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PubMed2001

[Cell death protection by anti-apoptotic factor].

Neurodegenerative disorders including ALS and Parkinson's disease are characterized by progressive loss of neuronal cell death. Apoptosis, a morphologically and biochemically defined form of cell death caused by active cellular signaling, has been long implicated in neurodegeneration. Recently, the basic molecular mechanism of apoptosis has been elucidated and a subset of cysteine proteases called caspases were shown to be the executioner of apoptosis. On the other hand, endogenous caspase inhibitor called inhibitor of apoptosis proteins (IAPs) were also identified. XIAP, the most potent apoptosis inhibitor among human IAPs, is shown to be direct and selective inhibitor for caspase-3, -7 and -9. We have very recently shown that XIAP has ubiquitin ligase activity which promotes the degradation of caspase-3 and this protease activity enhances the anti-apoptotic activity of XIAP. Regarding the involvement of apoptosis in neurodegenerative diseases, several lines of evidence indicated that caspases are involved in the pathogenesis of ALS and polyglutamine disease, suggesting the effectiveness of anti-apoptotic therapy for these diseases. Moreover, caspase-independent programmed cell death is also suggested to be involved in neurodegenerative disorders. Based on these findings, the therapeutic strategy for neurodegenerative disease should include both anti-apoptotic and anti-non-apoptotic cell death treatments.

Apoptosis↗

PubMed1994

Endocrine response to brain injury.

The neuroendocrine response (NER) is an essential component of the adaptive process to trauma, brain injury, and major surgery. While receiving additive humoral and neural afferent inputs, the brain nuclei responsible for the NER act mainly by efferent pathways to the hypothalamic-pituitary-adrenal (HPA) axis and the sympathoadrenal system, the activations of which induce subsequent circulatory and metabolic responses. The NER to brain injury is similar to the response observed in patients with extracerebral injury, even if the response after brain injury is extremely variable. Generally, there is a biphasic pattern, with a sympathoadrenal storm associated with variable and altered stimulation of the HPA during the ebb phase. The first phase is followed by a decrease in both responses while other endocrine changes develop, involving mainly the counter-regulatory, gonadal, and thyroid hormones. The outcome after brain injury is closely correlated with the intensity of these changes, particularly with catecholamine plasma levels and the severity of the low triiodothyronine syndrome. Alterations of the thyroid hormones are largely related to a reduction in peripheral deiodination of thyroxin. Recent research shows that increased free-radical production and decreased selenium (an antioxidant) serum levels play an important role in thyroid metabolism. Two major issues remain unsolved: a) the precise definition of cerebral death, since endocrine brain function is not abolished in the state currently defined as brain death; and b) the question of whether substitutive hormone therapy should be applied in severe brain injury.

Animals↗

PubMed2004

[Use of an artificial neural network for detecting excess deaths due to cholera in Ceará, Brazil].

OBJECTIVE: To evaluate recurrent neural networks as a predictive technique for time-series in the health field. METHODS: The study was carried out during a cholera epidemic which took place in 1993 and 1994 in the state of Ceará, northeastern Brazil, and was based on excess deaths having 'poorly defined intestinal infections' as the underlying cause (ICD-9). The monthly number of deaths with due to this cause between 1979 and 1995 in the state of Ceará was obtained from the Ministry of Health's Mortality Information System (SIM). A network comprising two neurons in the input layer, twelve in the hidden layer, one in the output layer, and one in the memory layer was trained by backpropagation using the fist 150 observations, with 0.01 learning rate and 0.9 momentum. Training was ended after 22,000 epochs. We compare the results with those of a negative binomial regression. RESULTS: ANN forecasting was adequate. Excessive mortality (number of deaths above the upper limit of the confidence interval) was detected in December 1993 and October/November 1994. However, negative binomial regression detected excess mortality from March 1992 onwards. CONCLUSIONS: The artificial neural network showed good predictive ability, especially in the initial period, and was able to detect alterations concomitant and a subsequent to the cholera epidemic. However, it was less precise that the binomial regression model, which was more sensitive to abnormal data concomitant with cholera circulation.

Binomial Distribution↗

PubMedDate not supplied

[Why are babies born at night at increased risk of early neonatal mortality?].

BACKGROUND: Increased perinatal and neonatal mortality rates have been previously reported in night-time births compared with births during the day. This effect has been attributed to decreased quality of medical care during the night. However, alternative explanations exist such as decreased birth-weight of night births. The objective of this study was to further investigate this relationship. MATERIALS AND METHODS: Data from 590,332 low risk births (singleton births, > or = 2500 g birth-weight, no major congenital anomaly) were obtained from the perinatal birth register of Hesse, Germany, 1990-2000. Outcome was defined as either death during labour or within 7 days of life. Night-time births were defined as births between 9.00 p.m. and 6.59 a.m., otherwise day-time births were assumed. Subgroup analyses and logistic regression analyses were performed to assess whether the excess mortality of night-births might be explained by other factors. RESULTS: Mortality rates were increased in night-time births (RR = 1.26; 95% CI = 0.94-1.70). This relationship was more pronounced in spontaneous births (RR = 1.58; 95% CI = 0.96-2.61) and emergency cesarean sections (RR = 1.76; 95% CI = 1.10-2.82). Significance persisted after adjusting for numerous potential confounders. CONCLUSION: Our results confirm an increased mortality risk for night-time births which could not be explained by other accessible risk factors. This suggests that the increased risk at night might be attributable to a reduced availability to provide appropriate medical care in delivery units at night. DISCUSSION: As mainly the presence of staff is decreased during the night, introduction of better designed shifts can be expected to reduce neonatal mortality.

Cesarean Section↗

PubMed1997

[The use of EEG in the diagnosis of brain death in France].

Scientific and modern conception of brain-death is rather recent, thus making possible organ transplantations. During the past three decades clinical criteria for brain-death have been defined. Electroencephalography (EEG) appears to be a complementary tool as it permits brain-death assessment. In France laws enforced respectively in 1968, 1978, 1991 and 1996 provide a framework for brain-death evaluation before organ transplantation and include EEG recording. Advantages and pitfalls of EEG in the diagnosis of brain-death are considered as this technique may be unreliable. Only evoked potential recordings can allow assessment and confirmation of brain stem death, which is a mandatory criterion. We recommend simultaneous EEG and either brain stem auditory or somatosensory evoked potential recordings to strengthen clinical criteria of brain-death and definitely prove it using objective electrophysiological criteria.

Brain Death↗

PubMedDate not supplied

How useful is postmortem examination in sudden infant death syndrome?

There exists great variability in the literature as to the percentage of cases of sudden and unexpected infant death in which definable causes can be identified. Review was undertaken of the clinical and family histories, death scene features including parental interviews, and pathological and microbiological features of 361 consecutive cases presenting as sudden and unexpected infant death with minimal preceding symptoms and signs to the Adelaide Children's Hospital over a 10-year period from 1983 to 1992. Three hundred and twenty-nine cases of SIDS were identified. Nine cases (2.5%) were attributed to accidental asphyxia based partly on death scene examination. This left only 23 cases (6.4%), which were due to a variety of other diverse entities including sepsis, volvulus with sepsis, congenital cardiac disease, probable metabolic disorders, heat stroke, and unclassifiable disorders. This relatively low figure lends support to definitions of SIDS that emphasize the importance of death scene investigation and clinical history review prior to postmortem examination.

Autopsy↗

PubMed1991

Long-term survival after resuscitation from ventricular fibrillation occurring before hospital admission.

Factors related to long-term (post-discharge) outcome following successful resuscitation from pre-hospital ventricular fibrillation by a physician-manned mobile coronary care unit were studied. Between 1 January 1966 and 31 December 1987, 190 patients were resuscitated from pre-hospital ventricular fibrillation (158 male; mean age 56 years). The aetiology of ventricular fibrillation was acute myocardial infarction in 131 patients (69 per cent), ischaemic heart disease without infarction in 48 (25 per cent) and other or unknown in 11 (6 per cent). Predicted actuarial survival rates at 1, 2, 5, 10 and 20 years were 76 per cent, 66 per cent, 41 per cent, 27 per cent and 12 per cent respectively. Of 128 recorded deaths over 20 years, 85 per cent were cardiac and 48 per cent were defined as sudden death outside hospital. Factors significantly associated with increased long-term mortality (p less than 0.05), based on analysis of 10 year actuarial life tables using the Lee-Desu statistic were ventricular fibrillation due to ischaemic heart disease without infarction rather than acute myocardial infarction, a history of previous myocardial infarction, a history of hypertension, digoxin and diuretic therapy before ventricular fibrillation and digoxin as discharge medication, and failure to stop smoking after discharge from hospital by patients who had been smoking prior to ventricular fibrillation. In addition, Cox's regression analysis showed that patient age greater than or equal to 60 years was significantly associated with increased long-term mortality. On multivariate analysis, factors independently associated with increased long-term mortality were ventricular fibrillation occurring before 1977, previous myocardial infarction or hypertension and digoxin as discharge medication.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

PubMed2006

Subarachnoid haemorrhage in patients > or = 75 years: clinical course, treatment and outcome.

BACKGROUND: The number of elderly patients being admitted with aneurysmal subarachnoid haemorrhage (SAH) has been increasing. Treatment of the aneurysm may be offset by the higher rate of surgical or endovascular complications. AIM: To study the clinical condition at onset, complications during clinical course, treatment and outcome in a consecutive series of elderly patients. METHODS: Patients who were > or = 75 years at the onset of SAH were selected from the databases of two hospitals. Data on clinical condition at onset (poor condition defined as World Federation of Neurological Surgeons (WFNS) Scale IV and V), clinical course, treatment and outcome were extracted. Univariate and multivariate regression analyses were carried out to identify predictors for in-hospital death and poor outcome, defined as death or dependency. RESULTS: The data of 170 patients were retrieved, of whom 25 (15%) patients were independent at discharge; none of these patients had been admitted in a poor condition. Poor clinical condition on admission (odds ratio (OR) 7.9; 95% confidence interval (CI) 3.7 to 17) and recurrent haemorrhage (OR 7.5; 95% CI 2.5 to 23) were the strongest predictors for in-hospital death. Recurrent haemorrhage was the strongest predictor for poor outcome in the subset of patients who were admitted in good clinical condition. In all, 10 of 47 (21%) patients were independent at discharge after neurosurgical clipping (n = 34) or endovascular coiling (n = 13). CONCLUSION: Elderly patients with SAH have a poor prognosis. The effect of the initial haemorrhage is the most common reason for poor outcome. For patients who are admitted in good clinical condition, the most important complication leading to poor outcome is recurrent haemorrhage. Treatment of the aneurysm in patients > or = 75 years is feasible, may improve the outcome and should be strongly considered in patients who are admitted in a good condition.

Age Factors↗

PubMed1994

Progression to AIDS or death following diagnosis with a class IV non-AIDS disease: utilization of a surveillance database.

Time to progression to an AIDS-defining disease or death was analyzed for residents of King County, Washington State, with selected class IV non-AIDS diagnoses. Relative to people with constitutional symptoms, the risk of progression to an AIDS-defining diagnosis was 1.4 [95% confidence interval (CI), 0.8-2.2), 1.6 (95% CI, 1.0-2.5), and 2.1 (95% CI, 1.3-3.5) times greater for people with a diagnosis of oral hairy leukoplakia, oral candidiasis, and multiple diseases, respectively. Relative to subjects with CD4 counts of > or = 200, the risk of progression to AIDS was greater for subjects with CD4 counts < 200; relative risks ranged from 2.3 (95% CI, 0.8-6.6) for subjects with constitutional symptoms and CD4 counts < 200 to 6.7 (95% CI, 3.3-13.6) for subjects diagnosed with oral hairy leukoplakia and CD4 counts > 200. However, the statistical test for interaction between CD4 count and diagnostic group was not significant (p = 0.62). Our findings are in general agreement with results from previous cohort studies and suggest the utility of surveillance databases for natural history studies of the course of HIV illness.

Acquired Immunodeficiency Syndrome↗

PubMed2006

p27(Kip1) and cyclin E expression and breast cancer survival after treatment with adjuvant chemotherapy.

BACKGROUND: Abnormal expression of the cell cycle regulatory proteins p27(Kip1) (p27) and cyclin E may be associated with breast cancer survival and relapse. We studied these markers in a clinical trial setting with patients with breast cancer treated by a uniform drug regimen so that treatment was not associated with variability in outcome. METHODS: We used tissue microarrays to evaluate the expression of p27 and cyclin E proteins by immunohistochemistry in tumor tissue from 2123 (68%) of 3122 patients with moderate-risk primary breast cancer who were enrolled in Southwest Oncology Group-Intergroup Trial S9313, in which patients were assigned to receive doxorubicin and cyclophosphamide administered concurrently (n = 1595) or sequentially (n = 1527). Disease-free and overall survival were equivalent in the two arms. Expression of the proteins was rated on a scale of 1-7, and the median value was used as the cut point. Log-rank tests and Cox regression analyses were used to assess associations with survival. Overall survival was defined as time to death from all causes; disease-free survival was defined as time to recurrence or death. All P values were from two-sided statistical tests. RESULTS: Lower p27 expression was associated with worse overall survival (unadjusted hazard ratio [HR] = 1.50, 95% confidence interval [CI] = 1.21 to 1.86) and disease-free survival (unadjusted HR = 1.31, 95% CI = 1.10 to 1.57) than higher p27 expression. Among hormone receptor-positive patients, lower p27 expression was associated with worse overall survival (HR = 1.42, 95% CI = 1.05 to 1.94) and worse disease-free survival (HR = 1.27, 95% CI = 0.99 to 1.63) than higher p27 expression after adjustment for treatment, menopausal status, tumor size, and number of positive lymph nodes. Among these patients, 5-year overall survival associated with higher p27 expression (0.91, 95% CI = 0.89 to 0.93) was similar to that associated with lower p27 expression (0.85, 95% CI = 0.82 to 0.87). No association between p27 expression and survival was found in hormone receptor-negative patients. Cyclin E expression was not statistically significantly associated with overall survival (HR = 1.12, 95% CI = 0.91 to 1.38) or disease-free survival (HR = 1.09, 95% CI = 0.92 to 1.29). CONCLUSIONS: Low p27 expression appears to be associated with poor prognosis, especially among patients with steroid receptor-positive tumors.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1998

A cell surface receptor defined by a mAb mediates a unique type of cell death similar to oncosis.

Cell death is mediated by distinct pathways including apoptosis and oncosis in response to various death signals. To characterize molecules involved in cell death, a panel of mAbs was raised by immunizing mice with apoptotic cells. One of these antibodies, designated anti-Porimin (for pro-oncosis receptor inducing membrane injury), was found to directly induce a unique type of cell death in Jurkat cells. Anti-Porimin defines a 110-kDa cell surface receptor on Jurkat cells. Functionally, anti-Porimin alone rapidly mediates pore formation on the plasma membrane and induces cell death without participation of complement. Both the cellular expression and functional characteristics of the Porimin antigen indicate that it is distinct from the CD95 (Fas/Apo-1) and other cell receptors known to induce apoptosis. Anti-Porimin-mediated cell death was preceded by cell aggregation, formation of plasma membrane pores, and the appearance of membrane blebs. More important, these cells show neither DNA fragmentation nor apoptotic bodies, but display lethal damage of the cell membrane. Cell death by anti-Porimin is distinct from complement-dependent cytolysis or complement-independent apoptosis but is similar to that described for oncosis, a form of cell death accompanied by the membrane damage followed by karyolysis. The induction of cell death by anti-Porimin may represent a unique cell surface receptor-mediated pathway of cell death in the human lymphoid system.

Animals↗

PubMed1994

Theological theses on the ethics of organ transplantation and on a law concerning the transplantation.

The message of the resurrection from the dead is relevant to human beings living and dying in the unity of body and soul. The personality of man is inseparable connected with this unit--even beyond death. Brain death only marks a (decisive) point during the process of dying, and it cannot be defined as the death of a human being (in general). Theological ethics object to this definition and to a new dualism of brain and body as well as of body and personality (i.e. soul), because this dualism socialises the organs of individuals and denies the personal dignity of disappearing life. Therefore, the explantation of organs must depend on a personal declaration of consent given by the adult sponsor himself. Each information given on organ transplants must clarify that the explanation of organs means an interruption of dying.

Brain Death↗

PubMed2004

Drosophila melanogaster as a model host for Staphylococcus aureus infection.

Staphylococcus aureus is an important pathogen of humans, causing a range of superficial and potentially life-threatening diseases. Infection of the fruit fly Drosophila melanogaster with S. aureus results in systemic infection followed by death. Screening of defined S. aureus mutants for components important in pathogenesis identified perR and pheP, with fly death up to threefold slower after infection with the respective mutants compared to the wild-type. Infection of D. melanogaster with reporter gene fusion strains demonstrated the in vivo expression levels of the accessory gene regulator, agr, alpha-toxin, hla, and a manganese transporter, mntA. The use of the green fluorescent protein as a reporter under the control of the agr promoter (P3) showed S. aureus microcolony formation in vivo. The disease model also allowed the effect of antibiotic treatment on the flies to be determined. D. melanogaster is a genetically tractable model host for high-throughput analysis of S. aureus virulence determinants.

Amino Acid Transport Systems, Neutral↗

PubMed1986

Epidemiology of ventricular tachycardia/ventricular fibrillation and sudden cardiac death.

Despite the difficulties correlating pathological data with acute clinical events in the field of sudden cardiac death, information useful to both the clinician and the epidemiologist has developed. Sudden cardiac death may be defined broadly. These definitions have varied, but it is now generally recognized that sudden cardiac death should reflect a time span of less than one hour. The epidemiology of sudden cardiac death incorporates many factors, including age, heredity, gender, and race. Coronary risk factors and the history of prior coronary heart disease constitute additional points of importance. Finally, clinical characteristics of the cardiac arrest patient are variable. Improving outcome in prehospital cardiac arrest victims involves a multifactorial approach involving rescue personnel, resuscitation technology, and the participation of the public.

Coronary Disease↗

PubMed2004

Measurement of apoptosis by DNA fragmentation.

Classical apoptotic cell death can be defined by certain morphological and biochemical characteristics that distinguish it from other forms of cell death. One such feature, which is a hallmark of apoptosis, is DNA fragmentation. In dying cells, DNA is cleaved by an endonuclease that fragments the chromatin into nucleosomal units, which are multiples of about 180-bp oligomers and appear as a DNA ladder when run on an agarose gel. Here, we present commonly used methods such as conventional agarose gel electrophoresis to analyze fragmented nuclei in cells. The various methods used are dependent on the extent of fragmentation or the amount of fragmented nuclei in a sample. Determining whether a cell exhibits DNA fragmentation can provide information about the type of cell death occurring and the pathways activated in the dying cell.

Apoptosis↗

PubMed2006

[Spatial distribution of mortality from acute myocardial infarction in Rio de Janeiro, Brazil].

The study analyzes the spatial distribution of mortality from acute myocardial infarction (AMI) in Rio de Janeiro, Brazil. Data from the Mortality Information System refers to the year 2000. Empirical Bayes smoothing technique was used to minimize random variation in mortality coefficients due to the population size in the geographic analytical units. Spatial distribution of AMI mortality in the city of Rio de Janeiro is heterogeneous and displays a pattern associated with a strong socioeconomic gradient. The decreased AMI risk in the West Side of the city fails to reflect the social inequality and limited access to healthcare services observed there. A more likely hypothesis is that the risk of AMI death was underestimated in the West Side, due to the high proportion of ill-defined causes of death in that region. In the rest of the city, the spatial pattern of AMI mortality showed higher values in poorer areas. The various hospitals treating AMI also show a clear pattern in their areas of influence.

Adult↗

PubMedDate not supplied

Variation in state-specific infant mortality risks.

Data from the National Infant Mortality Surveillance project were used to examine the State-specific variations in infant, neonatal, and postneonatal mortality and to examine some of the factors affecting the risks of death. The infant mortality risk, defined as the risk of death before 1 year of age to an infant born in the 1980 birth cohort, in the highest risk State was nearly three times that in the lowest risk State. Mortality risk ratios of two or greater were found when comparing high and low States for overall black infant mortality risks, overall neonatal mortality, neonatal mortality risks for black and white infants examined separately, neonatal mortality risks for low birth weight infants regardless of race, and overall postneonatal mortality and postneonatal mortality for white infants. The lowest State-specific black mortality risks were higher than the highest white risks for overall infant mortality and neonatal mortality. The differences between State extremes in mortality risks are greater than the differences between the United States and the Scandinavian countries with the lowest infant mortality.

Female↗

PubMed2002

Death, dying and donation: organ transplantation and the diagnosis of death.

Refusal of organ donation is common, and becoming more frequent. In Australia refusal by families occurred in 56% of cases in 1995 in New South Wales, and had risen to 82% in 1999, becoming the most important determinant of the country's very low organ donation rate (8.9/million in 1999). Leading causes of refusal, identified in many studies, include the lack of understanding by families of brain death and its implications, and subsequent reluctance to relegate the body to purely instrumental status. It is an interesting paradox that surveys of the public continue to show considerable support for organ donation programmes--in theory we will, in practice we won't (and don't). In this paper we propose that the Australian community may, for good reason, distrust the concept of and criteria for "whole brain death", and the equation of this new concept with death of the human being. We suggest that irreversible loss of circulation should be reinstated as the major defining characteristic of death, but that brain-dead, heart-beating entities remain suitable organ donors despite being alive by this criterion. This presents a major challenge to the "dead donor rule", and would require review of current transplantation legislation. Brain dead entities are suitable donors because of irreversible loss of personhood, accurately and robustly defined by the current brain stem criteria. Even the dead are not terminally ill any more.

Attitude to Death↗