrhythmias in the athlete.

Life-threatening ventricular arrhythmias in the athlete nearly always occur in the presence of structural heart disease. In the last few years, 2 new causes of life-threatening arrhythmias have been described in patients with normal hearts-that of the Brugada syndrome and that of commotio cordis. Non-life-threatening premature ventricular beats and even nonsustained ventricular tachycardia are not rare, and although usually benign, can be secondary to cardiomyopathies. Athletes with symptoms of syncope, especially if exertional, warrant a complete evaluation. The treatment of athletes and other individuals with life-threatening ventricular arrhythmias has been revolutionized by the implantable cardioverter defibrillator, a device that affords excellent protection from sudden death. Defining those athletes who would benefit from the implantable defibrillator is not always clear. Furthermore, participation in competitive athletics for athletes with life-threatening arrhythmias or structural heart disease known to put the athlete at risk for life-threatening arrhythmias is usually prohibited.

Adult↗

PubMed2006

Similar efficacy and safety of enteric-coated mycophenolate sodium (EC-MPS, myfortic) compared with mycophenolate mofetil (MMF) in de novo heart transplant recipients: results of a 12-month, single-blind, randomized, parallel-group, multicenter study.

BACKGROUND: Enteric-coated mycophenolate sodium (EC-MPS, myfortic) is an advanced formulation that delays the release of mycophenolic acid (MPA). Its efficacy and safety has been proven in several clinical trials in renal transplantation. METHODS: In a single-blind, multicenter trial, a total of 154 de novo heart transplant patients were randomized to either EC-MPS 1,080 mg twice daily or mycophenolate mofetil (MMF) 1,500 mg twice daily. Eligible patients included men or women aged 18 to 65 years, undergoing primary heart transplantation, who were treated with cyclosporine microemulsion and corticosteroids as basic immunosuppression. The primary study objective was to investigate the incidence of biopsy-proven and treated acute rejection, graft loss or death (defined as treatment failure) for EC-MPS vs MMF during the first 6 months of treatment in de novo heart transplant recipients. Secondary objectives included assessment of the overall safety and tolerability of EC-MPS vs MMF in the study population. RESULTS: The primary efficacy variable, treatment failure at 6 months, was similar for both treatments: 52.6% for EC-MPS and 57.9% for MMF (2-sided 95% confidence interval [CI]: -21.0% to 10.4%). At 12 months, treatment failure was 57.7% for EC-MPS and 60.5% for MMF (2-sided 95% CI: -18.4 to 12.7), and death and graft loss rate was 5.1% vs 9.2% for EC-MPS and MMF at 12 months, respectively (2-sided 95% CI: -12.2 to 4.1). The overall safety profile was similar for both groups. Significantly more patients on MMF had two or more study medication dose reductions during the treatment period. CONCLUSIONS: These 6- and 12-month results show that EC-MPS is therapeutically similar to MMF in de novo heart transplant recipients and has a comparable safety profile.

Adolescent↗

PubMed1995

Decisions about life-sustaining treatment. Impact of physicians' behaviors on the family.

BACKGROUND: Despite the growing availability of advance directives, most patients in the intensive care unit lack written directives, and, therefore, consultation with families about treatment decisions remains the rule. In the context of decision making about withdrawing life-sustaining treatments, we investigated which physician and nurse behaviors families find supportive and which behaviors increase the family's burden. METHODS: We conducted intensive 1- to 2-hour-long individual interviews using a semistructured interview protocol with 32 family members of patients without advance directives whose deaths followed a stay in the intensive care unit and withdrawal of treatment. We analyzed more than 700 pages of verbatim interview data using content analysis techniques and achieved more than 90% interrater agreement on data codes. RESULTS: Themes emerged as families identified selected physician and nursing behaviors as helpful: encouraging advanced planning, timely communication, clarification of families' roles, facilitating family consensus, and accommodating family's grief. Behaviors that made families feel excluded or increased their burden included postponing discussions about treatment withdrawal, delaying withdrawal once scheduled, placing the full burden of decision making on one person, withdrawing from the family, and defining death as a failure. CONCLUSIONS: Study findings provide an increased understanding of the unmet needs of families and serve to guide physicians and nurses in reducing actions that increase families' burdens as they participate in treatment withdrawal decisions.

Communication↗

PubMed2003

Environmental conditions unexpectedly affect the long-term extent of cell death following an hypoxic episode.

Previously we reported delayed cell death, defined by clear-cut cell loss 60 days after a nitrite-induced hypoxic episode. The loss of cells was not apparent two weeks after the treatment, although some changes in cellular appearance were observed at that time. A similar delayed loss of neurons in the hippocampus after hypoxia induced by blood vessel occlusion has also been found. In addition, we reported that the amount of methemoglobinemia induced by the sodium nitrite can be reduced by the stress produced by handling and the injection of saline 2 or 24 h before the nitrite administration. The degree of methemoglobin formed is directly related to cell death in certain areas of the brain, including regions within the hippocampus. Considering the many effects that can be produced by chronic and acute stress of several kinds and the length of time during which these effects manifest themselves, we undertook to determine the histologic effects of the stresses of transport on the neuroanatomic effects of sodium nitrite administration 60 days post administration. Comparisons were made of the effects of two methods of transport from the laboratory in which the animals (male CD-1 mice) were injected with the sodium nitrite or saline (Tufts Medical School) to the laboratory in which the histologic evaluations were made (Binghamton University). The animals began their travel several hours after the injections. One transport method was by commuter airline and the other was by automobile. All animals had the same transport from the supplier to the Boston location (truck). Thus, the stress of experimental interest occurred after the nitrite administration. Upon arrival at Binghamton University, the animals were housed at the University in their own colony room for 60 days before sacrifice. After sacrifice, sections from their brains were subjected to a number of histologic staining procedures, including PTAH, the Bielschowsky silver method, GFAP, and the standard Nissl procedure. Although special attention was paid to hippocampal areas, changes in cells in the habenulae and the linings of ventricular areas were also prominent. Surprisingly, the nitrite treatment before transport to Binghamton offered partial protection against the very substantial and lasting effects of the injections, transport, and handling found in the control animals. Differential effects caused by the two methods of transport were also noted.

Animals↗

PubMed2002

Mild hypothermia has minimal effects on the tolerance to severe progressive normovolemic anemia in Swine.

BACKGROUND: The benefits of hypothermia during acute severe anemia are not entirely settled. The authors hypothesized that cooling would improve tolerance to anemia. METHODS: Eight normothermic (38.0 +/- 0.5 degrees C) and eight hypothermic (32.0 +/- 0.5 degrees C) pigs anesthetized with midazolam-fentanyl-vecuronium-isoflurane (0.5% inspired concentration) were subjected to stepwise normovolemic hemodilution (hematocrit, 15%, 10%, 7%, 5%, 3%). Critical hemoglobin concentration (Hgb(CRIT)) and critical oxygen delivery (DO(2CRIT)), i.e., the hemoglobin concentration (Hgb) and oxygen delivery (DO2) at which oxygen consumption (VO2, independently measured by indirect calorimetry) was no longer sustained, and Hgb at the moment of death, defined prospectively as the point when VO2, decreased below 40 ml/min, were used to assess the tolerance of the two groups to progressive isovolemic anemia. RESULTS: At hematocrits of 15% and 10% (Hgb, 47 and 31 g/l), VO2 was maintained in both groups by an increase (P < 0.001) in cardiac output (CO) and extraction ratio (ER; P< 0.001) with unchanged mean arterial lactate concentration (L(art)). At hematocrit of 7% (Hgb, 22 g/l), all normothermic but no hypothermic animals had DO2-dependent VO2. No normothermic and three hypothermic animals survived to 5% hematocrit (Hgb, 15 g/l), and none survived to 3%. Hgb(CRIT) was 23 +/- 2 g/l and 19 +/- 6 g/l (mean +/- SD) in normothermic and hypothermic animals, respectively (P = 0.053). Hgb at death was 19 +/- 3 g/l versus 14 +/- 4 g/l (P = 0.015), and DO(2CRIT) was 8.7 +/- 1.7 versus 4.6 +/- 0.8 ml x kg(-1) x min(-1) (P < 0.001). CONCLUSION: During progressive normovolemic hemodilution in pigs, hypothermia did not significantly change Hgb(CRIT), but it decreased the Hgb at death, i.e., short-term survival was prolonged.

Anemia↗

PubMed1993

[Programmed death of cells (apoptosis)].

Apoptosis is a mode of cell death defined by characteristic morphological, biochemical and molecular changes. It was first described as a "shrinkage necrosis", and then this term was replaced by apoptosis to emphasize its role opposite mitosis in tissue kinetics. During apoptosis the cell decrease in size, loose contact with neighboring cells, and loose specialized surface elements such as microvilli and cell-cell junctions. A shift of fluid out of the cells causes cytoplasm condensation, which is followed by convolution of the nuclear and cellular outlines. In later stages of apoptosis the entire cell becomes fragmented, forming a number of plasma membrane-bounded apoptotic bodies which contain nuclear and or cytoplasmic elements. The ultrastructural appearance of necrosis is quite different, the main features being mitochondrial swelling, plasma membrane breakdown and cellular disintegration. Apoptosis occurs in many physiological and pathological processes. It plays an important role during embryonal development as programmed cell death and accompanies a variety of normal involutional processes in which it serves as a mechanism to remove "unwanted" cells. Apoptosis is associated with prostate atrophy after castration or atrophy of the adrenal cortex and thymus after administration of glucocorticoids. Apoptosis is involved in elimination of CD4 T lymphocytes in the course of HIV infection. The interest in apoptosis in oncology stems from the fact that it occurs in tumors, spontaneously as well as triggered by different antitumor drugs, radiation or after withdraw of growth factors. Spontaneous apoptosis may play a role in evolution of tumor malignancy.(ABSTRACT TRUNCATED AT 250 WORDS)

Apoptosis↗

PubMed1998

Amyloid beta-peptides inhibit Na+/K+-ATPase: tissue slices versus primary cultures.

Abeta1-40 (20 microM) has been reported to selectively inhibit Na+/K+-ATPase activity in rat primary hippocampal cultures after 2-6 days of exposure. We expanded these studies to include Abeta's effects on Na+/K+-ATPase activity in rat primary cortical cultures and hippocampal slices, and we correlated these effects with estimates of cell survival in rat brain primary cultures. Using optimized assay conditions, a 5-day exposure to 50 microM Abeta 25-35, 20 microM Abeta 1-40, and 20 microM Abeta 1-42 decreased Na+/K+-ATPase activity in rat primary cortical cultures 66%, 60%, and 22%, respectively. Abeta 25-35 (50 microM) at 24 h was the only condition that caused inhibition of Na+/K+-ATPase activity in the absence of cell death, defined as an extracellular shift in the localization of the cytoplasmic enzyme lactate dehydrogenase (LDH). We also found that hippocampal slices were sensitive to Abeta, exhibiting a 40-60% reduction in membrane Na+/K+-ATPase activity when exposed to 1-30 nM of Abeta 1-40 for 60 min. This inhibition was not readily reversible, as it withstood homogenization and repeated dilution and centrifugation. Additionally, this inhibition occurred only after amyloid incubation with intact hippocampal slices, not with disrupted membranes. The inhibition of Na+/K+-ATPase in brain slices by physiological, low nM concentrations of Abeta 1-40 is consistent with effects on neurotransmitter release and intrasynaptosomal calcium responses.

Amyloid beta-Peptides↗

PubMed1997

Perinatal mortality in Bavaria, Germany, after the Chernobyl reactor accident.

As has been shown by the authors of a paper recently published in this journal, a deviation from a long-term trend in perinatal mortality within the former Federal Republic of Germany occurred in 1987, i.e. 1 year following the Chernobyl disaster. It is the aim of this study to make a comparison between the areas of the state Bavaria. Germany, with different fallout levels as well as between the observed and expected numbers of perinatal deaths relating to these areas. The expected numbers of perinatal deaths, defined as external standard, were derived from the remainder of the former FRG. Testing an a priori formulated hypothesis revealed no differences in the temporal development of perinatal mortality between the areas with different fallout levels and subsequent exposure. Including May 1986 into the analysis revealed a significant increase during the first 3 months after the accident, which is due to an excess in May alone. Since no elevated radiation risks for the last days in utero are known, the additional Chernobyl radiation exposure is not plausible as a causative agent. Further analyses on stillbirths showed an increase in Southern Bavaria during the first 2 years following the accident. Later on, the rates were comparable to the expected values again.

Fetal Death↗