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There must be a defined, predisposing condition to fulfil the criteria of brainstem death in the UK. A patient presented recently in coma and with absent brainstem reflexes, but no diagnosis was initially obvious. A subsequent diagnosis of Guillain-Barré syndrome was made, and the patient made a full recovery.
Two general pathways for cell death have been defined, apoptosis and necrosis. Previous studies in Jurkat cells have demonstrated that the Fas-associated death domain (FADD) is required for Fas-mediated signaling to apoptosis and necrosis. Here we developed L929rTA cell lines that allow Tet-on inducible expression and FK506-binding protein (FKBP)-mediated dimerization of FADD, FADD-death effector domain (FADD-DED), or FADD-death domain (FADD-DD). We show that expression and dimerization of FADD leads to necrosis. However, pretreatment of the cells with the Hsp90 inhibitor geldanamycin, which leads to proteasome-mediated degradation of receptor interacting protein 1 (RIP1), reverts FKBP-FADD-induced necrosis to apoptosis. Expression and dimerization of FADD-DD mediates necrotic cell death. We found that FADD-DD is able to bind RIP1, another protein necessary for Fas-mediated necrosis. Expression and dimerization of FADD-DED initiates apoptosis. Remarkably, in the presence of caspase inhibitors, FADD-DED mediates necrotic cell death. Coimmunoprecipitation studies revealed that FADD-DED in the absence procaspase-8 C/A is also capable of recruiting RIP1. However, when procaspase-8 C/A and RIP1 are expressed simultaneously, FADD-DED preferentially recruits procaspase-8 C/A.
OBJECTIVE: To identify differences in causes of death between elderly Mexican Americans (MA) and non-Hispanic whites (NHW). DESIGN: Retrospective death certificate review. SUBJECTS: Elderly Mexican Americans and non-Hispanic Whites age 65 and over who died in Bexar County, Texas during 1989. MEASURES: Data obtained from chart review included age, sex, race/ethnicity, and cause of death. Age-adjusted and cause-specific mortality rates, odds ratios (OR), and 95% confidence intervals (CI) were calculated. RESULTS: Mexican Americans were at greater risk of dying in nine of the thirty causes of death examined. The mortality rates of MA subjects were higher than those of NHW from death caused by diabetes (OR = 3.19, CI = 2.27-4.49), renal failure (OR = 2.06, CI = 1.44-2.94), congestive heart failure (OR = 1.50, CI = 1.44-2.94), and multiple systemic diseases (OR = 2.59, CI = 1.89-3.57). Among the male subjects, MA had a greater risk than NHW of dying from myocardial infarction (OR = 1.83, CI = 1.15-2.90), coronary disease (OR = 1.37, CI = 1.07-1.75) and septicemia/pyuria (OR = 2.12, CI = 1.09-4.10). Among female subjects, MA had a greater likelihood of dying from cirrhosis (OR = 3.03, CI = 1.00-9.29). For only one of the causes of death was the risk lower among MA than NHW: MA female subjects had a lesser chance of dying from the chronic obstructive pulmonary disease (COPD) than NHW females (OR = 0.36, CI = 0.18-0.72). CONCLUSION: Mexican American elders have a greater risk of dying from non-insulin dependent diabetes mellitus and renal failure than their NHW counterparts. Elderly MA men have a greater risk of dying from cardiovascular disease than their NHW counterparts. Mexican American women may have a greater risk of dying from cirrhosis, but a lower risk of dying from complications of COPD. Finally, death from ill defined causes, such as multiple systemic diseases, may be a major under-acknowledged cause of death among older MA.
BACKGROUND: Throughout the past 50 years, heart disease has been the leading cause of death in the United States. Although declines in coronary heart disease (CHD) mortality have been noted, there is still uncertainty about the magnitude of the decline and whether the trend is similar for sudden cardiac death (SCD). METHODS AND RESULTS: We examined temporal trends in SCD and nonsudden CHD death in the Framingham Heart Study original and offspring cohorts from 1950 to 1999. SCD was defined as a death attributed to CHD with preceding symptoms that lasted less than 1 hour; all deaths were adjudicated by a physician panel. Log-linear Poisson regression was used to estimate CHD mortality and SCD risk ratios (RRs); RRs were adjusted for age and gender. There were 811 CHD deaths: 453 nonsudden and 358 SCDs. Ninety-one (20%) of nonsudden CHD deaths and 173 (48%) of SCDs were in subjects free of antecedent CHD. From 1950-1969 to 1990-1999, overall CHD death rates decreased by 59% (95% CI 47% to 68%, P(trend)<0.001). Nonsudden CHD death decreased by 64% (95% CI 50% to 74%, P(trend)<0.001), and SCD rates decreased by 49% (95% CI 28% to 64%, P(trend)<0.001). These trends were seen in men and women, in subjects with and without a prior history of CHD, and in smokers and nonsmokers. CONCLUSIONS: The risks of SCD and nonsudden CHD mortality have decreased by 49% to 64% over the past 50 years. These trends were evident in subjects with and without heart disease, which suggests important contributions of primary and secondary prevention to the decreasing risk of CHD death and SCD.
This study was conducted to assess the magnitude of maternal deaths in health units in Uganda, and the risk factors associated with such deaths. A retrospective study of maternal deaths in 20 hospitals and 54 randomly selected health centres was conducted in 12 randomly selected districts of Uganda. The reference period for documenting maternal deaths was September 1992 to September 1993. The International Classification of Diseases 10 was used to define a maternal death. Data on maternal deaths and associated risk factors was obtained from admission and patient case notes. SPSS/PC statistical package was used to carry out advanced statistical analysis. Log linear analysis was used to rank risk factors for maternal deaths. A total of 418 maternal deaths and 75,000 live births were recorded, giving a maternal mortality ratio of 557 per 100,000 live births. Three hundred and sixty (86.1%) mothers died within one hour of admission. The risk factors identified were inadequate antibiotic supply, intravenous drug fluids and blood for transfusion in health units; non-use of family planning, use of traditional medicine; mothers aged 15-19 and 30-50 years. Others included those who had a history of two or more abortions and stillbirths; parity of five and above; and living within a distance of more than 10 km to the nearest health unit. We conclude that the focus on risk factors for maternal deaths have policy implications.
Many would agree on the need to inform patients about the risks of medical conditions or treatments and to consider those risks in making medical decisions. The question is how to describe the risks and how to balance them with other factors in arriving at a decision. In this article, we present the thesis that part of the answer lies in defining an appropriate scale for risks that are often quite small. We propose that a convenient unit in which to measure most medical risks is the microprobability, a probability of 1 in 1 million. When the risk consequence is death, we can define a micromort as one microprobability of death. Medical risks can be placed in perspective by noting that we live in a society where people face about 270 micromorts per year from interactions with motor vehicles. Continuing risks or hazards, such as are posed by following unhealthful practices or by the side-effects of drugs, can be described in the same micromort framework. If the consequence is not death, but some other serious consequence like blindness or amputation, the microrisk structure can be used to characterize the probability of disability. Once the risks are described in the microrisk form, they can be evaluated in terms of the patient's willingness-to-pay to avoid them. The suggested procedure is illustrated in the case of a woman facing a cranial arteriogram of a suspected arterio-venous malformation. Generic curves allow such analyses to be performed approximately in terms of the patient's sex, age, and economic situation. More detailed analyses can be performed if desired. Microrisk analysis is based on the proposition that precision in language permits the soundness of thought that produces clarity of action and peace of mind.
SIDS cases were defined by examining all death certificates, in which sudden deaths were expected to be found from the years 1969-80 from the Central Statistical Office of Finland. The age limits were 28-364 days. If the death certificate did not give enough information as to whether the cause of death was explained or unexplained, autopsy records and microscopic specimens were examined. If the death was sudden, but no autopsy was done, no microscopic specimens were taken, or there were some slight findings which could have partly explained the death were classified as borderline cases. The mean annual incidence of SIDS in Finland was 0.41/1000 livebirths in 1969-80. In 1969-74 and 1975-80 the incidences were 0.31 and 0.51, respectively. The increasing tendency of SIDS was partly due to more borderline cases in the first period and partly due to more twins, and infants with small birth weight, dying of SIDS in the second period. Deaths at weekends and sleeping with parents in the second period were more common than in the first study period. In the SIDs group the young maternal age, low social class, family type unmarried couple or single mother, maternal anemia during pregnancy were more common than in the control group. Mothers of SIDS infants had more previous children and fewer visits and later first visit to prenatal clinics than control mothers. The duration of gestation was shorter and the mean birth weight and length were smaller in the SIDS case than in the control group. Twins were more common among SIDS infants than in the common population. The most important risk factor of SIDS was maternal smoking during pregnancy. The epidemiological results conform with the hypoxia hypotheses.
STUDY OBJECTIVES: Little is known regarding the potential effects of emergency medical services (EMS) on total heart disease mortality. Although EMS may provide health benefits in less acute cardiac conditions, its immediate, measurable, and direct effect on heart disease mortality is through resuscitation of persons suffering out-of-hospital cardiac arrest. The purpose of this study was to examine the involvement and potential mortality benefit of out-of-hospital EMS care of cardiac arrest on community heart disease mortality. METHODS: The investigation was an observational study of all persons with death events resulting from heart disease as defined by heart disease deaths and deaths averted (persons successfully resuscitated from out-of-hospital cardiac arrest by EMS) in a single county from January 1, 2000, through December 31, 2000. The county of study has a population of nearly 2 million people and is composed of urban, suburban, and rural components. State vital records and EMS reports were used to ascertain deaths resulting from heart disease and deaths averted. RESULTS: In the year 2000, 3,577 persons died as a result of heart disease, and 128 persons were successfully resuscitated and discharged from the hospital, for a total of 3,705 death events. EMS responded to 39% (1,428/3,705) of all heart disease death events and 57% (1,428/2,516) of out-of-hospital events, resulting in a 3.5% (128/3,705) reduction in overall heart disease mortality and a 5.1% (128/2,516) reduction in out-of-hospital mortality. CONCLUSION: EMS was involved in the majority of out-of-hospital heart disease death events, resulting in a measurable reduction in heart disease mortality.
Although cardiomyocyte (CM) apoptosis has been well described in both in vitro and in vivo models of ischemic heart disease, the intracellular pathways leading to CM death have not been fully characterized. To define the role of death receptor signaling in CM apoptosis, we constructed recombinant adenoviral vectors carrying wild-type (wt) or dominant negative (dn) forms of the death receptor adaptor protein FADD (Fas-associated death domain protein) and used these vectors to transduce rat neonatal CMs in models of hypoxia- and serum deprivation (SD)-induced apoptosis. The combination of SD and hypoxia induced rapid activation of caspase-3 and -8 as well as DNA fragmentation, reaching a plateau within 4-8 h. Adenoviral expression of FADD-dn inhibited caspase-8 activation as well as hypoxia/SD-induced apoptosis at 24 h in an moi (multiplicity of infection)-dependent manner. In contrast, adenoviral expression of FADD-wt increased apoptosis and caspase-3 activity in CMs under both normoxic and hypoxic conditions. Surprisingly, FADD-dn, as well as the specific caspase-8 inhibitor benzyloxycarbonyl-IETD-fluoromethylketone also inhibited the activation of caspase-9 and -3 in CMs subjected to hypoxia/SD. These data suggest a primary role for FADD/caspase-8 signaling that is necessary and sufficient for apoptosis of CMs subjected to hypoxia/SD.
We report on a retrospective study of maternal deaths in Malaysia that occurred within 24 hours of delivery, abortion or operative termination of the pregnancy (defined as sudden deaths) in the years 1995-1996. There were 131 sudden maternal deaths (20.6% of all maternal deaths); postpartum hemorrhage, obstetric embolisms, trauma and hypertensive disorders of pregnancy were the main causes. There was a disproportionately increased risk of sudden maternal deaths in the Chinese and the 'other bumiputra' racial groups. The proportion of mothers who had no obstetric risk factors in the pregnancy that led to death was 16.8%. Fourteen mothers died in transit Twenty mothers died after a cesarean section. The findings of this review emphasize the fact that caregivers in obstetrics need to be forever vigilant. All maternity staff need to be well trained in emergency care and there needs to be quick referral to centers that can provide expertise in handling these emergencies.
Active cell death in hormone-dependent cells was studied using cultured human mammary carcinoma cells (MCF-7) treated with the anti-estrogens (AEs) tamoxifen (TAM), 4-hydroxy-tamoxifen (OH-TAM) or ICI 164 384 (10(-8)-10(-5) M) as a model. The following results were obtained. (i) In untreated MCF-7 cells a wave of replication occurred in the first 5 days of culture. All three AEs caused a dose-dependent inhibition of cell replication. (ii) TAM and OH-TAM at 10(-5) M, but not ICI 164 384, caused lytic cell death (necrosis) within 24 h, which was not inhibited by estradiol (10(-9)-10(-6)M). (iii) Lower concentrations of TAM or OH-TAM (up to 10(-6) M) or ICI 164 384 induced a more gradual appearance of cell death beginning at day 3. This type of cell death was inhibited by estradiol (10(-9) M), indicating its active nature. (iv) Nuclei showed two distinct patterns of alteration: (a) apoptosis-like condensation and fragmentation of chromatin to crescent masses abutting the nuclear envelope; (b) condensation of the chromatin to a single, pyknotic mass in the center of the nucleus, detached from the nuclear envelope. Quantitative histological evaluation revealed the predominance of pyknosis. (v) Biochemical DNA analysis revealed that only a relatively small amount of the total DNA was finally degraded into low molecular weight fragments (20 kb and less). (vi) Active cell death, with both apoptotic and pyknotic nuclear morphology, was associated with extensive formation of autophagic vacuoles (AV).3-Methyladenine, a known inhibitor of AV formation, partially prevented cell death as detected by nuclear changes. (vii) ICI 164 384 was about 10 times more effective than TAM or OH-TAM at inhibiting DNA synthesis, but had equal potency in inducing active cell death. It is concluded that AEs have anti-proliferative and anti-survival effects on MCF-7 human mammary cancer cells in culture. These two effects are under separate control because they differ by kinetics, dose dependence and sensitivity to the various AEs. Active cell death in MCF-7 cells seems to be initiated by autophagy, in contrast to concepts of apoptosis, and thus corresponds to autophagic/ lysosomal or type II death as previously defined. This may be important because of biochemical and molecular differences between these various subtypes of active cell death.
We studied retrospectively a series of 96 patients (36 men, 60 women), older than 65 years of age (mean age: 70 +/- 4 years, range 65-82), operated upon for an intracranial meningioma from October 1978 to December 1988. Fifty-two patients (54%) were under 70, 32 between 71 and 75 and 12 over 75 (46%). The tumours were diagnosed for all the patients by CT scan. Thirty-four (35%) were located over the convexity, 24 (25%) in the falx/parasagittal region, 38 (40%) in the base, tentorium and posterior fossa. Neurological and physical conditions were assessed preoperatively and at the closing date in June 1989. Operative mortality was 16% (15/96). Patients were divided into two groups: poor outcome, defined by the death or a post-operative Karnofsky index less than or equal to 70 (n = 36), and good outcome defined by a Karnofsky index of 80 or more (n = 60). The two groups did not differ regarding age, sex ratio, tumour size and peritumoural oedema. The only predictors of poor outcome were poor preoperative general health condition (stage III of the American Society of Anesthesiology classification), (p less than 0.01), poor preoperative neurological condition (Karnofsky's index) (p less than 0.001), and location of the tumour on the base or in posterior fossa (p = 0.02).
ISS-IP1, a multicenter, randomized, 48-week open trial, was designed to compare the introduction of ritonavir or indinavir in patients with previous nucleoside experience and CD4+ cell counts below 50/mm3. Concomitant antiretroviral treatment with nucleoside analogs was allowed. Primary efficacy measures were survival and time to a new AIDS-defining event or death, analyzed through the whole period of observation by the intention-to-treat approach. Primary toxicity measures were time to treatment discontinuation and adverse events, grade at least 3/serious, analyzed by an on-treatment approach. Evaluation-of efficacy also included CD4+ cell and RNA response. The trial enrolled 1251 patients in 5 months. At baseline, mean CD4+ cell count was about 20 cells/mm3 and mean HIV RNA copy number was 4.9 log10/ml in both groups. Overall, 402 patients in the ritonavir group and 250 patients in the indinavir group permanently discontinued the assigned treatment (relative risk, 1.96; 95% CI, 1.68-2.30; p = 0.0001), with most of this difference dependent on a higher number of discontinuation for adverse events in the ritonavir group. After a mean follow-up of 307 days (ritonavir, 304; indinavir, 309), 124 deaths (ritonavir, 61; indinavir, 63; relative risk, 0.96; 95% CI, 0.67-1.36; p = 0.80) and 330 new AIDS-defining events (ritonavir, 170; indinavir, 160; relative risk, 1.05; 95% CI, 0.85-1.31; p = 0.60) were observed. CD4+ cell counts increased in both groups in patients still receiving treatment, with about 100 cells gained by week 24 and 150 cells gained by week 48. Body weight also increased over time in both groups. Analysis of RNA response showed a decrease of 1.5 log10 or higher in both treatment groups. Overall, 400 patients in the ritonavir group and 338 patients in the indinavir group developed at least one grade 3/serious new adverse event during follow-up (relative risk, 1.48; 95% CI, 1.28-1.72; p = 0.0001). Favorable CD4+ cell and RNA responses at 24 and 48 weeks were observed in both groups of patients remaining on treatment. Indinavir showed slightly better effects in sustaining RNA, CD4+ cell, and body weight responses. Ritonavir and indinavir results were comparable in terms of clinical outcome (survival and AIDS-defining events).
Many developing neural systems with peripheral projections depend on their target for trophic support during a critical period of natural cell death. Much less is known about central systems. That dopaminergic neurons of the substantia nigra may depend on their target, the striatum, during development is suggested by the presence of a natural apoptotic cell death event in these neurons that can be augmented by an early developmental axon-sparing striatal injury. To further assess the target dependence of these neurons, we have used the selective neurotoxin 6-hydroxydopamine to lesion their terminals within the striatum during development, while sparing intrinsic striatal target neurons. This lesion results in an induction of apoptotic cell death in phenotypically defined dopaminergic neurons that appears on the third postlesion day and persists until the tenth. This inducibility of cell death is dependent on developmental age: it is most marked before postnatal day (PND) 14. As late as PND42, inducibility is still detectable but much less so. In addition, at day 42 the morphology of cell death changes and becomes nonapoptotic in some cells. We conclude that terminal injury during a critical period of postnatal development, like axon-sparing target injury, induces augmented apoptotic death in mesencephalic dopaminergic neurons. These results suggest that these neurons have a period of target dependence. Regulation of this dependence is likely to influence the mature adult number of dopaminergic neurons.
Great progress in anaesthetic techniques has resulted in elimination or significant reduction of complications connected with the disease, operation technique or anaesthesia. However, sometimes a rapid increase in systemic metabolism occurs immediately after induction of anaesthesia and it may end in the patient's death. This syndrome defined as malignant hyperpyrexia (MH) was described for the first time by Denborough and Lovell (2). They reported 10 deaths of this type in one family. Later it was noticed that some patients may develop MH after inhalation anaesthetics or suxametonium. MH was observed more frequently in several groups of patients. It occurs rarely--1 to 15,000 cases after anaesthesia in children and 1 to 50,000 cases after anaesthesia in adults, but its sudden and rapid development becomes a great clinical problem.
BACKGROUND: Before highly active antiretroviral therapy (HAART) became available, cytomegalovirus was a major cause of opportunistic infection in HIV-infected patients and was associated with accelerated progression to AIDS and death. We have investigated whether cytomegalovirus viraemia remains a significant risk factor for progression of HIV disease and death in the era of HAART. METHODS: 374 patients whose CD4-cell count had ever been below 100 per microL were enrolled in a prospective study. Serial blood samples were tested for cytomegalovirus by PCR. Rates of new cytomegalovirus disease, new AIDS-defining disorders, and death were calculated over a median follow-up of 37 months after stratification according to baseline and most recent cytomegalovirus PCR status at any point during follow-up. FINDINGS: Of 2969 PCR assays, 375 (12.6%) were positive for cytomegalovirus DNA. 259 (69.3%) patients were persistently negative for cytomegalovirus by PCR; 15 were persistently positive; and 100 were intermittently positive and negative. In multivariate models, cytomegalovirus PCR-positive status as a time-updated covariate was significantly associated with increased relative rates of progression to a new AIDS-defining disorder (2.22 [95% CI 1.27-3.88] p=0.005) and death (4.14 [1.97-8.70] p=0.0002). INTERPRETATION: Detection of cytomegalovirus in blood by PCR continues to identify patients with a poor prognosis, even in the era of HAART. Randomised controlled clinical trials of drugs active against cytomegalovirus are needed to investigate whether this virus is a marker or a determinant of HIV disease progression.
BACKGROUND: The introduction of an effective antiplatelet therapy with aspirin and ticlopidine after the placement of coronary-artery stents has decreased the risk of thrombotic stent occlusions (TSO) and hemorrhagic complications. However, the use of ticlopidine is limited by hematological and gastrointestinal adverse effects. The safety and efficacy of clopidogrel after stenting remains to be established. METHODS AND RESULTS: After successful coronary stenting during elective or emergency percutaneous transluminal coronary angioplasty, 700 patients with 899 lesions were randomly assigned to receive a 4-week course of either 500 mg ticlopidine (n=345) or 75 mg clopidogrel (n=355), in addition to 100 mg aspirin. All the following clinical events reflecting TSO were included in the prespecified primary cardiac endpoint: cardiac death, urgent target vessel revascularization, angiographically documented TSO, or nonfatal myocardial infarction within 30 days. The primary noncardiac endpoint was defined as noncardiac death, stroke, severe peripheral vascular or hemorrhagic events, or any adverse event resulting in discontinuation of study medication. Cardiac events occurred in 17 patients [11 (3.1%) with clopidogrel and 6 (1.7%) with ticlopidine (P=0.24)]. The primary noncardiac endpoint was observed in 16 patients (4.5%) assigned to receive clopidogrel versus 33 patients (9.6%) assigned to receive ticlopidine (P=0.01). CONCLUSIONS: After the placement of coronary-artery stents in unselected patients, antiplatelet therapy with aspirin and clopidogrel seems to be comparably safe and effective as aspirin and ticlopidine. Noncardiac events were significantly reduced with clopidogrel.
BACKGROUND: To define infant care practices in maternity units and those subsequently adopted at home. Using these data, we evaluated the acceptance and application of recommendations issued by the previous public education campaign on infant sleeping position as related to sudden infant death syndrome. PATIENTS AND METHODS: A survey was carried out in two maternity units (Port-Royal and Créteil) and in one pediatric consultation unit (affiliated with Port-Royal maternity). RESULTS: The mixed position (side or back) is used equally with, respectively, 47% at Port-Royal and 45% at Créteil. The supine sleeping position (French public health recommendations) is used by 12% of the mothers at Port-Royal and by 40% at Créteil. It appears that hospital nurseries play an important role in determining the mother's preference for the sleeping position (64% at Port-Royal and 54% at Créteil), but it does not adequately explain all mothers' responses. However, as the infants mature (> two months old), the more spontaneously they changed their sleeping position. All the infants placed in a side sleeping position moved to a supine sleeping position during the night. Upon awakening, infants were found mostly in the supine position (in contrast to the national public education campaign). CONCLUSION: Our results show that mothers and hospital nurseries were distressed in terms of ensuring the supine sleeping position of the infant. New choices of sleeping positions were initiated by mothers. For example, they used the side position after feedings essentially in the case of reflux or during the daytime. The supine position was used when the mothers were assured that any problems had been avoided or only during the night.