The Myocardial Ischemia Reduction with Acute Cholesterol Lowering trial: MIRACuLous or not, it's time to change current practice

The Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) study was the first trial to assess whether statins might be of clinical benefit in those with recently unstable coronary disease. MIRACL found that high-dose atorvastatin was safe and reduced the incidence of the composite endpoint, death, non-fatal myocardial infarction, resuscitated sudden cardiac death or emergent rehospitalization for recurrent ischemia at 16 weeks when compared with placebo. Despite a number of important study limitations, MIRACL's findings and the prior observation that inpatient initiation of lipid-lowering therapy is associated with higher rates of subsequent utilization, suggest that it is prudent to begin statin therapy when patients present with an acute coronary syndrome.     

The Myocardial Ischemia Reduction with Acute Cholesterol Lowering (MIRACL) trial: a new frontier for statins?

The Myocardial Ischemia Reduction with Acute Cholesterol Lowering (MIRACL) Trial tested the hypothesis that intensive lowering of cholesterol with atorvastatin (80 mg/day) initiated 24-96 h after an acute coronary syndrome would, over 4 months, reduce the incidence of the composite endpoint of death, nonfatal infarction, resuscitated cardiac arrest, and recurrent symptomatic myocardial ischemia with new objective symptoms requiring emergency rehospitalization. This primary composite endpoint was reduced from 17.4% to 14.8% (P = 0.048) among the 3086 patients enrolled. The results of MIRACL suggest that patients with acute coronary syndromes should begin to receive this treatment before leaving hospital, irrespective of baseline levels of low-density lipoprotein-cholesterol.     

Intensive statin therapy in acute coronary syndromes: clinical benefits and vascular biology

PURPOSE OF REVIEW: The results of a landmark clinical study comparing intensive statin therapy with conventional statin therapy, in patients with acute coronary syndromes (ACS), are reviewed. The mechanisms behind these results are analysed drawing data from vascular and cell biology. RECENT FINDINGS: The Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction (PROVE IT-TIMI 22) study showed that intensive statin therapy with 80 mg of atorvastatin to achieve a low-density lipoprotein cholesterol of 62 mg/dl resulted in a 3.9% absolute and a 16% relative risk reduction in death or major cardiovascular events up to 2 years, compared to 40 mg of pravastatin, in patients with ACS. The results were especially significant as intensive statin therapy resulted in a very early benefit (<30 days) and occurred against a background of percutaneous coronary intervention (69%) for the index admission and high use of medications for secondary prevention. The PROVE IT and the Myocardial Ischaemia Reduction with Aggressive Cholesterol Lowering (MIRACL) C-reactive protein sub-study also showed that atorvastatin (80 mg) resulted in a significant reduction in markers of inflammation, whilst the Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) study showed that intensive statin therapy was associated with reduced progression of atherosclerosis compared with conventional doses of statins. SUMMARY: Intensive statin therapy results in a significant early reduction in adverse cardiac events in ACS patients which are sustained over 2 years. The early benefits seen are likely to result from modulation of inflammation, endothelial function and coagulation, i.e. the pleiotropic effects, whereas the greater reduction in low-density lipoprotein cholesterol results in reduced long-term events.     

Lipid management after acute coronary syndrome

PURPOSE OF REVIEW: Despite advances in medical therapy and percutaneous revascularization, patients with acute coronary syndrome face a high risk of early, recurrent cardiovascular events. Interventions targeting atherogenic lipoproteins may favorably modify this risk. RECENT FINDINGS: Two randomized clinical trials, MIRACL and PROVE-IT, demonstrated efficacy of early, intensive statin therapy after acute coronary syndrome. Recent observational and meta-analyses corroborate the findings of these trials. The benefit of intensive statin treatment appears to apply broadly to elderly as well as younger patients, and to patients with or without diabetes or metabolic syndrome. Randomized trials demonstrating the efficacy of early, intensive statin treatment after acute coronary syndrome employed fixed statin dosages, and there does not appear to be an initial or achieved LDL-cholesterol level below which benefit is absent. As such, broad application of intensive statin therapy after acute coronary syndrome may be preferable to titration of statin dose to achieve specific LDL goals. Low HDL-cholesterol predicts risk after acute coronary syndrome; therefore, pharmacologic interventions to raise HDL concentration or mimic its function may help reduce that risk. SUMMARY: Early, intensive statin therapy is safe and effective after acute coronary syndrome. Future research will determine whether drugs that raise or mimic HDL-cholesterol are effective adjuncts to statin therapy.     

Coronary heart disease mortality and radon exposure in the Newfoundland fluorspar miners’ cohort, 1950–2001

Kreuzer and coworkers recently reported no association between cumulative exposure to radiation and death from cardiovascular disease in a cohort of German uranium miners. Here, we report on the relationship between cumulative exposure to radon progeny and coronary heart disease among Newfoundland fluorspar miners. Previous analyses in this cohort found elevated death rates from coronary heart disease among those with higher cumulative radon exposure. However, this finding was based on a relatively small number of deaths and was not statistically significant. Since then, the follow-up of this cohort has been extended by 10 years until the end of 2001. Among the 2,070 miners in our study, 267 died from coronary heart disease. There was no trend evident between cumulative exposure to radon and the relative risk of death from coronary heart disease (P = 0.63). This finding was unchanged after adjusting for the lifetime smoking status that was available for approximately 54% of the cohort. Similarly, the cumulative radon exposure was found to be unrelated to deaths of the circulatory system, acute myocardial infarction, and cerebrovascular disease. These findings are consistent with those recently reported by Kreuzer and colleagues. We share their view that uncontrolled confounding for other coronary heart disease risk factors hinders the interpretation of the risk estimates.     

Relation of low diastolic blood pressure to coronary heart disease death in presence of myocardial infarction: the Framingham Study.

OBJECTIVE--To examine the hypothesis that a J curve relation between blood pressure and death from coronary heart disease is confined to high risk subjects with myocardial infarction. DESIGN--Cohort longitudinal epidemiological study with biennial examinations since 1950. SETTING--Framingham, Massachusetts, USA. SUBJECTS--5209 subjects in the Framingham study cohort followed up by a person examination approach. MAIN OUTCOME MEASURES--Coronary heart disease deaths and non-cardiovascular disease deaths in men and women with or without myocardial infarction relative to blood pressure. RESULTS--Among subjects without myocardial infarction non-cardiovascular disease deaths were twice to three times as common as coronary heart disease deaths. Furthermore, there was no significant relation between non-cardiovascular disease death and diastolic or systolic blood pressure. Also coronary heart disease deaths were linearly related to diastolic and systolic blood pressures. Among high risk patients (that is, people with myocardial infarction but free of congestive heart failure) death from coronary heart disease was more common than non-cardiovascular disease death. There was a significant U shaped relation between coronary heart disease death and diastolic blood pressure. Although there was an apparent U shaped relation between coronary heart disease death and systolic blood pressure, it did not attain statistical significance when controlling for age and change in systolic blood pressure from the pre-myocardial infarction level. None of the above conclusions changed when adjustments were made for risk factors such as serum cholesterol concentration, antihypertensive treatment, and left ventricular function. The U shaped relation between diastolic blood pressure and high risk subjects existed for both those given antihypertensive treatment and those not. CONCLUSIONS--These data suggest that an age and sex independent U curve relation exists for diastolic blood pressure and coronary heart disease deaths in patients with myocardial infarction but not for low risk subjects without myocardial infarction. The relation seems to be independent of left ventricular function and antihypertensive treatment.     

Revascularization in the acute coronary syndromes

Coronary heart disease is the leading cause of death worldwide, and occurs when the coronary arteries are unable to supply adequate oxygenated blood to the myocardium, which in turn can lead to ischemia and infarction of myocardial tissue. There are three options for revascularization in the setting of acute coronary syndromes. In select patients, coronary artery bypass surgery remains an option. Thrombolytics were initially the mainstay of therapy, which has now shifted to angioplasty, with or without stents, when readily available. Revascularization has been demonstrated to improve patient outcomes, and has evolved rapidly in the recent past.     

Seasonality and Coronary Heart Disease Deaths in United States Firefighters

United States firefighters have a high on‐duty fatality rate, and coronary heart disease is the leading cause. Seasonality affects the incidence of cardiovascular events in the general population, but its effects on firefighters are unknown. This study statistically examined the seasonal and annual variation of all on‐duty coronary heart disease deaths among US firefighters between 1994 and 2004 using the chi‐square distribution and Poisson regression model of the monthly fatality counts. It also examined the effect of ambient temperature (apparent as well as wind chill temperature) on coronary heart disease fatalities during the study span using a time‐stratified, case‐crossover study design. When grouped by season, we observed the distribution of the 449 coronary heart disease fatalities to show a relative peak in winter (32%) and relative nadir in spring (21%). This pattern was significantly different (p=0.005) from the expected distribution under the null hypothesis of season having no effect. The pattern persisted in additional analyses, stratifying the deaths by the type of duty in which the firefighters were engaged at the time of their deaths. In the Poisson regression model of the monthly fatality counts, the overall goodness‐of‐fit between the actual and predicted case counts was excellent (χ₄²=16.63; p=0.002). Two distinct peaks were detected: one in January–February and the other in August–September. Overall temperature was not associated with increased risk of on‐duty death. After allowing for different effects of temperature in mild/hot versus cold periods, a 1°C increase was not protective in cold weather; nor did it increase the risk of death in warmer weather. The findings of this study reveal statistical evidence for excess coronary heart disease deaths among firefighters during winter; however, the temporal pattern of coronary heart disease deaths was not linked to temperature variation. The seasonal pattern was also found to be independent of duty‐related risks.     

Antithrombotic therapy

Coronary heart disease is the leading cause of death in the US and the industrialized world. Ever since DeWood in 1980 demonstrated that a thrombus was the primary event leading to acute myocardial infarction and that they may subsequently lyse, the mainstay of therapy for the past 25 years has been antithrombotic therapy aimed at coronary thrombosis. There have been numerous advances in the treatment of acute coronary syndrome with antiplatelet, antithrombotic, and fibrinolytic agents that have significantly reduced morbidity and mortality. The role of various pharmaceutical agents in the different phases of acute coronary syndrome is a complex and ever changing field.7.     

Death feigning as an adaptive anti‐predator behaviour: Further evidence for its evolution from artificial selection and natural populations

Death feigning is considered to be an adaptive antipredator behaviour. Previous studies on Tribolium castaneum have shown that prey which death feign have a fitness advantage over those that do not when using a jumping spider as the predator. Whether these effects are repeatable across species or whether they can be seen in nature is, however, unknown. Therefore, the present study involved two experiments: (a) divergent artificial selection for the duration of death feigning using a related species T. freemani as prey and a predatory bug as predator, demonstrating that previous results are repeatable across both prey and predator species, and (b) comparison of the death‐feigning duration of T. castaneum populations collected from field sites with and without predatory bugs. In the first experiment, T. freemani adults from established selection regimes with longer durations of death feigning had higher survival rates and longer latency to being preyed on when they were placed with predatory bugs than the adults from regimes selected for shorter durations of death feigning. As a result, the adaptive significance of death‐feigning behaviour was demonstrated in another prey–predator system. In the second experiment, wild T. castaneum beetles from populations with predators feigned death longer than wild beetles from predator‐free populations. Combining the results from these two experiments with those from previous studies provided strong evidence that predators drive the evolution of longer death feigning.     

Evidence-based management of coronary artery disease in the elderly--current perspectives

Cardiovascular disease accounts for significant morbidity and mortality in the elderly. The clinical trial data available to guide therapy in this growing population subset are relatively limited. This review will focus on treatment approaches and recommendations obtained from subgroup analyses of elderly patients from major clinical trials for the management of chronic stable angina, acute coronary syndromes (unstable angina and non-ST-segment elevation myocardial infarction), and coronary revascularization. Recent advances in the treatment of stable angina have shown that use of angiotensin-converting enzyme inhibitors and lipid-lowering therapy as adjunctive measures show benefit in the elderly by reducing the occurrence of death, nonfatal myocardial infarction, and unstable angina. However, if patients experience disabling or unstable anginal symptoms despite effective medical therapy, coronary revascularization must be considered. Several clinical trials have shown a significant reduction in major adverse cardiac events when using intravenous glycoprotein receptor antagonists periprocedurally during percutaneous revascularization approaches in elderly patients with unstable angina or non-ST-segment elevation myocardial infarction, especially when these measures are performed as soon as possible. However, the success of myocardial revascularization by a percutaneous or surgical approach is highly dependent on the patient's associated comorbidities, especially in patients over age 80 years.     

Protecting the heart: a practical review of the statin studies

The aim of this review of the landmark HMG-CoA reductase inhibitors (statins) studies is to enable the clinician to draw practical lessons from these trials. The Scandinavian Simvastatin Survival Study (4S) established the importance of treating the hypercholesterolemic patient with established cardiovascular heart disease. The West of Scotland Coronary Prevention Study (WOSCOPS) showed the benefit of treating healthy hypercholesterolemic men who were nevertheless at high risk of developing cardiovascular heart disease in the future. The Cholesterol and Recurrent Events (CARE) study, a secondary prevention trial, proved the benefit of treating patients with myocardial ischemia and cholesterol levels within normal limits. This conclusion was confirmed by the Long-term Intervention With Pravastatin in Ischemic Disease (LIPID) study, another secondary prevention study that enrolled patients with a wide range of cholesterol levels (4-7 mmol/dL), into which the large majority of patients would belong. The importance of treating patients with established ischemic heart disease (IHD), and those at high risk of developing cardiovascular heart disease, regardless of cholesterol level, was being realized. The Air Force/Texas Coronary Artery Prevention Study (AFCAPS/TexCAPS) then showed that treatment can reduce adverse cardiovascular events even in the primary prevention of patients with normal cholesterol levels. The Myocardial Ischemia Reduction With Aggressive Cholesterol Lowering (MIRACL) trial showed that hypocholesterolemic therapy is useful in the setting of an acute coronary syndrome, while the Atorvastatin Versus Revascularisation Treatment (AVERT) study showed that aggressive statin therapy is as good as angioplasty in reducing ischemic cardiac events in patients with stable angina pectoris. Finally, the Heart Protection Study (HPS) randomized more than 20,000 patients, and the value of statins in reducing adverse cardiovascular events in the high-risk patient, including the elderly, women, and even in those with low cholesterol levels, is beyond doubt. The emphasis is now on the risk level for developing cardiovascular events, and treatment should target the high-risk group and not be dependent on the actual cholesterol level of the patient. It is interesting to compare the large amount of data on the value and safety of the statins with the much more limited and less convincing data on antioxidant vitamins.     

Rheumatoid arthritis is an independent risk factor for multi-vessel coronary artery disease: a case control study

The risk for cardiovascular (CV) disease is increased in rheumatoid arthritis (RA) but data on the burden of coronary atherosclerosis in patients with RA are lacking. We conducted a retrospective case-control study of Olmsted County (MN, USA) residents with RA and new-onset coronary artery disease (CAD) (n = 75) in comparison with age-and sex-matched controls with newly diagnosed CAD (n = 128). Angiographic scores of the first coronary angiogram and data on CV risk factors and CV events on follow-up were obtained by chart abstraction. Patients with RA were more likely to have multi-vessel coronary involvement at first coronary angiogram compared with controls (P = 0.002). Risk factors for CAD including diabetes, hypertension, hyperlipidemia, and smoking history were not significantly different in the two cohorts. RA remained a significant risk factor for multi-vessel disease after adjustment for age, sex and history of hyperlipidemia. The overall rate of CV events was similar in RA patients and controls; however, there was a trend for increased CV death in patients with RA. In a nested cohort of patients with RA and CAD (n = 27), we measured levels of pro-inflammatory CD4⁺CD28^null T cells by flow cytometry. These T cells have been previously implicated in the pathogenesis of CAD and RA. Indeed, CD4⁺CD28^null T cells were significantly higher in patients with CAD and co-existent RA than in controls with stable angina (P = 0.001) and reached levels found in patients with acute coronary syndromes. Patients with RA are at increased risk for multi-vessel CAD, although the risk of CV events was not increased in our study population. Expansion of CD4⁺CD28^null T cells in these patients may contribute to the progression of atherosclerosis.     

Genotype-guided antiplatelet therapy compared with conventional therapy for patients with acute coronary syndromes: a systematic review and meta-analysis

To evaluate whether genotype-guided antiplatelet therapy reduces the rates of cardiovascular events and bleeding events in patients with acute coronary syndrome (ACS). We systematically searched Pubmed, Embase and the Cochrane Central Register of Controlled Trials (CENTRAL) (searched in September 2018) for controlled studies evaluating genotype-guided antiplatelet therapy in ACS with percutaneous coronary intervention (PCI) or without PCI. The primary endpoint was a composite of death, myocardial infarction (MI), stroke, targeted vessel revascularization and/or major bleeding. A total of five studies involving 2900 patients were included. Compared with the conventional group, the genotype-guided group had a decreased risk of primary composite outcomes (RR= 0.54; 95% CI: 0.41–0.72; I² = 30%), death (RR = 0.54; 95% CI: 0.32–0.94; I² = 21%), MI (RR = 0.52; 95% CI: 0.31–0.88; I² = 49%), targeted vessel revascularization (RR = 0.59; 95% CI: 0.35–0.98; I² = 0%), but not for stroke (RR = 0.53; 95% CI: 0.22–1.24; I² = 0%) and bleeding events (RR = 0.80; 95% CI: 0.51–1.25; I² = 33%). Genotype-guided strategies could reduce the rates of cardiovascular events without increasing bleeding events compared with conventional treatment in ACS. Future multi-centre genotype-based randomized control trials are required to confirm these findings.     

Early detection of gastric cancer after Helicobacter pylori eradication due to endoscopic surveillance

Background

Helicobacter pylori eradication therapy is commonly performed to reduce the incidence of gastric cancer. However, gastric cancer is occasionally discovered even after successful eradication therapy. Therefore, we examined the prognosis of gastric cancer patients, diagnosed after successful H. pylori eradication therapy.

Materials and Methods

All‐cause death rates and gastric cancer‐specific death rates in gastric cancer patients who received successful H. pylori eradication treatment was tracked and compared to rates in patients who did not receive successful eradication therapy.

Results

In total, 160 gastric cancer patients were followed‐up for up to 11.7 years (mean 3.5 years). Among them, 53 gastric cancer patients received successful H. pylori eradication therapy prior to gastric cancer diagnosis. During the follow‐up period, 11 all‐cause deaths occurred. In the successful eradication group, the proportion of patients with cancer stage I was higher. The proportions of patients who received curative endoscopic therapy and endoscopic examination in the 2 years prior to gastric cancer diagnosis were also higher in the successful eradication group. Kaplan–Meier analysis of all‐cause death and gastric cancer‐specific death revealed a lower death rate in patients in the successful eradication group (P = .0139, and P = .0396, respectively, log‐rank test). The multivariate analysis showed that endoscopy within 2 years before cancer diagnosis is associated with stage I cancer.

Conclusions

Possible early discovery of gastric cancer after H. pylori eradication due to regular endoscopic surveillance may contribute to better prognosis of patients with gastric cancer.     

Evidence-based management of acute myocardial infarction in the elderly--current perspectives

Cardiovascular disease accounts for significant morbidity and mortality in the elderly. Despite several, large cardiovascular clinical trials, data to guide therapy in this growing population subset are relatively limited. This review focuses on treatment approaches and recommendations for the management of elderly patients with acute myocardial infarction (MI) obtained from subgroup analyses from major clinical trials.Treatment options for acute MI in the elderly have changed dramatically since the 1990s. Reperfusion therapy by primary percutaneous coronary intervention has superseded the use of thrombolytic therapy for the treatment of acute ST-elevation myocardial infarction (STEMI). Clinical trial data have demonstrated that even transferring patients to facilities that have primary angioplasty capabilities is better than thrombolytic therapy, if the anticipated transfer time is of acceptable duration. Additionally, adjunctive use of the intravenous glycoprotein (GP) receptor antagonist, abciximab, during primary angioplasty affords a reduction in the composite primary end point of death, reinfarction, and target vessel revascularization, with much of the benefit derived from the latter. Thrombolytic therapy, barring any contraindication, must be used when mechanical revascularization is not available; however, the risk for complications in the elderly is higher, especially for those 75 years and older. Studies investigating the use of thrombolytics plus GP receptor antagonists with and without percutaneous coronary intervention show questionable benefit in the elderly.     

Soluble urokinase plasminogen activator receptor as a long-term prognostic biomarker in acute coronary syndromes

Abstract

Purpose: The aim of our study was to analyse the long-term prognostic value of soluble urokinase plasminogen activator receptor (suPAR) in the setting of an acute coronary syndrome (ACS).

Methods: We included 340 patients with an ACS who underwent coronary angiography and plasma suPAR concentration was measured. Patients were classified into low suPAR concentrations (<2.6?ng/mL) and high suPAR concentrations (≥2.6?ng/mL) and long-term events were evaluated. suPAR prognostic value was assessed beyond a clinical model that included age, GRACE score, estimated glomerular filtration rate, cardiac troponin-I peak and left ventricular ejection fraction <40%.

Results: Higher suPAR concentrations were associated with an increased prevalence of cardiovascular risk factors. After multivariate adjustment, suPAR ≥2.6?ng/mL were independently associated with an increased risk of all-cause death (HR 2.3; 95%CI 1.2–4.4; p?=?.017), major adverse cardiovascular events (MACE) (HR 1.7; 95%CI 1.1–2.5; p?=?.020) and heart failure (HR 4.1; 95%CI 1.3–12.6; p?=?.015), but not with myocardial infarction. For long-term all-cause death significant improvement of reclassification and discrimination were seen after addition of suPAR to a clinical model.

Conclusions: In the setting of an ACS, suPAR is associated with long-term all-cause death, heart failure and MACE, and provides incremental prognostic value beyond traditional risks factors.     

Autophagy activity contributes to programmed cell death in Caenorhabditis elegans

The physiological relationship between autophagy and programmed cell death during C. elegans development is poorly understood. In C. elegans, 131 somatic cells and a large number of germline cells undergo programmed cell death. Autophagy genes function in the removal of somatic cell corpses during embryogenesis. Here we demonstrated that autophagy activity participates in germ-cell death induced by genotoxic stress. Upon γ ray treatment, fewer germline cells execute the death program in autophagy mutants. Autophagy also contributes to physiological germ-cell death and post-embryonic cell death in ventral cord neurons when ced-3 caspase activity is partially compromised. Our study reveals that autophagy activity contributes to programmed cell death during C. elegans development.     

Glutathione peroxidase 1 (<Emphasis Type="Italic">GPX1</Emphasis>) single nucleotide polymorphism Pro198→Leu: Association with life span and coronary artery disease

In this study, we genotyped polymorphism in GPX1 Pro198→Leu (C→T) rs 1050450 in four groups, i.e., patients with coronary artery disease, people who lived a long time (over 90 years), people who died early (before 55 years) from cardiovascular disease, and the Russian population as a control group. We have found a significant higher T-allele frequency in men with coronary artery disease, i.e., 34.84% (χ² = 5.228, p = 0.022; OR =1.46), and in men who died early from cardiovascular diseases, 38.16% (χ² = 6.461, p = 0.011; OR = 1.69) compared to men in the control group, 26.8%. Moreover, a significantly higher genotype TT frequency has been shown in patients with coronary artery disease and myocardial infarction before age 50, which is 19.44% compared to the control group, which was 7.28% (χ² = 9.55, p = 0.002). The TT frequency in individuals who lived a long time (4.39%) was the lowest and differed significantly from the group with coronary artery disease, which was 12.79% (χ² = 8.07, p = 0.0045), and from the subgroup with coronary artery disease with myocardial infarction before age 50, which was 19.44% (χ² = 14.49, p = 0.0001). Thus, our results indicate that the TT allele (Leu) of GPX1 Pro198→Leu (C > T) polymorphism is unfavorable for successful aging; it leads to predisposition to coronary artery disease, early myocardial infarction (before age 50), and early death (before age 55).     

Biochemical characterization of programmed cell death in NGF-deprived sympathetic neurons

Young sympathetic neurons die when deprived of nerve growth factor (NGF). Under such circumstances, cell death is appropriate to the developing nervous system and requires RNA and protein synthesis. We have hypothesized the existence of an endogenous death program within neurons that is suppressed by trophic factors. The extent and timing of required changes in the synthetic events that comprise the death program are unknown. In an effort to characterize the biochemical events that mediate the death program further, we performed several experiments on embryonic rat sympathetic neurons in vitro. The death program was blocked with cycloheximide when total protein synthesis was inhibited ≥80%. When protein synthesis was inhibited within 22 ± 4 h of NGF deprivation, death was prevented in half the neurons. Hence, we define the commitment point for protein synthesis to be 22 ± 4 h. Analogously, the commitment point for RNA synthesis was 26 ± 4 h and that for NGF rescue, 24 ± 4 h. We tested the ability of a wide variety of chemicals to interfere with the death program. Most compounds tested were unable to prevent neuronal death. Some treatments, however, did save NGF-deprived neurons and were subsequently characterized. These included ultraviolet light and agents that raise intracellular concentrations of cAMP. Finally, we looked for the neuronal expression in vitro and in vivo of genes that have been associated with programmed death in other cell types, including TRPM-2/SGP-2, polyubiquitin, TGFβ-1, c-fos, and c-myc. None of these genes showed significant activation associated with neuronal death. © 1992 John Wiley & Sons, Inc.