The aerosol box for intubation in coronavirus disease 2019 patients: an in-situ simulation crossover study.

The coronavirus disease 2019 pandemic has led to the manufacturing of novel devices to protect clinicians from the risk of transmission, including the aerosol box for use during tracheal intubation. We evaluated the impact of two aerosol boxes (an early-generation box and a latest-generation box) on intubations in patients with severe coronavirus disease 2019 with an in-situ simulation crossover study. The simulated process complied with the Safe Airway Society coronavirus disease 2019 airway management guidelines. The primary outcome was intubation time; secondary outcomes included first-pass success and breaches to personal protective equipment. All intubations were performed by specialist (consultant) anaesthetists and video recorded. Twelve anaesthetists performed 36 intubations. Intubation time with no aerosol box was significantly shorter than with the early-generation box (median (IQR [range]) 42.9 (32.9-46.9 [30.9-57.6])s vs. 82.1 (45.1-98.3 [30.8-180.0])s p = 0.002) and the latest-generation box (52.4 (43.1-70.3 [35.7-169.2])s, p = 0.008). No intubations without a box took more than 1 min, whereas 14 (58%) intubations with a box took over 1 min and 4 (17%) took over 2 min (including one failure). Without an aerosol box, all anaesthetists obtained first-pass success. With the early-generation and latest-generation boxes, 9 (75%) and 10 (83%) participants obtained first-pass success, respectively. One breach of personal protective equipment occurred using the early-generation box and seven breaches occurred using the latest-generation box. Aerosol boxes may increase intubation times and therefore expose patients to the risk of hypoxia. They may cause damage to conventional personal protective equipment and therefore place clinicians at risk of infection. Further research is required before these devices can be considered safe for clinical use.

Efficacy of Vitamin C Supplementation on Collagen Synthesis and Oxidative Stress After Musculoskeletal Injuries: A Systematic Review.

BACKGROUND: Recent investigations on the biochemical pathways after a musculoskeletal injury have suggested that vitamin C (ascorbic acid) may be a viable supplement to enhance collagen synthesis and soft tissue healing. PURPOSE: To (1) summarize vitamin C treatment protocols; (2) report on the efficacy of vitamin C in accelerating healing after bone, tendon, and ligament injuries in vivo and in vitro; and (3) report on the efficacy of vitamin C as an antioxidant protecting against fibrosis and promoting collagen synthesis. STUDY DESIGN: Systematic review; Level of evidence, 2. METHODS: A systematic review was performed, with the inclusion criteria of animal and human studies on vitamin C supplementation after a musculoskeletal injury specific to collagen cross-linking, collagen synthesis, and biologic healing of the bone, ligament, and tendon. RESULTS: The initial search yielded 286 articles. After applying the inclusion and exclusion criteria, 10 articles were included in the final analysis. Of the preclinical studies evaluating fracture healing, 2 studies reported significantly accelerated bone healing in the vitamin C supplementation group compared with control groups. The 2 preclinical studies evaluating tendon healing reported significant increases in type I collagen fibers and scar tissue formation with vitamin C compared with control groups. The 1 preclinical study after anterior cruciate ligament (ACL) reconstruction reported significant short-term (1-6 weeks) improvements in ACL graft incorporation in the vitamin C group compared with control groups; however, there was no long-term (42 weeks) difference. Of the clinical studies evaluating fracture healing, 1 study reported no significant differences in the rate of fracture healing at 50 days or functional outcomes at 1 year. Vitamin C supplementation was shown to decrease oxidative stress parameters by neutralizing reactive oxygen species through redox modulation in animal models. No animal or human studies reported any adverse effects of vitamin C supplementation. CONCLUSION: Preclinical studies demonstrated that vitamin C has the potential to accelerate bone healing after a fracture, increase type I collagen synthesis, and reduce oxidative stress parameters. No adverse effects were reported with vitamin C supplementation in either animal models or human participants; thus, oral vitamin C appears to be a safe supplement but lacks clinical evidence compared with controls. Because of the limited number of human studies, further clinical investigations are needed before the implementation of vitamin C as a postinjury supplement.

Lifestyle change reduces cardiometabolic risk factors and glucagon-like peptide-1 levels in obese first-degree relatives of people with diabetes.

BACKGROUND: Preventing type 2 diabetes in a real-world setting remains challenging. The present study aimed to assess the effectiveness of a lifestyle-based programme for individuals at high risk of developing type 2 diabetes as assessed by achieved weight loss, cardiovascular risk factors and glucagon-like peptide-1 (GLP-1). METHODS: Sixty-six obese individuals with history of diabetes in first-degree relatives participated in an 8-month lifestyle programme consisting of 12 × 1.25 h group education sessions led by dietitian and a weekly exercise programme. Before and after comparisons were made of fasting blood glucose, insulin, HbA1c, lipids, GLP-1 and quality of life (QoL). RESULTS: Fifty-four participants of whom the majority were women [47 females; mean (SD) body mass index 35.3 (2.8) kg m-2 ; age = 52 (10) years] completed the 8-month programme. Mean (SD) weight loss was 10.1 (6.0) kg (P < 0.001). Out of 54 participants, 36 lost more than 7% of their body weight and 47 lost more than 5%, with significant improvements in cardiovascular risk factors, glycaemia and QoL scores. The fall was observed in basal (P < 0.05 versus baseline) but not stimulated GLP-1 levels. In the subgroup of participants losing >10 kg, a correlation was found between weight change and change in both basal (r = 0.61, P < 0.05) and stimulated (r = 0.49, P < 0.05) GLP-1. CONCLUSIONS: An evidence-based lifestyle programme achieved sustained weight loss in obese first-degree relatives of individuals with type 2 diabetes associated with improvements in cardiometabolic risk factors and QoL without the 'voltage drop' of less benefit commonly seen when moving from the clinical trial experience into the real world.

Brain natriuretic peptide and NT-proBNP levels reflect pulmonary artery systolic pressure in trekkers at high altitude.

Our objective was to evaluate the utility of the natriuretic peptides BNP (brain natriuretic peptide) and NT-proBNP as markers of pulmonary artery systolic pressure (PASP) in trekkers ascending to high altitude (HA). 20 participants had BNP and NT-proBNP assayed and simultaneous echocardiographic assessment of PASP performed during a trek to 5150 m. PASP increased significantly (p=0.006) with ascent from 24+/-4 to 39+/-11 mm Hg at 5150 m. At 5150 m those with a PASP>/=40 mm Hg (n=8) (versus those with PASP<40 mm Hg) had higher post-exercise BNP (pg/ml): 54.5+/-36 vs. 13.4+/-17 (p=0.012). Their resting BNP at 5150 m was also higher: 57.3+/-43.4 vs. 12.6+/-13 (p=0.017). In those with a pathological (>/=400 pg/ml) rise in NT-proBNP at 5150 m (n=4) PASP was significantly higher: 45.9+/-7.5 vs. 32.2+/-6.2 mm Hg (p=0.015). BNP and NT-proBNP may reflect elevated PASP, a central feature of high altitude pulmonary oedema, at HA.

Severe acute mountain sickness, brain natriuretic peptide and NT-proBNP in humans.

AIM: To examine the response of brain natriuretic peptide (BNP) and NT-proBNP to high altitude (HA) both at rest and following exercise. METHODS: We measured NT-proBNP and BNP and Lake Louise (LL) acute mountain sickness (AMS) scores in 20 subjects at rest in Kathmandu (Kat; 1300 m), following exercise and at rest at 4270 and 5150 m. RESULTS: BNP and NT-proBNP (pg ml(-1) , mean ± SEM) rose significantly from Kat (9.2 ± 2 and 36.9 ± 6.6, respectively) to arrival at 4270 m after exercise (16.6 ± 4 and 152 ± 56.1, P=0.008 and P<0.001, respectively) and remained elevated the next morning at rest (28.9 ± 9 and 207.4 ± 65.1, P = 0.004 and P<0.001 respectively). At 5150, immediately following ascent/descent to 5643 m, BNP and NT-proBNP were 32.3 ± 8.8 and 301.1 ± 96.3 (P=0.003 and P<0.001 vs. Kat, respectively) and at rest the following morning were 33.3 ± 9.7 and 258.9 ± 89.5 (P=0.008 and P=0.001 vs. Kat respectively). NT-proBNP and BNP correlated strongly at 5150 m (ρ 0.905, P<0.001 and ρ 0.914, P<0.001 for resting and post-exercise samples respectively). At 5150 m, BNP levels were significantly higher among the four subjects with severe (LL score>6) AMS (58.4 ± 18.7) compared with those without (BNP 22.7 ± 8.6, P=0.048). There were significant correlations between change in body water from baseline to 5150 m with both BNP and NT-proBNP (ρ 0.77, P=0.001, ρ 0.745, P=0.002 respectively). CONCLUSION: In conclusion, these data suggest that BNP and NT-proBNP increase with ascent to HA both after exercise and at rest. We also report the novel finding that BNP is significantly greater in those with severe AMS at 5150 m.

The influence of liberal alcohol consumption on glucose metabolism in patients with type 1 diabetes: a pilot study.

BACKGROUND: Little is known about the consequences of excessive alcohol ingestion in patients with type 1 diabetes. AIM: To examine the metabolic effects of acute ingestion of liberal amounts of alcohol in patients with type 1 diabetes. DESIGN: A pilot study using a randomized, placebo controlled, double blind design in Hospital Clinical Research Unit. METHODS: The study included 10 patients with type 1 diabetes (seven male, age 43.9 +/- 9.0 years, duration of diabetes 17.3 +/- 13.8 years, HbA(1c) 8.0 +/- 1.5%) who had a standard 600-calorie lunch on two separate occasions, together with either white wine (men eight units, women six units), or an equivalent volume of alcohol-free wine. Bloods were collected before lunch and hourly for 4 h for glucose, intermediary metabolites, counter-regulatory hormones and inflammatory markers. RESULTS: There were no significant differences between alcohol and alcohol-free days in levels of glucose, triglycerides, free fatty acids, glycerol, cortisol and growth hormone. In contrast, lactate levels rose in response to the meal but with alcohol the overall response was augmented (P = 0.014). Beta-hydroxybutyrate levels were suppressed post-prandially on the alcohol-free day but were significantly elevated with alcohol (P < 0.001). CONCLUSION: A rise in ketones following alcohol ingestion occurred despite subjects being in a strictly controlled environment with no interruption in insulin administration. Such individuals might be at risk of significant ketosis in less-controlled circumstances where insulin administration might be more erratic. Patient education material should contain information to highlight these potential problems.

Pharmacokinetics of emtricitabine/tenofovir disoproxil fumarate and tacrolimus at steady state when administered alone or in combination.

OBJECTIVE: An open-label, randomized, 3-way crossover, drug-drug interaction study of the investigational anti-HBV combination agent, emtricitabine/tenofovir DF and the antirejection agent, tacrolimus was conducted in healthy volunteers to evaluate the potential for a pharmacokinetic interaction between these drugs. METHODS: Subjects received emtricitabine/tenofovir DF (200/300 mg q.d.) and tacrolimus (0.1 mg/kg/day) alone or in combination for 7 days, with a 2-week washout between successive treatments. Drug concentrations were measured by LC/MS/MS and steady state pharmacokinetic parameters were calculated for each drug using noncompartmental methods. RESULTS: The 90% confidence intervals (CIs) of the geometric least-squares mean ratio for AUCtau, Cmax and Ctau for each drug together vs. alone were within the predetermined no-effect boundaries of 80 - 125% (representing a maximum 20% effect), other than the upper limit of the 90% CI for tenofovir Cmax, which was just outside the 125% threshold. CONCLUSIONS: It was concluded that there was no clinically relevant pharmacokinetic interaction between emtricitabine/tenofovir DF and tacrolimus when administered together.

Group B streptococcus toxic shock-like syndrome in a healthy woman: a case report.

BACKGROUND: Toxic shock syndrome (TSS) is caused by Staphylococcus aureus infection. The disease entity manifests clinically as fever, hypotension, diffuse macular erythema that progresses to desquamation, and dysfunction of > 3 organ systems. Toxic shock-like syndrome (TSLS) has the same clinical manifestation as TSS but is caused by Streptococcus, usually group A, C or G. Here we report on a healthy woman who experienced group B Streptococcus (GBS)-related TSLS, possibly related to tampon use. CASE: A 37-year-old woman, gravida 1, para 1, met the diagnostic criteria for TSS/TSLS 5 days after her last tampon use. Blood, urine and vaginal cultures were positive only for GBS. Analysis of the blood isolate suggested a novel GBS superantigen. CONCLUSION: This is the second reported case of GBS causing tampon-associated TSS/TSLS. Up to 40% of healthy menstruating women are vaginally colonized with GBS. Superantigens elaborated by staphylococci and streptococci induce an immunologic mediator storm that affects the circulatory and end-organ systems to produce the clinical picture. Prompt medical therapy involves large-volume isotonic fluid resuscitation and antibiotic coverage with vancomycin and an antistaphylococcal beta-lactam. Clindamycin may dampen the immunologic response and endotoxin production. Corticosteroids and intravenous immunoglobulin may be useful adjuncts; however, nonsteroidal antiinflammatories should be avoided.

The isoflavone genistein inhibits LPS-stimulated TNFalpha, but not IL-6 expression in monocytes from hemodialysis patients and healthy subjects.

BACKGROUND: Whole blood and peripheral blood mononuclear cells from hemodialysis (HD) patients show increased production and secretion of inflammatory cytokines. We determined the contribution of blood monocytes to the production of inflammatory cytokines in whole blood from HD patients. METHODS: Whole blood and isolated mononuclear cells from HD patients and healthy control subjects were preincubated with the isoflavone genistein and stimulated with LPS. TNFalpha, IL-6 and IL-10 formation in the whole blood was measured with ELISA and intracellular cytokine formation in CD 14-positive monocytes was determined by flow cytometry. RESULTS: Unstimulated blood levels of TNFalpha, IL-6 and IL-10 were significantly elevated in HD patients compared to controls, but intracellular monocyte content of these cytokines was identical between groups. LPS induced a robust TNFalpha response in both whole blood and monocytes, and TNFalpha formation was 2.3-fold higher in blood from HD patients compared to controls. A similar trend was observed in monocytes. Conversely, LPS stimulation increased IL-6 levels >1000-fold in whole blood, albeit without a noticeable difference between groups. Only minor increases in monocyte IL-6 content were observed. The isoflavone genistein did not inhibit IL-6 formation and did not alter basal TNFalpha levels, but genistein selectively blocked LPS-induced TNFalpha formation in whole blood and monocytes from both groups. CONCLUSION: Intracellular levels of TNFalpha, IL-6 and IL-10 in monocytes are indistinguishable between HD patients and healthy controls. However, monocytes from HD patients are selectively primed for enhanced TNFalpha secretion in response to LPS. The selective inhibition of monocyte TNFalpha production by genistein may explain the anti-inflammatory action of this phytochemical observed in vivo.

Measurement of serum electrolytes and phosphate after sodium phosphate colonoscopy bowel preparation: an evaluation.

Our purpose was to observe the effects of sodium phosphate (NaP) colonoscopy preparation on serum electrolytes, phosphate, and calcium and to identify factors associated with any adverse effects. In an unselected group of 100 consecutive patients attending for out patient colonoscopy, 45% of patients had raised serum phosphate, which was positively correlated with creatinine and age. There was a negative association of phosphate with calcium; 16% of patients had hypocalcemia and 26% had hypokalemia. Patients taking ACE inhibitors, AT2 antagonists, or diuretics were associated with hyperphosphatemia. Significant electrolyte and metabolic disturbance from colonoscopy preparation has been shown with NaP preparation, without overt clinical effects. We recommend that elderly patients and those with significant comorbidity have their electrolytes and calcium measured, and diuretics and ACE inhibitors stopped, before NaP administration. Endoscopy units should be alert for patients who might be suffering from electrolyte disturbance postpreparation and be prepared to measure their electrolytes.

Incidence and management of abdominal sacrocolpopexy mesh erosions.

OBJECTIVE: This study was undertaken to evaluate the occurrence and management of mesh erosions in patients undergoing abdominal sacrocolpopexy. STUDY DESIGN: A retrospective chart review of the abdominal sacrocolpopexy procedure (n = 92) between 1997 and 2003 was performed. Patients with mesh erosion were identified. Incidence by graft type and treatment required for erosion resolution was analyzed with chi 2 and Fisher exact test. RESULTS: Erosions occurred in 7.6 % (7/92). Erosions were identified only in patients with Gore-Tex (3/33, 9%) or silicone-coated mesh (4/21, 19%) compared with none of 38 patients with polypropylene mesh (n = 24) or fascia (n = 14) grafts ( P = .068.). Partial excision of exposed graft resolved all 3 Gore-Tex erosions, compared with none of the silicone-coated mesh erosions ( P = .03). Complete graft removal was required to resolve silicone-coated mesh erosions. CONCLUSION: We observed a high rate of erosion with Gore-Tex and silicone-coated mesh. Partial graft excision was adequate for Gore-Tex erosions, but complete graft removal was necessary to resolve erosions associated with silicone-coated mesh.

The use of graft materials in anterior compartment pelvic reconstruction.

Since 1996, the number of reports in the urologic and gynecologic literature using synthetic and allograph prosthetics to enhance the durability of anterior compartment repairs have increased significantly. Central to the use of these prosthetics is long-term follow-up to demonstrate that their use actually confers a benefit to patients and surgeons alike. This review attempts to catalog those reports and the outcomes, with an emphasis on the cadaveric prolapse repair with sling, which is used by the authors for repair of anterior compartment prolapse with overt or occult genuine stress urinary incontinence.

Rapid enantiomeric quantification of an antiviral nucleoside agent (D,L-FMAU, 2'-fluoro-5-methyl-beta,D,L-arabinofurano-syluracil) by mass spectrometry.

A novel mass spectrometric method is applied to rapid, accurate (<1%) quantification of chiral Clevudine (L-FMAU, 2'-fluoro-5-methyl-beta,L-arabinofuranosyluracil), a potent antiviral nucleoside agent against hepatitis B virus. Transition metal bound complex ions containing the chiral drug are generated by electrospray ionization mass spectrometry and subjected to collision-induced dissociation. The ratio of the two competitive dissociation rates is related to the enantiomeric composition of the drug mixture, allowing the determination of enantiomeric contamination in the drug.

Anti-apoptotic role of telomerase in pheochromocytoma cells.

Telomerase is a protein-RNA enzyme complex that adds a six-base DNA sequence (TTAGGG) to the ends of chromosomes and thereby prevents their shortening. Reduced telomerase activity is associated with cell differentiation and accelerated cellular senescence, whereas increased telomerase activity is associated with cell transformation and immortalization. Because many types of cancer have been associated with reduced apoptosis, whereas cell differentiation and senescence have been associated with increased apoptosis, we tested the hypothesis that telomerase activity is mechanistically involved in the regulation of apoptosis. Levels of telomerase activity in cultured pheochromocytoma cells decreased prior to cell death in cells undergoing apoptosis. Treatment of cells with the oligodeoxynucleotide TTAGGG or with 3,3'-diethyloxadicarbocyanine, agents that inhibit telomerase activity in a concentration-dependent manner, significantly enhanced mitochondrial dysfunction and apoptosis induced by staurosporine, Fe2+ (an oxidative insult), and amyloid beta-peptide (a cytotoxic peptide linked to neuronal apoptosis in Alzheimer's disease). Overexpression of Bcl-2 and the caspase inhibitor zVAD-fmk protected cells against apoptosis in the presence of telomerase inhibitors, suggesting a site of action of telomerase prior to caspase activation and mitochondrial dysfunction. Telomerase activity decreased in cells during the process of nerve growth factor-induced differentiation, and such differentiated cells exhibited increased sensitivity to apoptosis. Our data establish a role for telomerase in suppressing apoptotic signaling cascades and suggest a mechanism whereby telomerase may suppress cellular senescence and promote tumor formation.

Altered calcium homeostasis and mitochondrial dysfunction in cortical synaptic compartments of presenilin-1 mutant mice.

Alzheimer's disease is characterized by amyloid beta-peptide deposition, synapse loss, and neuronal death, which are correlated with cognitive impairments. Mutations in the presenilin-1 gene on chromosome 14 are causally linked to many cases of early-onset inherited Alzheimer's disease. We report that synaptosomes prepared from transgenic mice harboring presenilin-1 mutations exhibit enhanced elevations of cytoplasmic calcium levels following exposure to depolarizing agents, amyloid beta-peptide, and a mitochondrial toxin compared with synaptosomes from nontransgenic mice and mice overexpressing wild-type presenilin-1. Mitochondrial dysfunction and caspase activation following exposures to amyloid beta-peptide and metabolic insults were exacerbated in synaptosomes from presenilin-1 mutant mice. Agents that buffer cytoplasmic calcium or that prevent calcium release from the endoplasmic reticulum protected synaptosomes against the adverse effect of presenilin-1 mutations on mitochondrial function. Abnormal synaptic calcium homeostasis and mitochondrial dysfunction may contribute to the pathogenic mechanism of presenilin-1 mutations.

Cryopreservation of rat cortical synaptosomes and analysis of glucose and glutamate transporter activities, and mitochondrial function.

Direct comparisons of synaptic functional parameters in brain tissues from different groups of experimental animals and different samples from post mortem human brain are often hindered by the inability to perform assays at the same time. To circumvent these difficulties we developed methods for cryopreservation and long-term storage of neocortical synaptosomes. The synaptosomes are suspended in a cryopreservation medium containing 10% dimethylsulfoxide and 10% fetal bovine serum, and are slowly cooled to -80 degreesC and then stored in liquid nitrogen. The function of plasma membrane glucose and glutamate transporters, and mitochondrial electron transport activity and membrane potential were measured in fresh, cryopreserved (CP), and non-cryopreserved freeze-thawed (NC) synaptosomes. Glucose and glutamate transporter activities, and mitochondrial functional parameters in CP synaptosomes were essentially identical to those in fresh unfrozen synaptosomes. Glucose and glutamate transport were severely compromised in NC synaptosomes, whereas mitochondrial function and cellular esterase activity were largely maintained. Electron paramagnetic resonance studies in conjunction with a protein-specific spin label indicated that cryopreservation did not alter the physical state of synaptosomal membrane proteins. These methods provide the opportunity to generate stocks of functional synaptosomes from different experiments or post mortem samples collected over large time intervals.

Amyloid beta-peptide induces apoptosis-related events in synapses and dendrites.

Synapse loss in cerebral cortex and hippocampus is a prominent feature of Alzheimer's disease (AD) that is correlated with cognitive impairment. Postsynaptic regions of dendrites are subjected to particularly high levels of calcium influx and oxidative stress as a result of local activation of glutamate receptors, and are therefore likely to be sites at which neurodegenerative processes are initiated in AD. Data suggest that neurons may die in AD by a process called apoptosis which involves a stereotyped series of biochemical changes that culminate in nuclear fragmentation, and that amyloid beta-peptide (Abeta) may play a role in such apoptosis. We now report that Abeta induces apoptosis-related biochemical changes in cortical synaptosomes, and in dendrites of cultured hippocampal neurons. Exposure of synaptosomes to Abeta resulted in loss of membrane phospholipid asymmetry, caspase activation, and mitochondrial membrane depolarization. Cytosolic extracts from synaptosomes exposed to Abeta induced chromatin condensation and fragmentation in isolated nuclei indicating that signals capable of inducing nuclear apoptosis can be generated locally in synapses. Exposure of cultured hippocampal neurons to Abeta resulted in caspase activation and mitochondrial membrane depolarization in dendrites and cell bodies. A caspase inhibitor prevented Abeta-induced mitochondrial membrane depolarization in synaptosomes, and mitochondrial membrane depolarization and nuclear apoptosis in cultured hippocampal neurons. Collectively, the data demonstrate that apoptotic biochemical cascades can be activated in synapses and dendrites by Abeta, and suggest that such 'synaptic apoptosis' may contribute to synaptic dysfunction and degeneration in AD.

Evidence for synaptic apoptosis.

Increasing evidence indicates that neurons die by apoptosis, an active form of cell death involving a relatively stereotyped series of biochemical changes that culminate in nuclear fragmentation, in many different developmental and pathophysiological settings. In contrast to most other cell types, neurons have elaborate morphologies with complex neuritic arbors that often extend great distances from the cell body. Neuronal death signals are likely to be activated at remote synaptic sites and, indeed, overactivation of glutamate receptors and underactivation of trophic factor receptors are implicated in neurodegenerative disorders. We now report that biochemical changes consistent with apoptosis are engaged locally in synapses. Exposure of cortical synaptosomes to staurosporine and Fe2+ resulted in loss of membrane phospholipid asymmetry, caspase activation, and mitochondrial alterations (membrane depolarization, calcium overload, and oxyradical accumulation) characteristic of apoptosis. The caspase inhibitor zVAD-fmk prevented mitochondrial membrane depolarization in synaptosomes. Studies of the effects of cytosolic extracts from synaptosomes exposed to apoptotic insults, on isolated nuclei, showed that signals capable of inducing nuclear apoptosis are generated locally in synapses. Exposure of cultured hippocampal neurons to staurosporine and glutamate resulted in caspase activation and mitochondrial membrane depolarization in dendrites, and zVAD-fmk prevented the membrane depolarization. Glutamate-induced increases in caspase activity were first observed in dendrites and later in the cell body, and focal application of glutamate to individual dendrites resulted in local activation of caspases. Collectively, the data demonstrate that apoptotic biochemical cascades can be activated locally in synapses and dendrites and suggest a role for such local apoptotic signals in synapse loss and neuronal death in neurodegenerative disorders that involve excessive activation of glutamate receptors.