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PubMed1998

Apoptotic cell death and nitric oxide: activating and antagonistic transducing pathways.

Nitric oxide (NO) is a unique diffusible molecular messenger that occupies central roles in mammalian pathophysiology. Overproduction of NO is important for nonspecific "host" defense, helping to kill tumors and intracellular pathogens. Cytotoxicity as a result of long-lasting NO generation is now established to initiate apoptosis. Apoptotic cell death defines morphological alterations and distinctive biochemical events that lead to cell demise. NO-mediated apoptosis comprises upregulation of the tumor suppressor protein p53, activation of proteases known as caspases, chromatin condensation, DNA laddering, and is associated with alterations in the expression of apoptotic associated proteins that belong to the Bc1-2 family. An active role of NO was established by blocking adverse effects by NO-synthase inhibitors. Overexpression of the classical antiapoptotic protein Bc1-2 rescued cells from apoptosis by attenuating signaling downstream of p53 and upstream of caspase activation. Accumulating evidence suggests that transducing mechanisms can intersect and therefore a cell response to a given stimulus may alter significantly. As a result, transducing pathways of NO are not only adapted to cytotoxicity but also refer to cell protection. Protection from NO-elicited apoptosis may result as a consequence of a diffusion controlled NO/O2- (superoxide) interaction. The NO/O2- interaction redirects the apoptotic initiating activity of radicals (NO or O2-) towards protection as long as reduced glutathione compensates the resultant oxidative stress. Further, NO-mediated protective principles are understood on the basis of gene transcription of protective proteins such as heat shock proteins, hemeoxygenase-1, or cyclooxygenase-2 that attenuate cell injury in a cell specific way. The crosstalk between destructive and protective principles as a result of NO formation will determine the role of NO in cell injury. The balance between pro- and anti-apoptotic signaling mechanisms, their activation or deactivation as a result of NO formation, will allow cells to cope with NO or to exit into apoptosis.

Animals↗

PubMed1985

Should child abuse and neglect be considered when a child dies unexpectedly?

Deaths during two years at a pediatric teaching hospital were studied to develop guidelines for clinicians who must decide when to explore the possibility of child abuse or neglect when a child dies unexpectedly. Unexpected deaths were defined as deaths occurring before arrival at the hospital or within ten days of hospitalization in children past the first month of life and unrelated to any previously known congenital anomaly or medical condition. There were 43 such deaths during two years. The majority (27) were due to natural causes. However, nine deaths were related to suspected child abuse or neglect (SCAN) and in three of those cases evidence of injury was found only at autopsy. The SCAN cases were more often mistaken for medical illness than for uninflicted injury, indicating that autopsy and postmortem skeletal survey are warranted whenever a child dies unexpectedly. The two factors "dead on arrival" and "1 year of age or less" had a positive predictive value for SCAN of 89% and a negative predictive value of 94%. The two factors identify a high-risk group requiring at least hospital-based investigation into the possibility of abuse or neglect. Reporting for SCAN is warranted when unsuspected trauma is found post mortem, there is direct physical or social evidence of child abuse or neglect, or the child is in the high-risk group and hospital-based investigation falls to eliminate the possibility that maltreatment contributed to the child's death.

Child↗

PubMed1983

Congenital and hereditary anomalies in the rhesus monkeys (Macaca mulatta) of Cayo Santiago.

During seven annual birth seasons, from January 1976 to July 1982, 963 infants were born in the Cayo Santiago, Puerto Rico, colony of free-ranging rhesus monkeys (Macaca mulatta). The reproductive rate for mature females, 4 years of age and older, ranged between 74.1% and 84.7%, with a cumulative mean of 80.8% over 7 years. Live births comprised 95.3% of the total and the secondary sex ratio was 109 male to 100 female births. No twinning was observed. Aborted and stillborn monkeys represented 4.7% of all births. The percentage of stillborn females was greater than that of males (4.0% vs. 3.1%). Neonatal death, defined as mortality within 48 hours postpartum, occurred in 0.8% of the live births. Two cases of congenital abnormalities were observed. The first was an anencephalic, acranial female and the second a congenitally blind male. Both infants were born to matrilineally unrelated 7-and 8-year-old multiparous females with no prior history of delivering malformed offspring. The incidence of each defect, based on 963 births, was 0.10%, with a cumulative incidence of 0.20% for all teratisms seen during the study. Multiple occurrences of a rare, nonpathological and nonlethal hereditary anomaly were also seen. Five "golden" macaques were born into two genetically distinct social groups within the last 2 years of observation. The incidence of this phenotype, based on five cases, was 0.52%, 52 times the expected rate (.01%).

Animals↗

PubMed1989

The role of repair in radiobiology.

Apart from cancer and mutation induction, radiobiological effects on mammals are mostly attributable to cell 'death', defined as loss of proliferative capacity. Survival curves relate retention of that capacity to radiation dose, and often manifest a quasi-threshold ('shoulder'). The shoulder is attributable to an initial mechanism of repair ('Q-repair') which is gradually depleted as dose increases. Another form of repair, which is not depleted ('P-repair'), increases the dose required to deliver an average of one lethal event per cell (dose 'D0'). Neither form of repair can unambiguously be linked with repair of defects in isolated DNA. An important initial lesion may well be disruption of the complex structural relationship between the DNA, nuclear membrane and associated proteins. One form of P-repair may be restoration of that structural relationship.

Animals↗

PubMed1999

European brain death codes: a comparison of national guidelines.

The majority of European countries have published recommendations for the diagnosis of brain death as a necessary prerequisite for organ donation. The concept of brain death as defining the death of the individual is accepted in all European countries; however, the guidelines for determining the total and irreversible loss of all brain functions differ somewhat in the various countries. While the clinical examination and documentation of the clinical signs of brain death are very uniform, there are significant differences in the guidelines for using technical confirmatory tests to corroborate the clinical signs. These range from rejecting all technical tests to accepting of multiple neurophysiological tests alone or in combination. The present study examined the similarities and differences in current concepts of brain death in the various European countries and their recommendations for the diagnosis of brain death. The diagnosis of brain death is based on a number of prerequisites, on the clinical diagnosis of deep coma, loss of all brainstem reflexes, and the demonstration of apnea. Neurophysiological tests are recommended by a number of national professional societies as confirmatory tests to confirm the clinical diagnosis of brain death and shorten otherwise necessary waiting periods of 6-12 h. Most brain death codes allow the use of electroencephalography, which must demonstrate electrocortical silence over a certain period. Evoked cerebral potentials can demonstrate the successive loss of activity of various afferent pathways and are accepted in some countries as a confirmatory test. Other neurophysiological tests which demonstrate the loss of cerebral perfusion can be implemented. Brain scintigraphy can confirm the loss of isotope uptake into the brain. Doppler sonography also demonstrates cessation of brain perfusion. Cerebral panangiography may also be used to demonstrate the loss of brain perfusion but is less desirable since it might endanger the patient.

Brain Death↗

PubMed2006

A novel paraptosis pathway involving LEI/L-DNaseII for EGF-induced cell death in somato-lactotrope pituitary cells.

We have recently reported that EGF triggers an original form of cell death in pituitary cell line (GH4C1) with a phenotype sharing some characteristics of both apoptosis (internucleosomal DNA fragmentation) and paraptosis (caspase-independence and cytoplasmic vacuolization). However, the endonuclease involved in EGF-induced DNA fragmentation has not been assessed so far. In the present work we therefore further explored the putative paraptosis involvement in EGF-induced cell death and asked whether L-DNaseII might be involved. Indeed, this endonuclease is known to mediate internucleosomal DNA fragmentation in caspase independent manner. Our Western blot, immunocytochemistry and enzymatic measurement assays show that EGF triggers a cleavage of Leukocyte Elastase Inhibitor (LEI) precursor into L-DNaseII, its subsequent enzymatic activation and nuclear translocation thus pointing to the involvement of this endonuclease pathway in caspase-independent DNA fragmentation. In addition, EGF-induced cell death can be blocked by paraptosis inhibitor AIP-1/Alix, but not with its anti-apoptotic C-terminal fragment (Alix-CT). Altogether these data suggest that EGF-induced cell death defines a novel, L-DNaseII-mediated form of paraptosis.

Animals↗

PubMed1992

Role of octreotide in the prevention of postoperative complications following pancreatic resection.

Though morbidity and mortality rates following pancreatic resection have improved in recent years, they are still around 35% and 5%, respectively. Typical complications, such as pancreatic fistula, abscess, and subsequent sepsis, are chiefly associated with exocrine pancreatic secretion. In order to clarify whether the perioperative inhibition of exocrine pancreatic secretion prevents complications, we assessed the efficacy of octreotide, a long-acting somatostatin analogue. We conducted a randomized, double-blind, placebo-controlled, multicenter trial in 246 patients undergoing major elective pancreatic surgery. Patients were stratified into a high-risk stratum (limited to patients with pancreatic and periampullary tumors) or low-risk stratum (patients with chronic pancreatitis). Patients received octreotide (3 x 100 micrograms) or placebo subcutaneously for 7 days perioperatively. Eleven complications were defined: death, leakage of anastomosis, pancreatic fistula, abscess, fluid collection, shock, sepsis, bleeding, pulmonary insufficiency, renal insufficiency, and postoperative pancreatitis. Two hundred patients underwent pancreatic head resection, 31 patients underwent left resection, and 15 patients had other procedures. The overall mortality rate within 90 days was 4.5%, with 3.2% in the octreotide group and 5.8% in the placebo group. The complication rate was 32% in the patients receiving octreotide (40 of 125 patients) and 55% in patients receiving placebo (67 of 121 patients) (p less than 0.005). In the patients in the high-risk stratum, complications were observed in 26 of the 68 (38%) patients treated with octreotide and in 46 of 71 (65%) patients given placebo (p less than 0.01). Whereas in patients in the low-risk stratum, the complication rate was 25% (14 of 57 patients) in those treated with octreotide and 42% (21 of 50 patients) in patients given placebo (p = NS). The perioperative application of octreotide reduces the occurrence of typical postoperative complications after pancreatic resection, particularly in patients with tumors.

Double-Blind Method↗

PubMed2006

Unintentional prescription drug overdose deaths in New Mexico, 1994-2003.

BACKGROUND: New Mexico has the highest rate of drug-induced mortality in the United States. The contribution of prescription drugs to the total overdose death rate has not been adequately described. METHODS: A total of 1,906 unintentional drug overdose deaths occurring in 1994 to 2003 in New Mexico were analyzed. Unintentional drug overdose death was defined as death caused by prescription, illicit, or a combination of drugs, as determined by a pathologist. Deaths were investigated annually by the medical examiner and data were analyzed in 2004-2005. Rates and trends of total and prescription drug overdose death were calculated, decedent characteristics were analyzed, and common drug combinations causing death were described. RESULTS: The rate of unintentional prescription drug overdose death increased by 179% (1.9 to 5.3/100,000) from 1994 to 2003. A high percentage of prescription drug overdose decedents were white non-Hispanic (63.2%) and female (43.9%). These decedents were older and less frequently had alcohol listed as an additional cause of death than decedents of other drug overdose categories. Of all deaths caused by prescription drug(s) (n =765), 590 (77.1%) were caused by opioid painkillers, 263 (34.4%) by tranquilizers, and 196 (25.6%) by antidepressants. CONCLUSIONS: The rate of prescription drug overdose death in New Mexico increased significantly over the 10-year study period. Comprehensive surveillance of drug overdose deaths is recommended to describe their occurrence in the context of both medical and diverted use of prescription drugs. Understanding decedent profiles and the potential risk factors for prescription drug overdose death is crucial for effective drug overdose prevention education among healthcare providers.

Adult↗

PubMed2006

Successful immune reconstitution decreases leukemic relapse and improves survival in recipients of unrelated cord blood transplantation.

Allogeneic hematopoietic stem cell transplantation (HSCT) is established therapy for selected patients with acute leukemia. After transplantation, antileukemic immune responses are believed to eliminate residual leukemia cells and decrease the likelihood of relapse. However, the clinical effect of successful antigen-specific immune reconstitution after HSCT on the likelihood of leukemic relapse and overall survival is not known. Pediatric recipients of unrelated cord blood transplants who underwent transplantation for acute leukemia were sequentially evaluated for their development of antigen-specific T-lymphocyte immunity to herpes viruses. The clinical effect of a positive antigen-specific response on relapse-free survival was determined. The presence of an antigen-specific response resulted in a relapse-free survival advantage (P = .0001), which was primarily due to a decrease in leukemic relapse (P = .003). Proportional hazards modeling for time to relapse and time to relapse or death defined 3 variables that were strongly associated with a poor outcome: female gender, poor remission status before transplantation, and negative antigen-specific T-lymphocyte proliferation. Notably neither acute nor chronic graft-versus-host disease had any effect on the incidence of leukemic relapse. Successful antigen-specific immune reconstitution after unrelated cord blood transplantation results in decreased leukemic relapse and improved overall survival.

Adolescent↗

PubMed2004

Symptom management in the older adult.

Palliative care begins at the time of diagnosis of a life-threatening illness and continues beyond the time of death. Defined in the broadest sense, the goal of palliative care is to provide aggressive symptom management and address the psychological and spiritual needs of the patient and the family. This article reviews the management of some symptoms commonly observed in older patients, highlighting treatment considerations specific to the older population. Ultimately the approach to symptoms must be individualized, and treatment decisions must reflect the patient's goals of care. Although symptom management in older patients may be challenging, it is possible to provide care that significantly enhances quality of life throughout the course of illness.

Aged↗

PubMed1984

Evaluation of the patient with sudden cardiac death.

Sudden cardiac death is defined as death from natural causes that occurs within one hour of the patient's collapse. Public education programs and the proliferation of rapidly deployable community life-support teams have resulted in the ability to deliver emergency medical care to many patients who suffer a cardiac arrest and who otherwise would have died suddenly. This article reviews the diagnostic evaluation and therapeutic management of the patient who has survived a cardiac arrest.

Anti-Arrhythmia Agents↗

PubMed1998

Different cell thresholds for commitment to death: a link between carcinogenesis and drug resistance.

All classes of anticancer drugs induce apoptosis both in vitro and in vivo. Because apoptosis is a genetically controlled process, this implies that death induced by these drugs is genetically controlled at loci different from those involved in their direct mechanisms of action. This is stimulus-response-coupling; the drugs provide the stimulus through imposition of cell damage. Failure to couple damage to the response of death characterizes a pleiotropic form of drug resistance. Different cell phenotypes have different thresholds for the engagement of death, which need not only be by apoptosis. The balance of expression of genes which promote or suppress active cell death defines these thresholds.

Journal Article↗

PubMed2002

Factors predictive of early death in patients receiving high-dose CHOP (ACVB regimen) for aggressive non-Hodgkin's lymphoma: a GELA study.

Death during the induction phase of chemotherapy remains a common event in patients with aggressive non-Hodgkin's lymphoma (NHL). In a series of patients with aggressive NHL homogeneously treated with intensive induction chemotherapy [ACVB (doxorubicin, cyclophosphamide, vindesine, bleomycin, prednisone) regimen], we determined the clinical and biological parameters that were predictive of early death. Early death was defined as death, for whatever reason, occurring within 100 d of randomization. Predictive factors were identified by logistic regression and an index predictive for individual risk of early death was designed. Among the 2210 patients treated with ACVB, there were 162 (7.3%) early deaths. There was no significant reduction in the rate of early death between 1987 and 1998. In a multivariate analysis, age > 60 years, Eastern Cooperative Oncology Group performance status > 1, serum lactate dehydrogenase > normal, serum albumin < 30 g/l, leucocyte counts > 10 x 10(9)/l and haemoglobin levels < 8.5 g/dl were found to be independent predictive factors for early death. An early death index was designed, enabling the evaluation of the individual risk of early death in young (range 2-31% risk of early death) and elderly patients (range 5-53%). Clinical and biological parameters available at diagnosis can help physicians identify patients with aggressive lymphoma at low or high risk of early death.

Adolescent↗

PubMed1994

Lack of telomere shortening during senescence in Paramecium.

Paramecium tetraurelia cells have a limited clonal life span and die after approximately 200 fissions if they do not undergo the process of autogamy or conjugation. To test the possibility that cellular senescence of this species is caused by telomere shortening, we analyzed the genomic DNA of the macronucleus during the clonal life span of P. tetraurelia. We found that telomeric DNA sequences were not shortened during the interval of decreased fission rate and cellular death, defined as senescence in these cells. However, the mean size of the macronuclear DNA was markedly decreased during the clonal life span. We present a model that expands upon previous proposals that accumulated DNA damage causes cellular senescence in P. tetraurelia.

Animals↗

PubMed1997

Coronary heart disease mortality and adjuvant tamoxifen therapy.

BACKGROUND AND PURPOSE: Data from randomized clinical trials in Scotland and Sweden testing the efficacy of tamoxifen therapy in patients with breast cancer have suggested that the drug may also reduce the risk of coronary heart disease. In view of these findings, we examined mortality from coronary heart disease among patients with early stage breast cancer who were enrolled in the National Surgical Adjuvant Breast and Bowel Project B-14 trial of tamoxifen therapy. METHODS: Deaths occurring among women who were randomly assigned to 5 years of either tamoxifen or placebo in the first phase of the B-14 trial were reviewed to determine the cause. Three categories of heart disease-related death were defined: 1) death from a definite fatal myocardial infarction, 2) death from definite fatal coronary heart disease/possible myocardial infarction, and 3) death from possible fatal coronary heart disease. Comparisons of the findings by treatment group were made on the basis of average annual hazard (i.e., death) rates and the corresponding relative hazard of death. RESULTS: The average annual death rate from coronary heart disease was lower for patients who received tamoxifen than for patients who received placebo, but the difference was not statistically significant. There were eight definite heart-related deaths (i.e., definite fatal myocardial infarction or definite fatal coronary heart disease/possible myocardial infarction) among the patients who received tamoxifen, yielding an average annual rate of 0.62 per 1000 patients. There were 12 definite heart-related deaths among the patients who received placebo, yielding an average annual rate of 0.94 per 1000. The corresponding relative hazard of death from definite fatal heart disease (tamoxifen versus placebo) was 0.66 (95% confidence interval = 0.27-1.61). Eleven deaths in the tamoxifen group and 10 deaths in the placebo group were classified as possible cases of fatal coronary heart disease. When these cases and the definite cases were considered together, the average annual death rate for the patients who received tamoxifen was 1.48 per 1000, and the rate for the patients who received placebo was 1.73 per 1000. The corresponding relative hazard of death was 0.85 (95% confidence interval = 0.46-1.58). CONCLUSIONS: The findings from the B-14 trial are consistent with the findings from the Scottish and the Swedish trials, suggesting that tamoxifen treatment reduces coronary heart disease among patients with breast cancer. Continued follow-up of the patients in these trials and in ongoing prevention trials is needed to accumulate enough data so that reliable conclusions can be drawn about the benefits of tamoxifen in preventing heart disease.

Adult↗

PubMed2005

Suicide in children and adolescents: a 10-year retrospective review.

Suicide is second only to accidents as the most common cause of death for children and adolescents age 10 to 19 in Canada. All of the pediatric cases that were referred to the Hamilton Regional Forensic Pathology Unit from 1993 to 2002 were reviewed. For the purpose of this study, pediatric deaths were defined as deaths in the age group of 1 day up to and including 19 years of age. Specific criteria for suicide were applied to each case, independent of the manner of death issued by the coroner. The criteria were 3-fold. First, homicide had to be ruled out by the police investigation and autopsy findings. Second, the method had to be consistent with self-infliction. Finally, there had to be some evidence of suicidal intent. Questionable cases were discussed among the authors, and if reasonable intent could not be established, then the case was excluded. The autopsy and police reports were examined in detail regarding age, sex, location and method of suicide, presence of suicide notes, and any contributing psychologic factors or stressors. Of the 501 pediatric autopsies performed during the 10-year period, 31 (6%) met the criteria of suicide. The majority of cases (87%) were in older adolescents (age 15 to 19), and the male to female ratio was 2.4:1. Psychologic factors were identified in some of the cases, including depressed mood (77%), suicidal ideation (45%), previous suicide attempts (23%), and drug or alcohol problems (19%). Most of the suicides (61%) occurred in the victim's home, and 12 (39%) cases left a suicide note. In 9 cases (29%), alcohol or street drugs were detected postmortem, though in 8 cases toxicology was not performed. Hanging (48%) was the most common method of suicide, followed by firearms (13%), poisoning (10%), drowning (10%), and blunt force vehicular trauma (10%). Almost 60% of the male suicides were by hanging. No specific trend was identified in the 9 female suicides. These results were compared with similar studies within Canada and other countries. Overall, the method of suicide is dictated by what is convenient and readily available, though the acceptance of various suicide methods can change over time. Suicide prevention efforts should be tailored to address local trends.

Adolescent↗

PubMed1984

Involvement of double-strand chromosomal breaks for mating-type switching in Saccharomyces cerevisiae.

The yeast S. cerevisiae switches a and alpha cell types by a transposition mechanism that replaces genetic information residing at the mating-type locus (MAT) with information copied from either of the two donor loci, HML and HMR. The donor HML and HMR loci contain the same genetic information as the MATa and MAT alpha alleles, yet they do not switch. Additionally, Strathern et al. (1982) have described an in vivo double-strand DNA break found at subgenomic levels (approximately 2% of MAT DNA) within the MAT locus but not within HML and HMR. We have examined the role of this double-strand DNA break in the switching process. Cell lineage studies show that strains containing deletions of the donor HML and HMR loci produce lethal progeny in the exact pattern described for MAT switching in standard strains. Our interpretation is that the double-strand MAT break in the deletion strains cannot be repaired because of the lack of the donor loci, resulting in cell death. We suggest that the double-strand DNA break is an initiating event for switching and that this event is lethal in the absence of the donor loci. MAT mutants isolated as survivors from this "pedigree of death" define a site required for switching where the double-strand break occurs. We have also examined marl mutant strains in which the donor loci are expressed and observed to switch (Klar et al. 1981a). The double-strand DNA cut appears at the HM loci in these strains. Thus, there is a strong correlation between the presence or absence of the double-strand break at each cassette and its ability or inability to switch as observed at the single cell level.

Alleles↗

PubMed1995

Sudden death and staged therapy for hemodynamic stabilization in patients enrolled in a heart transplantation program.

To investigate the impact of staged therapy for advanced heart failure on therapeutic endpoints, 236 consecutive patients (coronary artery disease/dilated cardiomyopathy in 61/175 patients, left ventricular ejection fraction 14% +/- 5%, New York Heart Association Class II/III/IV in 102/79/55 patients, respectively) with advanced heart failure were prospectively followed. One hundred thirty-seven patients enrolled from January 1989 to December 1991 were treated conventionally with digoxin, furosemide, and low dose angiotension converting enzyme (ACE) inhibition. Patients refractory to this therapy underwent urgent heart transplantation. Ninety-nine patients enrolled from January 1992 to August 1993 underwent staged therapy: stage 1: maximal tolerated ACE inhibition; stage 2: therapy with PGE1 for pre- and afterload reduction to achieve hemodynamic stabilization; or stage 3: refractory patients bridged to heart transplantation with continuous outpatient dobutamine. Sudden death was defined as death within 1 hour of symptoms if heart failure symptoms remained stable over the previous 7 days. Conventionally treated patients were followed for 10 +/- 9 months; patients who underwent staged therapy for 9 +/- 5 months. In the group of patients that underwent standard therapy, 39 of 137 (28%) patients died: 5 (13%) deaths occurred suddenly, and death due to progressive pump failure occurred in the remaining 34 (87%) patients. In the group of patients that underwent staged therapy, 25 of 99 (25%) patients died: 13 (52%) deaths occurred suddenly, and 12 (48%) deaths occurred due to progressive pump failure.(ABSTRACT TRUNCATED AT 250 WORDS)

Alprostadil↗